Clinical trial NCT03400033
Conditions: Anaemia
Keywords: CKD, EPO, rhEPO, Hemodialysis dependent, Daprodustat
Sponsor: GlaxoSmithKline
Start date: 2018-09-05; Completion date: 2020-06-19
Enrollment: 407 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This Phase 3 study in hemodialysis-dependent subjects with anemia will evaluate the efficacy and safety of daprodustat administered three-times weekly compared to epoetin alfa, the current standard of care. This study includes a 4 week Screening Period, a 52 week Treatment Period and a 4 to 6 week follow-up period. Each subject will remain in the study for up to 62 weeks. Approximately 402 subjects will be randomized to receive either daprodustat three times weekly or epoetin alfa three-times weekly or once weekly, depending on dose level.

Detailed description:

Arms: arm 1: Subjects randomized to this arm will receive daprodustat tablets titrated doses from 2 to 48 milligrams orally three-times weekly along with saline by IV route for the 52 weeks treatment period. arm 2: Subjects randomized to this arm will receive matching placebo tablets to daprodustat orally three-times weekly and Epoetin alfa by IV route for the 52 weeks treatment period.
Interventions: intervention 1: Daprodustat tablets intervention 2: Matching placebo tablets intervention 3: Epoetin alfa vials intervention 4: Saline vials or bags
Intervention descriptions: intervention 1: Round, biconvex, white, film-coated tablet in unit dose strengths 2 and 4 milligrams (7 millimeter tablets), 6, 8 and 10 milligrams (9 millimeter tablets) administered by the oral route. intervention 2: Matching placebo to daprodustat tablets supplied as round, biconvex, white, film-coated tablet in unit dose strengths 2 and 4 milligrams (7 millimeter tablets), 6, 8 and 10 milligrams (9 millimeter tablets) administered by the oral route. intervention 3: Single-dose, preservative-free vials in unit dose strengths of 2000, 3000, 4000 and 10,000 Units/milliliter administered by the IV route. intervention 4: 0.9% sodium chloride saline vials or bags administered by the IV route.

Protocol documents:
Prot_000.pdf: 
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TITLE PAGE
Protocol Title: A Phase 3 randomized, double-blind, active-controlled, parallel-group, 
multi-center study in hemodialysis participants with anemia of chronic kidney disease to 
evaluate the efficacy, safety and pharmacokinetics of three-times weekly dosing of 
daprodustat compared to recombinant human erythropoietin, following a switch from 
recombinant human erythropoietin or its analogs.
Protocol Number: 204837
Short Title: Anemia Studies in CKD: Erythropoiesis via a Novel PHI Daprodustat-
Three-times weekly dosing in Dialysis (ASCEND-TD)
Compound Number:
GSK1278863
Sponsor Name and Legal Registered Address: 
GlaxoSmithKline Research & Development Limited
980 Great West Road
Brentford
Middlesex, TW8 9GS
UK
Medical Monitor Name and Contact Information: Medical monitor information can 
be found in the Study Reference Manual.
Regulatory Agency Identifying Number(s):
IND Number: 101,291
EudraCT: 2017-004372-56
Approval Date: 15-NOV-2017
Copyright 2017 the GlaxoSmithKline group of companies.  All rights reserved.  
Unauthorized copying or use of this information is prohibited.


PPD
PPD


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TABLE OF CONTENTS
PAGE
1.
SYNOPSIS...............................................................................................................6
2.
SCHEDULE OF ACTIVITIES (SOA).........................................................................9
3.
INTRODUCTION....................................................................................................13
3.1.
Study Rationale ..........................................................................................13
3.2.
Background ................................................................................................14
3.3.
Benefit/Risk Assessment ............................................................................15
3.3.1.
Risk Assessment .........................................................................16
3.3.2.
Benefit Assessment.....................................................................25
3.3.3.
Overall Benefit:Risk Conclusion...................................................25
4.
OBJECTIVES AND ENDPOINTS...........................................................................25
5.
STUDY DESIGN ....................................................................................................30
5.1.
Overall Design ............................................................................................30
5.2.
Number of Participants ...............................................................................31
5.3.
Participant and Study Completion...............................................................31
5.4.
Scientific Rationale for Study Design ..........................................................32
5.5.
Dose Justification for Daprodustat ..............................................................32
6.
STUDY POPULATION...........................................................................................34
6.1.
Inclusion Criteria.........................................................................................34
6.2.
Exclusion Criteria........................................................................................35
6.3.
Lifestyle Restrictions...................................................................................37
6.4.
Screen Failures...........................................................................................37
6.5.
Participant Retention ..................................................................................37
7.
TREATMENTS.......................................................................................................38
7.1.
Treatments Administered............................................................................38
7.2.
Starting Dose and Dose Modification..........................................................39
7.2.1.
Participants Randomized to Daprodustat.....................................40
7.2.1.1.
Daprodustat Starting Dose .........................................40
7.2.1.2.
Daprodustat (and Placebo) Titration Doses ................41
7.2.2.
Participants Randomized to Epoetin Alfa .....................................42
7.2.2.1.
Epoetin Alfa Starting Dose..........................................42
7.2.2.2.
Epoetin Alfa (and Saline) Titration Doses ...................43
7.2.3.
Daprodustat and Epoetin Alfa Dose Adjustment Algorithm ..........44
7.2.4.
Temporary Study Treatment Interruption .....................................46
7.3.
Method of Treatment Assignment ...............................................................46
7.4.
Blinding.......................................................................................................46
7.5.
Preparation/Handling/Storage/Accountability..............................................47
7.6.
Treatment Compliance................................................................................48
7.7.
Concomitant Therapy..................................................................................49
7.7.1.
Permitted Medications and Non-Drug Therapies..........................49
7.7.2.
Prohibited Medications and Non-Drug Therapies.........................49
7.8.
Standard of Care ........................................................................................49
7.8.1.
Iron Management Criteria ............................................................50
7.9.
Rescue Therapy .........................................................................................50


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7.10.
Participants Changing Dialysis Modality .....................................................52
7.11.
Treatment after the End of the Study ..........................................................52
8.
DISCONTINUATION CRITERIA.............................................................................52
8.1.
Discontinuation of Study Treatment ............................................................52
8.1.1.
Procedures Following Discontinuation of Study Treatment ..........53
8.1.2.
Liver Chemistry Stopping Criteria ................................................53
8.1.3.
Study Treatment Restart..............................................................55
8.2.
Withdrawal from the Study..........................................................................55
8.2.1.
Withdrawal of Consent for Contact...............................................56
8.3.
Lost to Follow Up........................................................................................56
9.
STUDY ASSESSMENTS AND PROCEDURES .....................................................57
9.1.
Efficacy Assessments.................................................................................58
9.2.
Adverse Events...........................................................................................58
9.2.1.
Time Period and Frequency for Collecting AE and SAE 
Information...................................................................................58
9.2.2.
Method of Detecting AEs and SAEs.............................................59
9.2.3.
Follow-up of AEs and SAEs.........................................................59
9.2.4.
Regulatory Reporting Requirements for SAEs .............................59
9.2.5.
Events Referred to the Clinical Events Committee.......................60
9.2.6.
Other CV Events..........................................................................60
9.2.7.
Adverse Events of Special Interest ..............................................61
9.2.8.
Possible Suicidality Related Adverse Events ...............................61
9.2.9.
Pregnancy ...................................................................................61
9.3.
Treatment of Overdose...............................................................................62
9.4.
Safety Assessments ...................................................................................62
9.4.1.
Height and Weight .......................................................................63
9.4.2.
Blood Pressure and Heart Rate ...................................................63
9.4.3.
Electrocardiograms......................................................................63
9.4.4.
Ultrasound ...................................................................................64
9.4.5.
Clinical Laboratory Assessments .................................................64
9.5.
Pharmacokinetics .......................................................................................65
9.5.1.
PK Visit........................................................................................66
9.6.
Pharmacodynamics ....................................................................................66
9.6.1.
PD Visit (EPO and VEGF) ...........................................................67
9.7.
Genetics .....................................................................................................67
9.8.
Biomarkers .................................................................................................68
9.9.
Patient Reported Outcomes........................................................................68
9.10.
Participant Feedback Survey ......................................................................68
10. STATISTICAL CONSIDERATIONS........................................................................69
10.1.
Sample Size Determination ........................................................................69
10.1.1.
Sample Size Assumptions ...........................................................69
10.1.2.
Sample Size Sensitivity................................................................70
10.1.3.
Sample Size Re-Estimation or Adjustment...................................70
10.2.
Populations for Analyses ............................................................................70
10.3.
Statistical Analyses.....................................................................................71
10.3.1.
Efficacy Analyses.........................................................................71
10.3.1.1.
Multiplicity Strategy.....................................................73
10.3.2.
Safety Analyses...........................................................................73
10.3.3.
Other Analyses ............................................................................74


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10.3.3.1.
Patient Reported Outcome Analyses..........................74
10.3.3.2.
Pharmacokinetic/Pharmacodynamic Analyses ...........74
10.3.3.3.
Other Exploratory Analyses........................................75
10.3.4.
Interim Analyses ..........................................................................75
11. REFERENCES.......................................................................................................76
12. APPENDICES........................................................................................................78
12.1.
Appendix 1: Abbreviations and Trademarks................................................78
12.2.
Appendix 2: Study Governance Considerations..........................................81
12.2.1.
Regulatory and Ethical Considerations ........................................81
12.2.2.
Financial Disclosure.....................................................................81
12.2.3.
Informed Consent Process ..........................................................81
12.2.4.
Data Protection............................................................................82
12.2.5.
Committees Structure ..................................................................82
12.2.5.1.
Independent Data Monitoring Committee ...................82
12.2.5.2.
Clinical Events Committee..........................................82
12.2.6.
Publication Policy.........................................................................83
12.2.7.
Dissemination of Clinical Study Data ...........................................83
12.2.8.
Data Quality Assurance ...............................................................83
12.2.9.
Source Documents ......................................................................84
12.2.10. Study and Site Closure ................................................................84
12.3.
Appendix 3: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting .......................................86
12.3.1.
Definition of AE............................................................................86
12.3.2.
Definition of SAE..........................................................................87
12.3.3.
Definition of Cardiovascular Events .............................................88
12.3.4.
Recording AE and SAE................................................................88
12.3.5.
Reporting of SAE to GSK.............................................................90
12.4.
Appendix 4: Contraceptive Guidance and Collection of Pregnancy 
Information..................................................................................................92
12.5.
Appendix 5: Genetics..................................................................................95
12.6.
Appendix 6: Liver Safety Required Actions and Follow-up 
Assessments and Study Treatment Restart Guidelines ..............................96
12.6.1.
Liver Safety Required Actions and Follow-up 
Assessments ...............................................................................96
12.6.2.
Liver Safety Study Treatment Restart Guidelines.........................99
12.7.
Appendix 7: Stratification by Region - Region Groupings..........................101
12.8.
Appendix 8: Country-specific requirements...............................................102
12.8.1.
French Administrative Considerations and Specifics
Requirements ............................................................................102
12.8.2.
Country-Specific Requirements for Korea..................................105


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1.
SYNOPSIS
Protocol Title: A Phase 3 randomized, double-blind, active-controlled, parallel-group, 
multi-center study in hemodialysis participants with anemia of chronic kidney disease to 
evaluate the efficacy, safety and pharmacokinetics of three-times weekly dosing of 
daprodustat compared to recombinant human erythropoietin, following a switch from 
recombinant human erythropoietin or its analogs.
Short Title: Anemia Studies in CKD: Erythropoiesis via a Novel PHI Daprodustat-
Three-times weekly dosing in Dialysis (ASCEND-TD)
Rationale:
Based on its mechanism of action to stimulate erythropoiesis via inhibition of hypoxia-
inducible factor (HIF) prolyl hydroxylase enzymes, daprodustat is postulated to be able to 
raise and maintain hemoglobin (Hgb) without inducing the supraphysiologic 
erythropoietin (EPO) concentrations associated with recombinant human EPO (rhEPO)
therapy,
. Currently, there are three ongoing Phase 3 studies evaluating 
the safety and efficacy of once daily daprodustat versus a rhEPO active control. This 
Phase 3 study in hemodialysis-dependent participants with anemia will evaluate the 
efficacy and safety of daprodustat administered three-times weekly compared to epoetin 
alfa, the current standard of care.
Key Objectives and Endpoints:
Objective
Endpoint
Primary

To compare the effect of daprodustat to 
epoetin alfa on Hgb efficacy when 
administered three-times weekly to 
hemodialysis-dependent participants (non-
inferiority)

Mean change in Hgb between baseline and 
over the evaluation period (EP, mean over 
Weeks 28 to 52)
Principal Secondary (tested for superiority, adjusted for multiplicity)

To compare daprodustat administered 
three-times weekly to epoetin alfa on the 
use of intravenous (IV) iron

Average monthly IV iron dose 
(mg)/participant to Week 52 
Safety

To compare the safety and tolerability of 
daprodustat administered three-times 
weekly to epoetin alfa

Incidence and severity of AEs and serious 
adverse events (SAEs) including AEs of 
special interest and MACE
CCI
CCI
CCI


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Objective
Endpoint

Reasons for discontinuation of study 
treatment

Absolute values and changes from baseline 
in laboratory parameters, BP and heart rate 
(HR)
Overall Design:

This is a randomized, double-blind, active-controlled, parallel-group, multi-center 
study in hemodialysis-dependent participants who have anemia of chronic kidney 
disease (CKD) and are currently treated with rhEPO or its analogs.

This study includes a 4-week Screening Period, a 52-week Treatment Period and 
a Follow-up Period. 

The 52-week Treatment Period consists of:

The Stabilization Period (SP), defined as the period from Day 1 to Week 28 
(up to but excluding the Week 28 visit), during which study treatment will 
be dose-titrated to achieve and maintain Hgb in the target range.  

The Evaluation Period (EP), defined as the period from Week 28 to Week 
52, to assess long-term efficacy and safety. The study treatment may be 
dose-titrated, if needed, during this period to achieve or maintain Hgb level 
in the target range.

Randomization will be stratified by region. Following stratification, participants 
will be randomized 2:1 to daprodustat or epoetin alfa.

An external independent Clinical Endpoint Committee (CEC) will conduct 
blinded adjudication of all clinical events reported during this study that meet 
defined clinical definitions.  

Safety oversight will be provided by an external Independent Data Monitoring 
Committee (IDMC).
Number of Participants:
A sufficient number of participants, which is expected to be approximately 800 
participants, will be screened to achieve approximately 402 randomized participants (268 
to daprodustat and 134 to epoetin alfa) and approximately 360 evaluable participants (i.e., 
participants with at least one evaluable Hgb assessment during the EP).
Treatment Groups and Duration:

Each participant will remain in the study for up to 62 weeks, including a 4-week 
screening period, a 52-week treatment period, and a 4 to 6-week follow-up period.  


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
Participants will be randomized to either daprodustat administered three-times 
weekly or epoetin alfa (administered three-times weekly or once weekly, 
depending on dose level). 

Due to the difference in formulations between the investigational product and the 
active control (tablets versus IV injection), and in order to maintain the study 
blind, each participant will receive a tablet and an IV study treatment; one will be 
active and one will be inactive. Participants randomized to receive daprodustat 
will also receive saline IV injection. Participants randomized to receive epoetin 
alfa will also receive placebo tablets.

Adjustment of both study treatments (tablets and IV injection formulation) will 
follow a protocol-specified study treatment dose adjustment algorithm to achieve 
and maintain Hgb within the target range of 10.0 to 11.0 g/dL, inclusive. Dose 
changes will be made programmatically by the Interactive Response Technology 
(IRT) system for both study treatment arms.  

To ensure participants remain iron replete and to minimize the potential for iron 
overload during the study, the investigator will follow the iron management 
criteria from randomization until the end of the study treatment period. 

A rescue algorithm is provided to minimize participants having an inadequate 
response to the treatment for their anemia for an extended period of time and to 
enable consistency in the application of rescue therapy across the study.


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2.
SCHEDULE OF ACTIVITIES (SOA)
Table 1
Schedule of Activities
Procedure
Visit window of ±3 days for Weeks 2 to 8, and ±1 week 
for all other visits.
All visit timings are relative to Day 1.
All assessments will be performed pre-dialysis unless 
otherwise specified. 
Screening 
(Week -4)
Treatment Period: Day 1 through Week 52
Follow-up
Visit
(4 to 6 weeks 
after last dose)
Day 1 1
Full Study Visit 
Week 4, 16, 28, 40
Abbreviated 
Study Visit Week 
2, 6, 8, 12, 20, 24, 
32, 36, 44, 48
Week 52
Unscheduled 2
Informed consent
X
IRT system transaction 3
X
X
X
X
X
X
X
Inclusion and exclusion criteria 
X
X
Randomization 4
X
Study Treatment Dispensing 5, 6
X
X
X 7
X 7
Study Treatment Compliance 6
X
X 7
X
X 7
Participant reminder to report changes in health 8
X
Medical history (including past and current medical 
conditions, hospitalization and transfusion) 9
X 
Demography, height
X
Weight (pre- and post-dialysis) and EDW 10
X
X
X
X
X
X
X
SBP/DBP, HR (pre- and post-dialysis)
X
X (triplicate)
X
X
X (triplicate)
X
X
Kt/Vurea 11
X
X
X
12-lead ECG 12
X
X
Ultrasound of kidneys and adrenal glands 13
X
Estradiol and FSH (females only, if required) 14
X
Serum pregnancy test (WOCBP only) 15, 16
X
X
X
X
X
HemoCue Hgb
X
X
X
X
X
X
Hematology 17
X
X
X
X (Hgb only)
X
X
X
Clinical chemistry 17
X
X
X
X
X
X
Ferritin, total iron and UIBC 17
X
X
X
X
X


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Procedure
Visit window of ±3 days for Weeks 2 to 8, and ±1 week 
for all other visits.
All visit timings are relative to Day 1.
All assessments will be performed pre-dialysis unless 
otherwise specified. 
Screening 
(Week -4)
Treatment Period: Day 1 through Week 52
Follow-up
Visit
(4 to 6 weeks 
after last dose)
Day 1 1
Full Study Visit 
Week 4, 16, 28, 40
Abbreviated 
Study Visit Week 
2, 6, 8, 12, 20, 24, 
32, 36, 44, 48
Week 52
Unscheduled 2
Lipids (non-fasting) 17
X
X
X
iPTH, hsCRP, HbA1c 17, 18
X
Wk 28
X
Hepcidin 17, 19
X
Wk 4, 16, 28
X
PD: EPO, VEGF 17
X
X (once from Wk 28 to Wk 52) 20
PK
X
X (once from Wk 8 to Wk 52) 21
Stored samples for biomarkers 22
X
Wk 28
X
Genetic sample 23
X
Patient Global Impression of Severity (PGI-S) 24
X
Wk 28
Wk 8, 12
X
Patient Global Impression of Change (PGI-C) 24
Wk 28
Wk 8, 12
X
Non-serious AEs, SAEs, AEs of Special Interest, 
clinical events
X 25
X
X
X
X
X
X
Concomitant medication review
X
X
X
X
X
X
X
Iron therapy, transfusions, rescue medications 26, 27
X
X
X
X
X
X
X
Hospitalization or kidney transplant 26
X
X
X
X
X
DBP, diastolic blood pressure; ECG, electrocardiogram; EDW, estimated dry weight; FSH, follicle stimulating hormone; HbA1c, glycated hemoglobin; HR, heart rate; hsCRP, high 
sensitivity C-reactive protein; iPTH, intact parathyroid hormone; PD, pharmacodynamics; PK, pharmacokinetics; SBP, systolic blood pressure; UIBC, unsaturated iron binding capacity; 
VEGF, vascular endothelial growth factor; WOCBP, woman of childbearing potential.
Note: Pre-dialysis assessments should be performed in the following order, where applicable: patient reported outcomes, ECG, BP/HR, blood sample collection.
1.
All assessments to be performed pre-dose.
2.
If additional study treatment is required prior to the next scheduled study visit, it is not necessary to perform the unscheduled visit assessments other than dispensing study 
treatment.  
3.
Study treatment will be dispensed every 4±1 weeks, with the exception that it may be every 2 weeks ± 3 days up to the Week 6 visit. An IRT transaction will be required to 
dispense study treatment. Additional IRT transactions may occur if needed to dispense additional study treatment.
4.
In circumstances where randomization of an eligible participant cannot be completed at the Day 1 visit, the visit may be rescheduled up to 1 week later. Clinical laboratory 
assessments performed at the original visit, no more than 1 week prior, do not need to be repeated, except for the HemoCue hemoglobin and the Q2 hemoglobin.
5.
Study treatment will be dispensed, i.e., allocated to a specific participant, and stored at the dialysis center or research site. Participant may take study treatment tablets at home in 
preparation for PD visit. See Section 7 for further study treatment details.


