Clinical trial NCT04655027
Conditions: Anemia of Chronic Kidney Disease
Keywords: Recombinant Human Erythropoietin Roxadustat Coronavirus disease of 2019 Chronic kidney disease Anemia
Sponsor: AstraZeneca
Start date: 2021-02-22; Completion date: 2021-10-12
Enrollment: 25 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a Phase IV, randomized, active-controlled, open-label, parallel design, multicenter prospective study to evaluate the effect of roxadustat versus rHuEPO treatment on the gastrointestinal (GI) iron absorption in patients with anemia of Stage 4 and Stage 5 CKD.

Detailed description:
This is an open-label study, after eligibility confirmation patients will be randomized in a 1:1 ratio to either roxadustat or rHuEPO arms for 2 weeks.

The study will enroll eligible dialysis and non-dialysis patients ≥18 years of age, who have anemia of CKD, and are either dialysis-dependent (DD) and on a stable dose of rHuEPO within 4 weeks prior to screening, or are non-dialysis-dependent (NDD) and are being treated with rHuEPO (ie, on a stable dose of rHuEPO within 4 weeks prior to screening), or are rHuEPO -naïve at the time of screening.

Each patient will be contacted before the first Screening Visit (Visit 1) for the symptoms of coronavirus disease of 2019 (COVID-19) and for any contact with COVID-19 positive person within the past 14 days.

For each patient, the duration of participation in the study will be approximately 8 to 9 weeks divided into 3 periods: Screening Period (approximately 2-3 weeks); Treatment Period (2 weeks) and Post-Treatment Follow-up Period (4 weeks).

Arms: arm 1: Patients will receive oral dose of roxadustat three times a week (TIW) for 2- weeks during treatment period. arm 2: Patients will receive uniform brand of short acting intravenous or subcutaneous dose of rHuEPO two times a week (BIW) or TIW based upon their previous dose of rHuEPO for 2- weeks during treatment period.
Interventions: intervention 1: Roxadustat intervention 2: rHuEPO
Intervention descriptions: intervention 1: The starting dose of roxadustat will be in accordance with the China package insert, and will depend on the body weight of the patient: 100 mg (45 to \< 60 kg) or 120 mg (≥ 60 kg) in patients on dialysis; 70 mg (40 to \< 60 kg) or 100 mg (≥ 60 kg) in non-dialysis patients. intervention 2: The starting dose of rHuEPO will be in accordance to the dosage approved in rHuEPO China package insert (patients on weekly dose of 6000 IU \[dosing will BIW\], and patients on weekly dose of \>6000 IU \[dosing will TIW\]) and on patient's haemoglobin levels.

Protocol documents:
Prot_000.pdf: 
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Clinical Study Protocol 
Drug Substance
Roxadustat
Study Code
D5741C00002
Version
4.0
Date
06 July 2021
ALTAI: An Open-Label, Randomized, Active-Controlled, Parallel Design, 
Multicenter Phase IV Study to Investigate the Effect of Roxadustat versus 
Recombinant Human Erythropoietin (rHuEPO) on Oral Iron Absorption in 
Chinese Patients with Anemia of Chronic Kidney Disease (CKD)
Sponsor: AstraZeneca AB, 151 85 Södertälje, Sweden








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patients on a weekly dose of rHuEPO of 6000 IU, dosing will be BIW (ie, 3000 IU BIW) 
and for patients on a weekly dose of rHuEPO of >6000 IU, dosing will be TIW.  This is due 
to unavailability of 2000 IU prefilled syringes of rHuEPO. Section 1 (Protocol summary), 
Section 4 (Study design) and Section 6 (Study treatments) were updated to reflect this 
change.
Timepoints for dispensation of rHuEPO was clarified in Section 1 (Protocol summary).
The number of patients to be randomized was updated in Section 1 (Protocol summary), 
Section 4 (Study design) and Section 6 (Study treatments) to reflect a minimum of 
46 patients will be randomized, to allow some flexibility in the final number of randomized 
patients, as it will be difficult to control recruitment to stop at exactly 46 randomized 
patients.
The primary and secondary assessments text in Section 1 (Protocol summary), Section 8.1
(Efficacy assessments) and Section 9.4 (Statistical analyses) was updated to improve clarity
on stratification factors.
Footnote ‘a’ in the schedule of activities Table (Table 1- Section 1 [Protocol summary]) 
was updated to clarify that results from the Screening Period for transferrin saturation 
(TSAT), ferritin, vitamin B12, serum folate, alanine aminotransferase (ALT), aspartate 
aminotransferase (AST), high-sensitivity C-reactive protein (hs-CRP) and total bilirubin 
(TBL) must be available prior to starting the Run-in Period .
It was clarified in Section 1 (Protocol summary), Section 4 (Study design) and Section 6 
(Study treatments) that study treatment dosing must occur on the days of the ferrokinetic 
study (ie, on the days of Visit 4 and 6).
It was clarified in Section 5 (Study population) that inclusion criteria #8 and #9 would be 
obtained from the Screening Visit (Visit 1).
It was clarified in Section 5 (Study population) that inclusion criteria #12 and #13 referred 
to Visit 1 (Screening Period) and inclusion criteria #14 referred to both Visit 1 (Screening
Period) and Visit 2 (start of Run-in Period).
It was clarified in Section 5 (Study population) for inclusion criteria #14, that ALT or AST 
and TBL would be obtained from Visit 1, Screening Visit or Visit 2, start of Run-in Period. 
It was corrected in Section 5 (Study population) for inclusion criteria #14, that ALT or (not 
and) AST must be <3 x upper limit of normal (ULN).  There was a typographical error in 
the original protocol – and has been corrected to or.
Section 6.5 was updated to clarify that patients taking iron before the study could not 
change the dose during the Treatment Period.
New text on malignancy was added to Appendix B (Adverse events definitions and 
additional safety information) to reflect changes being made to the TransCelerate clinical 
study protocol template.




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TABLE OF CONTENTS
TITLE PAGE........................................................................................................................ 1
VERSION HISTORY........................................................................................................... 2
TABLE OF CONTENTS...................................................................................................... 7
1
PROTOCOL SUMMARY................................................................................ 11
1.1
Schedule of activities (SoA).............................................................................. 11
1.2
Synopsis ........................................................................................................... 17
1.3
Schema............................................................................................................. 24
2
INTRODUCTION............................................................................................ 25
2.1
Study rationale.................................................................................................. 25
2.2
Background ...................................................................................................... 26
2.3
Benefit/risk assessment..................................................................................... 26
2.3.1
Risk assessment and mitigation pertinent to COVID-19 pandemic .................... 28
3
OBJECTIVES AND ENDPOINTS................................................................... 28
4
STUDY DESIGN ............................................................................................. 29
4.1
Overall design................................................................................................... 29
4.1.1
Treatment duration and dosing.......................................................................... 30
4.1.2
Randomization.................................................................................................. 34
4.1.3
Dose of study treatments................................................................................... 34
4.2
Scientific rationale for study design .................................................................. 34
4.3
Justification for dose......................................................................................... 35
4.4
End of study definition...................................................................................... 35
5
STUDY POPULATION ................................................................................... 35
5.1
Inclusion criteria............................................................................................... 36
5.2
Exclusion criteria.............................................................................................. 38
5.3
Lifestyle restrictions ......................................................................................... 40
5.4
Screen failures .................................................................................................. 40
6
STUDY TREATMENTS.................................................................................. 41
6.1
Treatments administered................................................................................... 41
6.1.1
Investigational products.................................................................................... 41
6.1.2
Dose of study treatments................................................................................... 42
6.1.3
Additional treatments........................................................................................ 44
6.2
Preparation/handling/storage/accountability...................................................... 44
6.3
Measures to minimize bias: randomization and blinding ................................... 45
6.4
Treatment adherence......................................................................................... 45
6.5
Concomitant therapy......................................................................................... 45
6.5.1
Prohibited medications/therapy......................................................................... 46
6.5.2
Other concomitant treatment............................................................................. 46


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6.5.3
Rescue guidelines ............................................................................................. 46
6.6
Dose modification............................................................................................. 46
6.7
Treatment after the end of the study.................................................................. 47
7
DISCONTINUATION OF TREATMENT AND PATIENT WITHDRAWAL . 47
7.1
Discontinuation of study treatment.................................................................... 47
7.1.1
Temporary discontinuation from study treatment .............................................. 47
7.1.2
Permanent discontinuation from study treatment............................................... 47
7.1.3
Procedures for discontinuation of study treatment............................................. 48
7.2
Lost to follow-up .............................................................................................. 49
7.3
Withdrawal from the study................................................................................ 49
8
STUDY ASSESSMENTS AND PROCEDURES ............................................. 50
8.1
Efficacy assessments......................................................................................... 51
8.1.1
Primary efficacy assessments............................................................................ 51
8.1.2
Secondary efficacy assessments........................................................................ 52
8.2
Safety assessments............................................................................................ 53
8.2.1
Clinical safety laboratory assessments............................................................... 53
8.2.2
Physical examinations....................................................................................... 56
8.2.3
Vital signs......................................................................................................... 56
8.2.4
Electrocardiograms........................................................................................... 57
8.3
Collection of adverse events ............................................................................. 57
8.3.1
Method of detecting adverse events and serious adverse events......................... 57
8.3.1.1
Reporting of AEs/SAEs in relation to COVID-19 ............................................. 57
8.3.2
Time period and frequency for collecting adverse event and serious adverse 
event information.............................................................................................. 58
8.3.3
Follow-up of adverse events and serious adverse events.................................... 58
8.3.4
Adverse event data collection............................................................................ 58
8.3.5
Causality collection........................................................................................... 59
8.3.6
Adverse events based on signs and symptoms................................................... 59
8.3.7
Adverse events based on examinations and tests ............................................... 60
8.3.8
Hy’s Law.......................................................................................................... 60
8.3.9
Disease-under study (DUS)............................................................................... 61
8.3.10
Disease progression .......................................................................................... 61
8.4
Safety reporting and medical management........................................................ 61
8.4.1
Reporting of serious adverse events .................................................................. 61
8.4.2
Pregnancy......................................................................................................... 62
8.4.2.1
Maternal exposure ............................................................................................ 62
8.4.2.2
Paternal exposure.............................................................................................. 63
8.4.3
Overdose .......................................................................................................... 63
8.4.4
Medication error ............................................................................................... 63
8.5
Pharmacokinetics.............................................................................................. 64
8.6
Pharmacodynamics........................................................................................... 64
8.7
Genetics............................................................................................................ 64
8.8
Biomarkers ....................................................................................................... 64


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8.9
Health economics ............................................................................................. 64
9
STATISTICAL CONSIDERATIONS............................................................... 64
9.1
Statistical hypotheses........................................................................................ 64
9.1.1
Primary endpoint .............................................................................................. 64
9.1.2
Secondary endpoints......................................................................................... 65
9.2
Sample size determination ................................................................................ 65
9.3
Populations for analyses.................................................................................... 66
9.4
Statistical analyses............................................................................................ 66
9.4.1
Primary efficacy analyses ................................................................................. 67
9.4.2
Secondary efficacy analyses.............................................................................. 67
9.4.2.1
Multiple testing................................................................................................. 68
9.4.3
Subgroup analyses ............................................................................................ 68
9.4.4
Safety analyses ................................................................................................. 69
9.5
Interim analyses................................................................................................ 69
9.5.1
Data monitoring committee............................................................................... 69
10
REFERENCES................................................................................................. 70
11
SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS........................................................................................ 71
LIST OF TABLES
Table 1
Schedule of activities............................................................................... 12
Table 2
Study objectives....................................................................................... 28
Table 3
Initial dosing of rHuEPO for patients treated with an erythropoietic 
analogue at study entry ............................................................................ 43
Table 4
Laboratory variables ................................................................................ 55
Table 5
Summary of secondary endpoints to be analyzed ..................................... 68
Table 6
Hy’s Law laboratory kit for central laboratories ....................................... 88
LIST OF FIGURES
Figure 1
Study design............................................................................................ 24
LIST OF APPENDICES
Appendix A
Regulatory, Ethical and Study Oversight Considerations.......................... 71
Appendix B
Adverse Event Definitions and Additional Safety  Information................ 76
Appendix C
Handling of Human Biological Samples .................................................. 81


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Appendix D
Actions Required in Cases of Increases in Liver Biochemistry and 
Evaluation of Hy’s Law........................................................................... 83
Appendix E
Abbreviations .......................................................................................... 89


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1
PROTOCOL SUMMARY
1.1
Schedule of activities (SoA)
The schedule of activities (SoA) for the study is shown in Table 1 below.  The study consists 
of 3 periods: the Screening Period, Treatment Period and Follow-up Period.


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Table 1
Schedule of activities
Screening 
Perioda,b
Treatment Periodb
Discontinuationb,c
28-day Follow-up 
Periodc,d
Details in CSP or 
Appendix section 
Day 
< -21 > -14 
to 0
1
8
-1/+2 days
15 ± 2 days
43 ± 3 days
Visit
1, 1a and 
1be
2
3
4
5
Pre-screening telephone contactf
Section 4.1.1
Sign written ICF 
X
Section 5 and 
Appendix A 3
Swab test for active COVID-19
infectiong
X
Section 4.1.1
Eligibility criteria
X
X
Section 5
Demographics, medical and surgical 
history, and prior medication
X
Section 5
Hematology/hemostasish
Xi
X
X
X
X
Sections 5 and 8.2.1
HbA1C
X
Section 8.2.1
iPTH
X
Section 8.2.1
Physical examination, dry body weightj
X
Sections 5 and 8.2.2
Clinical chemistryk
X
X
X
X
Section 8.2.1
Urinalysisl
X
X
X
X
Section 8.2.1
Vital signsm
X
X
X
X
X
Sections 5 and 8.2.3
12-lead ECG
X
Section 8.2.4
Liver function testsn
X
X
X
X
Sections 5 and 8.2.1
Iron profileo
X
X
X
X
Sections 5 and 8.1
Hepcidin
X
X
X
Section 8.1
hs-CRP
X
X
X
X
Section 8.1


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Screening 
Perioda,b
Treatment Periodb
Discontinuationb,c
28-day Follow-up 
Periodc,d
Details in CSP or 
Appendix section 
Day 
< -21 > -14 
to 0
1
8
-1/+2 days
15 ± 2 days
43 ± 3 days
Visit
1, 1a and 
1be
2
3
4
5
Vitamin B12, folate
X
Sections 5 and 8.2.1
Terminate IV iron + TRIFERIC® in 
dialysatep
X
Section 5
Single dose of oral iron (12.5 mL 
[100 mg elemental iron]) administration
Xq
Xq
X
Section 6.1.3
Ferrokinetic study (T0r, 1, 2, 3 hours) 
Xq,r
Xq,r
X
Section 8.1
Concomitant medications
At every visit after Visit 1 and may be conducted by phone if not tied to a visit 
Section 6.5
Routine safety measurements
Adverse events
At every visit after Visit 1 and may be conducted by phone if not tied to a visit
Section 8.3
Serum pregnancy tests
X
X
Section 8.2.1
Study treatment administration
Randomizationt
X
Section 6.3 and 
Section 4.1.2
Study treatment dispensedu
X
Xv
Section 6
Study treatment (rHuEPO and 
roxadustat) compliance
X
X
X
Section 6
a
The Screening Period will be approximately 2-3 weeks long, but may be greater or lesser, to ascertain the Hb eligibility criteria with up to 3 Hb tests.  To 
check Hb eligibility criteria, Hb levels must be assessed twice, at least 7 days apart, during the Screening Period; Hb levels may be assessed up to 3 times 
(Visits 1, 1a and 1b) during the Screening Period.  The rHuEPO dose may be adjusted during the Screening Period for patients who were on rHuEPO before 
the Screening Period depending on the patient’s Hb levels, at the discretion of the Investigator, in accordance with the rHuEPO China Package Insert.  
Results for Screening Period assessments for TSAT, ferritin, vitamin B12, serum folate, ALT, AST, hs-CRP and TBL must be available prior to starting the 
Treatment Period.


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b
Each patient will be contacted within 24 h before a scheduled visit to confirm that he/she has no symptoms of COVID-19 infection and that he/she has had 
no contact with a known COVID-19 positive person within the past 14 days. If the patient reports symptoms or contact with a COVID-19-positive patient
within the past 14 days, the Investigator may ask the patient to be tested for active COVID-19 infection (swab test to rule out active COVID-19 infection), 
or withdraw the patient from the study, as is most suitable for the patient’s safety, at the Investigator’s discretion.  The study treatment and assessments may
be continued as planned until the swab test results are available, at the discretion of the Investigator. Patients who test positive on the swab test must be 
withdrawn from the study.  A patient who contacts the site at any time during the Treatment Period informing that he/she has symptoms suggestive of
COVID-19 may be asked to get tested for active COVID-19 infection, or be withdrawn from the study for safety reasons, at the Investigator’s discretion.  
Patients who test positive (for COVID-19) must be withdrawn from the study.  Any study assessments planned on the days of site visits may be completed 
via a telephone call and/or a visit to the patient’s home, as required, and if possible.  The handling of patients and their blood or urine samples will be done 
using sterile techniques and observing precautions for infection control and prevention.  Reasons for delayed site visits will be reported as protocol 
deviations. The actual dates when the visit-related assessments were completed will be recorded in the eCRFs.
c
Applicable for discontinuation prior to the end of the Treatment Period. Patients who discontinue study treatment early should be asked to return to the 
study site for the discontinuation visit within 7 days after the study treatment is stopped, and for the Follow-up Visit 28 days later unless consent to 
participate is withdrawn. Patients who withdraw prior to the end of the Treatment Period due to a positive COVID-19 test result should not attend the 
Discontinuation Visit or the 28-day Follow-up Visit at the study site.  The assessments planned for the Discontinuation and 28-day Follow-up Visit should 
be completed via a telephone call, as far as possible.  See Section 7.1.3 for details.
d
May be conducted over the phone.
e
All patients should attend Visits 1 and 1a at the clinical site.  All patients will be tested for COVID-19 infection at the first Screening Visit (Visit 1)g.  
Patients may attend Visit 1b at the clinical site, if needed, to assess Hb level (see footnote i).
f
Each patient will be contacted before the first Screening Visit (Visit 1) to confirm that he/she has no symptoms of COVID-19 and that he/she has had no 
contact with a known COVID-19 positive person within the past 14 days.  Only asymptomatic patients, or those who have had no contact with a known 
COVID-19 positive person within the last 14 days, will be asked to come to the site for informed consent and eligibility screening procedures.
g
All patients will be tested for COVID-19 infection at the first Screening Visit, using a swab test to rule out active infection for COVID-19.  If according to 
site procedures the test for COVID-19 infection cannot be performed at the first Screening Visit, the test should be performed as soon as possible thereafter 
but must be performed before the patient returns for the next study visit.  Patients who test positive must be withdrawn from the study.  All samples (blood 
and urine) for eligibility assessment will be collected at Visit 1 during the Screening Period, while the swab test results are awaited.  The handling of 
patients and their blood or urine samples will be done using sterile techniques and observing precautions for infection control and prevention.
h
Red blood cell, Hb, hematocrit, leukocyte count, leukocyte differential count, platelet count, MCV, reticulocytes.  On Days 1 and 15, blood samples for 
these assessments will be collected before time T0 (ie, before administration of the single dose of oral iron).  On Days 1, 8, and 15 hemoglobin levels 
will be tested in the central laboratory for all patients.  Additionally, for patients randomized to rHuEPO, Hb levels will be tested in the local laboratory on 
Days 1 and 8 for initial dose determination and dose adjustment.  The rHuEPO dose may be adjusted on Day 8 of the Treatment Period, depending on the 
patient’s Hb levels, for safety reasons as determined by the Investigator, in accordance with the rHuEPO China Package Insert.  On Day 15 (or at the 
discontinuation visit), Hb levels will be tested in the local laboratory for all patients who were on rHuEPO prior to the study, to decide what rHuEPO dose 
to re-start patients on, or another appropriate course of treatment for anemia, after study treatment stops. For patients who were rHuEPO-naïve before 
entering the study, Hb levels may be tested in the local laboratory on Day 15 (or at the Discontinuation Visit) at the discretion of the Investigator, to 
determine an appropriate course of treatment for anemia in each patient.
i
To check Hb eligibility criteria, Hb levels must be assessed in the central laboratory twice, at least 7 days apart, during the Screening Period; Hb levels may 
be assessed up to 3 times (Visits 1, 1a and 1b) during the Screening Period.


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j
Body weight for HD patients should be the patient’s dry weight.  Dry weight - also known as optimum postdialysis weight - is the postdialysis weight at 
which all or most excess body fluid has been removed. Weight for patients on PD should be obtained with a “dry” or empty peritoneal cavity (PD fluid 
fully drained).
k
Glucose, calcium, sodium, potassium, bicarbonate, chloride, BUN, creatinine, magnesium, phosphorus.
l
Urine dipstick glucose, protein and blood performed locally (applicable for non-dialysis-dependent patients, and dialysis-dependent patients who are not 
anuric).
m
Vital signs will include tympanic temperature, systolic and diastolic BP, pulse rate and respiratory rate.  Blood pressure should be measured prior to the 
hemodialysis procedure.  For patients on PD, BP should be measured in the morning prior to the patient performing the first exchange of the day.  Pulse rate 
and BP should be measured in triplicate after being comfortably at rest in a seated position with the back and feet supported (ie, by chair back and floor or 
platform, respectively) quietly for at least 5 minutes.
n
Alanine aminotransferase, AST, ALP, albumin, and TBL.
o
Serum iron, ferritin, TIBC, TSAT, transferrin, soluble transferrin receptor. On Days 1 and 15, blood samples for these assessments will be collected before
time T0 (ie, before administration of the single dose of oral iron).  Note that serum iron and TIBC are included in the ferrokinetic study and should not 
be taken as part of the iron profile as well on Days 1 and 15.  There is no need to collect duplicate sample for serum iron and TIBC. The sample collected 
before the single dose of oral iron is administered can serve for the iron profile as well.
p
Intravenous iron and TRIFERIC® in dialysate should be stopped at the Screening Visit (ie, at Visit 1) and should not be taken after stopping, throughout the 
Screening and Treatment Periods, but can be started again after the Treatment Period.
q
Must be conducted prior to randomization at Day 1 and prior to the hemodialysis procedures at Days 1 and 15.
r
The blood samples for the ferrokinetic study (serum iron and TIBC) must be taken immediately before the single dose of oral iron is administered (ie, 
immediately before time T0), and then at T1, T2 and T3 after the single dose of oral iron (sample for serum iron only).  The window of allowance for the 
ferrokinetic study blood sampling will be ±3 minutes.
s
Collect from female patients of childbearing potential only.
t
Results for Screening Period assessments for ALT, AST and TBL must be available before randomization. Randomization must occur after the 
ferrokinetic study has completed, ie, after collection of the T3 serum iron sample.  Patients will be randomly assigned in 1:1 ratio to either roxadustat or 
rHuEPO.  Study treatment to be administered after randomization at Day 1.
u
Patients will receive either roxadustat (orally) or rHuEPO (IV or SC) during the Treatment Period. Roxadustat will be administered TIW.  For patients on a
weekly dose of rHuEPO of 6000 IU, dosing will be BIW (ie, 3000 IU BIW) and for patients on a weekly dose of rHuEPO of >6000 IU, dosing will be TIW.  
The dose of study treatment administered will be recorded.
v
For patients randomized to the rHuEPO arm, Hb levels will be tested in the local laboratory on Day 8, and the rHuEPO dose may be adjusted depending on 
the patient’s Hb levels, for safety reasons, as determined by the Investigator.  Study treatment dispensation will only occur for patients on the rHuEPO arm, 
not patients on the roxadustat arm (as only the rHuEPO dose may be adjusted at this visit).  The roxadustat dose will not be adjusted during the Treatment 
Period; therefore, for patients on the roxadustat arm Hb samples will not be collected on Day 8 for testing in the local laboratory.


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ALP=alkaline phosphatase; ALT=alanine aminotransferase; AST=aspartate aminotransferase; BIW=2 times a week; BP=blood pressure; BUN=blood urea 
nitrogen; eCRF=electronic case report form; COVID-19=coronavirus disease of 2019; CSP=clinical study protocol; ECG=electrocardiogram; Hb=hemoglobin; 
HbA1C=hemoglobin A1C; HD=hemodialysis; hs-CRP=high-sensitivity C-reactive protein; ICF=informed consent form; iPTH=intact parathyroid hormone; 
IU=International Unit; IV=intravenous; MCV=mean corpuscular volume; PD=peritoneal dialysis; rHuEPO=recombinant human erythropoietin; 
SC=subcutaneous; TBL=total bilirubin; TIBC=total iron binding capacity; TIW=3 times a week; T0=time at which single dose of oral iron will be administered
at the start of ferrokinetic study; TSAT=transferrin saturation.