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6.
In circumstances where a new supply of study treatment (including a new dose) cannot be dispensed on the day of the study visit, the new supply of study treatment can be 
dispensed at the next dialysis session. Prior study treatment should be continued unless on dose interruption, e.g., Hgb ≥12 g/dL. Compliance is deferred until study treatment is 
returned.  
7.
At the Week 2, Week 6 or unscheduled visits, if dose is not changed, new study treatment does not need to be dispensed and use of existing study treatment is continued.
Compliance checking is required if new study treatment is dispensed.
8.
Participant will be instructed to promptly notify site staff in the event of any changes to his or her health. Health changes include new symptoms, medical problems (e.g., 
pregnancy, hospitalization), and medication changes.
9.
Medical history (including CV medical history/risk factors) will be assessed at screening (Week -4). Medical history will be re-assessed at Day 1 to confirm eligibility prior to 
randomization.   
10. Estimated Dry Weight (EDW) to be recorded in the eCRF only at Day 1, full study visits, and Week 52.
11. A historical Kt/Vurea measurement within the last 12 weeks can be used. If a Kt/Vurea measurement is not available, then a urea reduction ratio (URR) measurement is 
acceptable.
12. The Week -4 (screening) ECG must be performed pre-dialysis, and may be performed on any dialysis day from the Week -4 visit to the Day 1 visit, except during the first dialysis 
session of the week. The result of the screening ECG, including physician interpretation, must be available to confirm eligibility prior to randomization. All other ECG assessments 
may be performed either pre- or post-dialysis. See Section 9.4.3.
13. Ultrasound of the kidneys and adrenal glands will be performed between the Week -4 and Day 1 visits. If the results of the kidney and adrenal ultrasound require follow-up testing, 
then the screening period may be extended by 1 additional week. A documented ultrasound of the kidneys within the 6 months prior to screening may be used to assess entry 
criteria, provided the size and cyst category has been reported. If a more sensitive imaging study [e.g., magnetic resonance imaging (MRI), computed tomography (CT)] has been 
performed within this timeframe and a report is available, this may be used in place of the ultrasound. See Section 9.4.4.
14. Only required to confirm menopausal status if in question.
15. Repeat pregnancy test prior to study treatment re-administration if study treatment was interrupted for >7 days and there was also a lapse in contraceptive use, regardless of the 
reason for the interruption.
16. In Argentina only, pregnancy testing will be performed every 4 weeks for WOCBP as required by local law.
17. See details for laboratory assessments in Section 9.4.5.
18. HbA1c assessment is applicable only for participants with diabetes on Day 1 or diagnosed during the study.
19. At each visit specified in the table, a hepcidin sample will be collected prior to dosing with either study treatment and prior to administration of any iron supplementation.
20. Post-baseline PD samples (i.e., EPO and VEGF) may be taken during any week from Week 28 to Week 52, inclusive, preferably at the earliest opportunity. See Section 9.6 for 
additional details and requirements for the collection of PD samples.
21. Post-baseline PK samples will be taken at any one of the post-baseline visits indicated in the table, preferably at the earliest opportunity. See Section 9.5 for additional details and 
requirements for the collection of PK samples.
22. Biomarker samples will be collected and stored for potential future analysis for all participants, except if not permitted by local regulations or IRB/EC, or refused by participant.
23. Participation in genetics research is optional. A separate informed consent signature is required for participation. See Section 9.7 for additional details.
24. Participants who are unable to or require assistance to read must not complete the questionnaires. See Section 9.9 for additional details.
25. Only SAEs, which are assessed as related to study participation or a GlaxoSmithKline (GSK) product, are collected at this visit. See Section 9.2.1 for additional details.
26. Record in the eCRF, if applicable.
27. See details on Rescue in Section 7.9.


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Table 2
Schedule of Activities for Participants Who Permanently Discontinue Study Treatment
Procedure 
Early Treatment Discontinuation Visit 
(within 2 weeks of discontinuing study 
treatment)
Day 1 through Week 52 1
Week 4, 16, 28, 40, 52 ± 2 weeks
Un-scheduled
IRT system transaction
X
X
X
SBP/DBP, HR (pre- and post-dialysis)
X (triplicate)
X
X
12-lead ECG 2
X
Iron therapy, transfusions 3
X
X
X
Serum pregnancy test (WOCBP only)
X 4
HemoCue Hgb
X
X
X
Hematology 5
X
X
Clinical chemistry 5
X
X
Ferritin, total iron, UIBC, lipids, iPTH 5
X
Hospitalization, kidney transplant 3
X
X
X
Non-serious AEs, SAEs, AEs of Special Interest, 
clinical events
X
X
X
Review concomitant medications
X
X
X
PGI-S and PGI-C 6
X
1. Participants will attend those study visits up to Week 52 which have not been completed at the time of early treatment discontinuation. Phone visits are acceptable in exceptional 
circumstances.
2. ECG assessment may be recorded pre- or post-dialysis.
3. Record in the eCRF, if applicable.
4. Additional pregnancy test required at subsequent visit. Must be at least 4 weeks after the end of study treatment.
5. See details for laboratory assessments in Section 9.4.5.
6. Participants who are unable to or require assistance to read must not complete the questionnaires. See Section 9.9 for additional details.


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3.
INTRODUCTION
Daprodustat (GSK1278863) is a hypoxia-inducible factor prolyl hydroxylase inhibitor 
(HIF-PHI). Daprodustat is currently being investigated as a treatment for anemia of
chronic kidney disease (CKD) in both dialysis and non-dialysis participants. Previously 
conducted clinical trials have shown adequate safety and efficacy of daprodustat for up to 
24 weeks with doses up to 12 mg administered once daily and for up to 29 days with
doses up to 30 mg administered three-times weekly. Both pre-clinical and clinical data 
show that daprodustat stimulates erythropoietin (EPO) production, increases
erythropoiesis resulting in elevation of hemoglobin (Hgb) concentrations. These increases 
in Hgb are achieved with peak EPO exposures substantially lower than those observed 
with recombinant human erythropoietin (rhEPO) using either once daily or three-times 
weekly dosing schedules. Data from completed clinical and pre-clinical studies are 
provided in the Daprodustat Investigator’s Brochure (IB) [GSK Document Number 
RM2008/00267/08] and IB Supplements, if applicable.
Study 204837 is designed to match to the extent possible the once daily daprodustat 
cardiovascular (CV) outcomes study in dialysis-dependent participants [Study ID 
200807, GSK Document Number 2015N226659_05], in order to evaluate the three-times 
weekly regimen under conditions that are comparable to those in the once daily study. A 
separate analysis is planned that will utilize the data obtained from the larger CV
outcomes study in dialysis-dependent participants receiving once daily daprodustat and 
the same active comparator, epoetin alfa, to compare and assess the safety of three-times 
weekly daprodustat. 
3.1.
Study Rationale
Based on its mechanism of action to stimulate erythropoiesis via inhibition of HIF-prolyl 
hydroxylase enzymes, once daily daprodustat is postulated to be able to raise and 
maintain Hgb without inducing the supraphysiologic EPO concentrations associated with 
rhEPO therapy,
Currently, there are three ongoing Phase 3 studies evaluating 
the safety and efficacy of once daily daprodustat versus a rhEPO active control, and the 
rationale for conducting study 204837 is to determine if the safety and efficacy of 
daprodustat is similar when administered three-times weekly.
A recently completed Phase 2A clinical trial in hemodialysis-dependent participants with 
anemia showed that three-times weekly, orally administered daprodustat increases Hgb 
levels with a corresponding transient increase in EPO concentration over 29 days in 
participants switched from rhEPO or its analogs [Study ID 204836, GSK Document 
Number 2016N309671_00]. Furthermore, a Phase 2B clinical trial in hemodialysis-
dependent participants with anemia showed that once daily, orally administered 
daprodustat can maintain Hgb up to 24 weeks, also with plasma EPO concentration
within the physiological range [Study ID PHI113633, GSK Document Number
2014N219785_00]. Both three-times weekly administered daprodustat for 29 days and 
once daily administered daprodustat for up to 24 weeks displayed an adverse event (AE) 
CCI
CCI
CCI


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profile consistent with that expected for this patient population. Data from completed 
clinical studies are provided in the Daprodustat IB and IB Supplements, if applicable.
This Phase 3 study in hemodialysis-dependent participants with anemia will evaluate the 
efficacy and safety of daprodustat administered three-times weekly compared to epoetin 
alfa, the current standard of care.
In most clinical studies to date, daprodustat has been administered employing a once
daily regimen. However, several cost analysis studies have shown less frequent dosing of 
rhEPO and its analogs is economically beneficial with hemodialysis patients in both the 
US and Europe [Stephens, 2016; Burnier, 2009]. Since standard practice in many 
countries is to administer rhEPO and its analogs three-times weekly to match in-center
dialysis sessions, this study will assess the safety and efficacy of daprodustat 
administered three-times weekly to accommodate this less frequent dosing schedule. This 
study aims to demonstrate that daprodustat dosed three-times weekly is effective for 
maintaining Hgb in hemodialysis (HD) participants switched from rhEPO or its analogs. 
3.2.
Background
Anemia is a common complication of CKD. The cause of anemia in this population is 
multi-factorial, including relative or absolute deficiency of EPO, reduced iron availability 
related to chronic inflammation or acute infection, and gastrointestinal blood loss. 
Anemia is further exacerbated by shortened erythrocyte survival that is associated with 
the uremic milieu and hemodialysis procedure.
Current treatments for anemia of CKD include supplemental iron therapy (intravenous 
and/or oral), the use of rhEPO and its analogs, and blood transfusions. While existing 
therapies are useful and effective in treating anemia, they each have significant 
limitations.

Iron: Poor compliance is seen with oral iron therapy due to gastrointestinal 
intolerance and IV iron may have an increased risk of infection, congestive heart 
failure, iron overload or anaphylaxis [Agarwal, 2015]. 

rhEPO: In order to achieve target Hgb levels, which are lower than normal Hgb 
levels, treatment with IV rhEPO markedly increases EPO plasma concentrations 
to higher than normal levels. Treatment with rhEPOs has been associated with 
increased cancer-related morbidity and mortality and increased risk of major 
cardiovascular events (e.g., stroke, myocardial infarction and all-cause 
mortality) [FDA, 2011].

Blood transfusions: These are avoided when possible because of potential 
alloimmunization which can preclude the possibility of receiving a kidney 
transplant and risk of infection. 
Thus there is an unmet need for a safer alternative for treatment of anemia of CKD. 
Current clinical and nonclinical data suggest that daprodustat has the potential to provide 
similar or better efficacy to approved therapies with the potential for an improved safety 
profile, most notably compared to rhEPO and its analogs.


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3.3.
Benefit/Risk Assessment
A summary of the findings from clinical and non-clinical studies of daprodustat as well 
as more detailed information about the known and expected benefits and risks of
daprodustat may be found in the Daprodustat IB and IB Supplements, if applicable.


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3.3.1.
Risk Assessment
The potential risks of clinical significance and the mitigation strategies for this protocol taking into account the results of completed 
clinical and nonclinical studies with daprodustat are outlined below.  In addition to the mitigation strategies outlined, an IDMC will 
monitor accruing safety data for this trial (Section 12.2.5.1).
Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Daprodustat
Excessive erythropoiesis (polycythemia) leading to 
thrombosis and/or tissue ischemia
In animal studies, excessive erythropoiesis attributed to 
daprodustat was associated with vascular 
congestion/inflammation, microthrombi, and tissue 
ischemia in a number of organs.
Phase 2 dose-ranging studies, and associated statistical 
and exposure response modelling has informed Phase 3 
dose rationale, starting doses, dose steps, and dose 
adjustment scheme to optimize Hgb management.
Following review of clinical data received to date, this has 
not been identified as a safety concern for daprodustat.

Specific eligibility criteria related to requirements for 
entry Hgb are detailed in Section 6.1 and Section 
6.2.

Hgb will be closely monitored throughout the dosing 
period as outlined in the SoA in Section 2.

Specific guidance for dose adjustment, dose 
interruption, or discontinuation of daprodustat based 
on achieved Hgb (including rate of change) is 
provided in Section 7.2 and Section 8.1.

Unblinded monitoring of safety data by an IDMC in-
stream throughout the study.
Death, MI, stroke, heart failure, thromboembolic events, 
thrombosis of vascular access at Hgb levels which are 
within the normal range (i.e. not polycythemic conditions)
Marketed rhEPO and its analogs have been associated 
with an increased risk for death and serious cardiovascular 
events when used in patients with anemia of CKD.
In non-clinical studies, similar events were not observed at 
tolerated doses when hemoglobin/hematocrit within normal 
range for species.
The clinical data received to date are insufficient to 
conclude or refute this risk.

Specific eligibility criteria related to CV risk are 
outlined in Section 6.2.

Hgb will be closely monitored throughout the dosing 
period as outlined in the SoA in Section 2.

Unblinded monitoring of safety data by an IDMC in-
stream throughout the study.


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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Esophageal and gastric erosions
In animal studies, undesirable GI effects including emesis, 
abnormal feces and/or decreased food consumption/body 
weight loss and stomach erosions/ ulcers with hemorrhage 
were observed with daprodustat.  
In rats, stomach erosions were observed with intravenous 
and oral administration of daprodustat.
Stomach erosions/ulcers also reported in rats with 
marketed rhEPOs and its analogs.
In clinical trials to date with daprodustat, mild-moderate GI 
signs and symptoms represent the most frequently 
reported AE, however causal association has not been 
established.
Following review of clinical data received to date, GI 
erosions have not been identified as a safety concern for 
daprodustat.

Suspected GI bleeding or significant symptoms 
consistent with erosions or ulcers should be 
investigated diagnostically (i.e. endoscopic 
examination) as clinically warranted.

Unblinded monitoring of safety data by an IDMC 
instream throughout the study.
Cancer-related mortality and tumor progression and 
recurrence
Marketed rhEPO and its analogs have been associated 
with increased risk of cancer related morbidity and 
mortality when used in patients with cancer.
Administration of 60mg/kg daprodustat to mice caused 
minimal increases in circulating VEGF while significant 
EPO increases were observed.
There were no test article-related neoplastic findings in 2-
year rat (oral daprodustat) or mouse (daprodustat + 
subcutaneous injection of the 3 major human metabolites; 
M2, M3 and M13) carcinogenicity studies.
In clinical studies conducted to date, administration of 
daprodustat has been associated with:

Specific eligibility criteria related to personal history 
of malignancy or participants with complex kidney 
cyst are outlined in Section 6.2.

Stopping criteria for participants with treatment 
emergent malignancy are outlined in Section 8.1.

Unblinded monitoring of safety data by an IDMC 
instream throughout the study.


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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Once daily administration:

In studies up to 4-weeks duration, a dose-ordered 
increase in VEGF plasma concentrations was 
observed at doses ranging from 10 to 150 mg. 

In studies up to 24-weeks duration at doses up to 
25mg, changes in VEGF plasma concentration were 
variable but similar relative to control.

Systemic EPO concentrations within the physiologic 
range.
Three times weekly administration:

In studies up to 4-weeks duration at doses of 10 to 30 
mg:
o
Dose dependent increases in plasma VEGF 
and EPO concentrations were observed.
o
Pre-dose concentrations of EPO and VEGF 
were near or below baseline indicating no 
accumulation of EPO or VEGF after three 
times weekly dosing.
Following review of clinical data received to date, this has 
not been identified as a safety concern for daprodustat. 
Pulmonary artery hypertension (PAH)
A role for HIF-regulated pathways in the pathophysiology 
of PAH has been suggested based on well established 
effects of acute and chronic hypoxia in man on the 
pulmonary vasculature (vasoconstriction), and by findings 
in patients with naturally occurring mutations that result in 
decreased HIF degradation [Smith, 2006; Formenti, 2011].
There have been no histopathologic findings suggestive of 
PAH in pre-clinical safety studies with daprodustat (up to 
13-weeks duration in dogs, up to 2 years in rats and mice, 

Unblinded monitoring of safety data by an IDMC in-
stream throughout the study.


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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
and up to 39 weeks in monkeys.
Acute hypoxic challenge (rats):  Daprodustat produced 
increases in peak right ventricular pressure (PRVP) during 
acute hypoxia that were slightly higher than the vehicle 
control group. However, these hypoxia-induced PRVP 
changes were within the range of PRVP changes noted 
among untreated rats.
Results from a clinical study of acute hypoxic challenge in 
healthy volunteers demonstrated that short-term (5 days) 
therapy with daprodustat 5mg or 100mg has no clinically 
significant effect on transthoracic echocardiographic
(ECHO) estimates of pulmonary artery systolic pressure 
(PASP) under either normoxic or hypoxic conditions.
ECHO assessments performed in Phase 2b studies (24-
weeks treatment duration) did not identify any clinically 
meaningful changes in PASP in participants not on dialysis 
for daprodustat. In hemodialysis participants, mean 
absolute change from baseline in PASP was similar for 
both treatment groups; however, there was a numeric 
imbalance (Daprodustat: 8 [7%]; Control 0) in participants 
reaching the PASP PCI (>20 mmHg increase from 
baseline). Regarding this imbalance, there were a number 
of confounding factors in the study, most notably a 4.5:1 
randomization scheme and inconsistency in timing of 
ECHOs relative to dialysis day.  Additionally, 2 of 3 
participants with resolution of PASP on safety follow-up 
ECHOs had confounding conditions that could contribute 
to resolution other than discontinuation of study treatment; 
and there was no dose relationship for participants meeting 
the PASP PCI criterion. Overall, there is insufficient 
evidence to conclude a relationship to treatment with 
daprodustat.


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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Following review of clinical data received to date, this has 
not been identified as a safety concern for daprodustat.   
Cardiomyopathy
Published data suggest that cardiac effects of HIF 
stabilization are likely a function of the mechanism, extent, 
and duration of the effects, and can range from protective 
to detrimental depending upon the specific model and 
experimental conditions utilized.
With lifetime exposure to daprodustat in a 2-year rat oral 
carcinogenicity study, an exacerbation of rat spontaneous, 
progressive cardiomyopathy (PCM) (focal myofiber 
degeneration/necrosis with inflammatory infiltrates) was 
observed at doses of 0.8 mg/kg/day and above, although 
total incidence and severity distribution within any 
daprodustat-group were within historical control ranges.
This is consistent with an equivocal threshold for 
exacerbation of spontaneous, progressive cardiomyopathy 
at 0.8 mg/kg/day which is also the threshold dose for 
observing increased Hct values in individual rats.
Cardiomyopathy has not been associated with naturally 
occurring mutation in man which results in increased HIF 
stabilization.
ECHO assessments performed in phase 2b studies (24-
weeks treatment duration) did not identify any clinically 
meaningful changes in LVEF for daprodustat.
Following review of clinical data received to date, this has 
not been identified as a safety concern for daprodustat.

Unblinded monitoring of safety data by an IDMC in-
stream throughout the study.
Proliferative retinopathy, macular edema, choroidal 
neovascularization
Increases in local (ocular) VEGF production with retinal 
neovascularization and macular edema observed in 
diabetic retinopathy and to choroidal leakage, edema and 
neovascularization seen in age-related macular 

Unblinded monitoring of safety data by an IDMC in-
stream throughout the study.


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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
degeneration [Campochiaro, 2006].
Administration of 60 mg/kg daprodustat to mice caused 
minimal increases in circulating VEGF while significant 
EPO increases were observed.
Aside from congestion of retinal vessels and optic disc 
hyperemia secondary to markedly increased red cell mass, 
there were no ocular abnormalities observed in non-clinical 
trials.  
In clinical studies up to 4-weeks duration, a dose-ordered 
increase in VEGF plasma concentrations was observed at 
doses ranging from 10 to 150 mg administered once daily 
and from 10 to 30 mg administered three times weekly. In 
studies up to 24-weeks duration at doses up to 25 mg, 
changes in VEGF plasma concentrations were variable but 
similar relative to control.
Ophthalmologic assessments performed in phase 2b 
studies (24-weeks treatment duration) did not identify any 
clinically meaningful changes in proliferative retinopathy, 
macular edema, or choroidal neovascularization with 
daprodustat.
Following review of clinical data with daprodustat received 
to date, this has not been identified as a safety concern for 
daprodustat.
Exacerbation of rheumatoid arthritis
In inflamed rheumatic joints, activation of HIF- related 
genes secondary to decreased oxygen and pro-
inflammatory cytokines has been postulated to contribute 
to the neo-angiogenesis, proliferation and infiltration of 
rheumatoid synovial fibroblasts [Westra, 2010; Muz, 2009].

Unblinded monitoring of safety data by an IDMC in-
stream throughout the study.


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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
No abnormalities seen in non-clinical studies conducted to 
date for daprodustat.
Following review of clinical data received to date, this has 
not been identified as a safety concern for daprodustat.
Drug-drug interactions
Daprodustat is a substrate of CYP2C8: Co-administration 
of daprodustat with a strong CYP2C8 inhibitor (gemfibrozil)
increased the Cmax and AUC of daprodustat, 4- and 19-
fold, respectively, while co-administration of a weak 
inhibitor (trimethoprim) increased the Cmax and AUC of 
daprodustat by 1.3- and 1.5-fold, respectively. Population 
PK analysis from completed Phase 2 studies suggests that 
co-administration of daprodustat with a moderate CYP2C8 
inhibitor (clopidogrel) leads to a ~2-fold increase in AUC, 
with no clinically-significant increase in the measured Hgb 
response.  
Although CYP2C8 induction studies were not performed, 
co-administration of daprodustat with an inducer of 
CYP2C8 (e.g., rifampin/rifampicin) may decrease the 
exposure of daprodustat. 
Although co-administration of daprodustat with strong 
inhibitors and inducers of CYP2C8 is prohibited, 
inadvertent co-administration may occur.  Due to the 
known time delay in enhancing erythropoiesis by 
daprodustat, co-administration with strong CYP2C8 
inhibitors for up to 14 days is not anticipated to lead to 
immediate marked increases in hemoglobin levels. 
Therefore, there is adequate time to change to alternate 
therapy that does not inhibit CYP2C8. Additionally, as the 
time for maximum induction of CYP2C8 occurs 
approximately 10-14 days of dosing with rifampin [Brodie, 

Co-administration of daprodustat with strong 
CYP2C8 inhibitors (e.g., gemfibrozil) and inducers 
(e.g., rifampin/rifampicin) is not permitted as outlined 
in Section 7.7.2.