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1.2
Synopsis
Principal Investigator:
Beijing, China 100730
Protocol title: 
ALTAI: An Open-Label, Randomized, Active-Controlled, Parallel Design, Multicenter Phase 
IV Study to Investigate the Effect of Roxadustat versus Recombinant Human Erythropoietic 
(rHuEPO) on Oral Iron Absorption in Chinese Patients with Anemia of Chronic Kidney 
Disease (CKD)
Short title: 
Effect of Roxadustat versus rHuEPO on oral iron absorption in Chinese patients with anemia 
of CKD.
Rationale: 
Advanced stages of chronic kidney disease (CKD) are associated with a hypo-proliferative 
anemia as well as dysfunctional iron homeostasis.  Roxadustat is an orally administered drug 
for the treatment of anemia caused by CKD in patients who are either on dialysis or not. 
Roxadustat is currently approved in China for the treatment of anemia in patients with CKD, 
and is indicated for both, dialysis as well as non-dialysis patients.  Roxadustat 
pharmacologically stimulates erythropoiesis via the hypoxia inducible factor (HIF) pathway 
and in a manner consistent with the body’s normal homeostatic response to hypoxia, but under 
normoxic conditions.  In an open-label, randomized hemoglobin (Hb) correction study in 
anemic patients incident to hemodialysis (HD) or peritoneal dialysis (PD), roxadustat was well 
tolerated and corrected anemia in incident HD and PD patients, regardless of baseline iron 
repletion status or C-reactive protein (CRP) level and with oral or intravenous (IV) iron 
supplementation; it also reduced serum hepcidin levels (Besarab et al 2016).
This study will evaluate the effect of roxadustat versus recombinant human erythropoietic 
(rHuEPO) on oral iron absorption in patients with anemia in Stage 4 and Stage 5 CKD and 
will provide data to meet the medical need to a new standard of care in patients on dialysis 
and to treat anemia in non-dialysis patients.
PPD
PPD
PPD


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Objectives and Endpoints a
Primary objective:
Endpoint/variable:
Evaluate the main effect of roxadustat versus 
rHuEPO on gastrointestinal iron absorption.
The main treatment effect on the difference from 
baseline (Day 1) to Day 15 in log-transformed AUC of 
iron absorption from 0-3 hours based on the change in 
serum iron levels obtained just prior to T0 (time when 
single dose of oral iron is administered) and over a 
3-hour period.
Secondary objectives:
Endpoints/variables:
Assess the effect and interaction with key baseline 
variables of roxadustat versus rHuEPO on iron 
absorption.
The main treatment effect and key interaction effects on 
the difference from baseline (Day 1) to Day 15 in 
log-transformed AUC of iron absorption from 0-3 hours 
based on the change in serum iron levels obtained just 
prior to T0 (time when single dose of oral iron is 
administered) and over a 3-hour period.
Assess the effect and interaction with key baseline 
variables of roxadustat versus rHuEPO on the indices 
of iron metabolism (ie, serum iron, ferritin, TIBC, 
TSAT, transferrin, soluble transferrin receptor) and 
hepcidin levels.
The main treatment effect and key interaction effects on 
the difference from baseline (Day 1) to Day 15 prior to 
administration of oral iron: in serum iron, ferritin, TIBC, 
TSAT, transferrin, soluble transferrin receptor and 
hepcidin levels, log-transformed as appropriate.
Safety objective:
Endpoint/variable:
Safety evaluation.
Safety assessed by incidence of AEs, and measurement 
of vital signs (tympanic temperature, BP, pulse and 
respiratory rate), laboratory variables.
a
The primary and secondary objectives will be analyzed using the Full Analysis Set (FAS), see Section 9.3
for further details.
AE=adverse event; AUC=area under the curve; BP=blood pressure; rHuEPO=recombinant human 
erythropoietin; TIBC=total iron binding capacity; TSAT=transferrin saturation.
Overall design:
This is a Phase IV, randomized, active-controlled, open-label, parallel design, multicenter 
prospective study to evaluate the effect of roxadustat versus rHuEPO treatment on the 
gastrointestinal (GI) iron absorption in patients with anemia of Stage 4 and Stage 5 CKD.  
This study plans to screen a maximum of 104 patients, and randomize a minimum of 
20 patients and a maximum of 60 patients with anemia of CKD, from approximately 7 to 
10 sites in China.  Patient enrollment will be competitive across all sites and strata.
This study will enroll eligible dialysis and non-dialysis patients ≥ 18 years of age, who have 
anemia of CKD, and are either dialysis-dependent (DD) and on a stable dose of rHuEPO 
within 4 weeks prior to screening, or are non-dialysis-dependent (NDD) and are being treated 
with rHuEPO (ie, on a stable dose of rHuEPO within 4 weeks prior to screening), or are 
rHuEPO-naïve (ie, no treatment with erythropoietin stimulating agents [ESAs] for > 6 weeks)
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Study period:
Estimated date of first patient enrolled: Q1 2021
Estimated date of last patient completed: Q4 2021
Number of patients:
A maximum of 104 patients are planned to be screened to achieve a minimum of 20 and a 
maximum of 60 eligible randomized patients with anemia of CKD fulfilling all the inclusion 
criteria and none of the exclusion criteria.
The minimum sample size required to achieve a 2-sided significance level of 0.05 and power 
of 90% was calculated based on the assumption of a log scale. A conservative effect due to 
roxadustat has been assumed of 2.7-times baseline, and accounting for 20% of patients failing 
to take any study treatment or failing to provide a post-baseline area under the curve (AUC) 
measurement.  A conservative estimate of the standard deviation (SD), based on the estimated 
range of iron absorption was 0.4 on the log scale.  A sample size of 16-20 subjects (8-10 per 
treatment arm) is considered sufficient to achieve a 2-sided significance level of 0.05, and 
90% power, based on the primary endpoint of change from baseline in log(AUC). Patients are 
to be randomized in a 1:1 ratio. The calculations are based on a 2-sample t-test.
Treatments and treatment duration:
Each patient will be contacted before the first Screening Visit (Visit 1) to confirm that he/she 
has no symptoms of coronavirus disease of 2019 (COVID-19) and that he/she has had no 
contact with a known COVID-19 positive person within the past 14 days.  Only asymptomatic 
patients, or those who have had no contact with a known COVID-19 positive person within 
the last 14 days, will be asked to come to the site for informed consent and eligibility 
screening procedures.
For each patient, the duration of participation in the study will be approximately 8 to 9 weeks 
divided into 3 periods:
1. Screening Period: approximately 2-3 weeks.  Dialysis and non-dialysis patients with 
anemia of CKD, fulfilling the eligibility criteria, will be asked to provide informed consent to 
participate in this study.  Patients must provide written informed consent before any screening 
tests or assessments are performed.  All patients will be tested for COVID-19 infection at the 
first Screening Visit, using a swab test to rule out active COVID-19 infection.  If according to 
site procedures the test for COVID-19 infection cannot be performed at the first Screening 
Visit, the test should be performed as soon as possible thereafter but must be performed before 
the patient returns for the next study visit.  Patients who test positive (for COVID-19) must be 
withdrawn from the study.  Patients who test negative (for COVID-19) but do not meet the 
eligibility criteria must be withdrawn from the study.  Patients will be assessed for high-


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sensitivity CRP (hs-CRP) at the Screening Visit to check whether the measurement is either 
≤the upper limit of normal (ULN), or > the ULN. During the Screening Period, all patients 
on rHuEPO before entering the study will remain on their current rHuEPO treatment.  During 
the Screening Period, the rHuEPO dose may be adjusted for patients who were on rHuEPO 
before the Screening Period depending on the patient’s Hb levels, at the discretion of the 
Investigator, in accordance with the rHuEPO China Package Insert.  The Screening Period 
will be approximately 2-3 weeks long, but may be greater or lesser, to ascertain the Hb 
eligibility criteria with up to 3 Hb tests.
2. Treatment Period: 2 weeks.  For patients who are already on rHuEPO, the start of the 
Treatment Period (Day 1) should be scheduled to fit into the rHuEPO administration regimen 
(ie, rHuEPO dosing must occur on the day of the Randomization Visit, Visit 2, Day 1).  
Patients should be instructed not to take their rHuEPO dose in the morning before they attend 
the study site for the Randomization Visit (Visit 2, Day 1).
At Days 1 and 15, a ferrokinetic study will be done in all patients.  Immediately before time 
T0 of the ferrokinetic study, a blood sample will be collected to measure baseline serum iron 
level and total iron binding capacity (TIBC), immediately followed by administration of a 
defined single dose of oral liquid elemental iron containing FeSO4 (12.5 mL dose, comprising 
100 mg elemental iron).  Gastrointestinal iron absorption (serum iron level measured) will 
then be assessed at 1, 2 and 3 hours after the administration of the defined single dose of oral 
iron (T1, T2 and T3, respectively).  The window of allowance for the ferrokinetic study blood 
sampling will be ±3 minutes.
On Day 1, after the ferrokinetic study has completed (ie, after collection of the T3 serum iron 
sample), patients will be randomized in a 1:1 ratio to either rHuEPO treatment or to roxadustat 
treatment.  Patients will be centrally randomized by interactive voice response system (IVRS) 
and stratified by dialysis status (DD versus NDD). Within the NDD stratum, patients will be 
further stratified by rHuEPO exposure (NDD-rHuEPO-users vs NDD-rHuEPO-naïve).
Within the DD stratum, patients will be stratified by type of dialysis (HD vs PD). The study 
treatment (roxadustat or rHuEPO) will be administered at the study site at Day 1, after 
randomization.  All patients randomized to rHuEPO will receive a uniform brand of short-
acting rHuEPO according to the dosage approved in the rHuEPO China Package Insert.  
Patients who were previously on rHuEPO (before Screening) will receive a uniform brand of 
short-acting rHuEPO based upon their previous dose of rHuEPO, and according to the dosage 
approved in the rHuEPO China Package Insert.  For patients on a weekly dose of rHuEPO of 
6000 IU, dosing will be 2 times a week (BIW) and for patients on a weekly dose of rHuEPO 
of > 6000 IU, dosing will be 3 times a week (TIW).  The rHuEPO can be administered either 
IV or subcutaneously (SC) depending on the route of administration used by the 
dialysis-dependent patients before the Treatment Period.  The rHuEPO will be administered 
via the SC route for all patients who are NDD. The rHuEPO dose may be adjusted on Day 8


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of the Treatment Period, depending on the patient’s Hb levels, for safety reasons as 
determined by the Investigator, in accordance with the rHuEPO China Package Insert.  The 
rHuEPO dose may also be adjusted at any time during the Treatment Period by the 
Investigator for safety reasons.
Dosing of roxadustat and rHuEPO should be scheduled to occur on Visit 4 (Day 15).  On 
Day 15, patients randomized to the roxadustat group should take the roxadustat in the 
morning, at least 6 hours before the ferrokinetic study starts.  On Day 15, patients randomized 
to the to the rHuEPO group should take the rHuEPO within 1-2 hours before the ferrokinetic 
study.
All patients should not ingest any foods containing more than trace amounts of iron such as 
heme-rich foods, multivitamins with iron etc. for approximately 4 hours before and during the 
3 hours of the ferrokinetic study.  Patients are allowed limited small snacks with negligible 
amounts of iron during this 7-hour period.  Patients may resume their normal dietary intake 
following collection of blood at the T3 time point.  There is no restriction on drinking water, 
coffee or tea for the patient before the ferrokinetic study starts and during the ferrokinetic 
study.
Roxadustat will be administered orally TIW according to the dosage approved in the China 
Package Insert.  The roxadustat dose will not be adjusted during the 2-week Treatment Period, 
except for safety reasons at the discretion of the Investigator.
In the event of early study discontinuation after the Day 1 visit but prior to the Day 15 visit for 
a patient, the Investigator will seek to schedule a study discontinuation visit for the patient.  
Patients who withdraw prior to the end of the Treatment Period due to a positive COVID-19 
test result should not attend the Discontinuation Visit or the 28-day Follow-up Visit at the 
study site.  The assessments planned for the Discontinuation and 28-day Follow-up Visits
should be completed via a telephone call, as far as possible.
3. Post-Treatment Follow-up Period: 4 weeks.  After completing study treatment, all 
patients will continue for a 4-week Follow-up Period, to monitor safety (all adverse events 
[AEs] and serious adverse events [SAEs] will be collected during this Period).  Patients who 
discontinue study treatment early will also continue to this 4-week Follow-up Period unless 
consent to participate is withdrawn.  Activities that are planned during this 4-week Follow-up 
Period may be performed by phone.
Patients who withdraw prior to the end of the Treatment Period due to a positive COVID-19 
test result should not attend the Discontinuation Visit or the 28-day Follow-up Visit at the 
study site.  The assessments planned for the Discontinuation and 28-day Follow-up Visits
should be completed via a telephone call, as far as possible.


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After discontinuation of study treatment, patients who were on rHuEPO before entering the 
study may either be returned to their previously prescribed rHuEPO treatment, or be 
prescribed different agent(s) to treat their anemia by the Investigator, based on their local Hb 
levels and the discretion of the Investigator. For patients who were rHuEPO-naïve before 
entering the study, Hb levels may be tested in the local laboratory at the discretion of the 
Investigator, to determine an appropriate course of treatment for anemia in each patient.
Statistical methods:
Population for analyses
Full analysis set (FAS): The FAS will include all randomized patients who have complete 
baseline (Day 1) measurements for any efficacy analysis, with patients being analyzed as 
randomized, rather than as treated.  The FAS will be used for the primary endpoint and all 
secondary endpoints.
Per-protocol (PP) analysis set:  The PP analysis set will include all randomized patients who 
received at least 1 dose of study treatment, have baseline (Day 1) and at least 1 post-baseline 
iron absorption measurement, and are without major protocol violations.  The PP analysis set 
will be used as a sensitivity analysis population for the primary and secondary endpoints.
Safety analysis set: The safety analysis set will include all randomized patients receiving at 
least 1 dose of study treatment, with patients being analysed as treated, rather than as 
randomized.  The safety analysis set will be used for the safety endpoints.  Exposure to study 
treatment will also be presented using the safety analysis set.
Primary analyses
The primary endpoint for this study is the GI iron absorption change from baseline (Day 1) to 
Day 15.  This will be assessed via change from baseline (Day 1) to Day 15 in log-transformed 
AUC of iron absorption from 0-3 hours based on change in serum iron levels obtained just 
prior to T0 (time when single dose of oral iron is administered) and over a 3-hour period.  The 
difference in log (AUC) from baseline (Day 1) to Day 15 will be analyzed using an analysis of 
covariance (ANCOVA) model, adjusting for study treatment and baseline hs-CRP (≤ ULN, 
> ULN) level.  The result will be back-transformed to the original scale to aid interpretability.
Multiple imputation will be implemented for the primary and secondary analysis to account 
for missing data.  This will be described in more detail in the statistical analysis plan (SAP).
Secondary analyses
The secondary endpoints of interest assess direct treatment and interaction effects in iron 
absorption and the indices of iron metabolism (serum iron, ferritin, TIBC, transferrin 
saturation [TSAT], transferrin, soluble transfer receptor) and hepcidin levels are described as 
follows:


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
The relative difference in AUC from baseline (Day 1) to Day 15, adjusted for study 
treatment, baseline hepcidin value, and treatment interaction with baseline hepcidin value.
Treatment and interaction effects to be assessed.

The relative difference in AUC from baseline (Day 1) to Day 15, adjusted for study
treatment, baseline hs-CRP value and treatment interaction with baseline hs-CRP value.
Treatment and interaction effects to be assessed.

The relative difference in the indices of iron metabolism from baseline (Day 1) to Day 15, 
adjusted for study treatment and baseline hs-CRP level (≤ULN, > ULN). Treatment 
effect to be assessed.

The relative difference in the indices of iron metabolism from baseline (Day 1) to Day 15, 
adjusted for study treatment, baseline hepcidin value, and treatment interaction with 
baseline hepcidin value.  Treatment and interaction effects to be assessed.

The relative difference in the indices of iron metabolism from baseline (Day 1) to Day 15, 
adjusted for study treatment, baseline hs-CRP value and treatment interaction with
baseline hs-CRP value. Treatment and interaction effects to be assessed.
The hypotheses for these endpoints can be separated into 2 distinct groups, the relative 
difference in iron metabolism and the relative difference in AUC.  All hypotheses will follow 
the null hypothesis that there is no difference between AUC or iron metabolism when 
adjusting for various specified covariates or interactions.  The assessments for the secondary 
endpoints will be performed similar to those for the primary endpoints.  All endpoints will be 
analyzed using ANCOVA models.
Subgroup analyses
Sample size permitting, subgroup analyses will be performed for the primary and key 
secondary efficacy endpoints. Summary tables will be produced by strata (HD, PD, NDD) 
and, if there are sufficient numbers of patients in each strata, all statistical analysis of primary 
and secondary endpoints will be performed by strata (HD, PD, NDD). If a patient withdraws 
before Day 15, their discontinuation visit will be used as the postbaseline primary 
measurement.


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1.3
Schema
The general study design is summarized in Figure 1 .
Figure 1
Study design
The Screening Period will be approximately 2-3 weeks long, but may be greater or lesser, to ascertain the Hb 
eligibility criteria with up to 3 hemoglobin (Hb) tests.  During the Screening Period, all patients who were on 
rHuEPO before entering the study will remain on the rHuEPO treatment they received.  The rHuEPO dose may 
be adjusted for patients who were on rHuEPO before the Screening Period depending on the patient’s Hb levels, 
at the discretion of the Investigator, in accordance with the rHuEPO China Package Insert.
The ferrokinetic study on Day 1 must be completed prior to randomization and prior to the hemodialysis 
procedure at Days 1 and 15.  Patients will be randomly assigned in 1:1 ratio to either roxadustat or rHuEPO.  
Study treatment to be administered after randomization at Day 1.
*Ferrokinetic study at T0 (before single dose of oral iron [12.5 mL [100 mg elemental iron]), and 1, 2 and 
3 hours following the administration of a single dose of oral iron.  The window of allowance for the ferrokinetic 
study blood sampling will be ±3 minutes.
The blood samples for the ferrokinetic study (serum iron and TIBC) at the T0 timepoint must be taken 
immediately before the single dose of oral iron is administered.
On Days 1 8, and 15 hemoglobin levels will be tested in the central laboratory for all patients.  Additionally, for 
patients randomized to rHuEPO, Hb levels will be tested in the local laboratory on Days 1 and 8 for initial dose 
determination and dose adjustment.  The rHuEPO dose may be adjusted on Day 8 of the Treatment Period, 
depending on the patient’s Hb levels, for safety reasons, as determined by the Investigator, in accordance with 
the rHuEPO China Package Insert.  On Day 15 (or at the discontinuation visit), Hb levels will be tested in the 
local laboratory for all patients who were on rHuEPO prior to the study, to decide what rHuEPO dose to restart 
patients on, or another appropriate course of treatment for anemia, after study treatment stops.  For patients who 
were rHuEPO-naïve before entering the study, Hb levels may be tested in the local laboratory on Day 15 (or at 
the Discontinuation Visit) at the discretion of the Investigator, to determine an appropriate course of treatment 
for anemia in each patient.
D=day; DD=dialysis-dependent, Hb=hemoglobin; HD=hemodialysis; NDD=non-dialysis-dependent, 
PD=peritoneal dialysis; R=randomization; rHuEPO=recombinant human erythropoietin; TIBC=total iron binding 
capacity.


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2
INTRODUCTION
2.1
Study rationale
Advanced stages of chronic kidney disease (CKD) are associated with a hypo-proliferative 
anemia as well as dysfunctional iron homeostasis. The latter leads to functional iron 
deficiency, a process that describes multiple abnormalities in iron transport and utilization, 
including impaired gastrointestinal (GI) iron absorption. The latter appears to be mediated by 
paucity of hypoxia inducible factor (HIF)-2a, a subunit of HIF which boosts intestinal 
absorption of iron by upregulating duodenal cytochrome b and divalent metal transporter.
The prevalence of anemia increased as CKD progresses. The prevalence of anemia has been 
found to increase with the stage of CKD; from 8.4% at Stage 1 to 53.4% at Stage 5 (Stauffer 
and Fan 2014).
The prevalence of CKD is about 10.8% in China (Zhang et al 2012). According to the 2011 
Shanghai Dialysis Registry Report, the prevalence of end-stage renal disease (ESRD) is 
759 per million Chinese; the prevalence has almost doubled in the last 4 years when compared 
to 2007, at which time the prevalence was estimated to be 409.8 per million 
(http://sh.cnrds.org).
While recombinant human erythropoietin (rHuEPO) has been able to correct anemia in many 
patients with CKD, it has not been demonstrated to correct underlying iron dysmetabolism 
associated with CKD. Iron dysmetabolism and impaired GI absorption of iron is a 
well-recognized clinical phenomenon and is extensively described in the literature (Gupta and 
Wish 2017).  Recombinant human erythropoietin has not been demonstrated to correct this 
issue (Widness et al 1997).
Phase I and II clinical studies have suggested that the HIF-prolyl hydroxylase inhibitor 
(HIF-PHI), roxadustat, rectifies many of the abnormalities of iron dysmetabolism in CKD, 
including GI absorption (Besarab et al 2016).  This study is designed to expand evidence 
supporting enhanced GI iron absorption with roxadustat compared with rHuEPO in patients 
with anemia of Stage 4 and Stage 5 CKD.  In this study, patients with CKD who are either 
non-dialysis-dependent (NDD), or are dialysis-dependent (DD) and on a stable dose of 
rHuEPO, are planned to be recruited, with the comparator agent in this RCT being the current 
standard of care for anemia of CKD, rHuEPO analogues, otherwise known as erythropoiesis 
stimulating agents (ESAs).  Most NDD patients with anemia of CKD are not treated with 
rHuEPO analogues prior to starting dialysis. Furthermore, the GI absorption of iron may also 
be different in NDD patients with CKD-related anemia who have had prior exposure to 
rHuEPO analogues than those who are rHuEPO-naïve.  Therefore, this study will recruit both 
types of NDD patients: those who are rHuEPO-naïve as well as those who are rHuEPO-users, 
and have been on a stable dose of rHuEPO.


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2.2
Background
Roxadustat is an orally administered drug for the treatment of anemia caused by CKD in 
patients who are either on dialysis or not. Roxadustat is currently approved in China for the 
treatment of anemia of CKD patients, and is indicated for both dialysis and non-dialysis 
patients.
Roxadustat is a potent orally active HIF-PHI. Hypoxia inducible factor induces expression 
not only of erythropoietin (EPO), but also the erythropoietin receptor and proteins that 
promote iron reabsorption and recycling (Peyssonnaux et al 2008). Thus, roxadustat 
pharmacologically stimulates erythropoiesis via the HIF pathway and in a manner consistent 
with the body’s normal homeostatic response to hypoxia, but under normoxic conditions. In 
an open-label, randomized hemoglobin (Hb) correction study in anemic patients on
hemodialysis (HD) or peritoneal dialysis (PD), roxadustat corrected anemia in incident HD 
and PD patients, regardless of baseline iron repletion status or C-reactive protein (CRP) level 
and with oral or intravenous (IV) iron supplementation and also reduced serum hepcidin 
levels.  Roxadustat was well tolerated in this study (Besarab et al 2016).
A locally available short-acting rHuEPO, approved in China for the treatment of renal anemia 
for dialysis and non-dialysis patients, will be used as the comparator in this study.
This study will evaluate the effect of roxadustat versus rHuEPO on oral iron absorption in 
patients with anemia of Stage 4 and Stage 5 CKD and will provide data to meet the medical 
need to a new standard of care in patients on dialysis and to treat anemia of CKD in 
non-dialysis patients. The complications associated with ESAs including the need for 
IV/subcutaneous (SC) administration of ESAs, potential for anti-EPO antibody formation and 
pure red-cell aplasia, and EPO resistance and potential for transfusion-sparing can be reduced 
with roxadustat.
The clinical data collected thus far suggest that roxadustat is effective, generally safe and well 
tolerated in healthy adults, and in dialysis- and non-dialysis CKD patients with anemia.
A description of the chemistry, pharmacology, efficacy, and safety of roxadustat and rHuEPO
are provided in the respective China Package Inserts.  For additional information regarding 
roxadustat, please refer to the Investigator’s Brochure (IB).
2.3
Benefit/risk assessment
Patients across the continuum of CKD anemia were evaluated in the roxadustat global 
Phase III clinical development program (IB, Section 5.4.6).
In the NDD clinical program, roxadustat is superior to placebo for the treatment of anemia as 
measured by mean change in Hb. Compared with placebo, roxadustat effectively raises Hb 


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levels independently of baseline high sensitivity CRP (hs-CRP) categories or iron repletion 
status, reduces the need for rescue therapy (red blood cell [RBC] transfusion, IV iron, or 
ESA), and reduces LDL cholesterol. A key benefit for roxadustat patients is the clinically 
meaningful reduction in the need for RBC transfusions, currently the primary indication for 
treatment with ESA in the NDD population.
In the DD clinical program, roxadustat is statistically superior to epoetin alfa, the standard of 
care, for the treatment of anemia as measured by mean change in Hb. Roxadustat is also as 
effective as, or more effective than, epoetin alfa in increasing mean Hb levels in patients with 
elevated hs-CRP, and reducing the requirement for RBC transfusion. In addition, roxadustat 
demonstrates a clinically meaningful reduction in monthly IV iron supplementation, and 
reduces LDL cholesterol. Results from the incident dialysis (ID)-DD subpopulation are 
generally consistent with the overall DD population.
These results support the broad use of roxadustat to increase and maintain Hb levels and 
manage anemia for patients across the continuum of CKD anemia, including in those patients 
typically more difficult to treat with ESA. Roxadustat is effective in both the treatment of 
ESA-naïve patients requiring Hb correction and in patients converting from ESA treatment by 
maintaining sustained Hb levels.
The safety of roxadustat was evaluated against placebo in NDD CKD studies and against 
epoetin alfa in DD CKD studies.
For cardiovascular (CV) safety, the dialysis-dependent (DD) patients including incident 
dialysis (ID) patients (a sub-group of  DD patients who have been on dialysis for ≤4 months at 
the time of randomization) receiving roxadustat have a comparable risk of major adverse 
cardiovascular events (MACE, defined as stroke, myocardial infarction, all-cause death), 
MACE+ (events that comprised MACE plus hospitalized unstable angina and congestive heart 
failure), and all-cause mortality, compared with those who were treated with epoetin alfa.  The 
CV safety of roxadustat has also been established in non-dialysis patients compared to 
placebo. The risk of MACE, MACE+ or all-cause mortality is similar between the treatment 
groups (roxadustat compared to placebo).
The overall safety profile of roxadustat was generally comparable to placebo for NDD CKD 
patients and to epoetin alfa for DD and ID CKD patients for most of the safety issues 
evaluated.  A number of adverse drug reactions (ADRs) were identified, including vascular 
access thrombosis, deep vein thrombosis, and seizures.  Serious infection was considered an 
important potential risk, but causality was not established.  These risks are considered to be 
manageable with routine risk minimization activities.
The benefit-risk in this study is therefore deemed acceptable, when the study treatments are 
used in accordance with the rHuEPO and roxadustat China Package Inserts.


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2.3.1
Risk assessment and mitigation pertinent to COVID-19 pandemic
Given the circumstances of potentially relapsing pandemic or local epidemic with regard to 
the spread of coronavirus disease of 2019 (COVID-19), and considering that CKD patients 
have weakened immune systems, special attention will be paid to protect patients participating 
in the trial and clinical staff involved in the investigations against infection with COVID-19.  
Appropriate measures have been implemented into this protocol to detect COVID-19 disease 
at screening, safely conduct the clinical procedures in the trial, and to confirm the eligibility of 
study participants who have symptoms suggestive of COVID-19, or with a recent contact with 
a COVID-19 positive individual.
The Investigator will conduct a risk assessment of each individual participant, as well as an 
assessment of evolving pandemic conditions.  Appropriate risk-mitigation measures will be 
implemented to prioritize patient safety. All study-level discussions on risk assessment, to 
preserve data validity, mitigations and decisions will be documented, marked with start/stop 
dates where applicable on the Study Risk/Issue and Decisions Log and filed in the Trial 
Master File (TMF). The Institutional Review Board/Independent ethics committee (IRB/IEC)
will be consulted or notified, as required. Any urgent safety measures taken by the 
Investigator/Sponsor will promptly be communicated to the IRB/Health Authority, as 
required.
Details of study procedures, dose and study design justification are included in Section 4.
3
OBJECTIVES AND ENDPOINTS
Table 2
Study objectives
Primary objective a:
Endpoint/variable:
Evaluate the main effect of roxadustat versus 
rHuEPO on gastrointestinal iron absorption.
The main treatment effect on: the difference from 
baseline (Day 1) to Day 15 in log-transformed AUC 
of iron absorption from 0-3 hours based on the 
change in serum iron levels obtained just prior to T0 
(time when single dose of oral iron is administered) 
and over a 3-hour period (see Section 8.1).
Secondary Objectives a:
Endpoints/variables:
Assess the effect and interaction with key baseline 
variables of roxadustat versus rHuEPO on iron 
absorption.
The main treatment effect and key interaction effects 
on the difference from baseline (Day 1) to Day 15 in 
log-transformed AUC of iron absorption from 
0-3 hours based on the change in serum iron levels 
obtained just prior to T0 (time when single dose of 
oral iron is administered) and over a 3-hour period
(see Section 9.4.2).


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Assess the effect and interaction with key baseline 
variables of roxadustat versus rHuEPO on the indices 
of iron metabolism (ie, serum iron, ferritin, TIBC, 
TSAT, transferrin, soluble transferrin receptor) and 
hepcidin levels. 
The main treatment effect and key interaction effects 
on the difference from baseline (Day 1) to Day 15
prior to administration of oral iron: in serum iron, 
ferritin, TIBC, TSAT, transferrin, soluble transferrin
receptor and hepcidin levels, log-transformed as 
appropriate (see Section 9.4.2).
Safety Objective:
Endpoint/variable:
Safety evaluation.
Safety assessed by incidence of AEs, and 
measurement of vital signs (tympanic temperature, 
BP, pulse and respiratory rate), laboratory variables.
a
The primary and secondary objectives will be analyzed using the Full Analysis Set (FAS), see Section 9.3
for further details.
AE=adverse event; AUC=area under the curve; BP=blood pressure; rHuEPO=recombinant human 
erythropoietin; TIBC=total iron binding capacity; TSAT=transferrin saturation.
4
STUDY DESIGN
4.1
Overall design
This is a Phase IV, randomized, active-controlled, open-label, parallel design, multicenter 
prospective study to evaluate the effect of roxadustat versus rHuEPO treatment on the GI iron 
absorption in patients with anemia of Stage 4 and Stage 5 CKD.  This study is planned to 
screen a maximum of 104 patients and randomize a minimum of 20 patients and a maximum 
of 60 patients with anemia of CKD who are either rHuEPO-naïve or are currently treated with 
rHuEPO from approximately 7 to 10 sites in China.  Patient enrollment will be competitive 
across all sites and strata.
The study consists of 3 periods; the Screening Period, Treatment Period and Follow-up 
Period.  The enrolled patients will have 5 study visits.
This study will include:

Dialysis patients, defined as patients who have been on stable renal replacement therapy 
using HD or PD for >3 months, who have been on a stable dose of rHuEPO within 
4 weeks prior to screening.