Co-administration of daprodustat with moderate 
CYP2C8 inhibitors (i.e., clopidogrel, teriflunomide, 
deferasirox) should be performed with caution. If 
one of these medications is started, stopped or the 
dose is changed, Hgb should be monitored every 4 
weeks for 12 weeks as outlined in Section 7.7.1.

Co-administration of daprodustat with BCRP 
inhibitors [e.g., cyclosporine, HIV antivirals 
(atazanavir, lopinavir, ritonavir, tipranavir), lapatanib 
and curcumin] is not expected to produce clinically 
relevant increases in daprodustat exposure; 
however, periodic monitoring of hemoglobin will be 
performed as outlined in the SoA in Section 2 and 
specific guidance for dose adjustment or 
discontinuation is provided in Section 7.2 and 
Section 8.1.

Specific guidance on the management of potential 
drug-drug interactions and concomitant medications 
is provided in Section 7.7.

Hgb will be closely monitored throughout the dosing 


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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
2013; Ohnhaus, 1989], daprodustat systemic exposure will 
decrease over time which will result in a lag period before 
an effect on Hgb is recognized and is of clinical concern.
Daprodustat is an inhibitor of CYP2C8: A clinical drug 
interaction study between 25mg and 100mg daprodustat 
with a CYP2C8 substrate (pioglitazone) showed that there 
is no PK interaction at these doses of daprodustat. 
Daprodustat is a substrate of BCRP: Population PK 
analysis from Phase 2 studies suggested that while BCRP 
inhibitors were a covariate for daprodustat CL/F (8.6% 
lower clearance) the predicted change in exposure was not 
considered to be of clinical relevance. 
Daprodustat is an inhibitor of OATP1B1/1B3: A clinical
drug interaction study between 25mg and 100mg 
daprodustat with an OATP1B1/1B3 substrate 
(rosuvastatin) showed that there is no PK interaction at 
these doses of daprodustat.
period as outlined in the SoA in Section 2.

Specific guidance for dose adjustment, dose 
interruption, or discontinuation of daprodustat based 
on achieved Hgb is provided in Section 7.2 and
Section 8.1.

Unblinded monitoring of safety data by an IDMC in-
stream throughout the study.
Other
rhEPO risks (Control)
See risks outlined in table for daprodustat for excessive 
erythropoiesis (polycythemia) leading to thrombosis and/or 
tissue ischemia, death, MI, stroke, heart failure, 
thromboembolic events, thrombosis of vascular access, 
and for cancer-related mortality and tumor progression.
Uncontrolled hypertension
Pure red cell aplasia

See mitigation strategies outlined in table for 
daprodustat for excessive erythropoiesis 
(polycythemia) leading to thrombosis and/or tissue 
ischemia; death, MI, stroke, heart failure, 
thromboembolic events, thrombosis of vascular 
access; and for cancer-related mortality and tumor 
progression.

Specific eligibility criteria related to current 
uncontrolled hypertension are outlined in Section 6.2.

Specific eligibility criteria related to personal history of 


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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
pure red cell aplasia are outlined in Section 6.2.


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3.3.2.
Benefit Assessment
Study participants may benefit from the clinical efficacy that is expected with daprodustat 
based on previous trials with once daily dosing of daprodustat for up to 24 weeks and 
three-times weekly dosing of daprodustat for up to 29 days. Daprodustat may present 
several important advantages over rhEPO and its analogs. It is an oral medication and 
does not require cold-chain storage, as does rhEPO, thus increasing ease of use for 
patients and health care providers. After administration of three-times weekly
daprodustat, data suggest that equivalent increases in Hgb are achieved with EPO 
exposure lower than those observed with rhEPO. Treatment of anemia of CKD with 
rhEPO is associated with increased CV risk which is postulated to be related to the 
associated increases in EPO exposure with rhEPO [Szczech, 2008];
, 
. Other potential benefits include possibly improving iron 
availability for erythropoiesis, the potential to successfully treat rhEPO hyporesponders, 
and the potential to treat anemia without inducing rhEPO related hypertension.
3.3.3.
Overall Benefit:Risk Conclusion
Daprodustat demonstrates a positive benefit versus risk based on the evidence as follows. 
In clinical trials up to 24 weeks in duration, daprodustat treats Hgb to target range with a 
safety profile consistent with the patient population.
This protocol employs precautions to mitigate known and potential risks to enrolled 
participants (See Section 3.3.1). Given these precautions, as well as the potential benefit 
that daprodustat holds for the treatment of anemia of CKD compared to the current 
standard, the overall benefit risk balance is considered to be positive.
4.
OBJECTIVES AND ENDPOINTS
Objectives
Endpoints
Primary

To compare the effect of daprodustat to 
epoetin alfa on Hgb efficacy when 
administered three-times weekly to 
hemodialysis-dependent participants (non-
inferiority)

Mean change in Hgb between baseline 
and over the evaluation period (EP, mean 
over Weeks 28 to 52)
Principal Secondary (tested for superiority, adjusted for multiplicity)

To compare daprodustat administered 
three-times weekly to epoetin alfa on the 
use of intravenous (IV) iron

Average monthly IV iron dose 
(mg)/participant to Week 52 
Safety

To compare the safety and tolerability of 
daprodustat administered three-times 

Incidence and severity of AEs and serious 
adverse events (SAEs) including AEs of 
CCI
CCI
CCI


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Objectives
Endpoints
weekly to epoetin alfa
special interest and MACE

Reasons for discontinuation of study 
treatment

Absolute values and changes from 
baseline in laboratory parameters, BP and 
heart rate (HR)
Secondary (endpoints tested for superiority1, with no multiplicity adjustment)

To compare the effect of daprodustat 
administered three-times weekly to epoetin 
alfa on Hgb variability

Hgb change from baseline to Week 52 1

% time Hgb in analysis range (10 to 
11.5 g/dL) during the EP 1

N (%) responders, defined as mean Hgb 
within the Hgb analysis range 10 to 11.5 
g/dL during the EP

To compare daprodustat administered 
three-times weekly to epoetin alfa on the 
time to rescue

Time to stopping study treatment due to 
meeting rescue criteria

To compare the effect of daprodustat 
administered three-times weekly to epoetin 
alfa on BP

Change from baseline in SBP, DBP and 
mean arterial pressure (MAP) at Week 52 
and at the end of study treatment

Number of BP exacerbation events per 100 
patient years 

N (%) with at least one BP exacerbation 
event during study

To generate pharmacokinetic parameters 
of daprodustat and predominant 
metabolites following three-times weekly
dosing 

Plasma daprodustat, M2, M3, M4, M5, M6 
and M13 PK parameters pre-dose trough 
(Ctau) and Cmax

To compare daprodustat administered 
three-times weekly to epoetin alfa on 
global symptom severity and change

Change from Baseline at Weeks 8,12, 28, 
and 52 in PGI-S
Exploratory (no statistical testing planned)

To evaluate graphical relationships 
between exposure parameters and 
selected efficacy endpoints of daprodustat 
administered three-times weekly

Extrapolated Cmax of daprodustat vs. the 
percent time within the Hgb target range 
during the EP

Extrapolated Cmax of daprodustat vs. 
mean Hgb over the 52-week treatment 
period


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Objectives
Endpoints

Mean weekly daprodustat dose over 52 
weeks vs. the percent time within the Hgb 
target range during the EP

Mean weekly daprodustat dose over 52 
weeks vs. mean Hgb over the 52-week 
treatment period

To evaluate graphical relationships 
between daprodustat administered three-
times weekly against MACE and the 
combined safety endpoint of MACE + 
thromboembolic event + hospitalization for 
Congestive Heart Failure (CHF)

Extrapolated Cmax of daprodustat in 
participants without MACE compared to 
those with MACE (as well as for the 
combined safety endpoint of MACE + 
thromboembolic event + hospitalization for 
CHF) 

Mean weekly daprodustat dose in 
participants without MACE compared to 
those with MACE (as well as for the 
combined safety endpoint of MACE + 
thromboembolic event + hospitalization for 
CHF)

To compare the effect of daprodustat 
administered three-times weekly to epoetin 
alfa on BP and BP medication changes  

Observed and change from baseline in 
SBP, DBP and MAP by visit

Number of BP medications per participant 
by visit

Change from baseline in the number or 
dose of BP medications per participant by 
visit

N (%) of participants who had no change in 
the number or dose of BP medications 
from baseline by visit

N (%) of participants who had an increase 
in the number or dose of BP medications 
from baseline by visit 

N (%) of participants who had a decrease 
in the number or dose of BP medications 
from baseline by visit

To further compare the effect of 
daprodustat administered three-times 
weekly to epoetin alfa on Hgb variability

Hgb observed and change from baseline 
across all visits 

% of time Hgb is above, within and below 
the analysis range of 10 to 11.5 g/dL 
during the EP

Number (%) of participants with mean Hgb 


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Objectives
Endpoints
above, within and below the Hgb analysis 
range during the EP 

Number (%) of participants with a Hgb 
<7.5 g/dL during the EP

Number of times Hgb <7.5 g/dL during the 
EP

Number (%) of participants with a >1 g/dL 
increase in Hgb within any 2-week period 
(assessed at Week 2 through Week 8), or 
with a >2 g/dL increase in Hgb within any 
4-week period up to Week 52

Number (%) of participants with a >1 g/dL 
decrease in Hgb within any 2-week period 
(assessed at Week 2 through Week 8), or 
with a >2 g/dL decrease in Hgb within any 
4-week period up to Week 52

N (%) of participants with a Hgb value 
≥12 g/dL during the EP

Number of times Hgb ≥12 g/dL during the 
EP

% of time Hgb ≥12 g/dL during the EP

To compare the effect of daprodustat 
administered three-times weekly to epoetin 
alfa on measures of iron parameters

Observed and change from baseline in 
hepcidin, ferritin, transferrin saturation
(TSAT), total iron, total iron binding 
capacity (TIBC) across all visits 

Average quarterly ferritin

Average quarterly TSAT

Average quarterly IV iron dose/participant

N (%) of participants who met iron 
management criteria

N (%) of participants who reduced IV iron 
supplementation relative to baseline 
[defined as total iron (mg) over 4 weeks 
prior to randomization] during EP [defined 
as average monthly IV iron dose (mg) over 
Weeks 28 to 52]

To compare the effect of daprodustat 
administered three-times weekly to epoetin 
alfa on the need for red blood cell (RBC)

Number (%) of participants who receive at 
least one RBC or whole blood transfusion 


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Objectives
Endpoints
and whole blood transfusions
by Week 52

Number of RBC and whole blood
transfusions per 100 patient years 

Number of RBC and whole blood units per 
100 patient years

Characterize the pharmacodynamic (PD) 
effect of daprodustat administered three-
times weekly on EPO, vascular endothelial 
growth factor (VEGF) and RBC

Maximum observed change from baseline 
in EPO 

Maximum observed % change from 
baseline in VEGF

Change from baseline in hematocrit, RBC 
count, and reticulocyte count 

To compare the effect of daprodustat 
administered three-times weekly to epoetin 
alfa on lipid parameters. 

Observed and % change from baseline in 
lipid parameters by visit [total cholesterol, 
direct low density lipoprotein cholesterol 
(LDL-C), high density lipoprotein cholesterol 
(HDL-C)]

To evaluate the daprodustat dose 
adjustment scheme 

Assigned dose by visit and at Day 1, Week 
28, and Week 52

Most recent dose prior to Week 28, Week 
52 and end of study treatment

Number (%) of participants with 0, 1, 2, or 
>2 dose adjustments during the following 
periods:
o
Day 1 to < Week 28
o
Week 28 to < Week 52
o
Day 1 to < Week 52

Number of dose adjustments during the 
following periods:
o
Day 1 to < Week 28
o
Week 28 to < Week 52
o
Day 1 to < Week 52

Number of dose adjustments per year 
during Day 1 to < Week 52

Time dose held for Hgb ≥12 g/dL

To further compare daprodustat 
administered three-times weekly to epoetin 
alfa on global symptom severity and 
change

Shift tables (Baseline to Weeks 8, 12, 28, 
and 52) in PGI-S

N (%) of participants within each PGI-C 
symptom change level at Weeks 8, 12, 28, 
and 52
Conversion from g/dL to g/L is 1:10 and from g/dL to mmol/L is 0.6206.  For example, Hgb of 10.0 to 11.0 g/dL is 
equivalent to 100 to 110 g/L or 6.2 to 6.8 mmol/L.


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1.
Hgb change from baseline to Wk 52 is tested for non-inferiority, using the -0.75 g/dL margin used in the primary 
analysis. % time in range is tested first for non-inferiority, then for superiority. The non-inferiority margin for % time 
in range will be defined in the RAP.
5.
STUDY DESIGN
5.1.
Overall Design

This is a randomized, double-blind, active-controlled, parallel-group, multi-center 
study in hemodialysis-dependent participants, including combination methods
such as hemodiafiltration or hemofiltration with HD, who have anemia of CKD 
and are currently treated with rhEPO or its analogs.

This study includes a 4-week Screening Period, a 52-week Treatment Period and 
a Follow-up Period (Figure 1). 

The 52-week Treatment Period consists of:

The Stabilization Period (SP), defined as the period from Day 1 to Week 28
(up to but excluding the Week 28 visit), during which study treatment will 
be dose-titrated to achieve and maintain Hgb in the target range.  

The Evaluation Period (EP), defined as the period from Week 28 to Week 
52, to assess long-term efficacy and safety. The study treatment may be 
dose-titrated, if needed, during this period to achieve or maintain Hgb level 
in the target range.
Figure 1
Study Schematic

Each participant will remain in the study for up to 62 weeks. Participants who 
permanently discontinue study treatment will remain in the study.  


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
Randomization will be stratified by region (see Appendix 7). Following 
stratification, participants will be randomized 2:1 to daprodustat or epoetin alfa. 
Daprodustat will be administered three-times weekly and epoetin alfa will be 
administered once weekly or three-times weekly, depending on dose level 
(Section 7).

Due to the difference in formulations between the investigational product and 
active control (tablets versus IV injection), and in order to maintain the study 
blind, each participant will receive a tablet and an IV study treatment; one will be 
active and one will be inactive (Section 7). Participants randomized to receive 
daprodustat will also receive saline IV injection. Participants randomized to 
receive epoetin alfa will also receive placebo tablets.

PK samples will be collected from all study participants to enable exposure-
response and exposure-safety analyses (Section 9.5).

Adjustment of both study treatments (tablet and IV injection formulations) will 
follow a protocol-specified study treatment dose adjustment algorithm to achieve 
and maintain Hgb within the target range of 10.0 to 11.0 g/dL, inclusive (Section 
7.2). Dose changes will be made programmatically by the Interactive Response 
Technology (IRT) system for both study treatment arms.

To ensure participants remain iron replete and to minimize the potential for iron 
overload during the study, the investigator will follow the iron management 
criteria from randomization until the end of the study treatment period (Section 
7.8.1). 

A rescue algorithm is provided to minimize participants having an inadequate 
response to the treatment for their anemia for an extended period of time and to 
enable consistency in the application of rescue therapy across the study (Section 
7.9). 

An external independent Clinical Endpoint Committee (CEC) will conduct 
blinded adjudication of all clinical events reported during this study that meet 
defined clinical definitions as outlined in Section 9.2.5. 

Safety oversight will be provided by an external Independent Data Monitoring 
Committee (IDMC) (Section 12.2.5.1).
5.2.
Number of Participants
A sufficient number of participants, which is expected to be approximately 800 
participants, will be screened to achieve approximately 402 randomized participants (268 
to daprodustat and 134 to epoetin alfa) and approximately 360 evaluable participants (i.e., 
participants with at least one evaluable Hgb assessment during the EP). 
5.3.
Participant and Study Completion
A participant is considered to have completed the study if he or she has completed all 
study periods through the Week 52 visit. A participant who dies while on study is also 
considered to have completed the study.


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Completion of the Treatment Period will also be captured, and will be distinct from study 
completion.
The end of the study is defined as the date of the last visit of the last participant in the 
study or last scheduled procedure shown in the SoA or study contact for the last 
participant in the study globally, whichever is later.
5.4.
Scientific Rationale for Study Design

This study includes a Week -4 Screening Visit prior to randomization (Day 1). 
The screening period permits time to assess eligibility based on laboratory 
assessments and ultrasound evaluation.

The total treatment period will be 52 weeks in order to allow sufficient time to 
demonstrate efficacy. The SP from Day 1 to Week 28 allows participants to have 
their study treatment dose titrated to achieve the Hgb target range. This period of 
time provides the best opportunity for participants to be titrated to their optimal 
dose of study treatment prior to the EP, from Week 28 to Week 52. A percentage 
of participants may still need dose titration during the EP.

The selection of rhEPO as the active control (epoetin alfa) is based on clinical 
practice in the majority of participating countries. 

This study will be conducted in a double-blind fashion. Each participant will 
receive oral tablets (either daprodustat or matching placebo) and IV injections
(either epoetin alfa or saline). Each participant will receive one active study 
treatment and one inactive study treatment, depending upon the treatment arm to 
which the participant is randomized. See Section 7.2 for further information about
study treatment. Because it was not feasible to create a matching placebo/saline 
vial for the active control (epoetin alfa), the study treatment IV injections (either 
epoetin alfa or saline) will be prepared and administered by an unblinded nurse, or 
other properly qualified individual(s), in a manner that will maintain the blind.  
Further information about blinding considerations are presented in Section 7.4.

Participants will be randomized in a 2:1 ratio to daprodustat or epoetin alfa. More 
participants will be randomized to daprodustat compared to epoetin alfa in order 
to obtain an adequately sized safety database of HD patients exposed to 
daprodustat administered three-times weekly for a longer duration (i.e., over a 52-
week treatment period).
5.5.
Dose Justification for Daprodustat
Clinical practice (standard of care) in the treatment of anemia in CKD patients on HD 
often utilizes a three-times weekly regimen consistent with their hemodialysis schedule. 
GSK proposes to assess this regimen as part of the planned Phase 3 clinical program in 
hemodialysis patients.
In addition to administration on a three-times weekly dosing schedule, extended interval 
dosing (i.e., weekly to monthly) is also routinely used with rhEPO and its analogs. 


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Evidence with epoetin alfa (Epogen), with Dosing and Administration guidance for three-
times weekly dosing, has shown that increases in dosing interval (i.e., extended time 
between doses) can be achieved by a proportionate increase in the dose administered at 
each interval. As reported in a small study, epoetin alfa was administered subcutaneously 
at either 50 IU/kg three-times weekly, 10,000 IU/week, 20,000 IU every two weeks or 
40,000 IU every 4 weeks with consistent management of Hgb levels for all 4 regimens in 
anemia patients with CKD not on dialysis [McGowan, 2008]. As the daprodustat dose 
response with Hgb is generally linear between 4 and 24 mg once daily, it is anticipated 
that a similar time-proportional efficacy relationship will exist for daprodustat and the 
management of Hgb levels as the dosing is extended from once every day to three-times 
weekly. These data suggest that the efficacy of PHIs is most likely related to total dose or 
AUC, rather than Cmax or Cmin. Additionally, the time to reach the steady-state 
response is determined by the RBC lifespan which on average is 2 to 3 months.
Daprodustat starting doses were selected to reach the target Hgb concentration after 
approximately one RBC lifespan of treatment (almost 3 months, pharmacodynamic 
steady-state), without the need for any individual dose adjustments. However, due to the 
between-subject variability in Hgb response to a given dose of daprodustat, and the 
relatively narrow Hgb target range, individual dose adjustments of daprodustat are 
expected during the first few months of treatment. If an individual dose adjustment is 
necessary, the participant’s daprodustat dose will be increased or decreased through a 
series of dose steps, one dose step at a time.
The daprodustat starting doses and dose steps from the once daily Phase 3 study (200807) 
were selected based on exposure-response longitudinal modeling of Hgb data collected 
across the Phase 2 program and these doses serve as the foundation for the three-times 
weekly doses in this study. Similar to the Phase 3 study, the starting doses will be 
assigned based on the participant’s prior dose of rhEPO or its analogs at study entry. 
Covariate analyses elucidated that baseline Hgb, body-weight, and prior dose of rhEPO 
and its analogs were the most relevant covariates of Hgb response to daprodustat. 
Simulations showed the effect of body-weight was not clinically important for dosing, so 
the relationship between prior dose of rhEPO and its analogs and response was used to 
determine starting doses of daprodustat relative to a participant’s prior dose of rhEPO and 
its analogs.  These findings apply to daprodustat administered three-times weekly as well, 
and therefore prior dose of rhEPO or its analogs will also be used in the determination of 
the starting dose in the current study.
The once daily doses used in the 200807 study were converted to corresponding three-
times weekly doses using the estimated dose conversion ratio of approximately 2.0 that 
was determined in the Phase 2A three-times weekly daprodustat dose ranging study 
(204836). The dose conversion ratio was estimated by taking the ratio of three-times 
weekly daprodustat dose corresponding to the once daily dose that produced an 
equivalent Hgb response. Several approaches were explored to estimate the dose 
conversion ratio and the three-parameter Bayesian Emax dose-response models produced 
the most consistent estimates across the studied dose range. The ratio of approximately 
2.0 estimated by this approach was used to calculate the three-times weekly doses.


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The resultant three-times weekly starting doses of 8, 12, 16 and 24 mg were calculated by 
multiplying the once daily dosing algorithm by the conversion ratio estimated in study 
204836. These doses are estimated to maintain equivalent Hgb concentrations to that 
achieved in the participants on prior rhEPO therapy and its analogs. The actual starting 
dose for each participant will be individualized based upon their prior therapy of rhEPO 
or its analogs. The highest available dose of daprodustat in the dose adjustment scheme is 
48 mg administered three-times weekly.
Starting doses, dose steps, and elements of the dose adjustment scheme are provided in 
Section 7.2.
6.
STUDY POPULATION
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted.
6.1.
Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria 
apply at screening (Week -4) and randomization (Day 1), unless otherwise specified:
1.
Age: Participant must be 18 to 99 years of age inclusive, at the time of signing the 
informed consent.
Note: Country-specific age requirements for Korea are provided in Appendix 8, 
Section 12.8.2.
2.
RhEPO or its analogs: Use of any approved rhEPO or analog for at least 8 weeks 
prior to the screening visit and continuing during the screening period until 
randomization (Day 1). 
3.
Hemoglobin concentration (measured by HemoCue) within the following range: 
Hgb Range (inclusive)
Week -4

Hgb 8 to 11.5 g/dL1 (5 to 7.1 mmol/ L).

If Hgb is 11.6 to 11.9 g/dL2 (7.2 to 7.4 mmol/L), up to two retests are allowed; the 
retest value must be between 8 to 11.5 g/dL1 (5 to 7.1 mmol/ L).
Day 1

Hgb 8 to 11 g/dL1 (5 to 6.8 mmol/L) and receiving at least the minimum rhEPO or 
analog dose 3.

Hgb >11 to 11.5 g/dL1 (6.8 to 7.1 mmol/L) and receiving greater than the minimum 
rhEPO or analog dose 3. 
1.
Conversion from g/dL to g/L is 1:10, e.g., Hgb of 8 to 10 g/dL is equivalent to 80 to 100 g/L. 
2.
The first retest will use the original Week -4 blood sample. If the retest value is >11.5 g/dL, one additional
retest can be performed using a new blood sample on the study visit day. The final retest value is entered 
into the IRT system. Retests will be done prior to dialysis.
3.
Minimum rhEPO or analog dose: Epoetins (including biosimilars): 1500 units (U)/week intravenous (IV) 
or 1000 U/week subcutaneous (SC); Darbepoetin alfa: 20 g/4 weeks SC/IV; Methoxy PEG-Epoetin: 
30 g/month SC/IV.


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4.
Dialysis: On hemodialysis (including hemofiltration or hemodiafiltration) >90 days 
prior to screening and continuing during the screening period. 
5.
Frequency of Dialysis: On hemodialysis (in-center) ≥3 times per week.
6.
Sex: Male and female participants are eligible. A female participant is eligible to 
participate if she is not pregnant (see Appendix 4), not breastfeeding, and at least one 
of the following conditions applies:

Not a woman of childbearing potential (WOCBP) as defined in Appendix 4, or

A WOCBP who agrees to follow the contraceptive guidance in Appendix 4 from 
at least 28 days prior to first dose of study treatment and for at least 28 days
after the last dose of study treatment.
7.
Informed Consent: Capable of giving signed informed consent as described in 
Appendix 2 which includes compliance with the requirements and restrictions listed 
in the informed consent form (ICF) and in this protocol.
Note: Country-specific requirements for France for the informed consent process are 
provided in Appendix 8 (see Section 12.8.1, Item 3 for details).
8.
Other Study Eligibility Criteria Consideration: In France, a participant will be 
eligible for inclusion in this study if he or she is either affiliated to or beneficiary of a
social security category. 
Note: Country-specific requirements for France for inclusion in this study are 
provided in Appendix 8 (see Section 12.8.1 Item 1 for details).
6.2.
Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply at 
screening (Week -4) and at randomization (Day 1), unless otherwise specified:
CKD Related Criteria
1.
Kidney transplant: Planned living-related or living-unrelated kidney transplant 
within 52 weeks after randomization (Day 1).
Anemia Related Criteria
2.
Ferritin: ≤100 ng/mL (≤100 µg/L), at screening.
3.
Transferrin saturation (TSAT): ≤20%, at screening. If TSAT is 18 to 20%, then a 
retest using a new blood sample can be obtained within 7 days of the final laboratory 
report; the final retest value must be >20% to confirm eligibility.
4.
Aplasias: History of bone marrow aplasia or pure red cell aplasia.
5.
Other causes of anemia: Conditions, other than anemia of CKD, which can affect 
erythropoiesis.  A partial list can be found in the Study Reference Manual (SRM).


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Cardiovascular Disease
6.
MI or acute coronary syndrome within 8 weeks prior to screening through to 
randomization (Day 1).
7.
Stroke or transient ischemic attack within 8 weeks prior to screening through to 
randomization (Day 1).
8.
Heart failure (HF): Chronic Class IV HF, as defined by the New York Heart 
Association (NYHA) functional classification system. 
9.
Current uncontrolled hypertension as determined by the investigator that would 
contraindicate the use of rhEPO.
10. Bazett’s correction of QTc interval (QTcB) at Day 1: QTcB >500 msec, or QTcB 
>530 msec in participants with bundle branch block.  There is no QTc exclusion for 
participants with a predominantly ventricular paced rhythm.
Other Medical Conditions
11. Liver Disease: presence of any one of the following liver-related laboratory values 
or conditions, at screening, is exclusionary:

Alanine transaminase (ALT) >2x upper limit of normal (ULN);

Bilirubin >1.5x ULN; or
NOTE: Isolated bilirubin >1.5x ULN is acceptable if bilirubin is fractionated and 
direct bilirubin <35%.

Current unstable liver or biliary disease per investigator assessment, generally 
defined by the presence of ascites, encephalopathy, coagulopathy, 
hypoalbuminaemia, esophageal or gastric varices, persistent jaundice, or 
cirrhosis.
NOTE: Stable chronic liver disease (including asymptomatic gallstones, chronic 
hepatitis B or C, or Gilbert’s syndrome) are acceptable if participant otherwise meets 
entry criteria.
12. Gastrointestinal (GI) bleeding: Evidence of actively bleeding gastric, duodenal or 
esophageal ulcer disease OR clinically significant GI bleeding ≤ 8 weeks prior to 
screening through to randomization (Day 1).
13. Malignancy: History of malignancy within 2 years prior to screening through to 
randomization (Day 1), currently receiving treatment for cancer, or complex kidney 
cyst (e.g., Bosniak Category IIF, III or IV) >3 cm. 
Note: The only exception is localized squamous cell or basal cell carcinoma of the 
skin that has been definitively treated 8 weeks prior to screening.
Prior/Concomitant Therapy
14. Drugs and supplements: Use of a strong inhibitor of CYP2C8 (e.g., gemfibrozil) or 
a strong inducer of CYP2C8 (e.g., rifampin/rifampicin).


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Prior/Concurrent Clinical Study Experience
15. Severe allergic reactions: History of severe allergic or anaphylactic reactions or 
hypersensitivity to excipients in the investigational product (refer to daprodustat IB), 
or epoetin alfa (refer to product labeling).
16. Other interventional study participation: Use of another investigational agent 
within 30 days or within five half-lives of the investigational agent (whichever is 
longer) or currently participating in a study of an investigational device prior to 
screening through to randomization (Day 1).
17. Prior treatment with daprodustat: Any prior treatment with daprodustat for 
treatment duration of >30 days.
Other Exclusions
18. Other Conditions: Any other condition, clinical or laboratory abnormality, or 
examination finding that the investigator considers would put the participant at 
unacceptable risk, which may affect study compliance (e.g., intolerance to rhEPO) or 
prevent understanding of the aims or investigational procedures or possible 
consequences of the study.
6.3.
Lifestyle Restrictions
There are no lifestyle restrictions required for this study. Any restrictions of concomitant 
medications and non-drug therapies are described in Section 7.7.2.
6.4.
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study 
but are not subsequently randomized. A minimal set of screen failure information is 
required to ensure transparent reporting of screen failure participants 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 SAEs.
Participants who do not meet the criteria for participation in this study (i.e., screen 
failure) may be rescreened up to two additional times as soon as the investigator assesses 
they may meet eligibility criteria. Participants who are to be rescreened must sign a new 
informed consent form and will be assigned a new participant number. The association 
between the initial/prior screening participant number and the new participant number 
must be documented.
6.5.
Participant Retention

Participants will be educated on the importance of remaining in the study and 
attending scheduled study visits.

Investigators should make every effort to keep participants in the study, including 
those participants who have permanently discontinued study treatment. 


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
Should a participant fail to attend the clinic for a required study visit, the site should 
attempt to contact the participant and re-schedule the missed visit as soon as 
possible. The site should also counsel the participant on the importance of 
maintaining the assigned visit schedule. In cases where the participant does not 
return for the rescheduled visit, or cannot be reached to reschedule the missed visit, 
the site should make every effort to regain contact with the participant. The 
investigator (if allowed by local regulations) should obtain the name and phone 
number of a relative or friend to assist in contacting the participant.
7.
TREATMENTS
Study treatment is defined as the investigational treatment or marketed product (i.e., 
daprodustat, matching placebo tablets, epoetin alfa or saline) intended to be administered 
to a study participant according to the study protocol.  
7.1.
Treatments Administered
GSK will provide the following study treatments: daprodustat and matching placebo 
tablets and epoetin alfa. Saline will be obtained locally. Study treatments are described in
Table 3.  
Table 3
Description of Study Treatments
Study 
Treatment 
Name:
Daprodustat
Matching Placebo 
Tablets
Epoetin alfa
Saline
Dosage 
formulation:
Round, biconvex, 
white, film-coated 
tablet
Round, biconvex, 
white, film-coated 
tablet
Single-dose, 
preservative-free 
vials
Saline for IV use 
vials or bags
Unit dose 
strengths/ 
Dosage levels:
Unit dose strengths: 
7 mm tablets: 2 and 
4 mg
9 mm tablets: 6, 8 
and 10 mg
Dosage levels: 2, 4, 
8, 12, 16, 20, 24, 32 
and 48 mg
Dosages of 12 mg
and greater will be 
provided using 
multiples of available 
tablet strengths. 
Details are provided 
in Table 5.
7mm tablets to 
match 2 and 4 mg 
daprodustat tablets
9 mm tablets to 
match the 6, 8 and 
10 mg daprodustat
tablets
Dosage details are 
provided in Table 5.
Unit vial strengths: 
2000, 3000, 4000 
and 10,000 Units/mL
Dosage level details 
are provided in Table 
6.
0.9% sodium 
chloride 
Saline for IV use will 
be obtained locally; 
vial or bag size will 
vary.
Dosage details are 
provided in Table 6.


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Participants will discontinue their therapy with rhEPO or its analogs prior to 
randomization so that the randomization date (Day 1) coincides, as closely as possible, 
with the date of next scheduled administration of rhEPO or analog. Examples of 
switching will be provided in the SRM.
All study treatments should be taken in the clinic, with the exception that the blinded 
study treatment tablets may be taken at home prior to the study visit at which PD samples 
will be collected (see Section 9.6). The site must ensure that the date and time the 
participant took each dose of study treatment is documented. Participants will be given 
diary cards to record the date and time of any study treatment tablets taken at home. 
Additional instructions can be found in the SRM.
7.2.
Starting Dose and Dose Modification
Participants will be randomized to receive either daprodustat or epoetin alfa.  
Route of 
Administration 
Oral
Oral
Intravenous
Intravenous
Dosing 
instructions:
Participants will be 
dispensed the 
prescribed number of 
tablets. 
The dose will be 
administered on a 
dialysis day, and 
may be given before, 
during or after the 
dialysis session. 
Participant may take 
dose at home prior to 
PD sampling visit.
Participants will take 
tablets with water 
and can be taken 
without regard to 
food.
Participants will be 
dispensed the 
prescribed number 
of tablets. 
The dose will be 
administered on a 
dialysis day, and 
may be given before, 
during or after the 
dialysis session. 
Participant may take 
dose at home prior 
to PD sampling visit.
Participants will take 
tablets with water 
and can be taken 
without regard to 
food.
Site staff will 
withdraw the 
prescribed dose from 
each single-use vial 
into a syringe. 
Multiple vials may be 
required to achieve 
the prescribed dose. 
The dose will be 
administered to the 
participant during the 
dialysis session.
Site staff will 
withdraw the 
prescribed dose into 
syringe(s). 
The dose will be 
administered to the 
participant during the 
dialysis session.
Packaging and 
Labeling
Tablets will be 
provided in white, 
opaque high density 
polyethylene (HDPE) 
bottles with child-
resistant closures. 
Each bottle will be 
labeled as required 
per country 
requirement. 
Tablets will be 
provided in white, 
opaque high density 
polyethylene (HDPE)
bottles with child-
resistant closures. 
Each bottle will be 
labeled as required 
per country 
requirement.
Epoetin alfa will be 
provided in single-
use, preservative-
free vials. Each vial 
will be labeled as 
required per country 
requirement.
Not applicable 
(Saline for IV use will 
be obtained locally.)
Manufacturer
GlaxoSmithKline
GlaxoSmithKline
Janssen
Not available (Saline 
for IV use will be 
obtained locally) 


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In order to maintain the treatment blind, each participant will be administered both tablets 
and IV injections, with one formulation containing active study treatment and the other 
formulation being an inactive treatment. Refer to Section 7.4 for additional information 
regarding blinding.
Participants who are randomized to the daprodustat arm will receive the required number 
of daprodustat tablets to achieve the prescribed dosage of daprodustat based upon the 
starting dose and dose adjustment algorithms (see Section 7.2.1), and the required 
number of syringes with saline for IV administration to achieve the prescribed inactive 
treatment (see Section 7.2.2.2). 
Participants who are randomized to the epoetin alfa arm will receive the required number 
of vials of epoetin alfa to achieve the prescribed dosage of epoetin alfa based upon the 
starting dose and dose adjustment algorithms (see Section 7.2.2), and the required 
number of placebo tablets to achieve the prescribed inactive treatment (see Section 
7.2.1.2).  
The dose of both study treatments will be adjusted, based on the algorithm in Section 
7.2.3, in order to maintain Hgb concentrations in the target range. Any required dose 
adjustments should be started on the day of the study visit at which the dose adjustment 
was prescribed. In circumstances where a new supply of study treatment (including a new 
dose) cannot be dispensed on the day of the study visit, the new supply of study treatment 
can be dispensed at the next dialysis session, and the prior study treatment should be 
continued unless on a dose interruption.
7.2.1.
Participants Randomized to Daprodustat
Participants who are randomized to the daprodustat treatment arm will receive
daprodustat tablets and saline IV. A starting dose will be assigned for daprodustat as 
described in Table 4. A starting dose will be assigned for saline, following the algorithm 
described for epoetin alfa in Section 7.2.2.1. Dose levels will be titrated for both the 
active and inactive study treatments, and new containers dispensed for each treatment 
with each change in dose.  
7.2.1.1.
Daprodustat Starting Dose
The starting dose of daprodustat will be assigned based on prior rhEPO or analog dose at 
randomization, Day 1 (Table 4).


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Table 4
Daprodustat Starting Dose
  RhEPO or Analog Dose at Randomization (Day 1)
Daprodustat 
Dose
Epoetins (including biosimilars)
(U/week IV) 1
Darbepoetin
(g/4week SC/IV) 2
Methoxy PEG-Epoetin beta
(g/month SC/IV) 3, 4
(mg, three-
times weekly)
1500 to 2000 
20 to 30
30 to 40 
8
> 2000 to < 10000 
>30 to 150 
>40 to 180
12
10,000 to < 20000 
>150 to 300 
>180 to 360 
16
20,000  
>300   
>360   
24
PEG=polyethylene glycol
1.
Standardized rhEPO IV dose (U/week) = 161/113 * (epoetin SC dose (units) / (frequency) [Beserab, 2002]
2.
Conversion of 250 U:1 g (epoetin IV:darbepoetin alfa) utilized and rounded to the nearest available dose 
strength [Sterner, 2008] 
3.
Conversion of 1:1.2 g (darbepoetin alfa:methoxy PEG-epoetin beta) utilized and rounded to the nearest 
available dose strength  [Choi, 2013] 
4.
Conversion of 208 U:1 g (epoetin IV: methoxy PEG-epoetin beta)
7.2.1.2.
Daprodustat (and Placebo) Titration Doses
The available dose steps of daprodustat are outlined below (gray toned boxes indicate 
possible starting doses). Dose adjustments will result in the daprodustat dose being 
increased or decreased by one dose step at a time, as described in the dosing algorithm 
(Table 7). Participants who are receiving the highest dose of daprodustat (48 mg) and
require an additional dose increase, will maintain the same dose. Participants who are 
receiving the lowest dose of daprodustat (2 mg) and require an additional dose decrease
will receive placebo (0 mg) in order to maintain the blind. When a dose interruption is 
required by the dosing algorithm (Table 7), both daprodustat tablets and saline injections 
will be interrupted in order to maintain the blind.
Participants who are randomized to daprodustat treatment will also receive inactive 
treatment for the IV formulation (saline IV).  When a dose adjustment is required for 
these participants, their saline IV dose will be adjusted (in addition to the daprodustat 
dose) in order to maintain the blind, such that the number of syringes of saline to be 
administered match the number of vials/syringes required for the new corresponding 
epoetin alfa dose (Section 7.2.2.2, Table 6).


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Table 5
Tablet Combinations to Achieve Prescribed Daprodustat or Placebo
Treatment
Dosage 
Level 1
(mg)
Total 
Number 
of 
Tablets
Active Treatment for Daprodustat Randomized 
Participants 
Inactive (Placebo) 
Treatment for Epoetin 
Alfa Randomized 
Participants
7 mm 
Placebo
2 mg 
Dapro
4 mg 
Dapro
6 mg 
Dapro
8 mg 
Dapro
10 mg 
Dapro
7mm 
Placebo
9 mm 
Placebo
0
1
1
1
2
1
1
1
4
1
1
1
8
1
1
1
12
2
2
2
16
2
2
2
20
2
2
2
24
3
3
3
32
4
4
4
48
6
6
6
1.
Dose to be administered three-times weekly 
7.2.2.
Participants Randomized to Epoetin Alfa
Participants who are randomized to the epoetin alfa treatment arm will receive placebo 
tablets and epoetin alfa IV. A starting dose will be assigned for epoetin alfa as described 
in Section 7.2.2.1. A starting dose will be assigned for placebo, following the algorithm 
described for daprodustat in Table 4, and as shown in Table 5. Dose levels will be titrated 
for both the active and inactive study treatments, and new containers dispensed for each 
treatment with each change in dose.
7.2.2.1.
Epoetin Alfa Starting Dose
The starting dose(s) for participants receiving epoetin alfa are as follows:

For participants with a Day 1 Hgb ≤11.0 g/dL:

For participants already on epoetin alfa the starting dose will be the same as 
their currently scheduled dose, rounded to the nearest available study treatment 
dose. 

For participants receiving rhEPO analogs, the starting dose will be an IV epoetin 
alfa equivalent dose rounded to the nearest available study treatment dose. 
(Refer to Table 4 for conversion factors to determine equivalent epoetin alfa 
doses.)

For participants with a Day 1 Hgb >11.0 g/dL and 11.5g/dL:

For participants already on epoetin alfa the starting dose of IV epoetin alfa will 
be reduced from their current scheduled dose, rounded to the nearest study 
treatment dose, to the next lower available dose with the aim of maintaining Hgb 
within the range of 10.0 to 11.0 g/dL.


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
For participants receiving rhEPO analogs, the starting dose of IV epoetin alfa 
will be reduced from their current scheduled rhEPO analog equivalent dose, 
rounded to the nearest study treatment dose, to the next lower available dose of 
IV epoetin alfa with the aim of maintaining Hgb within the range of 10.0 to 11.0 
g/dL. (Refer to Table 4 for conversion factors to determine equivalent epoetin 
alfa doses.)
7.2.2.2.
Epoetin Alfa (and Saline) Titration Doses
Pre-defined dose steps of epoetin alfa are outlined in Table 6. Dose adjustments of
epoetin alfa will be made by increasing or decreasing the dose one step at a time, as 
described in the dosing algorithm (Table 7).  The epoetin alfa dose steps consist of a 
weekly dose change between 20 to 33% for most steps, except for an increase to a weekly 
dose of 3000 U, which is a 50% increase, or an increase to doses of 21,000 U per week or 
greater, which represent increases of approximately 10 to 15%.
Participants who are receiving the highest dose of epoetin alfa (i.e., 60,000 U/week) and 
require a dose increase will maintain the same dose. Participants who are receiving the 
lowest available dose of epoetin alfa (i.e., 1500 U/week IV) and require a dose decrease
will receive saline in order to maintain the blind. When a dose interruption is required by 
the dosing algorithm (Table 7), both epoetin alfa and placebo tablets will be interrupted 
in order to maintain the blind.
Participants who are randomized to epoetin alfa treatment will also receive inactive 
treatment for the tablet formulation (placebo tablets). When a dose adjustment is required 
for these participants, their placebo tablet dose will be adjusted (in addition to the epoetin 
alfa dose) in order to maintain the blind, such that placebo tablets matching the new 
corresponding daprodustat dose will be administered (Table 5).
Additional information about the delivery of the respective epoetin alfa doses is provided 
in the SRM.