Non-dialysis patients, defined as patients with Stage 4 or Stage 5 CKD as defined by 
Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula.  NDD patients
will be either rHuEPO-users (ie, on a stable dose of rHuEPO within 4 weeks prior to 
screening) or rHuEPO-naïve (ie, no treatment with ESAs for > 6 weeks prior to 
screening).
Patients will be assessed for hs-CRP at the Screening Visit to check whether the measurement 
is either ≤ the upper limit of normal (ULN), or > the ULN.


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For an overview of the study design see Figure 1, Section 1.3. For details on what is included 
in the efficacy and safety endpoints, see Section 3 Objectives and Endpoints.
The Screening Period will be followed by randomization (Day 1, Visit 2) at a 1:1 ratio to 
receive either roxadustat or rHuEPO for 2 weeks.  At Visit 2, all patients randomized to 
rHuEPO will receive a uniform brand of short-acting rHuEPO according to the dosage 
approved in the rHuEPO China Package Insert. Patients who were previously on rHuEPO 
(before Screening) will receive a uniform brand of short-acting rHuEPO based upon their 
previous dose of rHuEPO, and according to the dosage approved in the rHuEPO China 
Package Insert.  For patients on a weekly dose of rHuEPO of 6000 IU, dosing will be 2 times 
a week (BIW) and for patients on a weekly dose of rHuEPO of > 6000 IU, dosing will be 
3 times a week (TIW).  The rHuEPO can be administered either IV or SC depending on the 
route of administration used by the DD patients before the Treatment Period.  The rHuEPO 
will be administered via the SC route for all patients who are NDD.  On Days 1 and 15, 
immediately before time T0 of the ferrokinetic study, a blood sample will be collected to 
measure baseline serum iron level and total iron binding capacity (TIBC), immediately 
followed by administration of a defined single dose of oral iron after which the remaining 
blood samples for the ferrokinetic study will be collected over 3 hours to measure serum iron 
levels.  Serum levels of hepcidin and hs-CRP will be measured as biomarkers that reflect both 
altered iron metabolism and inflammation. Both biomarkers will be assessed throughout the 
study.  Safety will be evaluated in all consented patients.
4.1.1
Treatment duration and dosing
Each patient will be contacted over telephone before the first Screening Visit (Visit 1) to 
confirm that he/she has no symptoms of COVID-19 and that he/she has had no contact with a 
known COVID-19 positive person within the past 14 days.  Only asymptomatic patients, or 
those who have had no contact with a known COVID-19 positive person within the last 
14 days, will be asked to come to the site for informed consent and eligibility screening 
procedures.
For each patient, the duration of participation in the study will be approximately 8 to 9 weeks 
divided into 3 periods:
1. Screening Period: approximately 2-3 weeks. Dialysis and non-dialysis patients with 
anemia of CKD, fulfilling the eligibility criteria, will be asked to provide informed consent to 
participate in this study. All patients will be tested for COVID-19 infection at the first 
Screening Visit, using a swab test to rule out active COVID-19 infection.  If according to site 
procedures the test for COVID-19 infection cannot be performed at the first Screening Visit, 
the test should be performed as soon as possible thereafter but must be performed before the 
patient returns for the next study visit.  Patients who test positive (for COVID-19) must be 
withdrawn from the study.  Patients who test negative (for COVID-19) but do not meet the 


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eligibility criteria must be withdrawn from the study.  Patients must provide written informed 
consent before any screening tests or assessments are performed.  Patients will be assessed for 
hs-CRP at the Screening Visit to check whether the measurement is either ≤the ULN, or > the 
ULN.  During the Screening Period, all patients on rHuEPO before entering the study will 
remain on the rHuEPO treatment they received.  The rHuEPO dose may be adjusted for 
patients who were on rHuEPO before the Screening Period depending on the patient’s Hb 
levels, at the discretion of the Investigator, in accordance with the rHuEPO China Package 
Insert.  To check Hb eligibility criteria, Hb levels must be assessed twice, at least 7 days apart,
during the Screening Period; Hb levels may be assessed up to 3 times (Visits 1, 1a and 1b) 
during the Screening Period.  The Screening Period will be approximately 2-3 weeks long, but 
may be greater or lesser, to ascertain the Hb eligibility criteria with up to 3 Hb tests.  
Screening procedures will be performed according to the schedule of activities (SoA), Table 1.
2. Treatment Period: 2 weeks. Treatment Period procedures will be performed according to 
the SoA, Table 1 in all randomized patients. For patients who are already on rHuEPO, the 
start of the Treatment Period (Day 1) should be scheduled to fit into the rHuEPO 
administration regimen (ie, rHuEPO dosing must occur on the day of the Randomization Visit, 
Visit 2, Day 1).  Patients should be instructed not to take their rHuEPO dose in the morning 
before they attend the study site for the randomization visit (Visit 2, Day 1).
At Days 1 and 15, a ferrokinetic study will be done in all patients.  Immediately before time 
T0 of the ferrokinetic study, a blood sample will be collected to measure baseline serum iron 
level and TIBC, immediately followed by administration of a defined single dose of oral 
liquid elemental iron containing FeSO4 (12.5 mL dose, comprising 100 mg elemental iron).  
Gastrointestinal iron absorption (serum iron level measured) will then be assessed at 1, 2 and 
3 hours after the administration of the defined single dose of oral iron (T1, T2 and T3, 
respectively).  The window of allowance for the ferrokinetic study blood sampling will be 
±3 minutes.  Patients on HD will have their HD when the ferrokinetic study is completed ie, 
after the T3 timepoint.  For patients on PD, there are no timing restrictions for their PD in 
relation to the timing of the ferrokinetic study.
On Day 1, after the ferrokinetic study has completed (ie, after collection of the T3 serum iron 
sample), patients will be randomized in a 1:1 ratio to either rHuEPO treatment or roxadustat 
treatment.  Patients will be centrally randomized by interactive voice response system (IVRS)
and stratified by dialysis status (DD versus NDD) and by the following strata: NDD
(rHuEPO-users vs rHuEPO-naïve) and DD (PD vs HD).  The study treatment (roxadustat or 
rHuEPO) will be administered at the study site on Day 1, after randomization.  On Day 1, 
patients on HD, or PD can take their study treatment after randomization at any time before, 
during or after dialysis.


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Dosing of roxadustat and rHuEPO should be scheduled to occur on Visit 4 (Day 15).  On Day 
15, patients randomized to the roxadustat group should take the roxadustat in the morning, at 
least 6 hours before the ferrokinetic study starts.  On Day 15, patients randomized to the 
rHuEPO group should take the rHuEPO within 1-2 hours before the ferrokinetic study.
All patients should not ingest any foods containing more than trace amounts of iron such as 
heme-rich foods, multivitamins with iron etc. for approximately 4 hours before and during the 
3 hours of the ferrokinetic study.  Patients are allowed limited small snacks with negligible 
amounts of iron during this 7-hour period.  Patients may resume their normal dietary intake 
following collection of blood at the T3 time point.  There is no restriction on drinking water, 
coffee or tea for the patient before the ferrokinetic study starts and during the ferrokinetic 
study.
All patients randomized to rHuEPO will receive a uniform brand of short-acting rHuEPO 
according to the dosage approved in the rHuEPO China Package Insert.  Patients who were 
previously on rHuEPO (before Screening) will receive a uniform brand of short-acting 
rHuEPO based upon their previous dose of rHuEPO, and according to the dosage approved in 
the rHuEPO China Package Insert.  For patients on a weekly dose of rHuEPO of 6000 IU, 
dosing will be BIW and for patients on a weekly dose of rHuEPO of > 6000 IU, dosing will be
TIW.  The rHuEPO can be administered either IV or SC depending on the route of 
administration used by the DD patients before the Treatment Period.  The rHuEPO will be 
administered via the SC route for all patients who are NDD. For patients randomized to the 
rHuEPO arm, Hb levels will be tested in the local laboratory on Day 8, and the rHuEPO dose 
may be adjusted depending on the patient’s Hb levels, for safety reasons, as determined by the 
Investigator.  The rHuEPO dose may also be adjusted at any time during the Treatment Period 
by the Investigator for safety reasons.
Roxadustat will be administered orally TIW according to the dosage approved in the China 
Package Insert.  The roxadustat dose will not be adjusted during the Treatment Period;
therefore, for patients on the roxadustat arm Hb samples will not be collected on Day 8 for 
testing in the local laboratory.  The roxadustat dose may only be adjusted during the 2-week 
Treatment Period for safety reasons, as determined by the Investigator (see Section 6.6 for 
details).  Hemodialysis or PD patients can take roxadustat at any time before, during or after 
dialysis treatment.
Each patient will be contacted within 24 h before a scheduled visit to confirm that he/she has 
no symptoms of COVID-19 and that he/she has had no contact with a known 
COVID-19-positive person within the past 14 days. If the patient reports symptoms or contact 
with a COVID-19-positive patient, the Investigator may ask the patient to be tested for 
COVID-19 infection (swab test to rule out active COVID-19 infection), or withdraw the 
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discretion.  The study treatment and assessments may be continued as planned until the swab
test results are available, at the discretion of the Investigator.  Patients who test positive on the 
swab test must be withdrawn from the study.  A patient who contacts the site at any time 
during the Treatment Period informing that he/she has symptoms suggestive of COVID-19 
may be asked to get tested for active COVID-19 infection, or be withdrawn from the study for 
safety reasons, at the Investigator’s discretion.  Patients who test positive (for COVID-19) 
must be withdrawn from the study.
Any study assessments planned on the days of site visits may be completed via a telephone 
call and/or a visit to the patient’s home, as required, and if possible.  The handling of patients 
and their blood or urine samples will be done using sterile techniques and observing 
precautions for infection control and prevention.  Reasons for delayed site visits will be 
reported as protocol deviations.  The actual dates when the visit-related assessments were 
completed will be recorded in the electronic case report form (eCRFs).
In the event of early study discontinuation after baseline but prior to the Day 15 visit for a 
patient, the Investigator will seek to schedule a study discontinuation visit for the patient, 
including measurement of the primary efficacy assessments and other assessments according 
to the SoA, Table 1.
3. Post-Treatment Follow-up Period: 4 weeks. Post-Treatment Follow-up Period 
procedures to monitor safety will be performed according to the SoA, Table 1.  After 
completing study treatment, all patients will continue for a 4-week Follow-up Period, to 
monitor safety (all AEs and SAEs will be collected during this Period).  Patients who 
discontinue study treatment early will also continue to this 4-week Follow-up Period unless 
consent to participate is withdrawn.
Activities that are planned during this 4-week Follow-up Period may be performed by phone. 
Patients who withdraw prior to the end of the Treatment Period due to a positive COVID-19 
test result should not attend the Discontinuation Visit or the 28-day Follow-up Visit at the 
study site.  The assessments planned for the Discontinuation and 28-day Follow-up Visits
should be completed via a telephone call, as far as possible.
After discontinuation of study treatment, patients who were on rHuEPO before entering the 
study may either be returned to their previously prescribed rHuEPO treatment, or be 
prescribed different agent(s) to treat their anemia by the Investigator, based on their local Hb 
levels and the discretion of the Investigator. For patients who were rHuEPO-naïve before 
entering the study, Hb levels may be tested in the local laboratory at the discretion of the 
Investigator, to determine an appropriate course of treatment for anemia in each patient.


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4.1.2
Randomization
A maximum of 104 patients are planned to be screened to achieve a minimum of 20 and a 
maximum of 60 eligible randomized patients with anemia of CKD fulfilling all the inclusion 
criteria and none of the exclusion criteria.  Enrolled patients will be centrally randomized via 
an IVRS in a 1:1 ratio to receive either roxadustat or rHuEPO treatment.  At randomization, 
patients will be stratified by NDD (NDD-rHuEPO-users, NDD-rHuEPO-naïve), DD-PD, and 
DD-HD patients.
4.1.3
Dose of study treatments
For details on treatments given during the study, see Section 6.1 Treatments Administered.
Roxadustat will be administered orally TIW.  For patients on dialysis: dose of 100 mg for 
patients with body weight 45 to < 60 kg, or 120 mg for patients with body weight ≥60 kg; for 
non-dialysis patients: dose of 70 mg for patients with body weight 40 to < 60 kg, or 100 mg 
for patients with body weight ≥60 kg.  The roxadustat dose will not be adjusted during the 
2-week Treatment Period, except for safety reasons as judged by the Investigator.  The 
rHuEPO will be BIW or TIW as an IV or SC dose.  The rHuEPO can be administered either 
IV or SC depending on the route of administration used by the DD patients before the 
Treatment Period.  The rHuEPO will be administered via the SC route for all patients who are 
NDD.
For patients randomized to the rHuEPO arm, Hb levels will be tested in the local laboratory on 
Day 8, and the rHuEPO dose may be adjusted depending on the patient’s Hb levels, for safety 
reasons, as determined by the Investigator.  The roxadustat dose will not be adjusted 
depending on the patient’s Hb levels during the treatment period, therefore for patients on the 
roxadustat arm Hb samples will not be collected on Day 8 for testing in the local laboratory
(also see Section 6.6).
4.2
Scientific rationale for study design
This study is designed to investigate the effect of roxadustat versus rHuEPO treatment on the 
GI iron absorption in patients with anemia of CKD, on dialysis or non-dialysis-dependent at 
Stage 4 and 5.
This study is a randomized, parallel design with 2 treatment groups; roxadustat or rHuEPO 
and includes dialysis and non-dialysis patients. Performing a parallel design study instead of a 
crossover design will obviate the risk of “carry-over effects” from either study treatment, in 
this case roxadustat as rHuEPO has minimal influence on GI iron absorption.  The control 
group will receive rHuEPO, which allows a direct comparison of the effect of roxadustat on 
GI iron absorption.
The study population consists of patients with anemia associated with CKD; the target 
population for roxadustat.


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In this study, the first dose of study treatment will be given at Day 1. Gastrointestinal iron 
absorption will be assessed before the first dose of study treatment and will then be re-
assessed again in both groups after 2 weeks of study treatment exposure. Data on file on 
FG-2216, sister compound to roxadustat, has shown significant changes in GI iron absorption 
following oral dosing of iron in a population with anemia associated with CKD occurring 
2 weeks after initiation of FG-2216.
This is an open-label randomized study. Any potential bias will be reduced by central 
randomization of the patients. The endpoints are measuring levels rather than more subjective 
patient reported outcomes and will not be influenced by patient or Investigator knowledge of 
the study treatment.
4.3
Justification for dose
The roxadustat and rHuEPO doses used in this study are according to approved prescribing 
information available in the respective China Package Inserts.
Details on dose modifications are included in Section 6.6.
4.4
End of study definition
The end-of-study (EOS) is defined as the last expected visit/contact of the last patient
undergoing the study.
A patient is considered to have completed the study when he/she has completed his/her last
scheduled procedure shown in the SoA, Table 1.
See Appendix A 6 for guidelines for the dissemination of study results.
5
STUDY POPULATION
Prospective approval of CSP deviations to recruitment and enrollment criteria, also known as 
CSP waivers or exemptions, is not permitted.
Each patient should meet all of the inclusion criteria and none of the exclusion criteria for this 
study in order to be assigned/randomized to a study treatment.  Under no circumstances can 
there be exceptions to this rule.  Patients who do not meet the entry requirements are screen 
failures (Section 5.4). Rescreening of patients is allowed as detailed in Section 5.4.
In this CSP, “enrolled” patients are defined as those who sign informed consent.  “Screened” 
patients are defined as those who fulfil the inclusion/exclusion criteria and have not yet
entered the Treatment Period.  “Randomized” patients are defined as those who undergo 
randomization and receive a randomization number.


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For procedures for withdrawal of incorrectly enrolled patients see Section 7.3.
5.1
Inclusion criteria
Patients are eligible to be included in the study only if all of the following inclusion criteria 
and none of the exclusion criteria apply:
Informed consent
1
Provision of signed and dated, written informed consent form (ICF) prior to any 
mandatory study specific procedures, sampling, and analyses. 
The ICF process is described in Appendix A 3.
Age
2
Patient must be ≥18 years of age, at the time of signing the ICF.
Type of patient and disease characteristics
At Visit 1 prior to screening
Dialysis patients:
3
Patients receiving HD or PD for treatment of ESRD for at least 12 weeks.  Patients treated
with HD must have access consisting of an arteriovenous (AV) fistula, AV graft, or 
tunneled (permanent) catheter.  Patients on PD must have a functioning PD catheter in 
place.
4
Hemodialysis patients should be on 3x/week dialysis with evidence of achievement of 
adequate dialysis as defined by stdKt/V ≥2.1 in HD, and total (renal + PD) weekly Kt/V 
≥1.7 in PD documented twice during the 16 weeks preceding screening for the study.
5
Patients should be on a stable rHuEPO dose as defined by change in rHuEPO dose, not 
exceeding 20% within 4 weeks prior to screening.
Non-dialysis patients:
6
Patients with estimated glomerular filtration rate (eGFR) <30 mL/minute/1.73 m2, 
(calculated by central laboratory) corresponding to Stage 4 or Stage 5 CKD according to 
the Kidney Disease Outcomes Quality Initiative (KDOQI), and not receiving dialysis
(Levey et al 2006).
7
Patients should either be on a stable dose of rHuEPO for 4 weeks before screening 
(defined as not exceeding 20% within 4 weeks prior to screening) or be rHuEPO-naïve 
(no ESA treatment for > 6 weeks before screening).


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Dialysis and non-dialysis patients:
8
Patients agree not to take any new traditional Chinese medicine (TCM) and not to change, 
dose, schedule or brand of any TCM from beginning of the Screening Period through the 
end of the Follow-up Period.
At Visit 1 (screening)
9
Ferritin ≥50 ng/mL and transferrin saturation (TSAT) ≥15% in non-dialysis patients
(obtained from Visit 1, Screening Visit).
10 Ferritin ≥100 ng/mL and TSAT ≥20% in dialysis patients (obtained from Visit 1, 
Screening Visit).
Weight
11 At Visit 1 (screening), dry body weight 45 to 100 kg (inclusive).
During the Screening Period
12 Dialysis patients must have a mean Hb level of ≥ 9 to ≤ 12 g/dL based on the mean of the 
2 most recent central laboratory Hb values within 0.50 g/dL on 2 assays taken at least 
7 days apart during the Screening Period.
13 Non-dialysis patients must have a mean Hb level of ≥ 9 to ≤ 12 g/dL for rHuEPO-user 
patients and ≥ 7 and ≤ 10 g/dL for rHuEPO-naïve patients, based on the mean of the
2 most recent central laboratory Hb values within 0.50 g/dL on 2 assays taken at least 
7 days apart during the Screening Period.
At Visit 1 Screening
14 Serum folate level ≥lower limit of normal (LLN) (obtained from Visit 1, Screening 
Visit).
15 Serum vitamin B12 level ≥LLN (obtained from Visit 1, Screening Visit).
16 Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≤3 x ULN and 
total bilirubin (TBL) ≤1.5 x ULN (obtained from Visit 1, Screening Visit).
17 Negative test results on the swab test to rule out active COVID-19 infection at the 
Screening Visit.  If according to site procedures the test for COVID-19 infection cannot 
be performed at the first Screening Visit, the test should be performed as soon as possible
thereafter but must be performed before the patient returns for the next study visit.  Any 
participant who has had confirmed COVID-19 infection in the past, has fully recovered 
from symptoms at least 14 days prior to Screening, and has a negative swab test result for 
COVID-19 infection at Screening, may be included in the study.


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Reproduction
18 At the start of the Screening Period, negative serum pregnancy test for female patients of 
childbearing potential.
19 Female patients of childbearing potential and male patients (non-surgically sterile ie, 
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, depot progesterone or 
intrauterine device; and (2) a barrier method (condom or diaphragm).
Contraceptive methods must be practiced upon being randomized to the study and until at 
least 7 days after the last dose of study treatment.  Male patients must not donate or bank 
sperm during this same time period.
5.2
Exclusion criteria
Medical conditions
1
New York Heart Association Class III or IV congestive heart failure (CHF) at screening.
2
Acute coronary syndrome, stroke, seizure or a thrombotic/thromboembolic event (eg, 
deep vein thrombosis or pulmonary embolism) within 12 weeks prior to randomization.
3
History of severe, chronic, end-stage, or uncontrolled autoimmune liver disease with ALT 
> 3 x ULN, or AST > 3 × ULN, or total bilirubin > 1.5 × ULN.
4
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.
5
Known and untreated retinal vein occlusion or known and untreated proliferative diabetic 
retinopathy (risk for retinal vein thrombosis).
6
Systolic blood pressure (BP) ≥160 mm Hg or diastolic BP ≥95 mm Hg (confirmed by 
repeated measurement), within 2 weeks prior to randomization. Patients may be 
rescreened once BP is controlled.
7
History of prostate cancer, breast cancer, renal cell carcinoma 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.
8
Chronic inflammatory diseases such as rheumatoid arthritis, systemic lupus 
erythematosus (SLE), ankylosing spondylitis, psoriatic arthritis or active inflammatory 
bowel disease that is determined to be the principal cause of anemia.
9
Known hemosiderosis, hemochromatosis or hypercoagulable condition.
10 Any prior organ transplant or a scheduled organ transplantation date.
11 Any current condition leading to active significant blood loss.
12 Known allergy to the study treatment or any of its ingredients.


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13 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 safety or efficacy assessment or may interfere with study 
participation.
14 Intolerance of oral iron in the past as defined by stomach upset, nausea, vomiting, or 
diarrhea.
15 Active GI bleed.
16 Hospitalizations within the 12 weeks preceding study randomization for GI bleeding or
CHF.
17 Life expectancy <6 months.
18 Patients who are likely to be initiated on dialysis within the next 3 months per 
Investigator’s assessment at the time of screening.
19 Previous bowel resection.
20 Coeliac disease.
21 Gastroenteritis in the 4 weeks prior to randomization.
22 Cognitive disabilities, physical or psychiatric disease that in the opinion of the 
Investigator/clinician influence the patient’s adherence and successful completion of the 
study.
Prior/concomitant therapy
23 Any treatment with roxadustat or a HIF-PHI.
24 Any RBC transfusion within 6 weeks prior to the first Screening Visit, or during the 
Screening Period.
25 Has received another new chemical entity (defined as a compound which has not been 
approved for marketing) within the 12 weeks prior to Screening Visit.
26 Exposure to IV iron or use of TRIFERIC® in dialysate during the Screening Period (ie,
2 weeks before randomization [Day 1]).
27 Exposure to iron-chelating agent (eg, deferoxamine/desferrioxamine, deferiprone or 
deferaxirox therapy) within the 6 weeks prior to the first Screening Visit.
Prior/concurrent clinical study experience
28 Participation in any other clinical study that included drug treatment within at least 
4 weeks of screening. (Note: patients consented and screened, but not randomized in this 
study or a previous study are not excluded).
Other exclusions
29 Involvement in the planning and/or conduct of the study (applies to AstraZeneca and 
FibroGen staff and/or staff at the study site).


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30 Patient non-adherence to medications or missing > 1 dialysis treatments/month per the 
Investigator’s knowledge.
31 Previous randomization in the present study.
32 History of alcohol or drug abuse within 2 years prior to randomization.
5.3
Lifestyle restrictions
No restrictions are required.
5.4
Screen failures
Screen failures are defined as patients who signed the ICF to participate in the clinical study 
but are not subsequently entered in the Treatment Period.  A minimal set of screen failure 
information is required to ensure transparent reporting of screen failure patients to meet the 
Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to 
respond to queries from regulatory authorities.  Minimal information includes demography, 
screen failure details, eligibility criteria, and any SAE.
Patients who failed to meet 1 or more of the following eligibility criteria for participation in 
this study (screen failure) on initial evaluation may be rescreened once only, at the 
Investigator’s discretion:
Inclusion criteria for rescreening

Patients receiving or initiating HD or PD for treatment of ESRD for at least 12 weeks.
Patients treated with HD must have access consisting of an AV fistula, AV graft, or 
tunneled (permanent) catheter. Patients on PD must have a functioning PD catheter in 
place.

Patients (dialysis and non-dialysis, rHuEPO-users) must have a mean Hb level of ≥9 to 
≤12 g/dL based on the mean of the 2 most recent central laboratory Hb values within 
0.50 g/dL on 2 assays taken at least 7 days apart during the Screening Period.
Non-dialysis rHuEPO-naïve patients must have a mean Hb level of ≥7 and ≤10 g/dL 
based on the mean of the 2 most recent central laboratory Hb values within 0.50 g/dL on 
2 assays taken at least 7 days apart during the Screening Period.

Hemodialysis patients should be on 3x/week dialysis with evidence of achievement of 
adequate dialysis as defined by stdKt/V ≥2.1 in HD, and total (renal + PD) weekly 
Kt/V ≥1.7 in PD documented twice during the 3 months preceding evaluation for the 
study.

Negative swab test result to rule out active COVID-19 infection at the Screening Visit.  If 
according to site procedures the test for COVID-19 infection cannot be performed at the 
first Screening Visit, the test should be performed as soon as possible thereafter but must 
be performed before the patient returns for the next study visit.  Any participant who has 
had confirmed COVID-19 infection in the past, has fully recovered from symptoms at 


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least 14 days prior to Screening, and has a negative swab test result for COVID-19
infection at Screening may be included in the study.
Exclusion criteria for rescreening

Systolic BP ≥160 mmHg or diastolic BP ≥95 mmHg (confirmed by repeated 
measurement), within 2 weeks prior to randomization.

Any RBC transfusion during the Screening Period.

Hospitalizations within the 12 weeks preceding study randomization for GI bleeding or
CHF.

Exposure to IV iron or use of TRIFERIC® in dialysate during the Screening Period (ie, 
2 weeks before randomization [Day 1]).

Exposure to iron-chelating agent (eg, deferoxamine/desferrioxamine, deferiprone or 
deferaxirox therapy) within the 6 weeks prior to the first Screening Visit.

Gastroenteritis in the 4 weeks prior to randomization.
Rescreening is not allowed for any other criteria apart from those listed above.
Rescreened patients will be assigned a new patient number.  An extra file will be included in 
the eCRF to record the original enrollment code (ECode).  Rescreening will be documented so 
that its effect on study results, if any, can be assessed.
These patients should have the reason for study withdrawal recorded in the eCRF.
6
STUDY TREATMENTS
Study treatment is defined as any investigational product(s) (including marketed product 
comparator and placebo) or medical device(s) intended to be administered to a study 
participant according to the CSP. Study treatment in this study refers to roxadustat and 
rHuEPO.
6.1
Treatments administered
6.1.1
Investigational products
During the randomized Treatment Period, patients will be randomly assigned in 1:1 ratio to 
receive either roxadustat or rHuEPO for 2 weeks.
Patients will be provided roxadustat and rHuEPO and both treatments will be used according 
to their approved indication and dosage during the study.  Refer to roxadustat and rHuEPO 
China Package Inserts for further details on these study treatments.  For additional information 
regarding roxadustat, please refer to the IB.