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Table 6
Number of Vials and Vial Combinations to Achieve Prescribed 
Epoetin Alfa or Saline Treatment
Total 
Weekly 
Dose
(Units)
Dose and Frequency
Epoetin Alfa Randomized Participants 1
Inactive (Saline)
Treatment for 
Daprodustat 
Randomized 
Participants
Saline 3
(1 mL)
2000 U/ 
1mL
3000 U/ 
1mL
4000 U/ 
1mL
10000 U/ 
1mL
Saline 3
(1 mL)
0
0 U once a week
1
1
1500 4
1500 U once a week
0.75
0.75
2000
2000 U once a week
1
1
3000
3000 U once a week
1
1
4000
4000 U once a week
2
2
5000
5000 U once a week
1
1
2
6000
6000 U once a week
1
1
2
8000
8000 U once a week
2
2
10,000
10,000 U once a week
1
2
3
12,000
4000 U three times a week
1
1
15,000
5000 U three times a week
1
1
2
18,000
6000 U three times a week
1
1
2
21,000
7000 U three times a week
1
1
2
24,000
8000 U three times a week
2
2
27,000
9000 U three times a week
1
1
1
3
30,000
10,000 U three times a week
1
1
36,000
12,000 U three times a week
1
1
2
42,000
14,000 U three times a week
1
1
2
48,000
16,000 U three times a week
1
1
1
3
60,000
20,000 U three times a week
2
2
1.
The vial combinations used to achieve a specific weekly dose of epoetin alfa (and number of saline syringes for 
the corresponding inactive dose) may be adjusted by the sponsor based on changes to the commercial availability 
of epoetin alfa or other supply considerations. Any change to the vial combinations will be made globally across 
the study in order to maintain the blind, and it will be managed centrally through the IRT system. Details of any 
changes will be detailed in the SRM.
2.
Each epoetin alfa vial should be administered using a separate syringe.
3.
For saline doses, the number of ‘vials’ indicated in the table refers to the number of syringes containing 1 mL of 
saline that will be administered in order to maintain the blind.
4.
The 1500 U epoetin alfa dose will be achieved by administering 0.75 mL of a 2000 U/mL vial. The corresponding 
1500 U saline dose, for daprodustat randomized participants, will be achieved by administering 0.75 mL of saline.
7.2.3.
Daprodustat and Epoetin Alfa Dose Adjustment Algorithm
The dose adjustment algorithm for both daprodustat and epoetin alfa is provided in Table 
7. Dose adjustments, i.e., increase, decrease, maintain, or interrupt if Hgb ≥12g/dL, will 
be determined programmatically for both the daprodustat and epoetin alfa arms by an 
Interactive Response Technology (IRT) system to maintain Hgb concentrations within 
the range of 10.0 to 11.0 g/dL based on the HemoCue Hgb value measured every 2 or 4 
weeks, as specified in the SoA, and entered into the IRT by the Investigator or site staff.  


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When a dose adjustment is indicated, the dose of the active and inactive treatments will 
be titrated in order to maintain the blind, as described in Section 7.2.1 and Section 7.2.2.
Table 7
Study Treatment Dose Adjustment Schemes
HemoCue Hgb (g/dL) 
at current study visit 1
HemoCue Hgb change since last 
study visit 1
Randomized Treatment Dose 
Adjustment 5
<7.5 2
Any change
Repeat Hgb and average values 6; if 
confirmed, increase to the next higher 
dose step
7.5 to <9.5
Decreasing or No change 7
Increase to the next higher dose step   
7.5 to <9.5
Increasing 8
Maintain dose 
≥9.5 to <10 at two 
consecutive visits 
Decreasing or No change
Increase to the next higher dose step
≥9.5 to ≤11.5 
Any change 
Maintain dose 
>11 to ≤11.5 at two 
consecutive visits 
Increasing or No change
Decrease to the next lower dose step
>11.5 to <12 
Decreasing 
Maintain dose
>11.5 to <12
Increasing or No change
Decrease to the next lower dose step
12 3
Any change  
Repeat Hgb and average values 6; if 
confirmed, temporarily interrupt the dose 
and re-check Hgb at next study visit 1; 
restart at one dose step lower when Hgb 
<11.5 g/dL and provided it has been at 
least 2 weeks from the prior study visit.
Any 
>2 g/dL increase over 4 weeks
(>1 g/dL increase over 2 weeks 4)
Repeat Hgb and average values 6; if 
confirmed, decrease to the next lower 
dose step
Any
>2 g/dL decrease over 4 weeks
(>1 g/dL decrease over 2 weeks 4)
Repeat Hgb and average values 6, if 
confirmed, increase to the next higher 
dose step
1. Study visit refers to scheduled visits, i.e., every 2 weeks until Week 8, and then every 4 weeks through Week 52.  
2. This rule applies to any scheduled visit or unscheduled visit, provided it has been at least 2 weeks from the prior 
study visit.
3. This rule applies to any scheduled or unscheduled visit.
4. This rule applies to Week 2 through Week 8 visits only.
5. Those receiving the highest dose of study treatment who require a dose increase will maintain the same dose, 
while those receiving the lowest dose of study treatment that require a dose decrease will receive inactive study 
treatment (placebo/saline).
6. Repeat HemoCue Hgb at the same study visit to confirm Hgb (using the same sample) and take average.
7. No change may be redefined as an increase of <0.5 g/dL based on review of blinded instream Hgb data from the 
200807 study/ASCEND program.
8. Increasing may be redefined as an increase of ≥0.5 g/dL based on review of blinded instream Hgb data from the 
200807 study/ASCEND program.
Adjustments to the algorithm outlined in Table 7 may be implemented by the sponsor in 
order to maintain consistency with the 200807 study, if similar adjustments are made to 
the algorithm across the ASCEND program. 


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7.2.4.
Temporary Study Treatment Interruption
Every effort must be made to attend study visits and to continue study treatment; 
however, the site should contact GSK if a participant cannot return to the site on a 
temporary basis for any reason, including hospitalization, or in case of any unforeseen 
issue that prevents a participant from receiving study treatment.
In exceptional circumstances, local standard of care for anemia management during this 
time may be considered based on consultation with the GSK medical monitor.  If any 
non-study rhEPO or analogs are administered, doses should be recorded in the electronic 
case report form (eCRF).
Participants should return for study visits and restart administration of study treatment as 
soon as possible, unless the situation warrants permanent discontinuation of study 
treatment per Section 8.1.
7.3.
Method of Treatment Assignment
Randomization will be stratified by region, as defined in Appendix 7, and participants 
will be assigned in a 2:1 ratio to either the daprodustat or epoetin alfa treatment arm, 
respectively, in accordance with the randomization schedule. The randomization schedule 
will be computer generated by Pharmaceutical Product Development, LLC (PPD) prior to 
the start of the study, using the validated randomization system Prism.
Participants will be randomized centrally using an Interactive Response Technology 
(IRT) system. Once a randomization number has been assigned by the IRT system, it 
must not be re-assigned.
Before the study is initiated, the telephone number and/or the log-in information and 
directions for the IRT system will be provided to each site.
Study treatment will be dispensed at the study visits summarized in SoA.  
7.4.
Blinding
This is a double-blind study, in which the participant, investigator, site staff and the 
sponsor will remain blinded to each participant’s study treatment assignment throughout 
the course of the study, with the exception of a limited number of unblinded site staff
who are necessary to maintain the blind, as well as a limited number of sponsor staff. The 
dose level of each study treatment (tablet and IV formulations) will not be blinded. A 
detailed Blinding Plan will describe the procedures that will be implemented in order to 
minimize the extent to which the treatment assignment blind may be compromised.
In order to maintain the blind to the treatment assignment given the formulation 
differences between the study treatments, each participant will receive both a tablet 
formulation and an IV formulation, of which one is an active treatment and the other is 
inactive. For each participant, both the tablet and IV formulations (active and inactive 
treatments) will be dose adjusted based upon hemoglobin values as described in Section 
7.2.  


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In order to maintain the blind, unblinded site staff (e.g., study coordinator, nurse, or 
pharmacist) will be responsible for the handling, dispensation and preparation of 
unblinded study treatment (i.e., IV). Administration of study treatment will be done in a 
blinded fashion (e.g., IV formulation in blinded syringe) and may be performed by 
blinded site staff or unblinded site staff if required due to logistical considerations. To the 
extent possible, the unblinded site staff will take precautions during the dispensation and 
preparation of epoetin alfa and saline IV injections to minimize any risk of compromising 
the blind. Any discussion about study treatment that may occur between unblinded site 
staff and blinded individuals will occur in a blinded fashion. In situations where study 
treatment can be handled, dispensed or administered in a blinded fashion (e.g., tablets in 
blinded containers, IV formulation in blinded syringe), blinded site staff may perform 
that specific task. Further details and requirements for maintaining the blind are described 
in the Blinding Plan.
There will be a separate, unblinded sponsor team (e.g., study manager and medical 
monitor) with whom the unblinded site staff (e.g., study coordinator or nurse) will 
interact and communicate any study issues. Unblinded site staff will not communicate
directly with any blinded sponsor personnel.  
Unblinded monitors and the auditor(s), in the event of a Quality Assurance audit, will be 
allowed access to unblinded study treatment records at the site(s) to verify that 
randomization and dispensing has been done accurately.
The IRT will be programmed with blind-breaking instructions. The blind may be broken 
if, in the opinion of the investigator, it is in the participant’s best interest for the 
investigator to know the study treatment assignment. GSK must be notified before the 
blind is broken unless identification of the study treatment is required for a medical 
emergency in which the knowledge of the specific blinded study treatment will affect the 
immediate management of the participant’s condition (e.g., antidote is available). In this 
case, GSK must be notified within 24 hours after breaking the blind. The date and reason 
that the blind was broken must be recorded in the source documentation and eCRF, as 
applicable.
If a participant’s treatment assignment is unblinded, that participant may remain in the 
study, and may continue study treatment if appropriate.
GSK’s Global Clinical Safety and Pharmacovigilance (GCSP) staff may unblind the 
treatment assignment for any participant with an SAE. If the SAE requires that an 
expedited regulatory report be sent to one or more regulatory agencies, a copy of the 
report, identifying the participant’s treatment assignment, may be sent to investigators in 
accordance with local regulations and/or GSK policy.
7.5.
Preparation/Handling/Storage/Accountability
The unblinded site staff (e.g., nurse, study coordinator) 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.


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Only participants enrolled in the study may receive study treatment. Only authorized site 
staff may handle, prepare or administer study treatment, as described in Section 7.4. In 
order to maintain the blind (with respect to the participant, investigator and blinded site 
staff), careful consideration will be given to which site staff will be authorized to perform 
study treatment related tasks, in particular tasks involving unblinded study treatment. All 
study treatments must be stored in a secure, environmentally controlled, and monitored 
(manual or automated) area in accordance with the labeled storage conditions with access 
limited to authorized unblinded site staff. Maintenance of a temperature log (manual 
or automated) is required.
The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study treatment accountability, reconciliation, and record maintenance 
(e.g., receipt, reconciliation, and final disposition records). In this study, in order to 
maintain the blind, unblinded site staff will perform study treatment accountability, 
reconciliation, and record maintenance during the conduct of the study.  Further 
information related to blinding is provided in Section 7.4.
Further guidance and information for the final disposition of unused study treatment are 
provided in the SRM. 
Under normal conditions of handling and administration, study treatment is not expected 
to pose significant safety risks to site staff.  
A Material Safety Data Sheet (MSDS) or equivalent document describing occupational 
hazards and recommended handling precautions either will be provided to the 
investigator, where this is required by local laws, or is available upon request from GSK.
7.6.
Treatment Compliance
Participants will be dosed with daprodustat and placebo tablets at the site, and will 
receive study treatment directly from the site staff, with the exception that a participant 
may dose with blinded study treatment tablets at home in preparation for the collection of 
PD samples (see Section 9.6).  Epoetin alfa and saline will be intravenously administered 
to participants at the site. The details, including the date and time, of each dose 
administered in the clinic will be recorded in the source documents. Study treatment 
dosing details, including date and time, and dates for study treatment interruptions will be 
recorded in the eCRF.
When participants self-administer study treatment at home, i.e., blinded study treatment 
tablets taken prior to the collection of PD samples, compliance with daprodustat/placebo 
tablets will be assessed through querying the participant during the site visits and 
documented in the source documents and eCRF. In addition, the participant will be given 
a diary card to record the dose taken at home. A record of the number of blinded study 
treatment tablets dispensed to and taken by each participant must be maintained and 
reconciled with study treatment and compliance records.  


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7.7.
Concomitant Therapy
Any medication or vaccine (including over-the-counter or prescription medicines, 
vitamins, and/or herbal supplements) that the participant is receiving at the time of 
enrollment or receives during the study must be recorded in the eCRF, including the start 
and end dates of administration, the reason for use, and the route of administration.
Additional details (e.g., dose and frequency, changes in dose, reason for change, reason 
for addition or termination) will be recorded for certain medications at each visit (e.g., 
iron and anti-hypertensive medications).
The Medical Monitor should be contacted if there are any questions regarding 
concomitant or prior therapy.
7.7.1.
Permitted Medications and Non-Drug Therapies
Unless specified as a prohibited medication in Section 7.7.2, all concomitant medications 
should be considered permitted provided they are not contraindicated for the individual 
participant concerned.
Co-administration of daprodustat with moderate CYP2C8 inhibitors (e.g., clopidogrel, 
teriflunomide, deferasirox) should be performed with caution. If one of these 
medications is started, stopped or the dose is changed, Hgb should subsequently be 
monitored every 4 weeks for the following 12 weeks.
7.7.2.
Prohibited Medications and Non-Drug Therapies
Use of any of the following prescription drugs from screening (Week -4) until 7 days 
after the last dose of study treatment is prohibited and will constitute a protocol violation. 

Strong inhibitors of CYP2C8 (e.g., gemfibrozil)

Strong inducers of CYP2C8 (e.g., rifampin/rifampicin)
No other investigational treatments or investigational devices are permitted from 
screening (Week -4) until completion of the last study visit (or withdrawal from study), 
with the exception of the study treatments administered for this study.
7.8.
Standard of Care
During the study (from screening), investigators are expected to monitor the participant’s 
overall clinical status to ensure standards of care are met to enable consistency of practice 
with Kidney Disease Improving Global Outcomes (KDIGO) guidelines or local 
equivalent (e.g., phosphate and albumin).
For this study, specific iron management criteria and a dose adjustment algorithm for 
study treatment will apply. These were developed to reflect global clinical practice.


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7.8.1.
Iron Management Criteria
Participants must remain iron replete throughout the study. The investigator will follow 
the iron management criteria from randomization (Day 1) through Week 52 for 
participants who are receiving study treatment.
From Day 1 onwards, iron therapy will be administered if ferritin is ≤100 ng/mL and/or 
TSAT is ≤20%.  The investigator should choose the route of administration and dose of 
iron based on the participant’s iron status and local clinical practice.  
All iron (excluding multivitamins) must be stopped and cannot be administered if:

Ferritin >800 ng/mL and TSAT >20%, or 

TSAT >40% 
Investigators should be guided by local/regional guidelines and may stop administration 
of iron at a lower ferritin or TSAT level as long as participants are maintained at a ferritin 
>100 ng/mL and TSAT >20%.
7.9.
Rescue Therapy
A rescue algorithm is provided to minimize participants having an inadequate response to 
the treatment for their anemia for an extended period of time and to enable consistency in 
the application of rescue therapy across the study.  Details are provided in Table 8.
This rescue algorithm does not apply to participants with a low Hgb as a result of an 
acute or subacute event with an identifiable cause (e.g., GI bleed, blood loss due to 
surgery or from their vascular access).  In these cases, treatment should be directed to the 
specific cause and study treatment will be continued.  If a participant is transfused as part 
of the treatment, then study treatment will be maintained at the current dose (unless Hgb 
is ≥12 g/dL which requires a dose hold).


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Table 8
Rescue Algorithm for Anemia Management
Evaluate Participant for Rescue if:  

HemoCue Hgb remains <9 g/dL (at a scheduled study visit, Week 4 onwards) despite three 1
consecutive dose increases above the starting or post-rescue 2 dose (where HemoCue Hgb is <9 g/dL 
prior to each dose increase), or

HemoCue Hgb is <7.5 g/dL 3 despite a dose increase at the prior study visit 4.
Step 1:
Initial 
Intervention
The following actions will be taken for the initial intervention:

Continue with study treatment (increase dose if HemoCue Hgb <7.5 g/dL; otherwise 
maintain current dose)

A single course of IV iron up to 1000 mg, in addition to following the iron 
management criteria (Section 7.8.1), if clinically indicated.

Transfusion of up to two units of packed red blood cells (PRBC), if clinically 
indicated.
At the next study visit, in 4 ± 1 weeks after the initial intervention, recheck HemoCue Hgb
as described below in Step 2 (Rescue). Earlier checks of HemoCue Hgb may be 
obtained to advise further intervention as clinically indicated.
Step 2: 
Rescue 

Check HemoCue Hgb 4 ± 1 weeks after the initial intervention

Study treatment should be permanently discontinued and the participant
should be rescued according to local clinical practice:

If HemoCue Hgb remains <9 g/dL, despite initial intervention, based on the 
average of two HemoCue Hgb values 3, or

If more than two units of PRBC were needed for transfusion (and was not 
related to acute bleeding).
The participant will remain in the study, and follow the visit schedule in SoA, Table 2.
1.
Two consecutive dose increases if starting/post-rescue dose is daprodustat/placebo 24 mg or epoetin alfa/saline
42000 U per week; one dose increase if starting/post-rescue dose is daprodustat/placebo 32 mg or epoetin 
alfa/saline 48000 U per week; and no prior dose increase if starting/post-rescue dose is daprodustat/placebo 48
mg or epoetin alfa/saline 60000 U per week (top dose). This criterion applies to both study treatments for each 
participant, and is met when either study treatment reaches one of the specified doses; if both, then follow criteria 
based on highest dose level.
2.
For participants who were previously evaluated for rescue and who are able to continue in the trial, “post-rescue” 
dose is the dose of study treatment that a participant is receiving at the study visit after the initial intervention.
3.
Repeat HemoCue Hgb at the same study visit to confirm Hgb (using the same sample); take average of 2 values.
4.
A dose increase at the prior study visit is not required, if the dose was already at the top dose 
(daprodustat/placebo 48 mg or epoetin alfa/saline 60000 U per week).


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The study site will supply the rescue medication, which will be obtained locally. 
The date and time of rescue medication administration as well as the name and dosage 
regimen of the rescue medication must be recorded.
7.10.
Participants Changing Dialysis Modality
Participants changing dialysis modality from hemodialysis (includes hemodiafiltration 
and hemofiltration) to peritoneal dialysis or home hemodialysis will discontinue study 
treatment, and should be treated according to local clinical practice and standard of care
(see Section 8.1).  The participant will remain in the study, unless consent is withdrawn, 
and will follow the SoA, Table 2, for participants permanently discontinuing study 
treatment.
7.11.
Treatment after the End of the Study
Participants will not receive any additional treatment from GSK after completion of the 
study. The investigator is responsible for ensuring that consideration has been given to 
post-study care of the participant’s medical condition.
8.
DISCONTINUATION CRITERIA
8.1.
Discontinuation of Study Treatment
A participant may permanently discontinue study treatment at any time at his or her own 
request, or at the discretion of the investigator for safety or compliance reasons.  A 
participant must permanently discontinue study treatment for any of the pre-specified 
reasons below:

Participant receives a kidney transplant

Participant meets the criteria (Step 2 of algorithm) to receive rescue therapy 
(Section 7.9)

Participant becomes pregnant or intends to become pregnant during the study.

Liver chemistry abnormalities exceed the threshold criteria (Section 8.1.2)

Diagnosis of cancer (new or recurrent), with the exception of localized squamous 
cell or basal cell carcinoma of the skin.

Participant switches dialysis modality to peritoneal dialysis or home 
hemodialysis, or is switched to a standing dialysis schedule that is less often than 
three-times weekly.

Need for more than 14 days use of a prohibited medication (Section 7.7.2)
In all cases, the reason for study treatment discontinuation and the date of the last dose 
will be recorded in the participant’s eCRF.  


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8.1.1.
Procedures Following Discontinuation of Study Treatment
Participants who permanently discontinue study treatment will remain in the study.  
Participants will be asked to attend an Early Treatment Discontinuation visit and will be 
expected to attend study visits according to the SoA, Table 2, unless consent is actively 
withdrawn. 

Early Treatment Discontinuation visit: This visit should occur within 2 weeks of 
stopping study treatment. 

Remaining in-clinic visits: Study visits at Weeks 4, 16, 28, 40 and 52.  Phone visit 
is acceptable in exceptional circumstances.  
If a participant does not agree to continue attending in-clinic or phone visits, other 
follow-up options to collect study outcomes and vital status for up to 52 weeks after the 
participant’s randomization visit should be pursued according to local laws and 
regulations. If one of these alternate methods to collect study outcomes and vital status is 
acceptable to the participant, then the participant will be considered to have remained in 
the study and not to have withdrawn consent.
8.1.2.
Liver Chemistry Stopping Criteria
Liver chemistry stopping and increased monitoring criteria have been designed to 
assure participant safety and evaluate liver event etiology. These protocol guidelines are 
in alignment with FDA premarketing clinical liver safety guidance: 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM174090.pdf.
Discontinuation of study treatment for abnormal liver tests is required when:

A participant meets one of the conditions outlined in the algorithm.

In the presence of abnormal liver chemistries not meeting protocol-specified 
stopping rules, the investigator believes that study treatment discontinuation is 
in the best interest of the participant.


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Algorithm A: Phase III-IV Liver Chemistry Stopping and Increased Monitoring 
Algorithm
Liver Safety Required Actions and Follow up Assessments Section can be found in 
Appendix 6.


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Algorithm B: Phase III-IV Liver Chemistry Increased Monitoring Algorithm with 
Continued Therapy for ALT 3xULN but <8xULN
Liver Safety Required Actions and Follow up Assessments Section can be found in 
Appendix 6.
8.1.3.
Study Treatment Restart
If participant meets liver chemistry stopping criteria, do not restart study treatment unless
there is a clear underlying cause for the elevated liver enzymes other than drug-induced 
liver injury, and the following requirements are met:

GSK Medical Governance approval is granted

Ethics and/or IRB approval is obtained, if required, and

Separate consent for treatment restart is signed by the participant
Refer to Appendix 6 for full guidance. 
8.2.
Withdrawal from the Study
Every effort should be made to keep participants in the study. For participants that choose 
to withdraw consent or are lost to follow up, the reason for not completing the study will 
be recorded in the participant’s eCRF. 


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
A participant may withdraw from the study at any time at his or her own request, 
or may be withdrawn at any time at the discretion of the investigator for safety, 
behavioral, compliance or administrative reasons.

If the participant 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 participant withdraws from the study, he or she may request destruction of 
any samples taken and not tested, and the investigator must document this in the 
site study records.

Refer to the SoA (Section 2) for data to be collected at the time of study 
discontinuation and follow-up and for any further evaluations that need to be 
completed.
8.2.1.
Withdrawal of Consent for Contact
Specific wording is included in the informed consent form which permits participants to 
discontinue study treatment and study procedures, but states an expectation that 
follow-up information will always be required. Participants will agree to this at the time 
of consenting.
Withdrawal of consent from the study is expected to be a rare occurrence.  If a participant 
expresses a wish to withdraw consent from the study, the investigator will review the 
following contact options with the participant:

In-clinic and phone visits

Follow-up via medical records review and/or other treating physician

Follow-up via family member or other third party contact
If all of these options are refused, then no further study visits or study-related telephone 
contacts will be conducted and the participant will be considered to have withdrawn 
consent. The investigator will be required to document that all alternative options have 
been reviewed with the participant.
For these participants, information regarding vital status will continue to be collected 
from available sources including those in the public domain based on accepted local laws 
and regulations. Where permitted, a third party may be used to obtain information.
8.3.
Lost to Follow Up
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. 
The investigator should make every effort to contact any participant who has failed to 
attend a required study visit, and who has not withdrawn consent to follow-up contact.  
The following actions must be taken if a participant fails to return to the clinic for a 
required study visit:


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
The site must attempt to contact the participant and reschedule the missed visit 
as soon as possible and counsel the participant on the importance of maintaining 
the assigned visit schedule and ascertain whether or not the participant wishes to 
and/or should continue in the study.

Before a participant is deemed lost to follow up, the investigator or designee 
must make every effort to regain contact with the participant (where possible, 3 
telephone calls and, if necessary, a certified letter to the participant’s last known 
mailing address, or local equivalent methods). These contact attempts should be 
documented in the participant’s medical record.

As permitted by local regulations, a third party may be used to obtain alternative 
participant contact information that will be provided to the investigator. All 
attempts to contact the participant will be documented in the participant’s source 
notes and a final status contact will be recorded in the eCRF.

Should the participant continue to be unreachable, he or she will be considered 
to have withdrawn from the study with a primary reason of lost to follow-up. 
9.
STUDY ASSESSMENTS AND PROCEDURES

Study procedures and their timing are summarized in the SoA (Section 2). Pre-
dialysis assessments should be performed in the following order, where applicable: 
patient reported outcomes, ECG, BP/HR, blood sample collection.

Protocol waivers or exemptions are not allowed.

Immediate safety concerns should be discussed with the sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or 
discontinue study treatment.

Adherence to the study design requirements, including those specified in the SoA 
(Section 2), is essential and required for study conduct.

All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening 
log to record details of all participants screened and to confirm eligibility or record 
reasons for screening failure, as applicable. 

All visits should be referenced back to the Randomization visit (Day 1).  The 
allowable visit window is ±3 days for Week 2 to Week 8 visits, and ±1 week for all 
other visits; however, study visits must be no more than 5 weeks apart.  

In exceptional circumstances, minor changes to visit structure may be permitted after 
consultation with the Medical Monitor.

Because Hgb levels become more variable with increased time between dialysis 
sessions, the designated study visit should occur during the dialysis session with the 
shortest interval from the previous session. For participants on a three- to five-times 
weekly dialysis schedule, the designated study visit must not occur on the first 
dialysis session of the week, i.e., the dialysis session immediately following the 
longest interval between dialysis sessions.  For example, if on a Monday-
Wednesday-Friday schedule, the study visit should be on Wednesday or Friday.


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
Procedures conducted as part of the participant’s routine clinical management (e.g., 
renal and adrenal gland ultrasound) and obtained before signing of the ICF may be 
utilized for screening or baseline purposes provided the procedure met the protocol-
specified criteria and was performed within the time frame defined in the SoA
(Section 2).

The maximum amount of blood collected from each participant over the duration of 
the study, including any extra assessments that may be required, will not exceed 
375 mL. This blood volume does not include any repeat or unscheduled samples that 
may be taken.

Repeat or unscheduled samples may be taken for safety reasons or for technical 
issues with the samples.

Supplementary study conduct information is provided in the SRM. The SRM 
provides administrative and detailed technical information that does not impact 
participant safety.
9.1.
Efficacy Assessments

Planned time points for all Hgb efficacy assessments are listed in the SoA
(Section 2).  

GSK will supply a point-of-care Hgb analyzer (i.e., HemoCue) to each site for 
rapid Hgb measurements. Further details about the HemoCue device are provided 
in the SRM. 

Blood samples for measurement of Hgb concentrations via HemoCue and also by 
the central laboratory will be collected as specified in the SoA (Section 2).

Central laboratory Hgb values will be used for the primary efficacy analyses.  
HemoCue Hgb values may be used if central laboratory Hgb values are missing. 
Further details about handling of missing data are provided in the RAP. 
9.2.
Adverse Events
The definitions of an AE or SAE can be found in Appendix 3.
The investigator and any designees are responsible for detecting, documenting, and 
reporting events that meet the definition of an AE or SAE and remain responsible for 
following up AEs that are serious, considered related to the study treatment or the study, 
or that caused the participant to discontinue study treatment (see Section 8). 
Events should be reported as an AE or SAE according to the definitions in Appendix 3.
9.2.1.
Time Period and Frequency for Collecting AE and SAE 
Information

All SAEs will be collected from the start of study treatment until the follow-up 
visit at the time points specified in the SoA (Section 2). However, any SAEs 
assessed as related to study participation (e.g., study treatment, protocol-


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mandated procedures, invasive tests, or change in existing therapy) or related to 
a GSK product will be recorded from the time a participant consents to 
participate in the study.

All AEs will be collected from the start of treatment until the follow-up visit at 
the time points specified in the SoA (Section 2).

Medical occurrences that begin before the start of study treatment but after 
obtaining informed consent will be recorded on the Medical History/Current 
Medical Conditions section of the case report form (CRF) not the AE section.

All SAEs will be recorded and reported to the sponsor or designee immediately 
and under no circumstances should this exceed 24 hours, as indicated in 
Appendix 3. The investigator will submit any updated SAE data to the sponsor 
within 24 hours of it being available.

Investigators are not obligated to actively seek AEs or SAEs in former study 
participants. However, if the investigator learns of any SAE, including a death, 
at any time after a participant has been discharged from the study, and he/she 
considers the event to be reasonably related to the study treatment or study 
participation, the investigator must promptly notify the sponsor.

The method of recording, evaluating, and assessing causality of AEs and SAEs
and the procedures for completing and transmitting SAE reports are provided in 
Appendix 3.
9.2.2.
Method of Detecting AEs and SAEs
Care will be taken not to introduce bias when detecting AE and/or SAE. Open-ended and 
non-leading verbal questioning of the participant is the preferred method to inquire about 
AE occurrence. 
9.2.3.
Follow-up of AEs and SAEs
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. All SAEs, and non-serious AEs of special 
interest (as defined in Section 9.2.7), will be followed until the event is resolved, 
stabilized, otherwise explained, or the participant is lost to follow-up (as defined in 
Section 8.3). Further information on follow-up procedures is given in Appendix 3.
9.2.4.
Regulatory Reporting Requirements for SAEs

Prompt notification by the investigator to the sponsor of a SAE is essential so 
that legal obligations and ethical responsibilities towards the safety of 
participants and the safety of a study treatment under clinical investigation are 
met. 

The sponsor has a legal responsibility to notify both the local regulatory 
authority and other regulatory agencies about the safety of a study treatment 
under clinical investigation. The sponsor will comply with country-specific 
regulatory requirements relating to safety reporting to the regulatory authority, 


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Institutional Review Boards (IRB)/Independent Ethics Committees (IEC), and 
investigators.

Investigator safety reports must be prepared for suspected unexpected serious 
adverse reactions (SUSAR) according to local regulatory requirements and 
sponsor policy and forwarded to investigators as necessary.

An investigator who receives an investigator safety report describing a SAE or 
other specific safety information (e.g., summary or listing of SAE) from the 
sponsor will review and then file it along with the IB and will notify the 
IRB/IEC, if appropriate according to local requirements.
9.2.5.
Events Referred to the Clinical Events Committee
Investigators should refer any event suspected to be one of the events below to the 
Clinical Events Committee (CEC) for adjudication. See CEC Site Manual for full scope 
of reporting requirements.

All-cause mortality (CV and non-CV mortality)

Hospitalization for heart failure

Non-fatal MI

Non-fatal stroke

Thromboembolic events (vascular access thrombosis, deep vein 
thrombosis, pulmonary embolism)
Events referred to the CEC will be subjected to blinded adjudication using pre-specified 
diagnostic criteria.
When the investigator-reported event and the CEC assessment of the event differ, the 
CEC’s decision will be considered final. The detailed descriptions of the endpoint 
definitions used for adjudication are contained within the CEC Charter (available on 
request). 
Source documentation required to support the adjudication of the events is described in 
the CEC Site Manual.  
9.2.6.
Other CV Events
GSK has identified other CV events of interest for all clinical studies. Investigators will 
be required to fill out the specific CV event page of the eCRF for the following CV AEs 
and SAEs or any event that may potentially be one of the categories listed:

Arrhythmias  

Pulmonary hypertension (also an AE of special interest, see Section 9.2.7).

Valvulopathy

Revascularization


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The CV eCRFs are presented as queries in response to reporting of certain CV MedDRA 
terms. The CV information should be recorded in the specific cardiovascular section of 
the eCRF within one week of receipt of a CV Event data query prompting its completion.
9.2.7.
Adverse Events of Special Interest
The investigator or site staff will be responsible for detecting, documenting and reporting 
any events that may represent the AEs of special interest listed below (using preferred 
terms):

Death, myocardial infarction (MI), stroke, heart failure, thromboembolic events, 
thrombosis of vascular access (see also Section 9.2.5)

Thrombosis and/or tissue ischemia secondary to excessive erythropoiesis

Cardiomyopathy  

Pulmonary artery hypertension (see also Section 9.2.6)

Cancer-related mortality or tumor progression and recurrence 

Esophageal and gastric erosions

Proliferative retinopathy, macular edema, choroidal neovascularization 

Exacerbation of rheumatoid arthritis
The results of any investigation should be recorded on the AE or SAE page, as 
appropriate, and the relevant AE of special interest page of the participant’s eCRF.
9.2.8.
Possible Suicidality Related Adverse Events
If during the study there is an occurrence of an AE or SAE which in the investigator’s 
opinion, is possibly related to suicidality, the Possible Suicidality Related Adverse Events 
(PSRAE) eCRF form should be completed (in addition to the AE and SAE pages, as 
appropriate).
This event may include, but is not limited to, one that involves suicidal ideation, a 
preparatory act toward imminent suicidal behavior, a suicide attempt, or a completed 
suicide. The investigator will exercise his or her medical and scientific judgment in 
deciding whether an event is possibly related to suicidality.
9.2.9.
Pregnancy

Details of all pregnancies in female participants will be collected after the start of 
study treatment and until seven days after the last dose.

If a pregnancy is reported, the investigator should inform GSK within 2 weeks of 
learning of the pregnancy and should follow the procedures outlined in Appendix 4.

Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAEs.


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9.3.
Treatment of Overdose
There is no specific antidote for overdose with daprodustat. The expected manifestations 
of a daprodustat overdose include signs and symptoms associated with an excessive or 
rapid increase in Hgb concentration. Daprodustat is highly protein bound; thus, clearance 
of daprodustat by dialysis is very low and these are not effective methods to enhance the 
elimination of daprodustat. Daprodustat metabolites are, in part, cleared via dialysis. In 
the event of a suspected overdose, it is recommended that the appropriate supportive 
clinical care be instituted, as dictated by the participant’s clinical status. Additionally, 
participants should be monitored closely for CV events, increased HR, and hematologic 
abnormalities.
Consult the approved product label for information on overdose for epoetin alfa.
In the event of an overdose, the investigator/treating physician should:
1.
Contact the Medical Monitor immediately.
2.
Closely monitor the participant for AE/SAE and laboratory abnormalities until study 
treatment can no longer be detected systemically (at least 2 days).
3.
Obtain a plasma sample for PK analysis within 1 day from the date of the last dose of 
study treatment if requested by the Medical Monitor (determined on a case-by-case 
basis).
4.
Document the quantity of the excess dose as well as the duration of the overdosing in 
the eCRF.
Decisions regarding dose interruptions or modifications will be made by the investigator 
in consultation with the Medical Monitor based on the clinical evaluation of the 
participant.
9.4.
Safety Assessments
Planned time points for all safety assessments are provided in the SoA (Section 2).
Unscheduled visits will occur as medically necessary. Detailed procedures for obtaining 
each assessment are provided in the SRM.
Safety endpoints will include monitoring of safety events including deaths (Section 
9.2.5), other CV events (Section 9.2.6), AEs of special interest (Section 9.2.7), AEs, 
SAEs and AEs leading to discontinuation of randomized treatment, laboratory 
parameters, BP and HR.
Pre-specified events leading to permanent discontinuation of randomized treatment are 
described in Section 8.1. Liver chemistry stopping and follow-up criteria are described in 
Section 8.1.2 and Appendix 6.


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9.4.1.
Height and Weight

Height and weight will be measured as specified in the SoA (Section 2). Weight 
will be measured with the participant wearing indoor daytime clothing with no 
shoes. Weight will be measured pre- and post-dialysis. 

Estimated dry weight (EDW) will be reported at each study visit as specified in 
the SoA (Section 2).
9.4.2.
Blood Pressure and Heart Rate
Measurement of systolic blood pressure (SBP), diastolic blood pressure (DBP) and HR 
will be taken at the time points specified in the SoA (Section 2).  

On Day 1, Week 52, and at the Early Treatment Discontinuation visit (if 
applicable), BP and HR will be measured in triplicate. At all other visits, single 
measurements will be taken.

Measurements will be taken both pre-dialysis and post-dialysis.

Measurements will be taken with the participant in a semi-supine or seated 
position in the dialysis chair after at least a 5-minute rest period, pre- and post-
dialysis.
Measurement of SBP, DBP and HR will be performed before collection of blood samples 
for laboratory testing, where applicable (e.g., would not apply for post-HD 
measurement).
9.4.3.
Electrocardiograms

ECG measurements will be taken at the time points specified in the SoA
(Section 2). Full 12-lead ECGs will be recorded with the participant in a supine 
position. HR, PR interval, QRS duration, and QT (uncorrected) interval will be 
measured. QTcB will be calculated (machine-read or manually).

For the screening (Week -4) ECG, which may be conducted anytime between 
the Week -4 visit and the Day 1 visit, two additional ECGs are required if the 
screening ECG indicates prolonged QTc (see Section 6.2) using the automated 
or manually calculated QTcB value.  The average QTcB value of all three ECGs 
will be used to determine eligibility (see Section 6.2). Additional details are 
provided in the SRM.

ECG data will be over-read locally by a physician with experience in reading 
and interpreting ECGs.  The over-read of the screening ECG is required to 
confirm eligibility. Additional details are provided in the SRM.

ECGs that are performed prior to dialysis will be performed before 
measurement of SBP, DBP, and HR and before collection of blood samples for 
laboratory testing, where applicable (e.g., would not apply if ECG is performed 
post-HD).


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9.4.4.
Ultrasound
An ultrasound of the kidneys and adrenal glands will be performed prior to 
randomization (Day 1). It is understood that the adrenal glands will not always be able to 
be visualized. Non-visualization of the adrenals is not a reason to exclude the participant
from randomization. Further details are provided in the SRM.
A documented ultrasound of the kidneys within 6 months prior to screening may be used 
to assess entry criteria (see Section 6.2), provided the size and cyst category has been 
reported. If a more sensitive imaging study (e.g., MRI, CT) has been performed within 
this timeframe and a report is available, this may be used in place of the ultrasound.
9.4.5.
Clinical Laboratory Assessments

Refer to Table 9 for the list of clinical laboratory tests to be performed and to the 
SoA for the timing and frequency. Details for the preparation and shipment of 
samples are detailed in the SRM. 

The tests detailed in Table 9 will be performed by a central laboratory with the 
exception of HemoCue Hgb which will be performed at the clinical site. The 
results of each HemoCue Hgb assessment must be entered into the participant’s 
eCRF.

Blood samples for clinical laboratory tests will be collected prior to dialysis.

The investigator must review the laboratory report, document this review, and 
record any clinically relevant changes occurring during the study in the AE 
section of the CRF. The laboratory reports must be filed with the source 
documents. Clinically significant abnormal laboratory findings are those which 
are not associated with the underlying disease, unless judged by the investigator 
to be more severe than expected for the participant's condition.

All laboratory tests with values considered clinically significantly abnormal 
during participation in the study or within 7 days after the last dose of study 
treatment should be repeated until the values return to normal or baseline or are 
no longer considered significantly abnormal by the investigator or medical 
monitor. 

If such values do not return to normal or baseline within a period of time judged 
reasonable by the investigator, the etiology should be identified and the sponsor 
notified.

All protocol-required laboratory assessments, as defined in Table 9, must be 
conducted in accordance with the laboratory manual and the SoA (Section 2).

Protocol-specific requirements for inclusion or exclusion of participants are 
detailed in Section 6 of the protocol.

Additional tests may be performed at any time during the study as determined 
necessary by the investigator or required by local regulations.

Analyte results that could unblind the study (e.g., EPO) will not be reported to 
investigative sites or other blinded personnel until the study has been unblinded.


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Table 9
Protocol Required Laboratory Assessments
Laboratory 
Assessments
Parameters
Hematology
Platelet count
RBC indices:
WBC count with Differential:
RBC count
MCV
Neutrophils
Hemoglobin
MCH
Lymphocytes
Hematocrit
MCHC
Monocytes
Reticulocyte count
RDW
Eosinophils
Basophils
Clinical 
Chemistry 1
Potassium (serum)
AST
Albumin (serum)
Calcium (total and 
albumin-adjusted)
ALT
Urea (serum) 
Inorganic phosphate
Bilirubin (total, direct and 
indirect)
Iron 
parameters
Iron (serum)
Ferritin 
UIBC
Hepcidin 2
TIBC
TSAT
Lipid 
parameters
Total cholesterol
LDL-C (direct)
HDL-C
Other 
laboratory 
tests
Serum pregnancy test 3
hsCRP
HemoCue Hgb
Estradiol 4
iPTH
Stored sample (blood) 6
FSH 4
Erythropoietin (EPO)
HbA1c 5
Vascular Endothelial 
Growth Factor (VEGF)
WBC, white blood cells; MCV, mean corpuscular volume; MCH, mean corpuscular hemoglobin; MCHC, mean 
corpuscular hemoglobin concentration; RDW, red blood cell distribution width; AST, aspartate transaminase; ALT, 
alanine transaminase; UIBC, unbound iron binding capacity; TIBC, total iron binding capacity; TSAT, transferring 
saturation; LDL-C, low density lipoprotein-C; HDL-C, high density lipoprotein-C; 
1.
Details of liver chemistry stopping criteria and required actions and follow-up assessments after liver stopping or 
monitoring event are given in Section 8.1.2 and Appendix 6.
2.
At each visit specified in SoA, Section 2, a sample for hepcidin will be collected prior to dosing with either study 
treatment and prior to administration of any iron supplementation.
3.
For women of child-bearing potential (WOCBP) only.
4.
Screening only. As needed in postmenopausal women where their menopausal status is in doubt (see Inclusion 
Criteria Section 6.1).
5.
Only participants with diabetes.
6.
Refer to Section 9.8.
9.5.
Pharmacokinetics
Pharmacokinetic (PK) samples will be collected for measurement of plasma 
concentrations of daprodustat and its predominant metabolites. In order to maintain the 
blind, samples relative to the tablet formulation will be taken for all participants, 
regardless of treatment assignment.  Only samples from participants who are randomized 
to daprodustat will be analyzed.
Blood samples (6 in total) will be collected at the Day 1 visit pre-dose and at any one 
post-baseline visit between Week 8 and Week 52, inclusive, as specified in the SoA
(Section 2), preferably at the earliest opportunity.  The post-baseline samples will be 
collected at pre-dose and 0.5, 1, 2 and 3 hours post-dose. The actual date and time (24-


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hour clock time) of each sample will be recorded. Each plasma sample will be divided 
into 2 aliquots (1 each for PK and a back-up).
Drug concentration information that may unblind the study will not be reported to 
investigative sites or blinded sponsor personnel until the study has been unblinded.
The post-baseline PK visit can be repeated if necessary to obtain evaluable PK samples, 
e.g., samples from initial PK visit are damaged and not evaluable.
9.5.1.
PK Visit 
On the day of the scheduled (post-baseline) PK visit:

The participant will take the required dose of study treatment tablets in the clinic 
after the pre-dose sample is collected.