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6.1.2
Dose of study treatments
The starting dose of roxadustat will be calculated as per the China Package Insert. The 
recommended starting dose of roxadustat will depend on the body weight of the patient:
100 mg (45 to < 60 kg) or 120 mg (≥ 60 kg) in patients on dialysis (weight should be patient’s 
empty weight prior to instillation of dialysate); 70 mg (40 to < 60 kg) or 100 mg (≥60 kg) in 
non-dialysis patients.
Roxadustat doses must be administered at least 2 days apart but no more than 4 days apart (eg, 
Monday, Wednesday, Friday). Dosing of roxadustat should be scheduled to occur on the day 
of Visit 4 (Day 15).  Patients can take roxadustat at any time before or after dialysis treatment. 
On Day 1, roxadustat should be taken after the ferrokinetic study has completed.  On Day 15
roxadustat should be taken at least 6 hours before the ferrokinetic study starts.  The dose of 
roxadustat will not be adjusted during the study except for safety reasons as judged by the 
Investigator.
At Visit 2, all patients randomized to rHuEPO will receive a uniform brand of short-acting 
rHuEPO according to the dosage approved in the rHuEPO China Package Insert.  Patients 
who were previously on rHuEPO (before Screening) will receive a uniform brand of 
short-acting rHuEPO based upon their previous dose of rHuEPO, and according to the dosage 
approved in the rHuEPO China Package Insert.  For patients on a weekly dose of rHuEPO of 
6000 IU, dosing will be BIW and for patients on a weekly dose of rHuEPO of > 6000 IU, 
dosing will be TIW.  The rHuEPO can be administered either IV or SC depending on the route 
of administration used by the DD patients before the Treatment Period.  The rHuEPO will be 
administered via the SC route for all patients who are NDD.
For patients who were rHuEPO-users before Screening, the initial dose selection of rHuEPO 
will be based on the patient’s Hb levels, and average prescribed rHuEPO dose during the 
4 weeks prior to the Screening Visit.  For patients who are rHuEPO-naïve at study entry, the 
initial start dose of the study rHuEPO will be based on the patient’s Hb levels and will be in 
accordance with the rHuEPO China Package Insert.  Previously rHuEPO-naïve patients 
randomized to the rHuEPO arm may be trained by the site staff to self-administer SC injection 
on the day of randomization, if required.  The rHuEPO may also be administered by a 
qualified person at the study site or at another hospital.
For patients who are already receiving the uniform brand of rHuEPO that will be used for the 
study, the initial rHuEPO dosing regimen in the study (starting from Visit 2) should be 
equivalent to their prior rHuEPO dosing regimen, unless a dose adjustment is needed per the 
Investigator’s judgment.


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For patients on any other short-acting rHuEPOs, a conversion ratio of 1:1 (equivalent dose) to 
the study rHuEPO should be used unless a dose adjustment is needed per the Investigator’s 
judgment.
For patients on long-acting rHuEPOs, the initial dose of the study rHuEPO will be determined 
using the conversion table (see Table 3), unless a dose adjustment is needed per the 
Investigator’s judgment.
The study rHuEPO dose can be adjusted on Day 8 during the 2-week Treatment Period, 
depending on the patient’s Hb levels.  The rHuEPO dose may also be adjusted at any time 
during the Treatment Period by the Investigator for safety reasons, if judged necessary (see 
Section 6.6 for details).
For patients already on rHuEPO, dosing of rHuEPO should be scheduled to occur on the day 
of Visit 2 (Day 1).  Patients should be instructed not to take their rHuEPO dose in the morning 
before they attend for the randomization visit (Visit 2, Day 1).  On Day 1, patients randomized 
to rHuEPO should have rHuEPO administered after the ferrokinetic study has completed.  For 
patients randomized to rHuEPO, dosing of rHuEPO should be scheduled to occur on the day 
of Visit 4 (Day 15).  On Day 15, patients randomized to rHuEPO should have rHuEPO 
administered within 1-2 hours before the ferrokinetic study starts.
Table 3
Initial dosing of rHuEPO for patients treated with an erythropoietic 
analogue at study entry
Conversion ratio
Examples of converted initial epoetin 
alfa dose (IU/week) c
Darbepoetin alfa (μg/week) a
x 200
40 μg/week x 200 = 8,000 IU/week
Mircera® (μg/month) a
x 70 to 80
(Lower conversion ratio can be used 
for lower Mircera® dose)b
100 μg/month x 70 = 7,000 IU/week
200 μg/month x 80 = 16,000 IU/week
a
Mean weekly monthly dose prior to Screening Visit 1.
b
Per discretion of Investigator.
c
May be rounded if deemed necessary.
rHuEPO=recombinant human erythropoietin; IU=international unit.
Recombinant human erythropoietin must not be mixed with other drugs for injection.
If a patient misses a dose of study treatment (roxadustat or rHuEPO), the patient should make 
a note of this and inform the study site staff at their next study visit.  They should continue 
with the next scheduled dose.
Details on dose modifications are in Section 6.6.


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6.1.3
Additional treatments
All patients will receive the same brand of liquid oral iron containing FeSO4 to be 
administered as a single oral (liquid) dose of 12.5 mL (100 mg elemental iron) at Days 1 and 
15 for the ferrokinetic study.
6.2
Preparation/handling/storage/accountability
Recombinant human erythropoietin can be administered either IV or SC. Administration of 
rHuEPO will be performed by the Investigator or a qualified member of the site staff in HD
patients. In PD or NDD patients with CKD, rHuEPO can be self-administered SC by the 
patient or a caregiver after adequate training by site staff , unless the Investigator is of the 
opinion that the patient or caregiver is already adequately self-administering an rHuEPO 
analogue prior to the study. Previously rHuEPO-naïve patients randomized to the rHuEPO 
arm may be trained by the site staff to self-administer SC injection on the day of 
randomization.  The rHuEPO may also be administered by a qualified person at the study site 
or at another hospital.
On Day 15, patients randomized to the roxadustat group should take the roxadustat in the 
morning, at least 6 hours before the ferrokinetic study starts.  On Day 15, patients randomized
to the rHuEPO group should take the rHuEPO within 1-2 hours before the ferrokinetic study
starts.  The time a patient takes the roxadustat and rHuEPO should be recorded in the eCRF.
Details on food restrictions on Days 1 and 15 are in Sections 4.1.1 and 8.1.1.
The Investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study treatment received and any discrepancies are reported 
and resolved before use of the study treatment.
Only patients enrolled in the study may receive study treatment and only authorized site staff 
may supply or administer study treatment.  All study treatments must be stored in a secure, 
environmentally controlled, and monitored (manual or automated) area in accordance with the 
labelled storage conditions with access limited to the Investigator and authorized site staff.
The Investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study treatment accountability, reconciliation, and record maintenance 
(ie, receipt, reconciliation, and final disposition records).
Further guidance and information for the final disposition of unused study treatment are 
provided in the Investigator Manual.


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6.3
Measures to minimize bias: randomization and blinding
This is an open-label study in which a minimum of 20 patients and a maximum of 60 patients
will be randomized in a 1:1 ratio to either roxadustat or rHuEPO.  Results for Screening 
Period assessments for serum folate, vitamin B12, ALT, AST and TBL must be available 
before randomization. Randomization to treatment will be performed centrally using 
PAREXEL MATCH, an IVRS, in sequence and stratified by the following strata: NDD 
(rHuEPOuser, rHuEPO-naïve), DD-PD, and DD-HD patients. 
The use of a central randomization will be implemented to avoid selection bias.  Before the 
study is initiated, the telephone number and call-in directions for the IVRS will be provided to 
each study site.
If a patient withdraws from the study, then his/her enrollment/randomization ECode cannot be 
reused.  Withdrawn patients will not be replaced.
Tables ran prior to database lock will be presented using a dummy treatment list to ensure 
decision bias is minimized.
6.4
Treatment adherence
Any change from the dosing schedule, dose interruptions, dose reductions, dose 
discontinuations should be recorded in eCRF.
The Investigational Product Storage Manager is responsible for managing the study treatment
from receipt by the study site until the destruction or return of all unused study treatment.  The 
Investigator(s) is responsible for ensuring that the patient has returned all unused study 
treatment.  Patients who withdraw prior to the end of the Treatment Period due to a positive 
COVID-19 test result will be instructed to send any remaining study treatment to the study site 
by mail, when it is safe to do so.
6.5
Concomitant therapy
Concomitant medications are any prescription or over-the-counter preparations, including 
herbal products, TCM and “natural remedies”, used by a patient while participating in this 
clinical study.  Any medication or vaccine including over-the-counter or prescription 
medicines, vitamins, and/or herbal products and “natural remedies” that the patient is 
receiving at the time of screening or receives during the study must be recorded along with:

Reason for use

Dates of administration including start and end dates

Dosage information including dose and frequency


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Patients should not take any new TCM and should not change the dose, schedule or brand of 
any TCM from beginning the of the Screening Period through the end of the Follow-up
Period.
Patients taking oral iron before the study can continue taking this during the study. The dose 
of the oral iron should not be changed during the Treatment Period.  The oral iron should not 
be taken in the morning on the day of ferrokinetic procedures and on this day, patients will be 
given a defined single dose of oral liquid elemental iron containing FeSO4 used for the study.
For details of medications for which care should be taken when concomitantly administered 
with roxadustat or rHuEPO, refer to the respective China Package Inserts.
6.5.1
Prohibited medications/therapy
The following medications/therapies are prohibited during the study:

Any other investigational drug: from randomization until EOS

Any rHuEPO treatment during the Treatment Period, except for study treatment

Iron-chelating agents (eg, deferoxamine/desferrioxamine, deferiprone or deferaxirox 
therapy): from 6 weeks prior to the first Screening Visit until the end of the Treatment 
Period

Intravenous iron and TRIFERIC® in dialysate need to be stopped during the Screening 
Period (ie, 2 weeks before randomization [Day 1]), and should not be taken throughout 
the remaining Screening Period and the Treatment Period, but can be started again after 
the Treatment Period

Any vitamin C formulation: from randomization until EOS.
For details of prohibited medications, refer to the respective China Package Inserts.
6.5.2
Other concomitant treatment
Medication other than that described above is discouraged but may be given at the discretion 
of the Investigator if considered necessary for the patient’s safety and well-being.  All 
concomitant medications are to be recorded in the appropriate sections of the eCRF.
6.5.3
Rescue guidelines
If a patient’s medical condition requires rescue therapy, the patient should be treated at the 
Investigator’s discretion. Rescue therapy should be recorded in the eCRF.
6.6
Dose modification
The dose for roxadustat will not be adjusted during this study due to its short duration, except 
for safety reasons as judged by the Investigator.


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Change in rHuEPO dosing will be allowed both during Screening and Treatment Periods at 
the discretion of the Investigator for the patient’s safety and to maintain the patient’s Hb levels 
within the CSP defined range.  Ideally, dosage changes would not occur or would be minimal 
during the week leading up to and during the 2-week Treatment Period.  However, appropriate 
adjustments should occur as required to ensure patient safety.
6.7
Treatment after the end of the study
After discontinuation of study treatment, patients who were on rHuEPO before entering the 
study may either be returned to their previously prescribed rHuEPO treatment, or be 
prescribed a different agent(s) to treat their anemia by the Investigator, based on their local Hb 
levels and the discretion of the Investigator.  For patients who were rHuEPO-naïve before 
entering the study, Hb levels may be tested in the local laboratory at the discretion of the 
Investigator, to determine an appropriate course of treatment for anemia in each patient.
7
DISCONTINUATION OF TREATMENT AND PATIENT
WITHDRAWAL 
7.1
Discontinuation of study treatment 
Note that discontinuation from study treatment is NOT the same thing as a complete 
withdrawal from the study. See the SoA, Table 1, for data to be collected at the time of study
treatment discontinuation and follow-up and for any further evaluations that need to be 
completed.
7.1.1
Temporary discontinuation from study treatment
For patients needing treatment with prohibited concomitant medications, study treatment must 
be discontinued or interrupted temporarily.
For decisions around discontinuation, Parexel Medical can be consulted as appropriate.
7.1.2
Permanent discontinuation from study treatment

Patient decision: The patient is at any time free to discontinue treatment, without 
prejudice to further treatment

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 for which the Investigator thinks continued study treatment may put 
the patient at undue risk

Severe non-compliance with CSP

Pregnancy


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Each permanent discontinuation from study treatment should be communicated to the study 
team. For decisions around permanent discontinuation, Parexel Medical can be consulted as 
appropriate. Study assessments or follow-up should be continued in all cases if possible (see 
SoA, Table 1).
If a patient discontinues prematurely, the contraceptive method must be practiced until at least
7 days following final administration of study treatment.
7.1.3
Procedures for discontinuation of study treatment
The Investigator should instruct the patient to contact the study site before or at the time if 
study treatment is stopped.
A patient that decides to discontinue study treatment will always be asked about the reason(s) 
and the presence of any AEs.  The date of last intake of study treatment should be documented 
in the eCRF.  All study treatment should be returned by the patient at their next on-site study 
visit or unscheduled visit.  Patients permanently discontinuing study treatment should be given 
locally available standard of care therapy, at the discretion of the Investigator.
Discontinuation of study treatment, for any reason, does not impact on the patient´s 
participation in the study.  At the time that the patient discontinues study treatment, the patient 
should be asked to return to attend the discontinuation visit (to perform all assessments that 
would have been performed at Visit 4), within 7 days after the study treatment is stopped.  The 
patient will also attend the 28-day Follow-up Visit (28 ±3 days after the study treatment is 
stopped).  If the patient does not agree to attend these study visits in-person, a modified 
follow-up must be arranged to ensure the collection of endpoints and safety information.  This 
could be a telephone contact with the patient, a contact with a relative or treating physician, or 
information from medical records.  The approach taken should be recorded in the medical 
records.  A patient that agrees to modified follow-up is not considered to have withdrawn 
consent or to have withdrawn from the study. The patient should return all study treatment to 
the study site.
If a patient discontinues prematurely, the contraceptive method must be practiced until at least 
7 days following final administration of study treatment.
Patients who withdraw prior to the end of the Treatment Period due to a positive COVID-19 
test result should not attend the Discontinuation Visit or the 28-day Follow-up Visit at the 
study site.  The assessments planned for the Discontinuation and 28-day Follow-up Visits
should be completed via a telephone call, as far as possible.  These patients will be instructed 
to send any remaining study treatment to the study site by mail, when it is safe to do so.


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7.2
Lost to follow-up
A patient will be considered potentially lost to follow-up if he or she fails to return for 
scheduled visits and is unable to be contacted by the study site.
The following actions must be taken if a patient fails to return to the study site for a required 
study visit:

The study site must attempt to contact the patient and reschedule the missed visit as soon 
as possible and counsel the patient on the importance of maintaining the assigned visit 
schedule.

Before a patient is deemed lost to follow-up, the Investigator or designee must make 
every effort to regain contact with the patient or next of kin by eg, repeat telephone calls, 
certified letter to the patient´s last known mailing address or local equivalent methods. 
These contact attempts should be documented in the patient’s medical record.

Efforts to reach the patient should continue until the EOS. Should the patient be 
unreachable at the EOS, the patient should be considered to be lost to follow-up with 
unknown vital status at EOS and censored at latest follow-up contact.
7.3
Withdrawal from the study
A patient may withdraw from the study (eg, withdraw consent), at any time (study treatment
and assessments) at his/her own request, without prejudice to further treatment.
A patient may be withdrawn from the study at any time at the discretion of the Investigator or 
Sponsor for safety reasons.
If the patient reports symptoms on a pre-visit telephone call, reports contact with a COVID-19
positive patient within the past 14 days, the Investigator may ask the patient to be tested for 
COVID-19 infection (swab test to rule out active COVID-19 infection), or withdraw the 
patient from the study, as is most suitable for the patient’s safety, at the Investigator’s 
discretion.  The study treatment and assessments may be continued as planned until the swab
test results are available, at the discretion of the Investigator.  Patients who test positive on the 
swab test must be withdrawn from the study.  A patient who contacts the site at any time 
during the Treatment Period informing that he/she has symptoms suggestive of COVID-19 
may be asked to get tested for COVID-19 infection, or be withdrawn from the study for safety 
reasons, at the Investigator’s discretion.  Patients who test positive (for COVID-19) must be 
withdrawn from the study.  The assessments planned for the Discontinuation and 28-day 
Follow-up Visits should be completed via a telephone call, as far as possible.  Patients who 
withdraw prior to the end of the Treatment Period visit due to a positive COVID-19 test result 
will be instructed to send any remaining study treatment to the study site by mail, when it is 
safe to do so.


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A patient who considers withdrawing from the study must be informed by the Investigator 
about modified follow-up options (eg, telephone contact, a contact with a relative or treating 
physician, or information from medical records).
If the patient withdraws consent for disclosure of future information, the Sponsor may retain 
and continue to use any data collected before such a withdrawal of consent.
If a patient withdraws from the study, he/she may request destruction of any samples taken, 
and the Investigator must document this in the site study records.
A patient who withdraws consent will always be asked about the reason(s) and the presence of 
any AEs.  The Investigator will follow-up patients as medically indicated.
AstraZeneca or its delegate will request Investigators to collect information on patients’ vital 
status (dead or alive; date of death when applicable) at the EOS from publicly available 
sources, in accordance with local regulations.  Knowledge of the vital status at study end in all 
patients is crucial for the integrity of the study.
See SoA, Table 1, for data to be collected at the time of study treatment discontinuation and 
follow-up and for any further evaluations that need to be completed. All study treatment 
should be returned by the patient.
8
STUDY ASSESSMENTS AND PROCEDURES
Study procedures and their timing are summarized in the SoA, Table 1.
The Investigator will ensure that data are recorded on the eCRF. The Web-Based Data 
Capture (WBDC) system will be used for data collection and query handling.
The Investigator ensures the accuracy, completeness, legibility 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 
eCRFs will be archived at the study site.
Immediate safety concerns should be discussed with Parexel Medical immediately upon 
occurrence or awareness to determine if the patient should continue or discontinue study 
treatment.
Adherence to the study design requirements, including those specified in the SoA, Table 1 is 
essential and required for study conduct.
All Screening Period evaluations must be completed and reviewed to confirm that potential 
patients meet all eligibility criteria.  The Investigator will maintain a screening log to record 


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details of all patients screened and to confirm eligibility or record reasons for screening 
failure, as applicable.
Procedures conducted as part of the patient’s routine clinical management (eg, blood count)
and obtained before signing of the ICF may be utilized for screening or baseline purposes 
provided the procedures met the CSP-specified criteria and were performed within the time 
frame defined in the SoA, Table 1.
The maximum amount of blood collected from each patient over the duration of the study, 
including any extra assessments that may be required, will be included in the ICF. Repeat or 
unscheduled samples may be taken for safety reasons or for technical issues with the samples.
8.1
Efficacy assessments 
Ferrokinetic study and ferrokinetic measurements (serum iron, ferritin, TIBC, TSAT, 
transferrin, and soluble transferrin receptor), hs-CRP and hepcidin levels will be assessed 
during the Treatment Period at the timepoints included in the SoA, Table 1.
All ferrokinetic assessments will be obtained during the hours preceding the mid-week HD 
treatment for patients on HD to provide some degree of ideal weight achievement and avoid 
blood volume changes and associated interference with biochemical assays that might occur 
during the dialysis procedure itself.  On Days 1 and 15, blood samples for the ferrokinetic 
study (for serum iron and TIBC) will be taken immediately before the single dose of oral iron
(12.5 mL [100 mg elemental iron) is administered, and then after 1, 2 and 3 hours (each 
±3 minutes) after the single dose of oral iron (for serum iron only).
A central laboratory will perform the laboratory assessments required for efficacy 
assessments.  A central laboratory manual will be provided to all participating study sites with 
instructions on specimen collection, processing, storing and shipping to the central laboratory.
A local laboratory will be used to measure Hb levels to assess if dose adjustment of rHuEPO 
is needed (see Section 6.6).
8.1.1
Primary efficacy assessments
The primary endpoint for this study is the GI iron absorption change from baseline (Day 1) to 
Day 15. At Days 1 and 15, serum iron level and TIBC will be determined immediately 
followed by administration of a defined single dose of oral liquid elemental iron containing 
FeSO4 to all patients at time T0.  Serum iron level at 1, 2, and 3 hours (each ±3 minutes)
following administration of the single oral iron dose (timepoints T1, T2, and T3) will then be 
determined. Gastrointestinal iron absorption will then be assessed by the total area under the 
curve (AUC) adjusted for serum iron level from sample obtained just prior to T0.


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The primary endpoint is the relative difference in AUC for serum iron from baseline (Day 1) 
to Day 15 adjusted for study treatment and baseline hs-CRP level (≤ ULN, > ULN).  The 
model is described in Section 9.4.1.
The time the patient takes the single dose of oral iron and the collection time for each of the 
ferrokinetic study samples should be recorded in the eCRF.
On Day 1, after the ferrokinetic study has completed, the study treatment (roxadustat or 
rHuEPO) will be administered at the study site after randomization.
On Day 15, patients randomized to the roxadustat group should take the roxadustat in the 
morning, at least 6 hours before the ferrokinetic study.  On Day 15 patients randomized to the 
rHuEPO group should take the rHuEPO within 1-2 hours before the ferrokinetic study.  The 
time a patient takes the roxadustat and rHuEPO should be recorded in the eCRF.
All patients should not ingest any foods containing more than trace amounts of iron such as 
heme-rich foods, multivitamins with iron etc. for approximately 4 hours before and during the 
3 hours of the ferrokinetic study.  Patients are allowed limited small snacks with negligible 
amounts of iron during this 7-hour period.  Patients may resume their normal dietary intake 
following collection of blood at the T3 time point.  There is no restriction on drinking water, 
coffee or tea for the patient before the ferrokinetic study starts and during the ferrokinetic 
study.
Patients on HD will have their HD when the ferrokinetic study is completed (ie, after the T3 
timepoint). For patients on PD, there are no timing restrictions for their PD in relation to the 
timing of the ferrokinetic study.
8.1.2
Secondary efficacy assessments
The secondary endpoints of interest assess direct treatment and interaction effects in iron 
absorption and the indices of iron metabolism (serum iron, ferritin, TIBC, TSAT, transferrin, 
soluble transfer receptor) and hepcidin levels are described as follows*:

The relative difference in AUC from baseline (Day 1) to Day 15, adjusted for study 
treatment, baseline hepcidin value, and treatment interaction with baseline hepcidin value. 
Treatment and interaction effects to be assessed.

The relative difference in AUC from baseline (Day 1) to Day 15, adjusted for study 
treatment, baseline hs-CRP value, and treatment interaction with baseline hs-CRP value.
Treatment and interaction effects to be assessed.

The relative difference in the indices of iron metabolism from baseline (Day 1) to Day 15, 
adjusted for study treatment and baseline hs-CRP level (≤ULN, > ULN). Treatment 
effect to be assessed.


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
The relative difference in the indices of iron metabolism from baseline (Day 1) to Day 15, 
adjusted for study treatment, baseline hepcidin, and treatment interaction with baseline 
hepcidin value.  Treatment and interaction effects to be assessed.

The relative difference in the indices of iron metabolism from baseline (Day 1) to Day 15, 
adjusted for study treatment, baseline hs-CRP value and treatment interaction with 
baseline hs-CRP value. Treatment and interaction effects to be assessed.
The assessments for the secondary endpoints will be performed similar to those for the 
primary endpoints (see Section 8.1.1).
8.2
Safety assessments 
Safety will be assessed throughout the study. A complete baseline profile of each patient will 
be established through demographics, medical history (events before ICF signing) , clinical 
laboratory values, vital signs, and physical assessments. During the course of the study, vital 
signs (tympanic temperature, systolic and diastolic BP, pulse and respiratory rate) and
laboratory tests will be performed at regular intervals.
Adverse events, SAEs and ongoing concomitant medication usage will be monitored and 
recorded throughout the study. Serious adverse events 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. Serious adverse events
and AEs will be followed until resolved, stable or until the patient’s EOS visit. See 
Sections 8.3 and 8.4 for details on AE and SAE reporting.
Safety will be assessed through:

Adverse events

Laboratory parameters 

Vital signs (tympanic temperature, BP, pulse and respiratory rate)
Planned timepoints for all safety assessments are provided in the SoA, Table 1.
8.2.1
Clinical safety laboratory assessments
See Table 4 for the list of clinical safety laboratory tests to be performed and refer to the SoA, 
Table 1 for the timing and frequency.  All CSP-required laboratory assessments, as defined in 
Table 4 must be conducted in accordance with the central laboratory manual and the SoA, 
Table 1.
The Investigator should make an assessment of the available laboratory results with regard to 
clinically relevant abnormalities and should determine if any of the laboratory values are 
clinically significant.  The laboratory results should be signed and dated and retained at study
site as source data for laboratory variables.