The participant must not be on a dose interruption or be receiving a dose of 0 mg 
(tablets). If the participant’s study treatment is interrupted or decreased to a 0 mg on 
the day of the planned PK visit, then the PK samples should be collected at the next 
possible study visit up to Week 52, inclusive.

Record the date and actual time that the study treatment tablets were taken in the 
clinic, and the date and actual time of all PK samples collected. Samples may be 
collected within ± 20 minutes of the planned collection time.

Based on the time of dosing, samples may be obtained before, during, or after any 
dialysis procedure. The start and stop time of the dialysis procedure will also be 
recorded at this visit.
Plasma PK analysis will be performed under the control of GSK PTS-IVIVT-BIB, the 
details of which will be included in the SRM.  Concentrations of parent daprodustat and 
metabolites (GSK2391220 [M2], GSK2506104 [M3], GSK2487818 [M4], GSK2506102 
[M5], GSK2531398 [M6], and GSK2531401 [M13]) will be determined in plasma 
samples using the currently approved bioanalytical methods.  Raw data will be archived 
at the bioanalytical site.  
9.6.
Pharmacodynamics
Samples will be collected for measurement of EPO and VEGF at the Day 1 visit pre-dose 
and during any post-baseline week from Week 28 to Week 52, inclusive, as specified in 
the SoA (Section 2), preferably at the earliest opportunity. Refer to the SRM for more 
information regarding pharmacodynamics.
PD samples will be evaluated for both the daprodustat and epoetin alfa treatment arms.  
In order to maintain the blind, samples relative to both the tablet and IV formulation will 
be taken for all participants. Therefore, 2 sets of post-baseline PD samples will be taken; 
one set relative to each formulation. It is preferred that both sets of PD samples be taken 
in the same study week.


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9.6.1.
PD Visit (EPO and VEGF)

On the day of the (post-baseline) PD visit, the participant must not be on a dose 
interruption or be receiving a dose of 0 mg (tablets) or 0 U (IV). If the participant’s 
study treatment is interrupted or decreased to a 0 mg or 0 U dose on the day of the 
planned PD visit, then the PD samples should be collected at the next possible study 
visit up to Week 52, inclusive.

Samples relative to the IV formulation will be taken at pre-dose and within 15 
minutes after dosing with the study treatment IV injection. The dosing of the study 
treatment may occur at any time relative to the dialysis treatment, and follow local 
practices.

Samples relative to the tablets will be taken at pre-dose and 2, 4, 6 and 8 hours after 
dosing with the study treatment tablets. Samples will be collected within ± 30 
minutes of the planned collection time. These 5 samples may be taken either on one 
dialysis day or taken over 2 consecutive dialysis days, as outlined below:

All samples collected in one dialysis day: The pre-dose and the four post-dose 
samples may be collected in a single visit. The dosing of the study treatment 
may occur at any time relative to the dialysis treatment.

Samples collected over 2 consecutive dialysis days: 

The participant must receive the same dose of the tablet formulation on both 
consecutive dialysis days at which PD samples are taken. 

First dialysis session: This visit must not occur on the first dialysis day of the 
week (see Section 9). The pre-dose, and 2- and 4-hour post-dose samples are 
collected at this visit. The dosing of the study treatment may occur at any 
time relative to the dialysis treatment, but it is recommended that the 
participant be dosed prior to or at the start of the dialysis treatment.  

Second dialysis session: This visit will occur on the next dialysis day 
following the first visit, and must not occur on the first dialysis day of the 
week (see Section 9). The 6- and 8-hour post-dose samples are collected at 
this visit. The participant may take the required dose of study treatment 
tablets at home, approximately 4 to 5 hours prior to their scheduled dialysis 
treatment, to allow collection of the PD samples during the dialysis treatment. 
The participant will also be instructed to record the date and time of dosing in 
the diary card. Alternatively, if there are any concerns with the participant 
dosing at home, the participant may be dosed in the clinic.
The date and time of dosing of study treatments and the collection date and time of the 
PD samples will be recorded in the eCRF.
9.7.
Genetics
A 6 mL blood sample for DNA isolation will be collected from participants who have 
consented to participate in the genetics analysis component of the study. Participation is 
optional. Participants who do not wish to participate in the genetic research may still 
participate in the study.


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In the event of DNA extraction failure, a replacement genetic blood sample may be 
requested from the participant. Signed informed consent will be required to obtain a 
replacement sample unless it was included in the original consent.
See Appendix 5 for information regarding genetic research. Details on processes for 
collection and shipment and destruction of these samples can be found in SRM.
9.8.
Biomarkers
Blood (serum and plasma) samples will be collected and stored as outlined in the SoA
(Section 2) and in Table 9, for potential future analysis of biomarkers of CV risk and iron 
metabolism. Biomarker samples for storage will be collected from all participants, except 
if not permitted by local regulations or IRB/EC, or refused by participant.
9.9.
Patient Reported Outcomes
The patient-reported effect of daprodustat and rhEPO on global symptom severity and 
change will be assessed.  Symptom severity will be assessed using the Patient Global 
Impression of Severity (PGI-S) and overall symptom change using the Patient Global 
Impression of Change (PGI-C). 
The PGI-S is a 1-item questionnaire designed to assess participant’s impression of 
disease severity of their anemia of CKD. It is measured on a 5-point disease severity 
scale (absent, mild, moderate, severe, or very severe) during the past 24 hours.
The PGI-C is a 1-item questionnaire designed to assess a participant’s impression of 
symptoms change of their anemia of CKD. It is measured on a 7-point Likert-type 
response scale (very much improved, moderately improved, minimally improved, no 
change, minimally worse, moderately worse, or very much worse) since they first started 
the study.
All questionnaires used in this study have been translated, and culturally adapted for use 
in local country languages. Specific instructions on how the participant is to complete the 
scales and the process for data entry is provided in the SRM.
The questionnaires should be completed by the participant at a clinic visit, in the order 
specified (PGI-S then PGI-C), and before performing any of the following assessments: 
ECG, vitals or blood samples. Participants who are unable to or require assistance to read 
must not complete the questionnaires.
9.10.
Participant Feedback Survey
An optional smartphone mobile application (or “App”) or website may be made available 
for use by participants during the study. If available for use, participants may be asked for 
feedback on their experience during the study, in the form of an anonymized mobile 
application or website based survey. The purpose of this survey is for GSK to learn about 
participants’ experience in the study. 


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10.
STATISTICAL CONSIDERATIONS
The primary Hgb efficacy objective will assess the estimand defined as the comparative
treatment effect in mean Hgb change between baseline and EP (i.e., Weeks 28 to 52
inclusive) in all randomized participants who remain in follow-up throughout the period 
of stabilization and have at least one Hgb assessment during the EP (i.e., Weeks 28 to 52) 
regardless of adherence to study treatment. 
The analysis will test whether daprodustat is non-inferior to rhEPO according to the 
following statistical hypotheses:

Null: The difference in mean change in Hgb between baseline and EP, between 
treatment arms (daprodustat-epoetin alfa), is less than or equal to -0.75 g/dL.

Alternative: The difference in mean change in Hgb between baseline and EP, 
between treatment arms (daprodustat-epoetin alfa), is greater than -0.75 g/dL
The non-inferiority margin is pre-defined as -0.75 g/dL; selected to be consistent across
all clinical trials in the daprodustat Phase 3 clinical development program in participants 
with anemia of chronic kidney disease, and determined based upon a combination of 
clinical judgment, statistical reasoning and regulatory guidance for designing non-
inferiority trials.
Statistical significance of non-inferiority will be assessed at the one-sided 2.5% level. An
analysis of covariance (ANCOVA) model including randomization stratification factor,
baseline hemoglobin and treatment will be used to obtain a point estimate and the two-
sided 95% confidence interval (CI) for the treatment difference (daprodustat-rhEPO) and 
generate the p-value for the non-inferiority test. The non-inferiority p-value will show 
strength of evidence against the null hypothesis. Non-inferiority will be established if the 
lower limit of the two-sided 95% CI for the treatment difference is greater than -0.75 
g/dL.
10.1.
Sample Size Determination
10.1.1.
Sample Size Assumptions
The size of this study has been determined to be sufficient to meet the ICH E1 guideline 
for participant exposure, number and duration and to provide at least 90% power to test 
the primary non-inferiority hypothesis with a two-sided 95% CI.
Approximately 402 participants are planned to be randomized in a 2:1 ratio to 
daprodustat or rhEPO (268 to the daprodustat arm and 134 to the rhEPO arm), in order to 
provide at least 100 participants exposed to daprodustat for one year. Participants will be 
treated to achieve and maintain Hgb between 10 and 11 g/dL. The expected difference in 
mean Hgb change from baseline and the EP, between arms, is 0 g/dL and the anticipated 
between participant standard deviation (SD) is 1.5 g/dL, based on historical rhEPO trials 
and daprodustat clinical trial experience to date. With a prespecified non-inferiority 
margin of -0.75 g/dL, a two-sample T-test and assuming that up to approximately 10% of 


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participants will have no Hgb values measured during the EP, 402 randomized 
participants will provide >90% power to test the primary hypothesis.
With 402 randomized participants, it is anticipated that the difference in mean Hgb 
change from baseline between arms will be estimated with a precision of 0.33 g/dL (half 
width of the two-sided 95% CI) and the largest (most negative) difference between arms 
that would meet the statistical criterion for non-inferiority would be -0.42 g/dL.
Note: Country-specific requirements for France for the sample size consideration are 
provided in Appendix 8 (see Section 12.8.1, Item 2 for details).
10.1.2.
Sample Size Sensitivity
The following table illustrates the impact on power for the primary efficacy analysis
based on alternative assumptions for the between participant SD and the expected 
difference between the treatment groups.
Between 
participant 
Hgb SD (g/dL)
True difference between treatments in Hgb (g/dL)
(daprodustat – rhEPO)
0.1
0
-0.1
-0.2
-0.3
1
>99%
>99%
>99%
>99%
98%
1.25
>99%
>99%
>99%
98%
89%
1.5
>99%
>99%
97%
91%
76%
1.75
>99%
97%
91%
80%
63%
2
97%
92%
83%
69%
52%
10.1.3.
Sample Size Re-Estimation or Adjustment
No sample size re-estimation is planned for this study.
10.2.
Populations for Analyses
For purposes of analysis, the following populations are defined:
Population
Description
Screened 
All participants who sign the ICF
All Randomized (ITT)
All randomized participants.  This is the primary population for Hgb 
efficacy analyses.  Participants will be analyzed according to the 
treatment to which they were randomized.
Note: While the primary analysis of the primary parameter will 
exclude those randomized participants who do not have at least one 
Hgb assessment during the EP, the sensitivity analysis to define the 
“tipping point” as described in Section 10.3.1 will include all 
randomized participants.


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Population
Description
Per-Protocol (PP)
All ITT participants who are not major protocol violators.  This 
population will be the basis for a sensitivity analysis of the primary 
efficacy parameter.  Participants will be analyzed according to the 
treatment to which they were randomized.
Details will be defined in the RAP.
Safety
All randomized participants who take at least 1 dose of study 
treatment. Participants will be analyzed according to the treatment 
they actually received.
PK
All randomized participants for whom a PK sample was obtained 
and analyzed.  This will be the population used for all the PK 
displays.
Additional populations may be defined in the RAP.
10.3.
Statistical Analyses
10.3.1.
Efficacy Analyses
Endpoint
Statistical Analysis Methods
Primary
Mean change in Hgb between baseline and EP (Weeks 28-52): The 
primary efficacy estimand is to compare the effect of treatment for the 
evaluation of mean change from baseline in Hgb during a 24-week 
evaluation period (Weeks 28 to 52 inclusive) in all ITT participants with at 
least one Hgb during the EP.  The analysis will use an analysis of covariance 
(ANCOVA) model.  For each participant, the baseline Hgb will be the value 
obtained on Day 1, prior to taking randomized treatment, and Hgb during EP 
will be determined by calculating the mean of all available Hgb values 
between Weeks 28 to 52 inclusive regardless of adherence to randomized 
treatment. The ANCOVA model will include randomization stratification 
factor, baseline hemoglobin, and treatment. It will provide a point estimate 
and two-sided 95% CI for the treatment effect, together with the one-sided 
non-inferiority test p-value. Non-inferiority will be established if the lower limit 
of the two-sided 95% CI is greater than the margin of -0.75 g/dL. There will 
be no imputation for missing data but imputation will be explored via 
sensitivity analyses
Sensitivity and Supplementary Analyses: Sensitivity analyses for the 
primary estimand will include a multiple imputation-based “tipping point” 
analysis where assumptions are adjusted until non-inferiority is lost by 
imputing data for participants who did not fully complete the EP. A further 
supplementary analysis will evaluate efficacy in those participants who 
adhere to randomized treatment, defined as ITT participants with at least one 


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Endpoint
Statistical Analysis Methods
on-treatment Hgb during the EP (this approach corresponds to evaluating an 
efficacy estimand). A similar “tipping point” analysis as that described above 
for the primary analysis will be performed for this “on-treatment” analysis. In 
addition, a supplementary per-protocol analysis will estimate the treatment 
effect in participants who strongly adhere to the protocol, and sensitivity 
analyses to explore a shorter EP (Weeks 28 to 36) will be performed for the 
primary effectiveness estimand and “on-drug” efficacy estimand. Full details 
of all sensitivity and supplementary analyses will be provided in the RAP.
Covariates and Subgroups of Interest: The primary endpoint will be 
evaluated for a set of pre-specified subgroups to support the proposed 
indication. Subgroup analyses are aimed to assess for consistency with the 
overall result, they may have low power if the subgroup is small. Statistical 
models will be adjusted for the covariates used in the original analysis 
(randomization stratification factor and baseline hemoglobin), subgroup, 
treatment and treatment by subgroup interaction. Point estimates and two-
sided 95% CIs will be estimated (presented on Forest Plots) and the 
subgroup by treatment interaction p-value calculated. Subgroup analyses will 
not be adjusted for multiplicity. Further subgroups/covariates may be defined 
in the RAP.
Category
Subgroups
Age 
<65 years, ≥65 to <75 years, ≥75 years 
Gender 
Female, Male 
Race group 
American Indian or Alaskan Native, Asian, 
Black, Native Hawaiian or Other Pacific 
Islander, White, Mixed Race 
Ethnicity 
Hispanic, non-Hispanic 
Region 
Regions listed in Appendix 7
Country
Countries listed in Appendix 7
Dialysis vintage
0 to <2 years, 2 to <5 years, ≥5 years
Prior rhEPO dose 
<7,000 U/week, ≥7,000 U/week
rhEPO Hypo-responsiveness 
No, Yes (see RAP for definition)
Baseline Hgb 
<9 g/dL, 9 to <10 g/dL, 10 to 11 g/dL, >11 
g/dL
BMI 
<30 kg/m2, ≥30 kg/m2
Weight 
< 75kg, ≥75kg 
Baseline hsCRP
≤3 mg/L, >3 mg/L
United States
US, Non-US
Additional exploratory subgroups may be defined in the RAP. Additional 
subgroup analysis for other study endpoints may be performed, and will be 
defined in the RAP.
Principal 
Secondary
Conditional on the primary endpoint achieving non-inferiority at the one-sided 
2.5% level, statistical testing will progress to the principal secondary endpoint 
with a focus on superiority using a one-sided 2.5% significance level.


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Endpoint
Statistical Analysis Methods
For the principal secondary endpoint of average monthly IV iron dose up to 
Week 52 endpoint, IV iron use for all participants will be recorded in the 
eCRF and the average monthly IV iron dose up to week 52 while on 
treatment will be calculated. An ANCOVA model will be used to compare the 
difference in this average monthly IV iron dose per participant between arms, 
including factors for baseline dose, treatment and the randomization 
stratification factor.
Secondary
All analyses of secondary endpoints are of exploratory nature. Summary 
statistics along with nominal one-sided p-values and two-sided 95% 
confidence intervals will be used to describe the results.
Exploratory
Will be described in the reporting and analysis plan
Patient 
Reported 
Outcomes
Analysis to compare the participant reported effects of daprodustat and 
rhEPO on symptoms, as discussed in Section 9.9, will be described in the 
RAP.
10.3.1.1.
Multiplicity Strategy
The primary endpoint will be tested first for non-inferiority, using the lower limit of the
2-sided 95% confidence interval. Conditional on achieving statistical significance (i.e.,
passing the primary gate by establishing non-inferiority) the single principal secondary
endpoint will be tested for superiority using a one-sided 2.5% significance level. This 
two-step hierarchical strategy will preserve the study-wise Type I error rate at a one-sided 
2.5% level.
The additional secondary/exploratory endpoints, if tested, will not be adjusted for 
multiplicity. A nominal one-sided 2.5% significance level will be applied per test.
10.3.2.
Safety Analyses
All safety analyses will be performed on the Safety Population. 
Endpoint
Statistical Analysis Methods
Adverse Events
All AEs (i.e. Non-serious, serious, and AEs of special interest) will be 
descriptively summarized by treatment group.
Vital signs
Summary statistics at each visit will be generated by treatment group 
Laboratory data
Summary statistics at each visit will be generated by treatment group.  Number 
of participants who meet protocol defined stopping criteria (e.g. liver chemistry) 
will be summarized by treatment group. 
Randomized 
The number of participants who discontinued randomized treatment will be 


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Endpoint
Statistical Analysis Methods
treatment 
discontinuations
summarized by reason for discontinuation and treatment group.  The time to 
discontinuing randomized treatment will be presented graphically and assessed.
Cardiovascular 
Safety 
Endpoints
This study is not designed or sufficiently powered for formal statistical analyses 
to assess cardiovascular safety. With fewer than 80 first-occurrence MACE 
(defined as all-cause mortality, non-fatal MI, or non-fatal stroke) expected to 
occur during the trial, incidence rates and two-sided 95% CIs will be computed 
for the following mortality and CV composite or component endpoints: 1) MACE; 
2) MACE or a thromboembolic event (vascular access thrombosis, a 
symptomatic deep vein thrombosis or a symptomatic pulmonary embolism); 3) 
MACE or hospitalization for heart failure; 4) all cause mortality; 5) CV mortality; 
6) MI (fatal and non-fatal); 7) stroke (fatal and non-fatal); 8) CV mortality or non-
fatal MI; 9) all cause hospitalization.
Full details of all safety data reporting will be described in the RAP.
10.3.3.
Other Analyses
PK, pharmacodynamic, and biomarker exploratory analyses will be described in the RAP. 
10.3.3.1.
Patient Reported Outcome Analyses
Analysis to compare the participant reported effects of daprodustat and rhEPO on 
symptoms as discussed in Section 9.9, will be described in the RAP.
10.3.3.2.
Pharmacokinetic/Pharmacodynamic Analyses
The following plasma PK parameters will be determined for daprodustat and its 
predominant metabolites: Ctau (pre-dose) and Cmax.
Plasma daprodustat and metabolite concentration data will be listed and summarized by 
planned collection time and daprodustat dose administered at the PK visit.  PK parameter 
data will be listed and summarized by daprodustat dose administered at PK visit, and 
dose-normalized (per mg) PK parameter data will also be summarized.
The exploratory graphics described below will be created.  Based on these, and the 
efficacy and safety results obtained, post-hoc exploratory exposure-response/safety 
modeling may be conducted.  

Scatter plots of Cmax of three-times weekly dosed daprodustat extrapolated to 
daprodustat dose at the PK sample multiplied by the mean weekly daprodustat dose 
during the EP vs. the percent time within the Hgb target range during the EP

Scatter plots of Cmax of three-times weekly dosed daprodustat extrapolated to 
daprodustat dose at the PK sample multiplied by the mean weekly daprodustat dose 
over 52 weeks vs. mean Hgb over the 52-week treatment period 


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10.3.3.3.
Other Exploratory Analyses
The exploratory graphics described below will be created.  

Scatter plots of mean weekly daprodustat dose over the EP vs. the percent time 
within the Hgb target range during the EP

Scatter plots of mean weekly three-times weekly daprodustat dose over 52 weeks vs. 
mean Hgb over the 52-week treatment period

Boxplots of mean weekly three-times weekly daprodustat dose, while on study
treatment for participants without MACE, and before the event for participants with 
MACE or combined safety endpoint 

Boxplots of Cmax of three-times weekly dosed daprodustat extrapolated to 
daprodustat dose at PK sample multiplied by the daprodustat dose at the time of 
MACE or combined safety endpoint (or end of study if no endpoint) by participants 
with or without MACE or combined safety endpoint
10.3.4.
Interim Analyses
The IDMC will periodically receive unblinded safety reports containing clinical 
endpoints (whether adjudicated or pending adjudication) and SAEs, from an independent 
Statistical Data Analysis Center (SDAC) while Phase 3 studies with daprodustat are 
ongoing. The IDMC may recommend stopping this study for safety at any time.  
There are no plans to evaluate interim data for the purposes of stopping based on Hgb 
efficacy data.
Further details will be specified in the IDMC charter and RAP.