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For information on how AEs based on laboratory tests should be recorded and reported, see 
Section 8.3.7.
Additional safety samples may be collected if clinically indicated at the discretion of the 
Investigator.
The clinical chemistry and hematology will be performed at a central laboratory. The central 
laboratory will provide the site with the necessary material and instructions for the sampling.  
In exceptional circumstances and upon discussion with the Sponsor, local laboratory 
assessments may have to be undertaken to collect key information supporting an AE or SAE.
On Days 1 and 8, and 15 Hb levels will be tested in the central laboratory for all patients.  
Additionally, for patients randomized to rHuEPO, Hb levels will be tested in the local 
laboratory on Days 1 and 8 for initial dose determination and dose adjustment.  The rHuEPO 
dose may be adjusted on Day 8 of the Treatment Period, depending on the patient’s Hb levels, 
for safety reasons as determined by the Investigator, in accordance with the rHuEPO China 
Package Insert.  On Day 15 (or at the discontinuation visit), Hb levels will be tested in the 
local laboratory for all patients who were on rHuEPO prior to the study, to decide what 
rHuEPO dose to re-start patients on, or another appropriate course of treatment for anemia,
after study treatment stops.  For patients who were rHuEPO-naïve before entering the study,
Hb levels may be tested in the local laboratory on Day 15 (or at the discontinuation visit) at 
the discretion of the Investigator, to determine an appropriate course of treatment for anemia
in each patient. (see Section 6.6).  If there are local requirements for any local laboratory 
testing of safety laboratory parameters, these will be performed at the local laboratory, but 
will be deemed to be outside the requirements of the study and the results will not be collected 
as part of the study.  In such cases these samples will also be sent to the central laboratory for 
testing, as part of the study requirements.
The following laboratory variables will be measured (blood, serum or plasma will be specified 
in the laboratory manual):


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Table 4
Laboratory variables
Hematology/Hemostasis 
Clinical Chemistry
Hemoglobin (Hb)
Creatinine
Leukocyte count
Bilirubin, total
Leukocyte differential count (absolute count)
Alkaline phosphatase (ALP)
Platelet count
Aspartate transaminase (AST)
Red blood cell (RBC)
Alanine aminotransferase (ALT)
Hematocrit
Albumin
Mean corpuscular volume (MCV)
Potassium
Reticulocytes
Calcium, total
Glycated hemoglobin (HbA1C)
Sodium
Glucose
Urinalysis (Urine dipstick) *
Bicarbonate
Blood
Chloride
Protein
Blood urea nitrogen (BUN)
Glucose
Magnesium
Phosphorus
Additional Laboratory Analytes 
Vitamin B12
Iron Profile 
Folate
Serum iron
Intact parathyroid hormone (iPTH)
Ferritin
high sensitivity C-reactive protein (hs-CRP)
Total iron binding capacity (TIBC)
Hepcidin
Transferrin saturation (TSAT)
Test to Rule out COVID-19 infection
Swab test
Transferrin
Pregnancy tests
Soluble transferrin receptor
Serum human chorionic gonadotropin (hCG)
* Urine dipstick glucose, protein and blood performed locally (applicable only for non-dialysis-dependent 
patients, and dialysis-dependent patients who are not anuric).
Note. In case a patient shows an AST or ALT ≥3 x ULN together with TBL ≥2 x ULN 
please refer to Appendix D ‘Actions required in cases of increases in liver biochemistry and 
evaluation of Hy’s Law’, for further instructions.
If the patient reports symptoms or contact with a COVID-19 positive patient, the Investigator 
may ask the patient to be tested for COVID-19 infection (swab test to rule out active 
COVID-19 infection), or withdraw the patient from the study, as is most suitable for the 
patient’s safety, at the Investigator’s discretion.  The study treatment and assessments may be 
continued as planned until the swab test results are available, at the discretion of the 


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Investigator.  Patients who test positive on the swab test must be withdrawn from the study.  A 
patient who contacts the site at any time during the Treatment Period informing that he/she 
has symptoms suggestive of COVID-19 may be asked to get tested for active COVID-19
infection, or be withdrawn from the study for safety reasons, at the Investigator’s discretion.  
Patients who test positive (for COVID-19) must be withdrawn from the study.
Additional laboratory assessments performed for purposes other than general safety evaluation 
are also listed in Table 4.
8.2.2
Physical examinations
A complete physical examination will be performed at screening (Visit 1) and include an 
assessment of the following: general appearance, respiratory, cardiovascular, abdomen skin, 
head and neck (including ears, eyes, nose and throat), lymph nodes, thyroid, musculo-skeletal 
(including spine and extremities) and neurological systems.
Body weight will be measured at Screening Visit.  Patients should be in light indoor clothes
without shoes.  Weight for patients on PD should be obtained with a “dry” or empty peritoneal 
cavity (PD fluid fully drained).
Physical examination will be performed at timepoints as specified in the SoA, Table 1, 
Investigators should pay special attention to clinical signs related to previous serious illnesses, 
new or worsening abnormalities may qualify as AEs, see Section 8.3.7 for details.  Additional 
physical examinations can be performed at the discretion of the Investigator or as indicated by 
development of any new or changing patient symptoms and recorded in the eCRF.
8.2.3
Vital signs
The vital signs include tympanic temperature, systolic and diastolic BP, pulse rate and 
respiratory rate and will be assessed as outlined in the SoA, Table 1.
Blood pressure should be measured before the HD procedure when applicable. For patients 
on PD, BP should be measured in the morning prior to the patient performing the first 
exchange of the day.  Blood pressure and pulse rate should be measured with a completely 
automated device in triplicate with at least 1-minute intervals between measurements after 
being comfortably at rest in a seated position with the back and feet supported (ie, by chair 
back and floor or platform, respectively) quietly for at least 5 minutes. Manual techniques 
will be used only if an automated device is not available.  The position of the patient should be 
comfortable with the arm where the BP 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.  The same device should preferably be used for the patient during the 
course of the study and in the same arm.  The first reading of the BP and pulse rate should be 


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rejected.  The second and third readings should be averaged to give the measurement to be 
recorded in the eCRF.
8.2.4
Electrocardiograms
A 12-lead electrocardiogram (ECG) measurement will be obtained at screening as outlined in 
the SoA, Table 1, using an ECG machine that automatically calculates the pulse rate and 
measures PR, QRS, QT, and QTc intervals.
8.3
Collection of adverse events
The Investigator is responsible for ensuring that all staff involved in the study are familiar 
with the content of this section.
The definitions of an AE or SAE can be found in Appendix B.
Adverse events will be reported by the patient (or, when appropriate, by a caregiver, 
surrogate, or the patient’s legally authorized representative).
The Investigator and any designees are responsible for detecting, documenting, and recording 
events that meet the definition of an AE or SAE. For information on how to follow/up AEs 
see Section 8.3.3.
8.3.1
Method of detecting adverse events and serious adverse events
Care will be taken not to introduce bias when detecting AEs and/or SAEs.  Open-ended and 
non-leading verbal questioning of the patient is the preferred method to inquire about 
AE occurrences.
8.3.1.1
Reporting of AEs/SAEs in relation to COVID-19
All AEs/SAEs should be reported in line with instructions for safety reporting documented in 
the CSP.
For patients experiencing signs and symptoms indicating an infection, an attempt will be made
to determine whether the COVID-19 virus is the infectious organism and the AE will be 
recorded accordingly.  If a patient presents with clinical signs and symptoms suggestive of
COVID-19, a test will be requested where possible:
•
If the test is positive, record “COVID-19 positive” in the Adverse Event Field.
•
If the test is negative, record “COVID-19 negative” in the Adverse Event Field, along 
with the AE/SAE signs and symptoms and/or other diagnosis.
If a test has not been performed or result is not available and signs and symptoms, as judged 
by the Investigator, are suggestive of COVID-19 infection, record “COVID-19 suspected” in 


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the Adverse Event Field.  If the Investigator has other concurrent diagnoses for the patient’s 
signs and symptoms (eg, pneumonia), these will be recorded as separate AEs.
8.3.2
Time period and frequency for collecting adverse event and serious 
adverse event information 
All AEs and SAEs will be collected from the time of signature of informed consent 
throughout the Treatment Period and including the Follow-up Period.
All SAEs will be recorded and reported to the Sponsor or designee within 24 hours, as 
indicated in Appendix B.  The Investigator will submit any updated SAE data to the Sponsor
or designee within 24 hours of it being available.
All roxadustat Adverse Drug Reactions (ie, AEs that the Investigator considers that there is a 
reasonable possibility that the AE may have been caused by roxadustat) will be reported to the 
Sponsor or designee within 24 hours.
Investigators are not obligated to actively seek AE or SAE information in study patients who 
are no longer on the study. However, if the Investigator learns of any SAE, including a death, 
at any time after a patient’s last visit and he/she considers the event to be reasonably related to 
the study treatment or study participation, the Investigator should notify the Sponsor.
The method of recording, evaluating, and assessing causality of AE and SAE and the 
procedures for completing and transmitting SAE reports are provided in Appendix B.
8.3.3
Follow-up of adverse events and serious adverse events
After the initial AE/SAE report, the Investigator is required to proactively follow each patient
at subsequent visits/contacts.  All AEs will be followed until resolution, stabilization, the 
event is otherwise explained, or the patient is lost to follow-up.
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 EOS, if judged necessary.
8.3.4
Adverse event data collection
The following variables will be collected for each AE:

Adverse event (verbatim)

The date when the AE started and stopped

Maximum intensity grade per National Cancer Institute Common Terminology Criteria 
for Adverse Events (NCI-CTCAE) Grade version ≥5.0

Whether the AE is serious or not


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
Investigator causality rating against the study treatment (yes or no)

Action taken with regard to study treatment

Adverse event caused by patient’s withdrawal from study

Outcome
In addition, the following variables will be collected for SAEs:

Date AE met criteria for SAE

Date Investigator became aware of SAE

Adverse event is serious due to

Date of hospitalization

Date of discharge

Probable cause of death

Date of death

Autopsy performed

Causality assessment in relation to study procedure(s)

Causality assessment to other medication

Description of AE
8.3.5
Causality collection
The Investigator will assess causal relationship between study treatment and each AE, 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 study treatment?’
For SAEs, causal relationship will also be assessed for other medication and study procedures.
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 CSP.
8.3.6
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 site staff: ‘Have you had any health problems since the previous visit/you were 
last asked?’ or revealed by observation will be collected and recorded in the eCRF.  When 
collecting AEs, the recording of diagnoses is preferred (when possible) to recording a list of 
signs and symptoms.  However, if a diagnosis is known and there are other signs or symptoms 
that are not generally part of the diagnosis, the diagnosis and each sign or symptom will be 
recorded separately.


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8.3.7
Adverse events based on examinations and tests
The results from the CSP-mandated laboratory tests and vital signs will be summarized in the 
Clinical Study Report (CSR).
The Investigator should make an assessment of the available laboratory results with regard to 
clinically relevant abnormalities and should determine if any of the laboratory values are 
clinically significant.  The laboratory results should be signed and dated and retained at study 
site as source data for laboratory variables.
Any protocol-mandated laboratory values or vital signs from the baseline visit that the 
Investigator assesses to be clinically significant, should be reported in the medical history.  
Deterioration as compared to baseline of any protocol-mandated laboratory values or vital 
signs that the Investigator assesses to be clinically significant should be reported as AEs.  If 
deterioration of a laboratory value or vital sign meets the seriousness criteria, it should be 
reported as an SAE.  If the reason for discontinuation of study treatment is due to deterioration 
of a laboratory value or vital sign compared to baseline (whether or not considered clinically 
significant), this should be reported as an AE.  If a laboratory value or vital sign is outside the 
normal range, and the Investigator has assessed it as not clinically significant and study 
treatment has not been discontinued as a result of the laboratory value or vital sign, this does 
not need to be reported as an AE.
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 (eg, anemia versus low Hb 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 as compared with the 
baseline assessment will be reported as an AE unless unequivocally related to the 
disease-under study (DUS), see Sections 8.3.9 and 8.3.10.
8.3.8
Hy’s Law
Cases where a patient shows elevations in liver biochemistry may require further evaluation 
and occurrences of AST or ALT ≥ 3x ULN together with TBL ≥ 2x ULN may need to be 
reported as SAEs.  Please refer to Appendix D for further instruction on cases of increases in 
liver biochemistry and evaluation of Hy’s Law (HL).


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8.3.9
Disease-under study (DUS)
Symptoms of DUS are those which might be expected to occur as a direct result of CKD or
procedures to diagnose or treat the CKD. Events which are unequivocally due to DUS should 
not be reported as an AE during the study unless they meet SAE criteria or lead to 
discontinuation of the study treatment.
8.3.10
Disease progression
Disease progression can be considered as a worsening of a patient’s condition attributable to 
the disease for which the study treatment is being studied.  It may be an increase in the 
severity of the DUS and/or increases in the symptoms of the disease.  Worsening of anemia 
should not be considered an AE unless the worsening of anemia is associated with a cause 
other than the patient’s CKD.  Events, which are unequivocally due to disease progression, 
should not be reported as an AE during the study.
8.4
Safety reporting and medical management
8.4.1
Reporting of serious adverse events
All SAEs have to be reported, whether or not considered causally related to the study 
treatment, 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 1-day ie, immediately but no later than 
24 hours of when he or she becomes aware of it.
The designated AstraZeneca representative works with the Investigator to ensure that all the 
necessary information is provided to the FibroGen Drug Safety within 1 calendar day of 
initial receipt for all SAEs.  FibroGen Drug Safety will be responsible for processing all 
SAEs.
For fatal or life-threatening AEs 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 1 calendar day ie, immediately but no later than 24 hours of when he or she becomes 
aware of it.
The Investigator is obliged to report SAE to the appropriate local regulatory authorities, Ethics
Committees and AstraZeneca representative within 24 hours of SAE awareness.  
Safety information (SAEs, serious adverse drug reactions [SADRs], adverse drug reactions 
[ADRs] and suspected unexpected serious adverse reactions [SUSARS]) are to be reported by 


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Sponsor or Sponsor Representative to the appropriate local regulatory authorities within 
legally binding timelines. 
Once the Investigators or other site personnel indicate an AE is serious in the electronic data 
capture (EDC) system, an automated email alert is sent to the designated AstraZeneca 
representative.
If the EDC system is not available, then the Investigator or other study site staff reports a SAE 
to the appropriate AstraZeneca representative by telephone.
The AstraZeneca representative will advise the Investigator/study site staff how to proceed.
For further guidance on the definition of a SAE, see Appendix B of the CSP.
8.4.2
Pregnancy
All pregnancies and outcomes of pregnancy should be reported to the AstraZeneca
representative except for:

If the pregnancy is discovered before the study patient has received any study treatment.
If a pregnancy is reported, the Investigator should inform the Sponsor representative within 
24 hours of learning of the pregnancy.
Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, ectopic pregnancy) are considered SAEs.
8.4.2.1
Maternal exposure
If a patient becomes pregnant during the course of the study, study treatment should be 
discontinued immediately.
Pregnancy itself is not regarded as an AE unless there is a suspicion that the study treatment
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 ie, 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 
relevant information is provided to FibroGen Drug Safety within 1 calendar day.
The same timelines apply when outcome information is available.
The PREGREP module in the eCRF is used to report the pregnancy and the PREGOUT form 
is used to report the outcome of the pregnancy.
8.4.2.2
Paternal exposure 
Pregnancy of the patient’s partners is not considered to be an AE.  However, the outcome of 
all pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, normal 
birth or congenital abnormality), occurring from the date of the first dose until at least 7 days 
after the last dose of roxadustat and as indicated by previous studies (pre-clinical and clinical) 
should, if possible, be followed up and documented in the Pregnancy Report Form.  Consent 
from the partner must be obtained before the Pregnancy Report Form is completed and 
followed up as described in Section 8.4.2. 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.
8.4.3
Overdose
Refer to the respective China Package Insert for roxadustat and rHuEPO for information on
the management of study treatment overdose. 
AstraZeneca does not recommend specific treatment for an overdose.

An overdose with associated AEs is recorded as the AE diagnosis/symptoms on the 
relevant AE modules in the eCRF and on the Overdose eCRF module.

An overdose without associated symptoms is only reported on the Overdose eCRF 
module.
If an overdose on an AstraZeneca study treatment 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 the FibroGen Drug Safety within 1 calendar day.
8.4.4
Medication error
Medication errors with AstraZeneca study treatment are collected in all studies where 
medication error is possible.


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If a medication error occurs in the course of the study, then the Investigator or other site 
personnel initially reports to the appropriate AstraZeneca representatives within 1-day ie, 
immediately but no later than 24 hours of when he or she becomes aware of it.
The designated AstraZeneca representative will then work with the Investigator to ensure that 
all relevant information is completed within 1 calendar day.
The definition of a medication error can be found in Appendix B.
8.5
Pharmacokinetics
Pharmacokinetic parameters are not evaluated in this study.
8.6
Pharmacodynamics
Pharmacodynamic parameters are not evaluated in this study.
8.7
Genetics
Genetic testing is not evaluated in this study.
8.8
Biomarkers
Biomarkers are not evaluated in this study.
8.9
Health economics
Health economics/medical resource utilization and health economics parameters are not 
evaluated in this study. 
9
STATISTICAL CONSIDERATIONS 
This section highlights statistical considerations for this CSP.
Individual data will be presented in patient listings. All patient data listings will be sorted by 
treatment, site, dialysis status and patient.
9.1
Statistical hypotheses
Statistical testing will be conducted at a 2-sided significance level of 5%. A multiple testing 
strategy will be used as described in Section 9.4.2.1. Where appropriate, model-based point 
estimates, together with their 95% confidence intervals (CIs) will be presented along with the 
2-sided p-values for the tests.
9.1.1
Primary endpoint
The primary endpoint for this study is described in Section 8.1.1.  This will be assessed via
change from baseline (Day 1) at Day 15 in log-transformed AUC of iron absorption from 


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0-3 hours based on the change in serum iron levels obtained just prior to T0 (time when single 
dose of oral iron is administered) and over a 3-hour period. The hypothesis to be assessed is 
as follows:
H0: There is no difference in the average change from baseline in the ferrokinetic 
measurement between rHuEPO and roxadustat.
̅	
 = ̅
HA: There is a difference in the average change from baseline in the ferrokinetic measurement 
between rHuEPO and roxadustat.
̅	
 ≠̅
Where ̅	
 is the average change from baseline for the rHuEPO treatment group and 
̅ is the average change from baseline for the roxadustat treatment group.
9.1.2
Secondary endpoints
The secondary endpoints of interest are described fully in Section 8.1.2.  The hypotheses for 
these endpoints can be separated into 2 distinct groups, the relative difference in iron 
metabolism and the relative difference in AUC.  All hypotheses will follow the null 
hypothesis that there is no difference between AUC or iron metabolism when adjusting for 
various specified covariates or interactions.
9.2
Sample size determination
 
 
 
 
 
 
CCI


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9.3
Populations for analyses
For purposes of analysis, the following populations are defined: 
Population
Description
All-patients analysis set
The all-patients analysis set will consist of all patients who are screened for 
the study. This analysis set will be used for listings.
Full analysis set
The full analysis set (FAS), the primary efficacy analysis set, will include 
all randomized patients who have who have complete baseline (Day 1) 
measurements for any efficacy analysis.  The FAS will be used for the 
primary endpoint and all secondary endpoints. The FAS will also be used 
for the presentation of all demographic and disposition data.
Per-protocol analysis set
The per-protocol (PP) analysis set will include all randomized patients who 
received at least 1 dose of study treatment, have baseline (Day 1) and at 
least 1 post-baseline iron absorption measurement, and are without major 
protocol violations. Details for PP analysis set exclusion will be specified 
in the statistical analysis plan (SAP).  The PP analysis set will be used as a 
sensitivity analysis population for the primary and secondary endpoints.
Safety analysis set
The safety analysis set will include all randomized patients receiving at least 
1 dose of study treatment, with patients being analyzed as treated, rather 
than as randomized.  The safety analysis set will be used for the safety 
endpoints. Exposure to study treatment will also be presented using the 
safety analysis set.
9.4
Statistical analyses
Analyses will be performed by Parexel. A comprehensive statistical analysis plan (SAP) will 
be developed and finalized before database lock and will describe the patient populations to be 
included in the analyses, and procedures for accounting for missing, unused, and spurious 
data.  A stable SAP will be produced prior to first patient-in.  This section is a summary of the 
planned statistical analyses of the primary, secondary and safety endpoints.  Any deviations
from this plan or the SAP will be reported in the CSR.
All efficacy and safety variables will be summarized by study treatment groups using 
descriptive statistics (n, mean, SD, median, minimum and maximum for continuous data and 
n, frequencies and percentages for categorical data, including proportion of missingness). 
Data will be summarized by visit, randomization strata and site as applicable.
CCI


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Treatment and interaction effects will be evaluated via analysis of covariance (ANCOVA).
All analyses will involve the difference of log-transformed AUC and indices of iron 
metabolism. Results can be presented on the untransformed scale for interpretability.
Multiple imputations will be implemented for the primary and secondary analyses to account 
for missing data, due to the increased risk of this occurring during the COVID-19 pandemic.  
This will be described in further detail in the SAP.
The statistical methods and how the variables are presented will be further detailed in the 
SAP.
9.4.1
Primary efficacy analyses
The primary efficacy endpoint is described in (Section 8.1.1).  It is measured through change 
from baseline (Day 1) to Day 15 in log-transformed AUC of iron absorption from 0-3 hours 
based on the change in serum iron levels obtained just prior to T0 (time when single dose of 
oral iron is administered) and over a 3-hour period.
The AUC curve (for the calculation of the primary endpoint and associated secondary 
endpoints) will be determined for each patient at baseline (Day 1) and post-baseline, then the 
average of the changes from baseline (Day 1) will be evaluated for each treatment group. This 
is to be calculated for patient i as the sum of the area of each trapezium under the curve, 
adjusted for any iron present in sample obtained just prior to time T0. Let Pj be the serum 
iron level at timepoint Tj then the AUC for patient i at Visit X is
),+ = ,
-./01 + ./
2
−.23
4
/52
Let di be the change from baseline for patient i and is defined as:
+ = log() 67 18,+ −log() 9:;<+=;,+
The difference in log (AUC) from baseline (Day 1) to Day 15 will be analyzed using an 
ANCOVA model, adjusting for study treatment and baseline hs-CRP level (≤ULN, > ULN).
If a patient withdraws before Day 15, their discontinuation visit will be used as the 
post-baseline primary measurement.
9.4.2
Secondary efficacy analyses
The secondary efficacy endpoints for this study are outlined in Section 8.1.2.
The secondary endpoints of interest assess direct treatment and interaction effects in the 
indices of iron metabolism (ie, serum iron, ferritin, TIBC, TSAT, transferrin, soluble transfer 
receptor) and hepcidin levels are described in Table 5.  All endpoints will be analyzed using 
ANCOVA models.


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Table 5
Summary of secondary endpoints to be analyzed
Outcome of interest
Adjusted for
Variable(s) to be assessed
Relative difference in AUC a
Study treatment
Baseline hepcidin value
Treatment effect
Treatment-hepcidin interaction
Relative difference in AUC a
Study treatment
Baseline hs-CRP value
Treatment effect
Treatment-hs-CRP interaction
Relative difference in indices of 
iron metabolism b
Study treatment
Baseline hs-CRP level (≤ULN, 
> ULN)
Treatment effect
Relative difference in indices of 
iron metabolism b
Study treatment
Baseline hepcidin value
Treatment effect
Treatment-hepcidin interaction
Relative difference in indices of 
iron metabolism b
Study treatment
Baseline hs-CRP value
Treatment effect
Treatment-hs-CRP interaction
a
The absorption of iron over a 3-hour period, measured just prior to T0 and at T1, T2, T3.
b
Indices of iron metabolism (ie, serum iron, ferritin, TIBC, TSAT, transferrin, soluble transferrin receptor,
and hepcidin levels). These will be laboratory serum measurements.
AUC=area under the curve; hs-CRP=high sensitivity C-reactive protein; TIBC=total iron binding capacity; 
TSAT=transferrin saturation, ULN=upper limit of normal.
These secondary endpoints will be analyzed using ANCOVA models, similar to that described
in Table 5. The outcome variables (indices of iron metabolism and AUC) are to be 
log-transformed prior to analysis and the result back-transformed to the original scale to aid 
interpretability.  Log-transformed baseline hepcidin and log-transformed baseline hs-CRP are 
to be used as covariates.  The results will be back transformed to the original scale to aid 
interpretability.
9.4.2.1
Multiple testing
Let P1, P2,…Pn be the p-values for each of the n separate hypotheses tests.  The 
Holm-Bonferroni (Holm 1979) adjustment ranks these p-values from smallest to largest (P[1], 
P[2]…P[n]) and the associated hypotheses H(1), H(2)…H(n).
For a pre-specified significance level, α, let k be the smallest value for which .(>) >
@
=01A>
where n is the total number of p-values being adjusted for.
Testing of further p-values will stop, all corresponded preceding null hypotheses H(1), 
H(2)…H(k-1) will be rejected, and none of the rest of the null hypotheses H(k), H(k+1), 
H(k+2)…H(n) will be rejected. This ensures that the familywise error rate (FWER) ≤α.
9.4.3
Subgroup analyses
A subgroup analysis may be performed for the primary and key secondary endpoints. 
Summary tables will be produced by strata (HD, PD, NDD) and, if there are sufficient 


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numbers of patients in each strata, all statistical analysis of primary and secondary endpoints 
will be performed by strata (HD, PD, NDD). The subgroup analysis will be performed using 
the same analysis methods as described in Sections 9.4.1 and 9.4.2. Further details will be 
provided in the SAP.
9.4.4
Safety analyses
All safety analyses will be performed on the safety analysis set and will be analyzed
descriptively.
Adverse events (and also separately SAEs) will be summarized by study treatment group by 
incidence summaries by Medical Dictionary for Regulatory Activities (MedDRA) System 
Organ Class (SOC) and Preferred Term (PT).
Laboratory data for hematology, clinical chemistry and liver function test will be summarized
by visit and study treatment group.
Vital signs will be summarized by visit and study treatment group.
9.5
Interim analyses
No interim analysis will be conducted for this study. 9.4.1
9.5.1
Data monitoring committee 
No data monitoring committee (DMC) will be utilized for this study.


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10
REFERENCES
Besarab et al 2016
Besarab A, Chernyavskaya E, Motylev I, Shutov E, Kumbar LM, Gurevich K, et al. 
Roxadustat (FG-4592): Correction of anemia in incident dialysis patients. J Am Soc Nephrol 
2016; 27: 1225-33.
Gupta and Wish 2017
Gupta N, Wish JB. Hypoxia Inducible Factor Prolyl Hydroxylase Inhibitors: A Potential New 
Treatment for Anemia in Patients with CKD. Am J Kidney Dis 2017;69(6):815-26.
Holm 1979
Holm, S. A simple sequentially rejective multiple test procedure. Scand J Stat 1979: 6 (2): 
65-70.
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.
Peyssonnaux et al 2008
Peyssonnaux C, Nizet V, Johnson RS. Role of the hypoxia inducible factors HIF in iron 
metabolism. Cell Cycle 2008;7(1):28-32.
Stauffer and Fan 2014
Stauffer ME and Fan T. Prevalence of anemia in chronic kidney disease in the United States. 
PLOS ONE. 2014; 9(1): 1-4.
Widness et al 1997
Widness JA, Lombard KA, Ziegler EE, Serfass RE, Carlson SJ, Johnson KJ, et al.  
Erythrocyte incorporation and absorption of 58Fe in premature infants treated with 
erythropoietin. Pediatr Res.  1997; 41 (3): 416-23.
Zhang et al 2012
Zhang L, Wang F, Wang L, Wang W, Liu B, Liu J, et al.  Prevalence of chronic kidney 
disease in China: a cross-sectional survey. Lancet 2012; 379:815-22.


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11
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS
Appendix A
Regulatory, Ethical and Study Oversight Considerations
A 1
Regulatory and ethical considerations
This study will be conducted in accordance with the Clinical Study Protocol (CSP) and with 
the following:

Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical Sciences 
(CIOMS) International Ethical Guidelines

Applicable International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use (ICH) Good Clinical Practice (GCP) Guidelines

Applicable laws and regulations
The CSP, CSP amendments, informed consent form (ICF), Investigator’s Brochure (IB) if 
applicable, and other relevant documents (eg, advertisements) must be submitted to an 
institutional review board (IRB)/independent ethics committee (IEC) by the Investigator and 
reviewed and approved by the IRB/IEC before the study is initiated.
Any amendments to the CSP will require IRB/IEC approval before implementation of changes 
made to the study design, except for changes necessary to eliminate an immediate hazard to 
study patients.
The Investigator will be responsible for the following:

Providing written summaries of the status of the study to the IRB/IEC annually or more 
frequently in accordance with the requirements, policies, and procedures established by 
the IRB/IEC

Notifying the IRB/IEC of serious adverse events (SAEs) or other significant safety 
findings as required by IRB/IEC procedures

Providing oversight of the conduct of the study at the site and adherence to requirements 
of ICH guidelines, the IRB/IEC, and all other applicable local regulations
The study will be performed in accordance with the AstraZeneca policy on Bioethics and 
Human Biological Samples.
A 2
Financial disclosure
Investigators and sub-Investigators will provide the Sponsor with sufficient, accurate financial 
information as requested to allow the Sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities.  Investigators 


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are responsible for providing information on financial interests during the course of the study 
and for 1 year after completion of the study.
A 3
Informed consent process
The Investigator or his/her representative will explain the nature of the study to the patient or 
his/her legally authorized representative and answer all questions regarding the study.  
Patients must be informed that their participation is voluntary. Patients or their legally 
authorized representative will be required to sign a statement of informed consent that meets 
the requirements of local regulations, ICH guidelines, where applicable, and the IRB/IEC or 
study site.
The medical record must include a statement that written informed consent was obtained 
before the patient was enrolled in the study and the date and time the written consent was 
obtained.  The authorized person obtaining the informed consent must also sign the ICF.
Patients must be re-consented to the most current version of the ICF(s) during their 
participation in the study.
A copy of the ICF(s) must be provided to the patient or the patient’s legally authorized
representative.
If a patient’s partner becomes pregnant in the period from the date of the first dose until at 
least 7 days after the last dose of roxadustat, then the partner is asked to sign the “Adult Study 
Informed Consent Form for Pregnant Partners of Study patients” and provide information 
about the pregnancy accordingly.
Patients who are rescreened are required to sign a new ICF.
A 4
Data protection
Each patient will be assigned a unique identifier by the Sponsor.  Any patient records or data 
sets transferred to the Sponsor will contain only the identifier; patient names or any 
information which would make the patient identifiable will not be transferred.
The patient must be informed that his/her personal study-related data will be used by the 
Sponsor in accordance with local data protection law.  The level of disclosure must also be 
explained to the patient.  
The patient must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the Sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities.


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A 5
Committees structure
The safety of all AstraZeneca clinical studies is closely monitored on an ongoing basis by 
AstraZeneca representatives in consultation with Patient Safety.  Issues identified will be 
addressed; for instance, this could involve amendments to the CSP and letters to Investigators.
A 6
Dissemination of clinical study data
A description of this clinical study will be available on http://astrazenecaclinicaltrials.com as 
will the summary of the main study results when they are available. The clinical study and/or 
summary of study results may also be available on other websites according to the regulations 
of the countries in which the study is conducted.
A 7
Data quality assurance
All patient data relating to the study will be recorded on electronic case report form (eCRF)
unless transmitted to the Sponsor or designee electronically (eg, laboratory data).  The 
Investigator is responsible for verifying that data entries are accurate and correct by physically 
or electronically signing the eCRF.
The Investigator must maintain accurate documentation (source data) that supports the 
information entered in the eCRF.
The Investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.
The Sponsor or designee is responsible for the data management of this study including 
quality checking of the data.
Study monitors will perform ongoing source data verification to confirm that data entered into 
the eCRF by authorized site personnel are accurate, complete, and verifiable from source 
documents; that the safety and rights of patients are being protected; and that the study is 
being conducted in accordance with the currently approved CSP and any other study 
agreements, ICH GCP, and all applicable regulatory requirements.
Records and documents, including signed ICFs, pertaining to the conduct of this study must 
be retained by the Investigator for 15 years after study completion unless local regulations or 
institutional policies require a longer retention period.  No records may be destroyed during 
the retention period without the written approval of the Sponsor.  No records may be 
transferred to another location or party without written notification to the Sponsor.


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A 8
Source documents
Source documents provide evidence for the existence of the patient and substantiate the 
integrity of the data collected.  Source documents are filed at the Investigator’s site.
Data reported on the eCRF that are transcribed from source documents must be consistent 
with the source documents or the discrepancies must be explained.  The Investigator may need 
to request previous medical records or transfer records, depending on the study.  Also, current 
medical records must be available.
Definitions of what constitutes source data can be found in the source data agreement and 
computerized data check list for electronic source data.
A 9
Study and site closure
The Sponsor designee reserves the right to close the study sites or terminate the study at any 
time for any reason at the sole discretion of the Sponsor.  The study may be stopped if, in the 
judgement of AstraZeneca, study patients are placed at undue risk because of clinically 
significant findings that:

Meet individual stopping criteria or are otherwise considered significant 

Are assessed as causally related to study treatment

Are not considered to be consistent with continuation of the study
Regardless of the reason for termination, all data available for the patient at the time of 
discontinuation of follow-up must be recorded in the eCRF. All reasons for discontinuation of 
study treatment must be documented.
In terminating the study, the Sponsor will ensure that adequate consideration is given to the 
protection of the patient’s interests.
Study sites will be closed upon study completion.  A study site is considered closed when all 
required documents and study supplies have been collected and a study site closure visit has 
been performed.
The Investigator may initiate study site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the Sponsor or Investigator may include but 
are not limited to:

Failure of the Investigator to comply with the CSP, the requirements of the IRB/IEC or 
local health authorities, the Sponsor’s procedures, or GCP guidelines

Inadequate recruitment of patients by the Investigator


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
Discontinuation of further study treatment development
A 10
Publication policy
The results of this study may be published or presented at scientific meetings.  If this is 
foreseen, the Investigator agrees to submit all manuscripts or abstracts to the Sponsor before 
submission.  This allows the Sponsor to protect proprietary information and to provide 
comments.
The Sponsor will comply with the requirements for publication of study results.  In 
accordance with standard editorial and ethical practice, the Sponsor will generally support 
publication of multicenter studies only in their entirety and not as individual site data.  In this 
case, a coordinating Investigator will be designated by mutual agreement.
The Sponsor publishes clinical study and other medically important research results, whether 
positive, negative or inconclusive, while protecting patient confidentiality.
Authorship will be determined by mutual agreement and in line with International Committee 
of Medical Journal Editors authorship requirements.


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Appendix B
Adverse Event Definitions and Additional Safety Information
B 1
Definition of adverse events
An adverse event (AE) 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 (eg, nausea, chest pain), signs (eg, 
tachycardia, enlarged liver) or the abnormal results of an investigation (eg, laboratory 
findings, electrocardiogram [ECG]). 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.
B 2
Definitions of serious adverse event
A serious adverse event (SAE) is an AE occurring during any study phase (ie, screening, 
run-in, treatment, follow-up) and 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 or incapacity

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
Adverse Events for malignant tumours reported during a study should generally be assessed as 
SAEs. If no other seriousness criteria apply, the ‘Important Medical Event’ criterion should 
be used. In certain situations, however, medical judgement on an individual event basis 
should be applied to clarify that the malignant tumour event should be assessed and reported 
as a non-serious AE. For example, if the tumour is included as medical history and 
progression occurs during the study, but the progression does not change treatment and/or 
prognosis of the malignant tumour, the AE may not fulfil the attributes for being assessed as 
serious, although reporting of the progression of the malignant tumour as an AE is valid and 
should occur. Also, some types of malignant tumours, which do not spread remotely after a 
routine treatment that does not require hospitalization, may be assessed as non-serious; 
examples include Stage 1 basal cell carcinoma and Stage 1A1 cervical cancer removed via 
cone biopsy.


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B 3
Definition of adverse drug reactions 
An adverse drug reaction (ADR) is the development of an undesirable medical condition or 
the deterioration of a pre-existing medical condition following or during exposure to a 
medicinal product, suspected to be causally related to the product.
B 4
Life-threatening
‘Life-threatening’ means that the patient 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 
patient’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).
B 5
Hospitalization
Outpatient treatment in an emergency room is not in itself a serious AE, although the reasons 
for it may be (eg, bronchospasm, laryngeal edema).  Hospital admissions and/or surgical 
operations planned before or during a study are not considered AEs if the illness or disease 
existed before the patient was enrolled in the study, provided that it did not deteriorate in an 
unexpected way during the study.
B 6
Important medical event or medical treatment
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, hospitalization, disability or incapacity but may jeopardize the patient or may require 
medical treatment 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 intravenous
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 anemia requiring blood transfusion, etc.) or 
convulsions that do not result in hospitalization

Development of drug dependency or drug abuse


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B 7
Intensity rating scale:
The Investigator should use the National Cancer Institute (NCI) Common Terminology 
Criteria for Adverse Events (CTCAE) version ≥5.0. 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 (eg,
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
It is important to distinguish between serious and severe AEs.  Severity is a measure of 
intensity whereas seriousness is defined by the criteria in Appendix B 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 Appendix B 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 Appendix B 2.
B 8
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 patient 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?


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
No alternative cause.  The AE cannot be reasonably explained by another etiology such as 
the underlying disease, other drugs, other host or environmental factors.

Re-challenge experience.  Did the AE reoccur if the suspected drug was reintroduced 
after having been stopped? AstraZeneca would not normally recommend or support a 
re-challenge.

Laboratory tests.  A specific laboratory investigation (if performed) has confirmed the 
relationship.
In difficult cases, other factors could be considered such as:

Is this a recognized feature of overdose of the drug?

Is there a known mechanism?
Causality of ‘related’ is made if following a review of the relevant data, there is evidence for a 
‘reasonable possibility’ of a causal relationship for the individual case.  The expression 
‘reasonable possibility’ of a causal relationship is meant to convey, in general, that there are 
facts (evidence) or arguments to suggest a causal relationship.
The causality assessment is performed based on the available data including enough 
information to make an informed judgement.  With limited or insufficient information in the 
case, it is likely that the event(s) will be assessed as ‘not related’.
Causal relationship in cases where the disease-under study has deteriorated due to lack of 
effect should be classified as no reasonable possibility.
B 9
Medication error
For the purposes of this clinical study a medication error is an unintended failure or mistake in 
the treatment process for an AstraZeneca study treatment that either causes harm to the patient
or has the potential to cause harm to the patient.
A medication error is not lack of efficacy of the drug, but rather a human or process related 
failure while the drug is in control of the study site staff or patient.
Medication error includes situations where an error:

Occurred

Was identified and intercepted before the patient received the drug

Did not occur, but circumstances were recognized that could have led to an error
Examples of events to be reported in clinical studies as medication errors:

Drug name confusion

Dispensing error eg, medication prepared incorrectly, even if it was not actually given to 
the patient


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
Drug not administered as indicated, for example, wrong route or wrong site of 
administration

Drug not taken as indicated eg, tablet dissolved in water when it should be taken as a 
solid tablet 

Drug not stored as instructed eg, kept in the fridge when it should be at room temperature 

Wrong patient received the medication (excluding interactive voice response system 
[IVRS] errors)

Wrong drug administered to patient (excluding IVRS errors)
Examples of events that do not require reporting as medication errors in clinical studies:

Errors related to or resulting from IVRS – including those which lead to one of the above 
listed events that would otherwise have been a medication error 

Patient accidentally missed drug dose(s) eg, forgot to take medication

Accidental overdose (will be captured as an overdose)

Patient failed to return unused study treatment or empty packaging

Errors related to background and rescue medication, or standard of care medication in 
open-label studies, even if an AstraZeneca product 
Medication errors are not regarded as AEs, but AEs may occur as a consequence of the 
medication error.


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Appendix C
Handling of Human Biological Samples
C 1
Chain of custody of biological samples
A full chain of custody is maintained for all samples throughout their lifecycle.
The Investigator at each site keeps full traceability of collected biological samples from the 
patients while in storage at the site until shipment or disposal (where appropriate).
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 will keep oversight of the entire life cycle through internal procedures, 
monitoring of study sites, auditing or process checks, and contractual requirements of external 
laboratory providers.
Samples retained for further use will be stored in the AstraZeneca-assigned biobanks and will 
be registered by the AstraZeneca Biobank Team during the entire life cycle.
If required, AstraZeneca will ensure that remaining biological samples are returned to the site 
according to local regulations or at the end of the retention period, whichever is the sooner.
C 2
Withdrawal of informed consent for donated biological samples 
If a patient withdraws consent to the use of donated biological samples, the samples will be 
disposed of/destroyed, and the action documented.  If samples are already analyzed, 
AstraZeneca is not obliged to destroy the results of this research.
As collection of the biological sample(s) is an integral part of the study, then the patient is 
withdrawn from further study participation.
The Investigator:

Ensures patients’ withdrawal of informed consent to the use of donated samples is 
notified immediately to AstraZeneca

Ensures that biological samples from that patient, if stored at the study site, are 
immediately identified, disposed of /destroyed, and the action documented

Ensures the organization(s) 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 organizations 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.


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C 3
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 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 types 1 and 2. They are assigned the following United 
Nations (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 study 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

International Airline Transportation Association compliant courier and packaging 
materials should be used for packing and transportation and packing should be done by an 
IATA certified person, as applicable

Samples routinely transported by road or rail are subject to local regulations which 
require that they are also packed and transported in a safe and appropriate way to contain 
any risk of infection or contamination by using approved couriers and 
packaging/containment materials at all times. The IATA 650 biological sample 
containment standards are encouraged wherever possible when road or rail transport is 
used


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Appendix D
Actions Required in Cases of Increases in Liver Biochemistry 
and Evaluation of Hy’s Law
D 1
Introduction
This Appendix describes the process to be followed in order to identify and appropriately 
report potential Hy’s law (PHL cases and Hy’s Law (HL) cases).  It is not intended to be a 
comprehensive guide to the management of elevated liver biochemistries.
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 PHL 
criteria at any point during the study.
All sources of laboratory data are appropriate for the determination of PHL and HL events; 
this includes samples taken at scheduled study visits and other visits including central and all 
local laboratory evaluations even if collected outside of the study visits; for example, PHL 
criteria could be met by an elevated alanine aminotransferase (ALT) from a central laboratory 
and/or elevated total bilirubin (TBL) from a local laboratory.
The Investigator will also review adverse event (AE) data (for example, for AEs that may 
indicate elevations in liver biochemistry) for possible PHL events.
The Investigator participates, together with AstraZeneca clinical project representatives, in 
review and assessment of cases meeting PHL criteria to agree whether 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 study treatment.
The Investigator is responsible for recording data pertaining to PHL/HL cases and for 
reporting serious AEs (SAEs) and AEs according to the outcome of the review and assessment 
in line with standard safety reporting processes.
D 2
Definitions
Potential Hy’s Law (PHL)
Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) ≥ 3× upper limit of 
normal (ULN) together with TBL ≥ 2×ULN at any point during the study following the start 
of study treatment irrespective of an increase in alkaline phosphatase (ALP).
Hy’s Law (HL)
Aspartate aminotransferase or ALT ≥ 3× ULN together with TBL ≥2×ULN, where no other 
reason, other than the study treatment, can be found to explain the combination of increases, 
eg, elevated ALP indicating cholestasis, viral hepatitis, another drug.


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For PHL and HL the elevation in transaminases must precede or be coincident with (ie, on the 
same day) the elevation in TBL, but there is no specified time frame within which the 
elevations in transaminases and TBL must occur.
D 3
Identification of potential Hy’s Law cases
In order to identify cases of PHL it is important to perform a comprehensive review of 
laboratory data for any patient who meets any of the following identification criteria in 
isolation or in combination:

ALT ≥3 × ULN

AST ≥3 × ULN

TBL ≥2 × ULN
When a patient meets any of the PHL identification criteria, in isolation or in combination, the 
central laboratory will immediately send an alert to the Investigator (and also to the 
AstraZeneca representative).
The Investigator will also remain vigilant for any local laboratory reports where the PHL 
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 without delay

Complete the appropriate unscheduled laboratory electronic case report form (eCRF)
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 Appendix D 2 for definition) by 
reviewing laboratory reports from all previous visits (including both central and local 
laboratory results)
D 4
Follow-up
D 4.1
Potential Hy’s Law criteria not met
If the patient does not meet PHL criteria the Investigator will:

Perform follow-up on subsequent laboratory results according to the guidance provided in 
the Clinical Study Protocol (CSP).
D 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.


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
Within 1 day of PHL criteria being met, the Investigator will report the case as an SAE of 
PHL; serious criteria ‘Important medical event’ and causality assessment ‘yes/related’ 
according to CSP process for SAE reporting.

For patients that met PHL criteria prior to starting study treatment, the Investigator is not 
required to submit a PHL SAE unless there is a significant change in the patient’s 
condition.

The Study Physician contacts the Investigator, to provide guidance, discuss and agree an 
approach for the study patients’ follow-up (including any further laboratory testing) 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. Completes follow-up SAE Form as required.

Investigate the etiology of the event and perform diagnostic investigations as 
discussed with the Study Physician.  This includes deciding which the tests available 
in the HL laboratory kit should be used.

Complete the 3 Liver eCRF Modules as information becomes available.
D 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.
As soon as possible 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 
study treatment, to ensure timely analysis and reporting to health authorities within 
15 calendar days from the date PHL criteria were met.  The AstraZeneca Global Clinical Lead 
or equivalent 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.
Where 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 eCRF.

If the alternative explanation is an AE/SAE, update the previously submitted PHL SAE 
and AE eCRFs accordingly with the new information (reassessing event term; causality 
and seriousness criteria) following the AstraZeneca standard processes.


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If it is agreed that there is no explanation that would explain the ALT or AST and TBL
elevations other than the study treatment:

Send updated 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 15 calendar days 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:

Provides any further update to the previously submitted SAE of PHL, (report term now 
‘Hy’s Law case’) ensuring causality assessment is related to study treatment and 
seriousness criteria is medically important, according to CSP process for SAE reporting.

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 still met.  Update the previously submitted PHL SAE report 
following CSP process for SAE reporting, according to the outcome of the review and 
amending the reported term if an alternative explanation for the liver biochemistry 
elevations is determined.
D 6
Actions required for repeat episodes of Potential Hy’s Law
This section is applicable when a patient meets PHL criteria on study treatment and has 
already met PHL criteria at a previous on study treatment visit.
The requirement to conduct follow-up, review, and assessment of a repeat occurrence(s) of 
PHL is based on the nature of the alternative cause identified for the previous occurrence.  
The Investigator should determine the cause for the previous occurrence of PHL criteria being 
met and answer the following question:
Was the alternative cause for the previous occurrence of PHL criteria being met found to be 
the disease-under study (eg, chronic or progressing malignant disease, severe infection or liver 
disease), 
If No: Follow the process described in Appendix D 4.2 for reporting PHL as an SAE.
If Yes: Determine if there has been a significant change in the patient’s condition compared 
with when PHL criteria were previously met.

If there is no significant change, no action is required.


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
If there is a significant change, follow the process described in Appendix D 4.2 for 
reporting PHL as an SAE.
Note: A ‘significant’ change in the patient’s condition refers to a clinically relevant 
change in any of the individual liver biochemistry parameters (ALT, AST or TBL) in 
isolation or in combination, or a clinically relevant change in associated symptoms.  The 
determination of whether there has been a significant change will be at the discretion of 
the Investigator; this may be in consultation with the Study Physician if there is any 
uncertainty.
D 7
Laboratory tests
The list below represents the standard, comprehensive list of follow-up tests which are 
recommended but not mandatory when using a central laboratory. For studies using a local 
laboratory, the list may be modified based on clinical judgement. If required, additional 
assistance on which tests could be used to evaluate other potential causes of liver dysfunction 
consult with the Hepatic Safety Knowledge Group. Any test results need to be recorded.


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Table 6
Hy’s Law laboratory kit for central laboratories
Additional standard chemistry and coagulation 
tests
gamma-glutamyl transferase (GGT)
Lactate dehydrogenase (LDH)
Prothrombin time
International normalized ratio (INR)
Viral hepatitis
Immunoglobulin M (IgM) anti-hepatitis A virus (HAV)
IgM and immunoglobulin G (IgG) anti-hepatitis B core 
antibody (HBc)
Hepatitis B surface antigen (HbsAg)
Hepatitis V virus deoxyribonucleic acid (HBV DNA)
IgG anti-hepatitis C virus (HCV)
Hepatitis C virus ribonucleic acid (HCV RNA) a
IgM anti-hepatitis E virus (HEV)
HEV RNA
Other viral infections
IgM and IgG anti-cytomegalovirus (CMV)
IgM and IgG anti-herpes simplex virus (HSV)
IgM and IgG anti-Epstein-Barr virus (EBV)
Alcoholic hepatitis
Carbohydrate deficient transferrin (CD-transferrin) b
Autoimmune hepatitis
Antinuclear antibody (ANA)
Anti-Liver/Kidney Microsomal Ab (Anti-LKM)
Anti-Smooth Muscle Ab (ASMA)
Metabolic diseases
alpha-1-antitrypsin
Ceruloplasmin
Iron
Ferritin
Transferrin
Transferrin saturation
a
HCV RNA is only tested when IgG anti-HCV is positive or inconclusive.
b
Carbohydrate deficient transferrin (CD-transferrin) is not available in China. Study teams should amend this 
list accordingly.
REFERENCES
Aithal GP, Watkins PB, Andrade RJ, Larrey D, Molokhia M, Takikawa H et al: Case 
definition and phenotype standardization in drug-induced liver injury. Clinical Pharmacology 
and Therapeutics 2011; 89(6):806-15.
FDA Guidance for Industry (issued July 2009) ‘Drug-induced liver injury: Premarketing 
clinical evaluation’


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Appendix E
Abbreviations
Abbreviation 
Explanation
ADR
Adverse drug reactions
AE
Adverse event
ALP
Alkaline phosphatase
ALT
Alanine aminotransferase 
ANCOVA
Analysis of covariance
AST
Aspartate aminotransferase
AUC
Area under the curve
AV
Arteriovenous 
BIW
2 times a week
BP
Blood pressure
CHF
Congestive heart failure
CKD
Chronic kidney disease
CKD-EPI
Chronic Kidney Disease Epidemiology Collaboration
CONSORT
Consolidated Standards of Reporting Trials
COVID-19
Coronavirus disease of 2019
CRP
C-reactive protein
CSR
Clinical study report
CSP
Clinical study protocol
CV
cardiovascular
DD
Dialysis-dependent
DILI
Drug-induced liver injury
DMC
Data monitoring committee
DUS
Disease-under study
ECG
Electrocardiogram
ECode
Enrollment code
eCRF
Electronic case report form
eGFR
Estimated glomerular filtration rate
EDC
Electronic data capture
EOS
End of study
EPO
Erythropoietin
ESA
Erythropoiesis stimulating agent
ESRD
End-stage renal disease
FAS
Full analysis set
FWER
Familywise error rate


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Abbreviation 
Explanation
GCP
Good Clinical Practice
GI
Gastrointestinal
Hb
Hemoglobin
HD
Hemodialysis
HIF
Hypoxia inducible factor
HL
Hy’s Law
hs-CRP
High-sensitivity C-reactive protein
IATA
International Airline Transportation Association
IB
Investigator’s Brochure
ICF
Informed consent form
ICH
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use
ID
Incident dialysis
IEC
Independent ethics committee
IRB
Institutional review board
IU
International Unit
IV
Intravenous
IVRS
Interactive voice response system
KDOQI
Kidney Disease Outcomes Quality Initiative
MACE
Major adverse cardiovascular events
MedDRA
Medical Dictionary for Regulatory Activities
LLN
Lower limit of normal
NDD
Non-dialysis dependent
NCI-CTCAE
National Cancer Institute Common Terminology Criteria for Adverse Events
PD
Peritoneal dialysis
PHI
Prolyl hydroxylase inhibitor
PHL
Potential Hy’s law
PP
Per-protocol
PT
Preferred Term
QT
Interval between the Q and T waves of an electrocardiogram
RBC
Red blood cell
rHuEPO
Recombinant human erythropoietin
SADRs
Serious adverse drug reactions
SAE
Serious adverse event 
SAP
Statistical analysis plan
SC
Subcutaneous


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Abbreviation 
Explanation
SD
Standard deviation
SoA
Schedule of activities
SOC
System Organ Class
SUSAR
Suspected unexpected serious adverse reactions
TIBC
Total iron binding capacity
TBL
Total bilirubin
TCM
Traditional Chinese medicine
TIW
3 times a week
TMF
Trial Master File
TSAT
Transferrin saturation
ULN
Upper limit of normal
UN
United Nations
WBDC
Web-Based Data Capture


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Statistical Analysis Plan
Study Code
D5741C00002
Edition Number
2.0
Date
20 NOV 2020
ALTAI: An Open-Label, Randomized, Active-Controlled, Parallel 
Design, Multicenter Phase IV Study to Investigate the Effect of 
Roxadustat versus Recombinant Human Erythropoietin 
(rHuEPO) on Oral Iron Absorption in Chinese Patients with 
Anemia of Chronic Kidney Disease (CKD)


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ALTAI: An Open-Label, Randomized, Active-Controlled, Parallel Design, 
Multicenter Phase IV Study to Investigate the Effect of Roxadustat versus 
Recombinant Human Erythropoietin (rHuEPO) on Oral Iron Absorption in 
Chinese Patients with Anemia of Chronic Kidney Disease (CKD)
Author
Date
Note: Signed off electronically
PPD


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TABLE OF CONTENTS
TITLE PAGE........................................................................................................................ 2
SIGNATURE OF PAREXEL BIOSTATISTICS LEAD ....................................................... 3
TABLE OF CONTENTS...................................................................................................... 4
LIST OF ABBREVIATIONS ............................................................................................... 8
AMENDMENT HISTORY................................................................................................. 10
1
STUDY DETAILS ........................................................................................... 11
1.1
Study objectives................................................................................................ 11
1.2
Study design ..................................................................................................... 12
1.3
Number of subjects........................................................................................... 14
2
ANALYSIS SETS ............................................................................................ 16
2.1
Definition of analysis sets................................................................................. 16
2.1.1
All-patients analysis set .................................................................................... 16
2.1.2
Full analysis set ................................................................................................ 16
2.1.3
Per-protocol analysis set ................................................................................... 16
2.1.4
Safety analysis set............................................................................................. 16
2.2
Violations and deviations.................................................................................. 16
3
PRIMARY AND SECONDARY VARIABLES ............................................... 18
3.1
Efficacy variables ............................................................................................. 18
3.1.1
Primary efficacy variable: GI iron absorption.................................................... 18
3.1.2
Secondary efficacy variables............................................................................. 18
3.2
Safety assessment ............................................................................................. 18
4
ANALYSIS METHODS................................................................................... 20
4.1
General principles............................................................................................. 20
4.1.1
Multiple testing................................................................................................. 21
4.1.2
Handling of missing data .................................................................................. 22
4.1.2.1
Multiple imputation for missing visits............................................................... 22
4.1.2.2
Partial or missing dates ..................................................................................... 23
4.2
Analysis methods.............................................................................................. 23
4.2.1
Patient disposition............................................................................................. 23
4.2.2
Protocol deviations ........................................................................................... 24
4.2.3
Demographics and other baseline characteristics............................................... 24
4.2.4
Medical and surgical history ............................................................................. 25
4.2.5
Concomitant medication ................................................................................... 25
4.2.6
Exposure........................................................................................................... 26
4.2.7
Treatment Compliance...................................................................................... 26
4.3
Statistical analyses............................................................................................ 27
4.3.1
Primary efficacy endpoint................................................................................. 27
4.3.2
Secondary efficacy endpoints............................................................................ 28
4.3.3
Safety assessment analysis................................................................................ 31


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4.3.3.1
Adverse events.................................................................................................. 32
4.3.3.2
Laboratory variables ......................................................................................... 33
4.3.3.3
Vital signs......................................................................................................... 33
4.3.3.4
Electrocardiogram............................................................................................. 34
4.3.3.5
Physical examination ........................................................................................ 35
5
INTERIM ANALYSES.................................................................................... 36
6
CHANGES OF ANALYSIS FROM PROTOCOL............................................ 37
7
REFERENCES................................................................................................. 38
8
APPENDIX ...................................................................................................... 39
Appendix A: TELVC limits for laboratory variables ........................................................... 40
Appendix B: TELVC limits for vital signs .......................................................................... 54
Appendix C: TELVC limits for ECG .................................................................................. 57


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LIST OF TABLES
Table 1 Criteria for Assessing Important Protocol Deviations ............................................. 17
Table 2 Seed for Multiple Imputation.................................................................................. 22
Table 3 Criteria for Potentially Clinically Significant Vital Signs........................................ 34
Table 4 Criteria for Potentially Clinically Significant ECG ................................................. 35


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LIST OF FIGURES
Figure 1
Study design............................................................................................ 13


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LIST OF ABBREVIATIONS
Abbreviation or special 
term
Explanation
ATC
Anatomical therapeutic chemical
AE
Adverse event 
ALT
Alanine aminotransferase
AST
Aspartate aminotransferase
ANCOVA
Analysis of covariance
AUC
Area under the curve 
BP
Blood pressure 
CI
Confidence interval 
CKD
Chronic kidney disease
CRP
C-reactive protein
CSP
Clinical study protocol 
DCO
Data cut off
DD
Dialysis dependent
ECG
Electrocardiogram 
eCRF
Electronic case report form 
eGFR
estimated Glomerular Filtration Rate
EOS
End of study
FAS 
Full analysis set
FSGS
Focal Segmental Glomerulosclerosis
FWER
Familywise error rate
GI
Gastrointestinal
Hb
Hemoglobin 
HD
hemodialysis
hs-CRP
High sensitivity C-reactive protein
MedDRA
Medical Dictionary for Regulatory Activities
NDD
Non-dialysis dependent
PCS
Potentially Clinically Significant
PD
Peritoneal dialysis
PP
Per-protocol
rHuEPO
Recombinant human erythropoietin
TEAE
Treatment emergent adverse event
TELVC
Treatment emergent laboratory/vital signs change
TESAE
Treatment emergent serious adverse event


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Abbreviation or special 
term
Explanation
TIBC
Total iron binding capacity
TLF 
Tables, listings and figures 
TSAT
Transferrin saturation
ULN
Upper limit of normal
WHO 
World Health Organization


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AMENDMENT HISTORY
Category*:
Change refers to
Date
Description of change
In line with the 
CSP?
Rationale
Other
20 Nov 2020
Run-in period removed
Yes
Protocol amendment #2 approved 
24 June 2020.
Statistical analysis method for the 
primary or secondary endpoints
20 Nov 2020
Models are updated to account for 
new strata from protocol 
amendment
Yes
Protocol amendment #2 approved 
24 June 2020.
Other
20 Nov 2020
ECG text updated because only 
measured once (not triplicate).
Yes
Protocol amendment #2 approved 
24 June 2020.
Other
20 Nov 2020
Number of subjects screened 
increased to account for 
potentially higher screen failure 
rate due to COVID-19 pandemic.
Yes
Protocol amendment #2 approved 
24 June 2020.
Statistical analysis method for the 
primary or secondary endpoints
20 Nov 2020
Subgroup analyses has been 
added for the primary and 
secondary efficacy endpoints 
within the DD and NDD 
subgroups (DD-rHuEPO users,
NDD-rHuEPO users, NDD-
rHuEPO naïve)
Yes
Protocol amendment #2 approved 
24 June 2020.
Statistical analysis method for the 
primary or secondary endpoints
20 Nov 2020
Details of multiple imputation 
methods have been added to 
Section 4.1.2
Yes
Protocol amendment #2 approved 
24 June 2020.
* Pre-specified categories are 
Primary or secondary endpoints; Statistical analysis method for the primary or secondary endpoints; Derivation of primary or secondary endpoints; Multiple 
Testing Procedure; Data presentations; Other


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1
STUDY DETAILS
1.1
Study objectives
Primary objective a:
Endpoint/variable:
Evaluate the main effect of roxadustat 
versus rHuEPO on gastrointestinal iron 
absorption.
The main treatment effect on: the difference 
from baseline (Day 1) to Day 15 in 
log-transformed AUC of iron absorption 
from 0-3 hours based on the change in 
serum iron levels obtained just prior to T0 
(time when single dose of oral iron is 
administered) and over the subsequent 3-
hour period following oral administration 
(see Section 4.3.1).
Secondary Objectives a:
Endpoints/variables:
Assess the effect and interaction with key 
baseline variables of roxadustat versus 
rHuEPO on iron absorption.
The main treatment effect and key 
interaction effects on the difference from 
baseline (Day 1) to Day 15 in log-
transformed AUC of iron absorption from 0-
3 hours based on the change in serum iron 
levels obtained just prior to T0 (time when 
single dose of oral iron is administered) and 
over the subsequent 3-hour period following 
oral administration (see Section 4.3.2).
Assess the effect and interaction with key 
baseline variables of roxadustat versus 
rHuEPO on the indices of iron metabolism 
(ie, serum iron, ferritin, TIBC, TSAT, 
transferrin, soluble transferrin receptor) and 
hepcidin levels.
The main treatment effect and key 
interaction effects on the difference from 
baseline (Day 1) to Day 15 prior to 
administration of oral iron: in serum iron,
ferritin, TIBC, TSAT, transferrin, soluble 
transferrin receptor and hepcidin levels, log-
transformed as appropriate (see Section 
4.3.2).
Safety Objective:
Endpoint/variable:
Safety evaluation.
Safety assessed by incidence of AEs, and
measurement of vital signs (tympanic 


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temperature, BP, pulse and respiratory rate), 
laboratory variables (see Section 4.3.3).
a
The primary and secondary objectives will be analyzed using the Full Analysis Set (FAS), see Section 2.1
for further details.
AE=Adverse event; AUC=Area under the curve; BP=Blood pressure; rHuEPO=recombinant human 
erythropoietin; TIBC=total iron binding capacity; TSAT=transferrin saturation.
1.2
Study design
This is a Phase IV, randomized, active-controlled, open-label, parallel design, multicenter 
prospective study to evaluate the effect of roxadustat versus recombinant human 
erythropoietin (rHuEPO) treatment on the gastrointestinal (GI) iron absorption in patients with 
anemia of Stage 4 and Stage 5 chronic kidney disease (CKD). The study consists of 3 periods; 
the Screening Period, Treatment Period and Follow-up Period. The enrolled patients will have 
a maximum of 7 study visits (Figure 1).
This study will enroll eligible dialysis and non-dialysis patients who are either 
dialysis-dependent (DD) and are being treated with rHuEPO 4 weeks prior to screening, or are 
non-dialysis-dependent (NDD) and are being treated with rHuEPO (stable dose within 4 
weeks prior to screening), or are rHuEPO-naïve at screening (no treatment with erythropoietin 
stimulating agents [ESAs] for > 6 weeks). At randomization, patients will be stratified by the 
following: Non-Dialysis Dependent rHuEPO-users (NDD-rHuEPO users),  NDD-rHuEPO-
naïve, dialysis dependent patients on peritoneal dialysis (DD-PD), dialysis dependent patients 
on hemodialysis (DD-HD) with approximately equivalent number of patients in each stratum. 
Patients will be assessed for hs-CRP at the Screening Visit to check whether the measurement 
is either ≤ the upper limit of normal (ULN), or > the ULN, to control the number of inflamed
patients being randomized in the study (maximum of 23 low hs-CRP patients will be 
randomized).
The Screening Period will be followed by randomization (Day 1, Visit 2) at a 1:1 ratio to
receive either roxadustat or rHuEPO for 2 weeks.  At Visit 2, all patients randomized to
rHuEPO will receive a uniform brand of short-acting rHuEPO according to the dosage 
approved in the rHuEPO China Package Insert.  Patients who were previously on rHuEPO 
(before Screening) will receive a uniform brand of short-acting rHuEPO based upon their 
previous dose of rHuEPO, and according to the dosage approved in the rHuEPO China 
Package Insert.  For patients on a weekly dose of rHuEPO of 6000 IU, dosing will be 2 times 
a week (BIW) and for patients on a weekly dose of rHuEPO of > 6000 IU, dosing will be 
3 times a week (TIW).  For DD patients, the rHuEPO can be administered either IV or SC 
depending on the route of administration used before the Treatment Period.  The rHuEPO will 
be administered via the SC route for all patients who are NDD.  On Days 1 and 15, 
immediately before time T0 of the ferrokinetic study, a blood sample will be collected to 
measure baseline serum iron level and total iron binding capacity (TIBC), immediately 


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followed by administration of a defined single dose of oral iron after which the remaining 
blood samples for the ferrokinetic study will be collected over 3 hours to measure serum iron 
levels.  Serum levels of hepcidin and hs-CRP will be measured as biomarkers that reflect both 
altered iron metabolism and inflammation.  Both biomarkers will be assessed throughout the 
study.  Safety will be evaluated in all consented patients.
Figure 1
Study design
*
The Screening Period will be approximately 2-3 weeks long, but may be greater or lesser, to ascertain the Hb 
eligibility criteria with up to 3 hemoglobin (Hb) tests.  During the Screening Period, all patients who were on 
rHuEPO before entering the study will remain on the rHuEPO treatment they received.  The rHuEPO dose may 
be adjusted for patients who were on rHuEPO before the Screening Period depending on the patient’s Hb levels, 
at the discretion of the Investigator, in accordance with the rHuEPO China Package Insert.
The ferrokinetic study on Day 1 must be completed prior to randomization.  Patients will be randomly assigned 
in 1:1 ratio to either roxadustat or rHuEPO.  Study treatment to be administered after randomization at Day 1.
*Ferrokinetic study at T0 (before single dose of oral iron [12.5 mL [100 mg elemental iron]), and 1, 2 and 3 
hours following the administration of a single dose of oral iron.
The blood samples for the ferrokinetic study (serum iron and TIBC) at the T0 timepoint must be taken 
immediately before the single dose of oral iron is administered.
On Days 1, 8, and 15 hemoglobin levels will be tested in the central laboratory for all patients.  Additionally, for 
patients randomized to rHuEPO, Hb levels will be tested in the local laboratory on Days 1 and 8 for initial dose 
determination and dose adjustment.  The rHuEPO dose may be adjusted on Day 8 of the Treatment Period, 
depending on the patient’s Hb levels, for safety reasons, as determined by the Investigator, in accordance with 
the rHuEPO China Package Insert.  On Day 15 (or at the discontinuation visit), Hb levels will be tested in the 
local laboratory for all patients who were on rHuEPO prior to the study, to decide what rHuEPO dose to restart 
patients on, or another appropriate course of treatment for anemia, after study treatment stops.  For patients who 
were rHuEPO-naïve before entering the study, Hb levels may be tested in the local laboratory on Day 15 (or at 
the Discontinuation Visit) at the discretion of the Investigator, to determine an appropriate course of treatment 
for anemia in each patient.
D=day; DD=dialysis-dependent, NDD=non-dialysis-dependent, R=randomization; rHuEPO=recombinant human 
erythropoietin.


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1.3
Number of subjects
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CCI


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CCI


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2
ANALYSIS SETS
2.1
Definition of analysis sets
For purposes of analysis, the following populations are defined.
2.1.1
All-patients analysis set 
The all-patients analysis set will consist of all patients who are screened for the study. This 
analysis set will be used for listings.
2.1.2
Full analysis set
The full analysis set (FAS) includes all randomized patients who have complete baseline (Day 
1) measurements for any of the efficacy endpoints (as defined in Sections 4.3.1 and 4.3.2), 
with patients being analyzed as randomized, rather than as treated. The FAS will be used for 
the primary endpoint and all secondary endpoints. The FAS will also be used for the 
presentation of all demographic and disposition data.
2.1.3
Per-protocol analysis set 
The per-protocol (PP) analysis set will include all randomized patients who received at least 1 
dose of study treatment, have baseline (Day 1) and at least 1 post-baseline iron absorption 
measurement, and are without important protocol violations. The PP analysis set will be used 
as a sensitivity analysis population for the primary and secondary endpoints. Section 2.2
describes the protocol violations which are considered important for this study. 
2.1.4
Safety analysis set 
The safety analysis set will include all randomized patients receiving at least 1 dose of study 
treatment, with patients being analyzed as treated, rather than as randomized. The safety 
analysis set will be used for the safety endpoints. Exposure to study treatment will also be 
presented using the safety analysis set.
2.2
Violations and deviations
Important protocol deviations are defined in Table 1. Important protocol deviations will be 
summarized by treatment group and overall and presented in a data listing. Important protocol 
deviations relating specifically to the global pandemic of COVID-19 will be presented 
separately.


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Table 1 Criteria for Assessing Important Protocol Deviations
Number
Important Protocol Deviations
Level of Deviation a
1
Violation of inclusion or exclusion criteria. The key inclusion criteria 
are numbers 9 and 10. The key exclusion criteria are numbers 14, 15,
24, and 26. The full list of inclusion and exclusion criteria is available 
in the CSP.
Subject
2
Administration of wrong type or dose of study drug (i.e. the one not 
randomized to).
Visit
3
Administration of prohibited concomitant medication or non-drug 
therapy as defined in the protocol.
Visit
4
Study drug compliance <75%, where drug compliance is measured by 
comparing dispensed and returned drug (see Section 4.2.7).
Visit
5
Any transfusion or rescue therapy received during or within a week of 
the randomized treatment period. 
Visit
6
Any of the two doses of oral iron are missed 
Subject
a
Subject-level deviations refer to important protocol deviations that will cause subjects to be excluded from 
the Per Protocol set, and therefore all their collected data from analyses based on this population. Visit-level 
deviations refer to important protocol deviations that will cause only some data for subjects to be excluded 
from analyses based on the Per Protocol set, while the subjects remain in the Per Protocol set given that they 
did not meet any subject-level deviations. Data to be excluded from the Per Protocol analyses could be 
either data from a certain date, at which the deviation was met for the first time, onwards to the end of the 
study, or data during a period defined by the start and end dates of the deviation.


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3
PRIMARY AND SECONDARY VARIABLES
3.1
Efficacy variables
3.1.1
Primary efficacy variable: GI iron absorption
The primary outcome for this study is the GI iron absorption change from baseline (Day 1) to 
Day 15. At Days 1 and 15, serum iron level and TIBC will be determined followed by 
administration of a defined single dose of oral liquid elemental iron containing FeSO4 to all 
patients at time T0. Serum iron level at 1, 2, and 3 hours following administration of the single 
oral iron dose (timepoints T1, T2, and T3) will then be determined. Gastrointestinal iron
absorption will then be assessed by the total area under the curve (AUC) adjusted for serum 
iron level from sample obtained just prior to T0. Iron absorption data will be provided by
Covance, with log-transformations to be done during programming, where applicable. The 
primary endpoint is defined in Section 4.3.1.
3.1.2
Secondary efficacy variables
The secondary outcomes of interest assess direct treatment and interaction effects in iron 
absorption and the indices of iron metabolism and hepcidin levels and are described in Section 
4.3.2. The relative change from baseline (Day 1) to Day 15 will be calculated for the 
following variables: 

Serum iron

Ferritin

TIBC

TSAT 

Transferrin

Soluble transfer receptor

Hepcidin
3.2
Safety assessment 
Safety will be assessed throughout the study. A complete baseline profile of each patient will
be established through demographics, medical history (events before ICF signing), clinical
laboratory values, vital signs, and physical assessments. During the course of the study, vital
signs (tympanic temperature, systolic and diastolic BP, pulse and respiratory rate) and 
laboratory tests will be performed at regular intervals.
Adverse events, SAEs and ongoing concomitant medication usage will be monitored and
recorded throughout the study. Serious adverse events 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. Serious adverse events and 


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AEs will be followed until resolved, stable or until the patient’s End of Study (EOS) visit. 
Safety will be assessed by evaluating the following:

Frequency counts and incidence rates of treatment-emergent adverse events (TEAEs) and 
treatment-emergent serious adverse events (TESAEs)

Changes from baseline in vital signs and physical examination

Mean change from baseline in clinical laboratory values

Frequency counts and incidence rates of clinically significant changes from baseline in 
vital signs and ECG values.


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4
ANALYSIS METHODS
4.1
General principles
The following general principles will be followed throughout the study:

Continuous variables will be summarized by the number of observations, mean, standard 
deviation, median, minimum, and maximum. Categorical variables will be summarized 
by frequency counts and percentages for each category; including proportion of 
missingness.

The minimum and maximum will be reported to the same number of decimal places as 
the raw data recorded in the database. The mean and median will be reported to one more 
decimal place, and the standard deviation will be reported to two more decimal places, 
than the raw data recorded in the database.

Percentages will be presented to one decimal place.

SAS® version 9.3 or later will be used for all analyses.
Study Day 1 is defined as the date of 1st dose of randomized study treatment. For visits (or 
events) that occur on or after first dose, study day is defined as (date of visit [event] - date of 
first dose of randomized treatment + 1). For visits (or events) that occur prior to first dose, 
study day is defined as (date of visit [event] - date of first dose of randomized treatment). 
All efficacy variables, safety variables and patient characteristics will be summarized by study 
treatment groups using descriptive statistics. Data will be summarized by visit and
randomization strata as applicable. 
For safety variables, the last observation before the first dose of randomized treatment will be 
considered the baseline measurement unless otherwise specified. 
In all summaries, change from baseline variables will be calculated as the post-treatment value 
minus the value at baseline. The percentage change from baseline will be calculated as 
(postbaseline value - baseline value) / baseline value ×100. 
The primary endpoint, all secondary efficacy endpoints, study population and demography 
data will be summarized and analyzed based on the FAS. The safety analysis set will be used 
for the safety endpoints. The PP analysis set will be used as a sensitivity analysis population 
for the primary and secondary endpoints. 
All statistical tests will be conducted at a 2-sided significance level of 5% unless otherwise 
specified. Where appropriate, model-based point estimates, together with their 95% 
confidence intervals (CIs) will be presented along with the 2-sided p-values for the tests.


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The primary analysis will be performed when all patients have completed Day 15, and will 
include production of all the tables, listings and figures (TLF), which will be specified and 
finalized in a separate TLF shell document before database lock. A final analysis will be 
performed when all patients have completed the study and will include production of all TLFs. 
4.1.1
Multiple testing
For each of the secondary endpoints, the Holm-Bonferroni method will be implemented to 
control the familywise error rate (FWER) for each of the treatment effect p-values (Holm 
1979). Both the unadjusted error (based on a significance level α=0.05) and a Holm-
Bonferroni adjusted significance level will be implemented due to multiple testing. 
Let P1, P2…Pn be the p-values for each of the n separate hypotheses tests. The 
Holm-Bonferroni adjustment ranks these p-values from smallest to largest (P[1], P[2]…P[n]) and 
the associated hypotheses H(1), H(2)…H(n). 
For a pre-specified significance level, α, let k be the smallest value for which P(k)>
α
n+1-k where 
n is the total number of p-values being adjusted for. 
Testing of further p-values will stop, all corresponding preceding null hypotheses H(1), 
H(2)…H(k-1) will be rejected, and none of the rest of the null hypotheses H(k), H(k+1), 
H(k+2)…H(n) will be rejected. This ensures that the FWER ≤α.
The adjusted p-values are calculated as follows: 
 = 

 {( − + 1)} , ℎ {} ≡
(, 1)     ℎ !
" #$ ℎ%# ℎ
Primary endpoint 
The primary endpoint will be tested at a significance level of 0.05.  If significant then all 
secondary endpoints will be assessed using the Holm-Bonferroni method described above. If 
the primary endpoint is not significant (p>0.05) then testing will stop and the null hypotheses 
for the secondary endpoints will be accepted. 
Secondary endpoints 
If multiple testing is applied to the secondary endpoints, then the following rules will apply. 
Each model is described in section 4.3.2, with a corresponding number. For models (1) the 
FWER will be implemented across the seven treatment-effect p-values. 
For models (2) and (3), these will be tested against a nominal p-value of 0.05 and will be 
treated as exploratory. 


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4.1.2
Handling of missing data
4.1.2.1
Multiple imputation for missing visits
Multiple imputations (MI) will be implemented for the primary and secondary analyses to 
account for missing data, due to the increased risk of this occurring during the COVID-19 
pandemic.  
For the primary and secondary efficacy analysis, MI will be used as the primary analysis 
method. This will be implemented on the raw data values on the log scale for the respective 
endpoint. If a subject has missing Day 15 but has an early discontinuation visit, the early 
discontinuation visit will be allocated as Day 15. Any subject with missing post-baseline
measurement will have their data imputed. It will be conducted with the following steps (using 
AUC of iron absorption as an illustrative example, but applicable to all iron indices data):

Step 1 - Imputation preparation step: Create a dataset, one for each treatment group, of 
subjects with observed values and those needing estimation by multiple imputation. 
Subjects with missing baseline data will be excluded.

Step 2 – Imputation step: For each treatment group separately, missing Day 15 values 
will be imputed using Monotone Regression in SAS PROC MI. The imputation model 
will include the stratum variable (NDD-rHuEPO user, NDD-rHuEPO naïve, DD-HD, 
DD-PD), the baseline hs-CRP level (≤ULN, >ULN), the Day 1 value and the day 15 
value (observed or missing). A total of 200 imputations will be performed using a seed 
of 1456. Note that a different seed will be used for each endpoint and each model 
within an endpoint, as shown in Table 2.

Step 3 – Derivation step: Set the two treatment group imputed datasets together. 
Derive  as described in Section 4.3.1.

Step 4 – Analysis step: Perform the ANCOVA analysis as described in Section 4.3.1
by imputation.

Step 5 – Pooling step: Combine the results from the 200 ANCOVA analyses using 
Rubin’s rules in PROC MIANALYZE. Back-transformation of estimated to the 
original scale (as appropriate) will be performed after the pooling step. 
Table 2 Seed for Multiple Imputation
Endpoint
Seed (Model 1)
Seed (Model 2)
Seed (Model 3)
AUC iron 
absorption
1456
3209
4291
Serum iron
687
290
4210
Ferritin
9341
1321
7897
TIBC
6782
9200
6172
TSAT
2935
3401
201
Transferrin
5340
637
7222


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Endpoint
Seed (Model 1)
Seed (Model 2)
Seed (Model 3)
Soluble transfer 
receptor
4782
2221
102
Hepcidin
3817
38882
2032
4.1.2.2
Partial or missing dates
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.
Where dates are missing or partially missing, medications will be assumed to be concomitant, 
unless there is clear evidence (through comparison of partial dates) to suggest that the 
medication started prior to the first dose or after the last dose of randomized treatment.
Partial AE and concomitant medication start dates will be imputed as follows:
Imputation of Partial Start Dates

If only the month and year are specified and the month and year of first dose is not the 
same as the month and year of the start date, then use the 1st of the month

If only the month and year are specified and the month and year of first dose is the same 
as the month and year of the start date, then use the date of first dose

If only the year is specified, and the year of first dose is not the same as the year of the 
start date, then use the 1st of January of the year of the start date

If only the year is specified, and the year of first dose is the same as the year of the start 
date, then use the date of first dose

If the start date is completely unknown and the stop date is unknown or not prior to the 
date of first dose, then use the date of first dose.
Imputation of Partial Stop Dates

If only the month and year are specified, then use the last day of the month

If only the year is specified, then use December 31st of that year

If the stop date is completely unknown, do not impute the stop date.
In the event of ambiguity or incomplete data which makes it impossible to determine whether 
a medication was concomitant, or an adverse event was treatment emergent, the medication 
will be considered as concomitant or the adverse event will be considered treatment emergent.
4.2
Analysis methods
4.2.1
Patient disposition 
The total number of patients screened (including screening failures), re-screened, randomized, 
patients who received any randomized treatment and patients who did not receive any 


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randomized treatment, patients who completed randomized treatment and patients who 
discontinued treatment and the reason for treatment discontinuation, patients who completed 
the study and patients who discontinued the study and the reason for study discontinuation
will be summarized by treatment group and overall. 
The number and percentage of patients included in the analysis sets and the number of patients 
recruited by center will be also presented by treatment group and overall.
By-subject listings of patient disposition and analysis set exclusions will be presented.
4.2.2
Protocol deviations
All identified important protocol deviations, as described in Section 2.2, will be listed and 
summarized for the FAS by treatment group and overall. All protocol deviations will be
identified and classified as important or not important before database lock.
A by-subject listing of important protocol deviations will be presented.
4.2.3
Demographics and other baseline characteristics
Demographic and baseline subject characteristics will be listed and summarized for the FAS
by treatment group and overall. Standard descriptive statistics will be presented for the 
continuous variables of:

Age (years)

Weight (kg)

eGFR (mL/min/1.73m2) at screening 

Duration of dialysis

Duration of CKD
In addition to the standard descriptive statistics, the geometric mean and CV (%) will be 
presented for the following: 

Serum iron AUC

Serum iron

Ferritin

TIBC

TSAT

Transferrin

Soluble transfer receptor

Hepcidin 


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The total counts and percentages of patients will be presented for the categorical variables of:

Age group (years) (≥18-<50, ≥50-<65, ≥65-<75, ≥75)

Weight (kg) (<70, ≥70-<100, ≥100 kg) 

Sex (male, female)

Race (Black or African American, Asian, White, other)

Ethnic group (Hispanic or Latino, not Hispanic or Latino) 

Dialysis history

Type of dialysis (PD, HD)

Hemodialysis access type (arteriovenous fistula, arteriovenous graft, tunneled 
catheter, other)

rHuEPO use during 4 weeks prior to Visit 2

frequency (every week, 2 times per week, 3 times per week, 4 times per week, QM
[every month], other), dose, route (parenteral, intravenous, subcutaneous, 
intraperitoneal, unknown, not applicable)

Baseline CKD, most likely etiology (ischaemic/hypertensive nephropathy, chronic 
glomerulonephritis, renal artery stenosis, chronic pyelonephritis (infectious), chronic 
interstitial nephritis, obstructive nephropathy, cystic kidney disease - policystic kidney 
disease, cystic kidney disease - medullary kidney disease, cystic kidney disease -
medullary sponge kidney, cystic kidney disease – other, diabetic nephropathy - type 1, 
diabetic nephropathy - type 2, unknown, other)

Chronic Glomerulonephritis Type (IgA nephropathy, focal segmental glomerulosclerosis 
[FSGS], membranous nephropathy, minimal change, lupus nephritis, other primary or 
secondary glomerulonephritis)

rHuEPO status at randomization (rHuEPO-user, rHuEPO-naïve)

hs-CRP (≤ULN [10.0 mg/L], >ULN [10.0 mg/L])

eGFR category (<10 mL/min/1.73m2, 10-<15 mL/min/1.73m2, 15-<30 mL/min/1.73m2, 
≥30mL/min/1.73m2)
4.2.4
Medical and surgical history 
All reported relevant medical and abdominal and pelvic surgical history will be coded using 
the most recent version of the Medical Dictionary for Regulatory Activities (MedDRA) and 
summarized (number and percentage of patients) for the FAS by system organ class (SOC) 
and preferred term (PT), for each treatment group and overall. 
4.2.5
Concomitant medication
Prior and concomitant medications are defined as follows:

Prior medications are medications taken prior to or during screening with a stop date prior 
to the first dose of randomized treatment.


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
Concomitant medications are medications with or without a stop date on or after the date 
of first dose of randomized treatment (and could have started prior to or during 
treatment).
Concomitant medication will be summarized using frequency tables by Anatomical 
therapeutic chemical (ATC) classification code (based on World Health Organization (WHO) 
classification) based on the FAS. Intravenous iron, rHuEPO and triferic in dialysate during the 
4 weeks prior to Visit 1 will be listed. A by-subject listing of all concomitant medications 
taken on entry and during the study will be presented for randomized subjects.
4.2.6
Exposure 
The following descriptive statistics will be produced for the Safety Analysis Set, by treatment 
group:

Total exposure to study treatment (weeks) = (min(last dose date, death date) - first dose 
date +1) / (365.25/52)

Time on study – defined as the time in days from the start date of treatment to the date of 
last study assessment or the date of withdrawal.
The following summaries will be produced for the Safety Analysis Set, by treatment group:

Number of and reasons for dose interruptions

Number of and reasons for dose reductions 
4.2.7
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 based on the FAS as follows:

Descriptive statistics will be summarized by the two treatment groups 

Percent compliance will be categorized according to the following three categories:

<50% or ≥150% (significant drug non-compliance)

≥50% and <75% or >125% and <150% (moderate drug non-compliance)

≥75%, ≤125% (drug compliance)


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4.3
Statistical analyses 
4.3.1
Primary efficacy endpoint 
The primary efficacy endpoint is measured through change from baseline (Day 1) to Day 15 in 
log-transformed AUC of iron absorption from 0-3 hours based on the change in serum iron 
levels obtained just prior to T0 (time when single dose of oral iron is administered) and over a 
3-hour period. If a patient withdraws before Day 15, their discontinuation visit will be used as 
the post-baseline primary measurement. Multiple imputation, as described in Section 4.1.2.1, 
will be implemented on missing data for subjects with no post-baseline primary measurement.
The AUC curve (for the calculation of the primary endpoint and associated secondary 
endpoints) will be determined for each patient at baseline (Day 1) and post-baseline, then the 
average of the changes from baseline (Day 1) will be evaluated for each treatment group. This 
is to be calculated for patient i as the sum of the area of each trapezium under the curve, 
adjusted for any iron present in sample obtained just prior to time T0. Let Pj be the serum iron 
level at timepoint Tj then the AUC for patient i at Visit X is
AUCx,i= '
(
Pj+1+Pj
2
-P0)
2
j=0
Let di be the change from baseline for patient i and is defined as:
 = log(-./)0123, −log(-./)4156786,
The difference in log (AUC) from baseline (Day 1) to Day 15 will be analyzed using an 
ANCOVA model, adjusting for study treatment, stratum (NDD-rHuEPO-users, 
NDD-rHuEPO-naïve, DD-PD, and DD-HD patients), and baseline hs-CRP level (≤ULN, 
> ULN).
A summary table will be presented to show the change from baseline (Day 1) to Day 15 in 
log-transformed AUC of iron absorption, by treatment group. Estimates of the geometric 
mean and coefficient of variation in each treatment group will also be presented. A separate 
table will show the treatment group comparisons, along with estimates, 95% CIs, and p-values 
from the ANCOVA model. Estimates will be back-transformed (exponentiated) and presented 
on the original scale.
Should the residuals in the primary analysis fail to satisfy normality, AUC will be analyzed on 
the original observation scale instead. The following procedure will be used. If the 
Shapiro-Wilks test rejects the null hypothesis of normality of the residuals at a significance 
level of 0.05 and the residuals present with left skew when analyzing the difference in 
log(AUC), the change in AUC will be analyzed as the difference in AUC. A second test of 
normality will be conducted. If the Shapiro-Wilk test rejects the null hypothesis of normality 


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of the residuals when analyzed on the untransformed scale and the residuals present with right 
skew, then the analysis will revert to the log scale.
In the event that the AUC instead will be evaluated on the untransformed scale (Section 1.3), 
the absolute difference in AUC from baseline (Day 1) to Day 15 will be analyzed using a type 
III sum of squares ANCOVA model, adjusting for study treatment, stratum (NDD-rHuEPO 
users, NDD-rHuEPO-naïve, DD on hemodialysis [DD-HD], and DD on peritoneal dialysis 
[DD-PD], and baseline hs-CRP (≤ ULN, > ULN) level. 
If any of the values required to calculate the AUC are missing, then the following rules will 
apply:

If either measurement for timepoints T0 or T1 are missing, then the AUC cannot be 
reasonably calculated and will be deemed missing.

Else If only T2 is missing, then the midpoint for T1 and T3 should be used.

Else If T3 or T2 and T3 are missing, then LOCF from T1 should be used.
A sensitivity analysis will be performed, which will exclude all patients with any missing 
measurements required for the AUC calculation. 
The hypothesis to be assessed is as follows:
H0: There is no difference in the average change from baseline in the ferrokinetic measurement 
between rHuEPO and roxadustat.
HA: There is a difference in the average change from baseline in the ferrokinetic measurement 
between rHuEPO and roxadustat.
A subgroup analysis will be performed on the primary and secondary efficacy endpoints 
within the DD and NDD subgroups (DD-HD, DD-PD, NDD-rHuEPO-users, 
NDD-rHuEPO-naïve).
4.3.2
Secondary efficacy endpoints
The secondary efficacy outcomes for this study are outlined in Section 3.1.2. The secondary 
endpoints of interest assess direct treatment and interaction effects in the indices of iron 
metabolism (ie, serum iron, ferritin, TIBC, TSAT, transferrin, soluble transfer receptor) and 
hepcidin levels, and are described below. When hs-CRP level or hs-CRP interaction is 
included in the below models, this refers to the continuous measurement of baseline hs-CRP. 


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Relative difference in AUC
2. The relative difference in AUC from baseline (Day 1) to Day 15, adjusted for study 
treatment, stratum (NDD-rHuEPO-users, NDD-rHuEPO-naïve, DD-PD, and DD-HD), 
baseline hepcidin value, and treatment interaction with baseline hepcidin value.  Treatment 
and interaction effects to be assessed.
3. The relative difference in AUC from baseline (Day 1) to Day 15, adjusted for study 
treatment, stratum (NDD-HuEPO-users, NDD-rHuEPO-naïve, DD-PD, and DD-HD), 
baseline hs-CRP value and treatment interaction with baseline hs-CRP value.  Treatment 
and interaction effects to be assessed.
Relative difference in serum iron
1.
The relative difference in serum iron from baseline (Day 1) to Day 15, adjusted for study 
treatment, stratum (NDD-rHuEPO users, NDD-rHuEPO-naïve, DD-PD, and DD-HD) and 
baseline hs-CRP level (≤ ULN, > ULN).  Treatment effect to be assessed.
2.
The relative difference in serum iron from baseline (Day 1) to Day 15, adjusted for study 
treatment, stratum (NDD-rHuEPO-users, NDD-rHuEPO-naïve, DD-PD, and DD-HD), 
baseline hepcidin value and treatment interaction with baseline hepcidin value.  
Treatment and interaction effects to be assessed.
3.
The relative difference in serum iron from baseline (Day 1) to Day 15, adjusted for study 
treatment, stratum (NDD-rHuEPO-users, NDD-rHuEPO-naïve, DD-PD, and DD-HD), 
baseline hs-CRP value and treatment interaction with baseline hs-CRP value.  Treatment 
and interaction effects to be assessed.
Relative difference in ferritin
1.
The relative difference in ferritin from baseline (Day 1) to Day 15, adjusted for study 
treatment, stratum (NDD-rHuEPO users, NDD-rHuEPO-naïve, DD-PD, and DD-HD) and 
baseline hs-CRP level (≤ ULN, > ULN).  Treatment effect to be assessed.
2.
The relative difference in ferritin from baseline (Day 1) to Day 15, adjusted for study 
treatment, stratum (NDD-rHuEPO-users, NDD-rHuEPO-naïve, DD-PD, and DD-HD), 
baseline hepcidin value and treatment interaction with baseline hepcidin value.  
Treatment and interaction effects to be assessed.
3.
The relative difference in ferritin baseline (Day 1) to Day 15, adjusted for study 
treatment, stratum (NDD-rHuEPO-users, NDD-rHuEPO-naïve, DD-PD, and DD-HD), 
baseline hs-CRP value and treatment interaction with baseline hs-CRP value.  Treatment 
and interaction effects to be assessed.
Relative difference in TIBC
1.
The relative difference in TIBC from baseline (Day 1) to Day 15, adjusted for study 
treatment, stratum (NDD-rHuEPO users, NDD-rHuEPO-naïve, DD-PD, and DD-HD) and 
baseline hs-CRP level (≤ ULN, > ULN).  Treatment effect to be assessed.
2.
The relative difference in TIBC from baseline (Day 1) to Day 15, adjusted for study 
treatment, stratum (NDD-rHuEPO-users, NDD-rHuEPO-naïve, DD-PD, and DD-HD), 


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baseline hepcidin value and treatment interaction with baseline hepcidin value.  
Treatment and interaction effects to be assessed.
3.
The relative difference in TIBC from baseline (Day 1) to Day 15, adjusted for study 
treatment, stratum (NDD-rHuEPO-users, NDD-rHuEPO-naïve, DD-PD, and DD-HD), 
baseline hs-CRP value and treatment interaction with baseline hs-CRP value.  Treatment 
and interaction effects to be assessed.
Relative difference in TSAT
1.
The relative difference in TSAT from baseline (Day 1) to Day 15, adjusted for study 
treatment, stratum (NDD-rHuEPO users, NDD-rHuEPO-naïve, DD-PD, and DD-HD) and 
baseline hs-CRP level (≤ ULN, > ULN).  Treatment effect to be assessed.
2.
The relative difference in TSAT from baseline (Day 1) to Day 15, adjusted for study 
treatment, stratum (NDD-rHuEPO-users, NDD-rHuEPO-naïve, DD-PD, and DD-HD), 
baseline hepcidin value and treatment interaction with baseline hepcidin value.  
Treatment and interaction effects to be assessed.
3.
The relative difference in TSAT from baseline (Day 1) to Day 15, adjusted for study 
treatment, stratum (NDD-rHuEPO-users, NDD-rHuEPO-naïve, DD-PD, and DD-HD), 
baseline hs-CRP value and treatment interaction with baseline hs-CRP value.  Treatment 
and interaction effects to be assessed.
Relative difference in transferrin
1.
The relative difference in transferrin from baseline (Day 1) to Day 15, adjusted for study 
treatment, stratum (NDD-rHuEPO users, NDD-rHuEPO-naïve, DD-PD, and DD-HD) and 
baseline hs-CRP level (≤ ULN, > ULN).  Treatment effect to be assessed.
2.
The relative difference in transferrin from baseline (Day 1) to Day 15, adjusted for study 
treatment, stratum (NDD-rHuEPO-users, NDD-rHuEPO-naïve, DD-PD, and DD-HD), 
baseline hepcidin value and treatment interaction with baseline hepcidin value.  
Treatment and interaction effects to be assessed.
3.
The relative difference in transferrin from baseline (Day 1) to Day 15, adjusted for study 
treatment, stratum (NDD-rHuEPO-users, NDD-rHuEPO-naïve, DD-PD, and DD-HD), 
baseline hs-CRP value and treatment interaction with baseline hs-CRP value.  Treatment 
and interaction effects to be assessed.
Relative difference in soluble transfer receptor
1.
The relative difference in soluble transfer receptor from baseline (Day 1) to Day 15, 
adjusted for study treatment, stratum (NDD-rHuEPO users, NDD-rHuEPO-naïve, 
DD-PD, and DD-HD) and baseline hs-CRP level (≤ ULN, > ULN).  Treatment effect to 
be assessed.
2.
The relative difference in soluble transfer receptor from baseline (Day 1) to Day 15, 
adjusted for study treatment, stratum (NDD-rHuEPO-users, NDD-rHuEPO-naïve, 
DD-PD, and DD-HD), baseline hepcidin value and treatment interaction with baseline 
hepcidin value.  Treatment and interaction effects to be assessed.


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3.
The relative difference in soluble transfer receptor from baseline (Day 1) to Day 15, 
adjusted for study treatment, stratum (NDD-rHuEPO-users, NDD-rHuEPO-naïve, 
DD-PD, and DD-HD), baseline hs-CRP value and treatment interaction with baseline 
hs-CRP value.  Treatment and interaction effects to be assessed.
Relative difference in hepcidin
1.
The relative difference in hepcidin from baseline (Day 1) to Day 15, adjusted for study 
treatment, stratum (NDD-rHuEPO users, NDD-rHuEPO-naïve, DD-PD, and DD-HD) and 
baseline hs-CRP level (≤ ULN, > ULN).  Treatment effect to be assessed.
2.
The relative difference in hepcidin from baseline (Day 1) to Day 15, adjusted for study 
treatment, stratum (NDD-rHuEPO-users, NDD-rHuEPO-naïve, DD-PD, and DD-HD), 
baseline hepcidin value and treatment interaction with baseline hepcidin value.  
Treatment and interaction effects to be assessed.
3.
The relative difference in hepcidin from baseline (Day 1) to Day 15, adjusted for study 
treatment, stratum (NDD-rHuEPO-users, NDD-rHuEPO-naïve, DD-PD, and DD-HD), 
baseline hs-CRP value and treatment interaction with baseline hs-CRP value.  Treatment 
and interaction effects to be assessed.
These secondary endpoints will be analyzed using ANCOVA models, similar to that described 
in Section 4.3.1. The outcome variables (indices of iron metabolism and AUC) are to be 
log-transformed prior to analysis and the result back-transformed to the original scale to aid 
interpretability. Log-transformed baseline hepcidin and baseline hs-CRP are to be used as 
covariates. When back-transformed onto the original scale these estimates become exponents 
of hepcidin and hs-CRP. 
A summary table will be presented to show the outcomes of interest, by treatment group. 
Estimates of the geometric mean and coefficient of variation in each treatment group will also 
be presented. A separate table will show the treatment group comparisons, along with 
estimates, 95% CIs, and p-values from the ANCOVA models, as described above. Figures to 
show the relationship between hepcidin values and hs-CRP values and the relative change 
from baseline in outcomes of interest on both the log-transformed and original scales will be 
produced to show the moderating effects of hepcidin and hs-CRP in the models, to aid 
interpretation on the original scale.
A subgroup analysis will be performed on the primary and secondary efficacy endpoints 
within the DD and NDD subgroups (DD-HD, DD-PD, NDD-rHuEPO-users, 
NDD-rHuEPO-naïve).
4.3.3
Safety assessment analysis 
All safety analyses will be performed on the safety analysis set and will be analyzed 
descriptively. Safety parameters include adverse events (AE), laboratory parameters, vital 


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signs, ECG variables and physical examinations. For each safety variable, the last assessment 
before the first dose of randomized treatment will be considered the baseline measurement for 
all analyses, unless specified otherwise.
4.3.3.1
Adverse events
Adverse events will be coded using the most recent version of MedDRA. 
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 
randomized treatment. 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 patient exposure year (PEY) of subjects reporting 
TEAEs in each treatment group will be tabulated by system organ class and preferred term; by 
system organ class; by system organ class, preferred term, and relationship to study 
medication as assessed by the investigator. If more than one event occurs with the same 
preferred term for the same subject, the subject will be counted only once for that preferred 
term using the most severe and most related occurrence for the summarization by severity and 
by relationship to the study medication. 
The event rate per 100 PEY is defined as
(
!
" #$ !"9:   ℎ-;
!
 #$ %   $# -;    
 # + 28 %) × 365.25 × 100
The distribution of TEAEs by severity and relationship to study medication will be 
summarized by treatment group.
A summary of adverse events in any category will be presented by treatment. The incidence of 
common (≥10% 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 system organ class, preferred term and treatment group, sorted in decreasing 
overall (across treatments) frequency. The summaries of TESAEs, TESAEs that are related to 
study medication and TEAEs leading to discontinuation of study medication will be presented 
overall, and by treatment compliance category (See Section 4.2.7). Moreover, TEAEs leading 
to hospitalization will also be presented. Related deaths will be summarized separately by 
treatment group, system organ class and preferred term. TEAEs with outcome of deaths will 
also be presented. In addition, all fatal SAEs (i.e., events that caused death) will be 
summarized. Summaries of the number of subjects with related AEs and related SAEs will be 
presented by treatment group, system organ class and preferred term. The number of subjects 
with AEs with maximum severity will be presented by treatment group, system organ class 
and preferred term. 


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Listings will be presented of subjects with SAEs, AEs leading to discontinuation, and subjects 
who died. A listing will be presented of subjects with AEs, detailing whether these are SAEs, 
AEs leading to discontinuation, or result in death. A listing will be presented for AEs related 
to COVID-19 pandemic. 
4.3.3.2
Laboratory variables
Descriptive statistics for laboratory values, mean percent changes and selected treatment-
emergent laboratory/vital signs change (TELVC) from baseline at each assessment time point 
will be presented by treatment group for the following laboratory variables:

Hematology: Hb, leukocyte count, leukocyte differential count, platelet count, red blood 
cell count, hematocrit, mean corpuscular volume, reticulocytes, HbA1c.

Chemistry: creatinine, total bilirubin, alkaline phosphatase, aspartate transaminase,
alanine aminotransferase, albumin, potassium, total calcium, sodium, glucose, 
bicarbonate, chloride, blood urea nitrogen, magnesium, phosphorus. 

Serum iron, ferritin, TIBC, TSAT, transferrin, soluble transferrin receptor.

Urinalysis: blood, protein, glucose (for non-dialysis patients and dialysis-dependent 
patients who are not anuric).

Vitamin B12, folate, intact parathyroid hormone, hepcidin and hs-CRP.
The laboratory values will be presented in SI units.
Potential Hy’s law 
The following summaries will include the number (%) of patients who have: Elevated alanine 
aminotransferase (ALT), aspartate aminotransferase (AST), and total bilirubin during the 
study. ALT or AST ≥3×ULN and total bilirubin ≥2×ULN during the study (potential Hy’s 
law): the onset date of ALT or AST elevation should be prior to or on the date of total 
bilirubin elevation.
Liver biochemistry test results over time for patients with elevated ALT or AST (i.e., 
≥3×ULN) and elevated total bilirubin (i.e., ≥2×ULN) at any time will be plotted.
Individual patient data where ALT or AST plus total bilirubin are elevated at any time will be
listed (i.e., ALT and/or AST ≥3×ULN and total bilirubin ≥2×ULN, at any time).
4.3.3.3
Vital signs
Descriptive statistics for vital signs and their changes from baseline at each visit and at the end 
of study will be presented by treatment group for the following variables:  

Tympanic temperature 

Systolic and diastolic blood pressure 


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
Pulse rate 

Respiratory rate 
Blood pressure at baselines is defined as the last non-missing prior to first dose of randomized 
treatment. In the event more than 1 vital sign value is recorded at a certain visit, the average of 
these measurements will be used for analysis. 
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 3 below. The number and 
percentage of subjects with post-baseline PCS values will be tabulated by treatment group. 
Table 3 Criteria for Potentially Clinically Significant Vital Signs
Vital Sign Parameter
Flag
Criteriaa
Observed Value
Change
Systolic Blood Pressure 
(mmHg)
High
≥170
Increase of ≥20
Low
≤90
Decrease of ≥20
Diastolic Blood Pressure 
(mmHg)
High
≥110
Increase of ≥15
Low
≤45
Decrease of ≥15
Pulse Rate (bpm)
High
≥120
Increase of ≥20
Low
≤50
Decrease of ≥20
b
A post-baseline pre-dialysis or post-dialysis value is considered as a PCS value if it meets both criteria for 
observed value and change from pre-dialysis or post-dialysis baseline
4.3.3.4
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. 
Descriptive statistics for ECG variables (PR, QRS, QT, QTcF) will be presented by treatment 
group.
ECG values are PCS if they meet or exceed the upper limit values listed in Table 4 below. The 
number and percentage of subjects with PCS values will be tabulated by treatment group. The 
numerator is the total number of subjects with a PCS ECG value at screening.


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Table 4 Criteria for Potentially Clinically Significant ECG
ECG Parameter
Unit
High Limit
QRS interval
Msec
≥150
PR interval
Msec
≥250
QTc interval
Msec
>500
4.3.3.5
Physical examination 
Incidence of physical examination abnormalities will be summarized for the screening visit by 
treatment group.


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5
INTERIM ANALYSES
No interim analysis specific to this study will be conducted. 


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6
CHANGES OF ANALYSIS FROM PROTOCOL
To account for multiple testing, the Holm-Bonferroni method will be applied for each of the 
secondary endpoints if the primary endpoint is significant p<0.05. This is in the CSP in 
section 9.4.2.1; however, it has been expanded on here. 


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7
REFERENCES
Besarab et al 2016
Besarab A, Chernyavskaya E, Motylev I, Shutov E, Kumbar LM, Gurevich K, et al. 
Roxadustat (FG-4592): Correction of anemia in incident dialysis patients. J Am Soc Nephrol 
2016; 27: 1225-33.
Holm 1979
Holm, S. A simple sequentially rejective multiple test procedure. Scandinavian Journal of
Statistics 1979: 6 (2): 65–70.


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8
APPENDIX 


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Appendix A: TELVC limits for laboratory variables
AZ Safety Review Limits
Laboratory Variable
Unit
Unit
Range
Lower Limit
Higher Limit
Clinical Chemistry
Alanine Aminotransferase  
(ALT)
CV/SI
U/L
Female (18-69 years): 6-34 U/L
Female (>69 years): 6-32 U/L
Male (18-69 years): 6-43 U/L
Male (>69 years): 6-35 U/L 
Alkaline Phosphatase (ALP)
CV/SI
U/L
Female (18-50 years): 31-106 U/L
Female (>50-80 years): 35-123 U/L
Female (>80-90 years): 35-135 U/L
Male (>18 years): 35≈129 U/L
Aspartate Aminotransferase 
(AST)
CV/SI
U/L
Female: 9-34 U/L
Male: 11-36 U/L
Total Bilirubin
CV
mg/dL
0.2-1.2 mg/dL
CCI


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AZ Safety Review Limits
Laboratory Variable
Unit
Unit
Range
Lower Limit
Higher Limit
SI
umol/L
Gamma-Glutamyl Transferase 
(GGT)
CV/SI
U/L
Female (18-59 years): 4-49 U/L
Female (≥60 years): 5-50 U/L
Male (18-59 years): 10-61 U/L
Male (≥60 years): 10-50 U/L
Calcium
CV
mg/dL
8.3-10.6 mg/dL
SI
mmol/L
2.07 - 2.64 mmol/L
CCI


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AZ Safety Review Limits
Laboratory Variable
Unit
Unit
Range
Lower Limit
Higher Limit
Creatinine (Excluding 
measurements taken after 
initiation of dialysis)
CV
mg/dL
Female (18-70 years): 0.4-1.1 
mg/dL
Female (70-80 years): 0.4-1.2 
mg/dL
Female (>80 years): 0.4-1.4 mg/dL
Male (18-50 years): 0.5-1.2 mg/dL
Male (50-70 years): 0.5-1.3 mg/dL
Male (70-80 years): 0.5-1.5 mg/dL
Male (>80 years): 0.5-1.6 mg/dL
SI
umol/L
CCI


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Potassium
CV
mEq/L
3.4-5.4 mEq/L
CCI


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SI
mmol/L
CCI


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AZ Safety Review Limits
Laboratory Variable
Unit
Unit
Range
Lower Limit
Higher Limit
Sodium
CV
mEq/L
18-59 years: 132-147 mEq/L
>59 years: 135-145 mEq/L
SI
mmol/L
18-59 years: 132-147 mmol/L
>59 years: 135-145 mmol/L
Total Protein
CV
g/dL
18-59 years: 6.1-8.4 g/dL
≥60 years: 6.0-8.0 g/dL
CCI


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AZ Safety Review Limits
Laboratory Variable
Unit
Unit
Range
Lower Limit
Higher Limit
SI
g/L
18-59 years: 61-84 g/L
≥60 years: 60-80 g/L
Albumin
CV
g/dL
18-69 years: 3.3-4.9 g/dL
69-80 years: 3.3-4.6 g/dL
>80 years: 3.0-4.6 g/dL
CCI


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AZ Safety Review Limits
Laboratory Variable
Unit
Unit
Range
Lower Limit
Higher Limit
SI
g/L
18-69 years: 33-49 g/L
69-80 years: 33-46 g/L
>80 years: 30-46 g/L
Chloride
CV
mEq/L
94-112 mEq/L
SI
mmol/L
94-112 mmol/L
Magnesium
CV
mg/dL
18-80 years: 1.5-3.1 mg/dL
>80 years: 1.5-2.0 mg/dL
CCI


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AZ Safety Review Limits
Laboratory Variable
Unit
Unit
Range
Lower Limit
Higher Limit
SI
mmol/L
18-80 years: 0.62-1.27 mmol/L
>80 years: 0.62-0.82 mmol/L
Bicarbonate
CV
mEq/L
18-70 years: 17.0-30.6 mEq/L
>70 years: 17.0-32.0 mEq/L
SI
mmol/L
18-70 years: 17.0-30.6 mmol/L
>70 years: 17.0-32.0 mmol/L
Phosphorus
CV
mg/dL
2.2-5.1 mg/dL
SI
mmol/L
0.71-1.65 mmol/L
CCI


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20 NOV 2020
CONFIDENTIAL AND PROPRIETARY
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AZ Safety Review Limits
Laboratory Variable
Unit
Unit
Range
Lower Limit
Higher Limit
Glucose, random
CV
mg/dL
70-100 mg/dL
SI
mmol/L
3.9-5.6 mmol/L
Urea (BUN)
CV
mg/dL
18-70 years: 4-24 mg/dL
70-80 years: 4-29 mg/dL
>80 years: 4-34 mg/dL
SI
mmol/L
0.710-1.65 mmol/L
Lactate dehydrogenase
CV
U/L
53-234 U/L
SI
ukat/L
0.884-3.901
Hematology
CCI


Statistical Analysis Plan 
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D5741C00002 – 2.0
20 NOV 2020
CONFIDENTIAL AND PROPRIETARY
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AZ Safety Review Limits
Laboratory Variable
Unit
Unit
Range
Lower Limit
Higher Limit
Hemoglobin (Hb)
CV
g/dL
Female (12-59 years): 11.6-16.4 
g/dL
Female (≥60 years): 11.5-15.8 g/dL
Male (12-59 years): 12.7-18.1 g/dL
Male (≥60 years): 12.5-17.0 g/dL
Hepcidin, Quant
CV/SI
ng/mL
Highly sensitive C-Reactive 
Protein
CV
mg/dL
CCI


Statistical Analysis Plan 
AstraZeneca
D5741C00002 – 2.0
20 NOV 2020
CONFIDENTIAL AND PROPRIETARY
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AZ Safety Review Limits
Laboratory Variable
Unit
Unit
Range
Lower Limit
Higher Limit
Platelet Count
CV/SI
10^9/L
12-60 years: 140-400 * 10^9/L
>60 years: 130-394 * 10^9/L
White Blood Cell Count 
(Leukocyte/Leucocyte)
CV/SI
10^9/L
3.80-10.70 * 10^9/L
Neutrophils, Particle 
Concentration
CV/SI
10^9/L
1.96-7.23 * 10^9/L
Eosinophils, Particle 
Concentration
CV/SI
10^9/L
0.00-0.57 * 10^9/L
Basophils, Particle 
Concentration
CV/SI
10^9/L
0.00-0.20 * 10^9/L
CCI


Statistical Analysis Plan 
AstraZeneca
D5741C00002 – 2.0
20 NOV 2020
CONFIDENTIAL AND PROPRIETARY
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AZ Safety Review Limits
Laboratory Variable
Unit
Unit
Range
Lower Limit
Higher Limit
Lymphocytes, Particle 
Concentration
CV/SI
10^9/L
18-59 years: 0.91-4.28 * 10^9/L
≥60 years 0.80-3.00 * 10^9/L 
Monocytes, Particle 
Concentration
CV/SI
10^9/L
0.12-0.92 * 10^9/L
Iron Profile
Iron
CV
ug/dL
Female: 30-160 ug/dL
Male: 45-160 ug/dL
SI
umol/L
Female: 5.4-28.6 ug/dL
Male: 8.1-28.6 ug/dL
Transferrin (Fe Binding Sites)
CV
ng/mL
210-450 ug/dL
SI
umol/L
37.6-80.6 umol/L
Ferritin
CV
ng/mL
Female: 11.0-306.8 ng/mL
Male: 23.9-336.2 ng/mL
SI
ug/L
Female: 11.0-306.8 ug/L
Male: 23.9-336.2 ug/L
CCI


Statistical Analysis Plan 
AstraZeneca
D5741C00002 – 2.0
20 NOV 2020
CONFIDENTIAL AND PROPRIETARY
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AZ Safety Review Limits
Laboratory Variable
Unit
Unit
Range
Lower Limit
Higher Limit
Transferrin Saturation 
CV
%
Female: 15-50%
Male: 20-50%
SI
fract 
TIBC
Female: 0.15-0.50
Male: 0.20-0.50
LLN: Lower limit of normal, values provided by the laboratory; ULN Upper limit of normal, values provided by the laboratory
CCI


Statistical Analysis Plan 
AstraZeneca
D5741C00002 – 2.0
20 NOV 2020
CONFIDENTIAL AND PROPRIETARY
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Appendix B: TELVC limits for vital signs
Vital Sign 
Parameter
Unit
Unit
Observed Value
Change from 
Baseline
AZ Safety Review Limits
Systolic Blood 
Pressure
mmHg
High
≥170
Increase of ≥20
Low
≤90
Decrease of ≥20
CCI


Statistical Analysis Plan 
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D5741C00002 – 2.0
20 NOV 2020
CONFIDENTIAL AND PROPRIETARY
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Vital Sign 
Parameter
Unit
Unit
Observed Value
Change from 
Baseline
AZ Safety Review Limits
Diastolic Blood 
Pressure (mmHg)
mmHg
High
≥110
Increase of ≥15
Low
≤50
Decrease of ≥15
Pulse Rate
bpm
High
≥120
Increase of ≥20
CCI


Statistical Analysis Plan 
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D5741C00002 – 2.0
20 NOV 2020
CONFIDENTIAL AND PROPRIETARY
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Vital Sign 
Parameter
Unit
Unit
Observed Value
Change from 
Baseline
AZ Safety Review Limits
Low
≤50
Decrease of ≥20
CCI


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20 NOV 2020
CONFIDENTIAL AND PROPRIETARY
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Appendix C: TELVC limits for ECG
ECG Parameter
Unit
Higher Limit
Change from 
Baseline
AZ Safety Review Limits
QRS interval
Msec
≥150
≥20
PR interval
Msec
≥250
≥20
QTc interval 
Msec
>500
>450
> 30 
> 60
CCI


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