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11.
REFERENCES
Agarwal R, Kusek JW, Pappas MK.  A randomized trial of intravenous and oral iron in 
chronic kidney disease. Kidney Int. 2015; 88:905-14.
Beserab A, Reyes C, Hornberger J. Meta-Analysis of Subcutaneous Versus Intravenous 
Epoetin in Maintenance Treatment of Anemia in Hemodialysis Patients. Am J of Kidney 
Dis, Vol 40, No 3 (September), 2002: pp 439-446.
Brodie, M. J.; Mintzer, S.; Pack, A. M.; Gidal, B. E.; Vecht, C. J.; Schmidt, D. Enzyme 
induction with antiepileptic drugs: Cause for concern? Epilepsia 2013, 54(1):11–27.
Burnier M, Douchamps JA, Tanghe A, Demey J, Perrault L, Foster CE, et al. Less 
frequent dosing of erythropoiesis stimulating agents in patients undergoing dialysis: a 
European multicentre cost study. J Med Econ. 2009,12:77-86.
Campochiaro et al., Ocular versus Extraocular Neovascularization: Mirror Images or 
Vague Resemblances; Invest Ophthalmol & Vis Sci 2006. 47:462-474.
Choi P, Farouk M, Manamley N, Addison J. Dose Conversion Ratio in Hemodialysis 
Patients Switched from Darbepoetin Alfa to PEG-Epoetin Beta: AFFIRM Study. Adv 
Ther. 2013; 30:1007–1017
FDA Drug Safety Communication: Modified dosing recommendations to improve the 
safe use of erythropoiesis-stimulating agents (ESAs) in chronic kidney disease. Safety 
Announcement issued June 24, 2011.  Link: 
http://www.fda.gov/Drugs/DrugSafety/ucm259639.htm#sa
Formenti et al., Cardiopulmonary function in two human disorders of the hypoxia-
inducible factor (HIF) pathway: von Hippel-Lindau disease and HIF-2{alpha} gain-of-
function mutation.  FASEB J. 2011, 25(6): 2001-2011.
GlaxoSmithKline Document Number 2014N219785_00. Study ID PHI113633. A Phase 
2B, randomized, blinded, dose-ranging, active-controlled, parallel-group, multi-center 
study to evaluate the dose response relationship of GSK1278863 over the first 4 weeks of 
treatment and evaluate the safety and efficacy of GSK1278863 over 24 weeks in 
hemodialysis-dependent subjects with anemia associated with chronic kidney disease 
who switch from recombinant human erythropoietin. 15-Dec-2015.
GlaxoSmithKline Document Number 2015N226659_05. Study ID 200807. A Phase 3 
randomized, open-label (sponsor-blind), active-controlled, parallel-group, multi-center, 
event driven study in dialysis subjects with anemia associated with chronic kidney 
disease to evaluate the safety and efficacy of daprodustat compared to recombinant 
human erythropoietin, following a switch from erythropoietin-stimulating agents. Anemia 
Studies in CKD: Erythropoiesis via a Novel PHI Daprodustat-Dialysis (ASCEND-D). 05-
Oct-2017.
GlaxoSmithKline Document Number 2016N309671_00. Study ID 204836. A 29-day, 
randomized, double-blinded, placebo-controlled, parallel-group, multi-center study to 


2016N279035_00
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77
evaluate the efficacy, safety and pharmacokinetics of three-times weekly dosing of 
GSK1278863 in hemodialysis-dependent subjects with anemia associated with chronic 
kidney disease who are switched from a stable dose of an erythropoiesis-stimulating 
agent. Report Date 27-SEP-2017. 
GlaxoSmithKline Document Number RM2008/00267/08.  Daprodustat (GSK1278863) 
Investigator’s Brochure. 01-Aug-2017.
McGowan T, Vaccaro NM, Beaver JS, Massarella J, Wolfson M. Pharmacokinetic and 
pharmacodynamics profiles of extended dosing of epoetin alfa in anemic patients who 
have chronic kidney disease and are not on dialysis. Clin J Am Soc Nephrol 2008; 3: 
1006-1014.
Muz et al., The role of hypoxia and HIF-dependent signaling events in rheumatoid 
arthritis, Arthritis Research & Therapy 2009. 11:201-210.
Ohnhaus, E. E.; Breckenridge, A. M.; Park, B. K. Urinary Excretion of 6-
Hydroxycortisol and the Time Course Measurement of Enzyme Induction in Man. 
European Journal of Clinical Pharmacology 1989, 36:39-46.
Smith et al., Mutation of von Hippel–Lindau Tumour Suppressor and Human 
Cardiopulmonary Physiology PLOS 2006. 3:1176-1186.
Stephens JM, Emerson LC, Spry LA, Caloyeras JP, Anderson ER, Reitan JF, et al. Time 
savings of weekly versus three-times-per-week administration of erythropoiesis 
stimulating agents in United States dialysis patients. Curr Med Res Opin. 2016; 32:313-
20.
Sterner G, Prutz KG. Letter to Editor: Conversion from epoetin beta to darbepoetin: what 
is the equivalent dose? Nephrol Dial Transplant. 2008; 23: 4084
Szczech L.A, Barnhart HX, Inrig JK, Reddan DN, Sapp S, Califf RM, et al. Secondary 
analysis of the CHOIR trial epoetin-alpha dose and achieved Hgb outcomes. Kidney Int. 
2008; 74:791-798.
Westra et al., Hypoxia-Inducible Factor-1 as Regulator of Angiogenesis in Rheumatoid 
Arthritis - Therapeutic Implications.  Current Medicinal Chemistry 2010. 17:254-263.


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12.
APPENDICES
12.1.
Appendix 1: Abbreviations and Trademarks
Abbreviations
AE
Adverse event
AESI
Adverse event of special interest
ALT
Alanine transaminase
ANCOVA
Analysis of Covariance
ANSM
L'Agence nationale de sécurité du médicament et des 
produits de santé 
AST
Aspartate transaminase
BP
Blood pressure
CEC
Clinical Events Committee
CHF
Congestive Heart Failure
CI
Confidence interval
CKD
Chronic kidney disease
CNIL
Commission Nationale de I’Informatique et des Libertés
CPK
Creatine phosphokinase 
CRA
Clinical Research Assistant 
CT
Computed tomography
CTR
Clinical Trials Register
CV
Cardiovascular
DBP
Diastolic blood pressure
ECG
Electrocardiogram
eCRF
Electronic case report form
EDW
Estimated dry weight
EP
Evaluation period
EPO
Erythropoietin
ESA
Erythropoiesis-stimulating agent
FDA
Food and Drug Administration
FSH
Follicle stimulating hormone
GCP
Good Clinical Practice
GCSP
Global Clinical Safety and Pharmacovigilance
GI
Gastrointestinal
GSK
GlaxoSmithKline
HbA1c
Glycated hemoglobin
HD
Hemodialysis
HDL-c
High density lipoprotein-C
HDPE
High density polyethylene
Hgb
Hemoglobin
HIF
Hypoxia-inducible factor
HIF-PHI
Hypoxia inducible factor prolyl hydroxylase inhibitor 
HR
Heart rate
HRT
Hormone replacement therapy


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hsCRP
High sensitivity C-reactive protein
IB
Investigator’s Brochure
ICH
International Council for Harmonization
IDMC
Independent Data Monitoring Committee
IEC
Independent Ethics Committee
iPTH
Intact parathyroid hormone
IRB
Institutional Review Board
IRT
Interactive Response Technology
ITT
Intent-to-treat
IV
Intravenous
KDIGO
Kidney Disease Improving Global Outcomes
KDOQI
Kidney Disease Outcomes Quality Initiative
LDH
Lactate dehydrogenase 
LDL-C
Low density lipoprotein-C
M2
GSK2391220, M2 metabolite of GSK1278863 
(daprodustat)
M3
GSK2531403 and GSK2506104, stereoisomers of the M3 
chiral metabolite of GSK1278863 (daprodustat)
M4
GSK2487818, M4 metabolite of GSK1278863 
(daprodustat)
M5
GSK2531399 and GSK2506102, stereoisomers of the M5 
chiral metabolite of GSK1278863 (daprodustat)
M6
GSK2531398 and GSK2531407, stereoisomers of the M6 
chiral metabolite of GSK1278863 (daprodustat)
M13
GSK2531400 and GSK2531401, stereoisomers of the M13 
chiral metabolite of GSK1278863 (daprodustat)
MACE
Major adverse cardiovascular event
MAP
Mean arterial pressure
MCH
Mean corpuscular hemoglobin
MCHC
Mean corpuscular hemoglobin concentration
MCV
Mean corpuscular volume
MedDRA
Medical Dictionary for Regulatory Activities
MI
Myocardial infarction
MRI
Magnetic resonance imaging
MSDS
Material Safety Data Sheet
NYHA
New York Heart Association
PASP
Pulmonary artery systolic pressure
PD
Pharmacodynamic
PEG
Polyethylene glycol
PGI-C
Patient Global Impression of Change
PGI-S
Patient Global Impression of Severity
PHI
Prolyl hydroxylase inhibitor
PK
Pharmacokinetic
PP
Per protocol
PPD
Pharmaceutical Product Development, LLC
PRBC
Packed red blood cells


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PSRAE
Possible Suicidality Related Adverse Events 
QC
Quality control
QT
Q-T interval
QTc
Q-T interval corrected for heart rate
QTcB
Bazett’s correction of QT interval
RAP
Reporting and Analysis Plan
RBC
Red blood cell
RDW
Red blood cell distribution width
rhEPO
Recombinant human erythropoietin 
SAE
Serious adverse event
SBP
Systolic blood pressure
SC
Subcutaneous
SD
Standard deviation
SDAC
Statistical Data Analysis Center
SRM
Study Reference Manual
TIBC
Total iron binding capacity
TSAT
Transferrin saturation
U
Units
UIBC
Unsaturated iron binding capacity
ULN
Upper limit of normal
US
United States
VEGF
Vascular endothelial growth factor
WBC
White blood cells
Trademark Information
Trademarks of the GlaxoSmithKline 
group of companies
Trademarks not owned by the 
GlaxoSmithKline group of companies
NONE
Epogen
HemoCue
MedDRA


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12.2.
Appendix 2: Study Governance Considerations
12.2.1.
Regulatory and Ethical Considerations

This study will be conducted in accordance with the protocol and with:

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 ICH Good Clinical Practice (GCP) Guidelines

Applicable laws and regulations

The protocol, protocol amendments, ICF, Investigator Brochure, and other 
relevant documents (e.g., advertisements) must be submitted to an IRB/IEC by 
the investigator and reviewed and approved by the IRB/IEC before the study is 
initiated. 

Any amendments to the protocol will require IEC/IRB approval before 
implementation of changes made to the study design, except for changes 
necessary to eliminate an immediate hazard to study participants. 

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/EC

Notifying the IRB/IEC of SAE 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 21 CFR, ICH guidelines, the IRB/IEC, European 
regulation 536/2014 for clinical studies (if applicable), and all other 
applicable local regulations
12.2.2.
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 are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study.
12.2.3.
Informed Consent Process

The investigator or his/her representative will explain the nature of the study to 
the participant or his/her legally authorized representative and answer all 
questions regarding the study. 


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
Participants must be informed that their participation is voluntary. Participants 
or their legally authorized representative will be required to sign a statement of 
informed consent that meets the requirements of 21 CFR 50, local regulations, 
ICH guidelines, Health Insurance Portability and Accountability Act (HIPAA) 
requirements, where applicable, and the IRB/IEC or study center. 

The medical record must include a statement that written informed consent was 
obtained before the participant was enrolled in the study and the date the written 
consent was obtained. The authorized person obtaining the informed consent 
must also sign the ICF.

Participants 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 participant or the participant’s 
legally authorized representative. 

Participants who are rescreened are required to sign a new ICF.
12.2.4.
Data Protection

Participants will be assigned a unique identifier by the sponsor. Any participant 
records or datasets that are transferred to the sponsor will contain the identifier 
only; participant names or any information which would make the participant 
identifiable will not be transferred. 

The participant 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 participant. 

The participant 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.
12.2.5.
Committees Structure
In addition to GSK, medical governance will also be provided by the following 
independent committees. Additional information about each committee is included in the 
respective committee charter which is available upon request.
12.2.5.1.
Independent Data Monitoring Committee
An IDMC will be utilized in this study to ensure external objective review of safety and 
efficacy data in order to protect the ethical and safety interests of participants and to 
protect the scientific validity of the study.  The schedule of any planned interim analysis 
and the analysis plan for IDMC review is described in the charter.
12.2.5.2.
Clinical Events Committee
An external independent Clinical Events Committee (CEC) blinded to study treatment 
allocation will adjudicate all events reported during this study that constitute events of 
MACE, thromboembolic events and hospitalization for heart failure, as outlined in 


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Section 9.2.5. Further details are contained within the CEC Charter (available on 
request).
12.2.6.
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.

Authorship will be determined by mutual agreement and in line with 
International Committee of Medical Journal Editors authorship requirements.
12.2.7.
Dissemination of Clinical Study Data

Where required by applicable regulatory requirements, an investigator signatory 
will be identified for the approval of the clinical study report.  The investigator 
will be provided reasonable access to statistical tables, figures, and relevant 
reports and will have the opportunity to review the complete study results at a 
GSK site or other mutually-agreeable location.

GSK will also provide the investigator with the full summary of the study 
results.  The investigator is encouraged to share the summary results with the 
study participants, as appropriate.

GSK will provide the investigator with the randomization codes for their site 
only after completion of the full statistical analysis.

The procedures and timing for public disclosure of the results summary and for 
development of a manuscript for publication will be in accordance with GSK 
Policy.

A manuscript will be progressed for publication in the scientific literature if the 
results provide important scientific or medical knowledge.
12.2.8.
Data Quality Assurance

All participant data relating to the study will be recorded on printed or electronic 
CRF unless transmitted to the sponsor or designee electronically (e.g., 
laboratory data). The investigator is responsible for verifying that data entries 
are accurate and correct by physically or electronically signing the CRF. 

The investigator must maintain accurate documentation (source data) that 
supports the information entered in the CRF. 


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
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 CRF by authorized site personnel are accurate, complete, 
and verifiable from source documents; that the safety and rights of participants 
are being protected; and that the study is being conducted in accordance with the 
currently approved protocol and any other study agreements, ICH GCP, and all 
applicable regulatory requirements. 

Records and documents, including signed ICF, pertaining to the conduct of this 
study must be retained by the investigator for 25 years from the issue of the final 
Clinical Study Report (CSR)/ equivalent summary 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. 
12.2.9.
Source Documents

Source documents provide evidence for the existence of the participant and 
substantiate the integrity of the data collected. Source documents are filed at the 
investigator’s site.

Data reported on the CRF or entered in 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.

Definition of what constitutes source data can be found in the study specific 
monitoring plan.
12.2.10.
Study and Site Closure
GSK or its designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of GSK. 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 protocol, the requirements of the 
IRB/IEC or local health authorities, the sponsor's procedures, or GCP guidelines


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
Inadequate recruitment of participants by the investigator

Discontinuation of further study treatment development


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12.3.
Appendix 3: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting
12.3.1.
Definition of AE
AE Definition

An AE is any untoward medical occurrence in a clinical study participant, temporally 
associated with the use of a study treatment, whether or not considered related to the 
study treatment.

NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a study treatment.
Events Meeting the AE Definition 

Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) 
or other safety assessments (e.g., ECG, radiological scans, vital signs 
measurements), including those that worsen from baseline, considered clinically 
significant in the medical and scientific judgment of the investigator (i.e., not related 
to progression of underlying disease).

Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition.

New conditions detected or diagnosed after study treatment administration even 
though it may have been present before the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
treatment or a concomitant medication. Overdose per se will not be reported as an 
AE/SAE unless it is an intentional overdose taken with possible suicidal/self-
harming intent. Such overdoses should be reported regardless of sequelae.

"Lack of efficacy" or "failure of expected pharmacological action" per se will not be 
reported as an AE or SAE. Such instances will be captured in the efficacy 
assessments. However, the signs, symptoms, and/or clinical sequelae resulting from 
lack of efficacy will be reported as AE or SAE if they fulfill the definition of an AE 
or SAE. 

The signs, symptoms, and/or clinical sequelae resulting from lack of efficacy will be 
reported as AE or SAE if they fulfill the definition of an AE or SAE. Also, "lack of 
efficacy" or "failure of expected pharmacological action" constitutes an AE or SAE.
Events NOT Meeting the AE Definition 

Any clinically significant abnormal laboratory findings or other abnormal safety 


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assessments which are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the participant’s condition.

The disease/disorder being studied or expected progression, signs, or symptoms of 
the disease/disorder being studied, unless more severe than expected for the 
participant’s condition.

Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that 
leads to the procedure is the AE.

Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).

Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present 
or detected at the start of the study that do not worsen.
12.3.2.
Definition of SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met (e.g., hospitalization for signs/symptoms of the disease under study, 
death due to progression of disease).
A SAE is defined as any untoward medical occurrence that, at any dose:
a.
Results in death
b.
Is life-threatening
The term 'life-threatening' in the definition of 'serious' refers to an event in which the 
participant was at risk of death at the time of the event. It does not refer to an event, 
which hypothetically might have caused death, if it were more severe.
Requires inpatient hospitalization or prolongation of existing hospitalization
In general, hospitalization signifies that the participant has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for observation 
and/or treatment that would not have been appropriate in the physician’s office or 
outpatient setting. Complications that occur during hospitalization are AE. If a 
complication prolongs hospitalization or fulfills any other serious criteria, the event is 
serious. When in doubt as to whether “hospitalization” occurred or was necessary, the AE 
should be considered serious.
Hospitalization for elective treatment of a pre-existing condition that did not worsen from 
baseline is not considered an AE.
Results in persistent disability/incapacity

The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.

This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 


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and accidental trauma (e.g., sprained ankle) which may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption.
Is a congenital anomaly/birth defect
Other situations:

Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that may 
not be immediately life-threatening or result in death or hospitalization but may 
jeopardize the participant or may require medical or surgical intervention to prevent 
one of the other outcomes listed in the above definition. These events should usually 
be considered serious.
Examples of such events include invasive or malignant cancers, intensive treatment 
in an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse.
12.3.3.
Definition of Cardiovascular Events
Cardiovascular Events (CV) Definition:
Investigators will be required to fill out the specific CV event page of the CRF for the 
following AEs and SAEs:

Arrhythmias

Valvulopathy

Pulmonary hypertension

Revascularization
12.3.4.
Recording AE and SAE
AE and SAE Recording

When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory, and diagnostics reports) 
related to the event.

The investigator will then record all relevant AE/SAE information in the CRF.

It is not acceptable for the investigator to send photocopies of the participant’s 
medical records to GSK in lieu of completion of the GSK /AE/SAE CRF page.

There may be instances when copies of medical records for certain cases are 
requested by GSK. In this case, all participant identifiers, with the exception of the 
participant number, will be redacted on the copies of the medical records before 
submission to GSK.


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
The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not 
the individual signs/symptoms) will be documented as the AE/SAE.
Assessment of Intensity
The investigator will make an assessment of intensity for each AE and SAE reported 
during the study and assign it to 1 of the following categories: 

Mild: An event that is easily tolerated by the participant, causing minimal discomfort 
and not interfering with everyday activities.

Moderate: An event that causes sufficiently discomfort and interferes with normal 
everyday activities.

Severe: An event that prevents normal everyday activities. An AE that is assessed as 
severe should not be confused with an SAE. Severe is a category utilized for rating 
the intensity of an event; and both AE and SAE can be assessed as severe.
An event is defined as ‘serious’ when it meets at least 1 of the predefined outcomes 
as described in the definition of an SAE, NOT when it is rated as severe.
Assessment of Causality

The investigator is obligated to assess the relationship between study treatment and 
each occurrence of each AE/SAE.

A "reasonable possibility" of a relationship conveys that there are facts, evidence, 
and/or arguments to suggest a causal relationship, rather than a relationship cannot 
be ruled out.

The investigator will use clinical judgment to determine the relationship.

Alternative causes, such as underlying disease(s), concomitant therapy, and other 
risk factors, as well as the temporal relationship of the event to study treatment 
administration will be considered and investigated.

The investigator will also consult the Investigator’s Brochure (IB) and/or Product 
Information, for marketed products, in his/her assessment.

For each AE/SAE, the investigator must document in the medical notes that he/she 
has reviewed the AE/SAE and has provided an assessment of causality.

There may be situations in which an SAE has occurred and the investigator has 
minimal information to include in the initial report to GSK. However, it is very 
important that the investigator always make an assessment of causality for 
every event before the initial transmission of the SAE data to GSK.

The investigator may change his/her opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality 
assessment.

The causality assessment is one of the criteria used when determining regulatory 


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reporting requirements.
Follow-up of AE and SAE

The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by GSK to 
elucidate the nature and/or causality of the AE or SAE as fully as possible. This may 
include additional laboratory tests or investigations, histopathological examinations, 
or consultation with other health care professionals.

If a participant dies during participation in the study or during a recognized follow-
up period, the investigator will provide GSK with a copy of any post-mortem 
findings including histopathology.

New or updated information will be recorded in the originally completed CRF.

The investigator will submit any updated SAE data to GSK within 24 hours of 
receipt of the information.
12.3.5.
Reporting of SAE to GSK
SAE Reporting to GSK via Electronic Data Collection Tool

The primary mechanism for reporting SAE to GSK will be the electronic data 
collection tool.

If the electronic system is unavailable, then the site will use the paper SAE data 
collection tool (see next section) in order to report the event within 24 hours.

The site will enter the SAE data into the electronic system as soon as it becomes 
available.

The investigator or medically-qualified sub-investigator must show evidence within 
the eCRF (e.g., check review box, signature, etc.) of review and verification of the 
relationship of each SAE to IP/study participation (causality) within 72 hours of SAE 
entry into the eCRF.

After the study is completed at a given site, the electronic data collection tool will be 
taken off-line to prevent the entry of new data or changes to existing data.

If a site receives a report of a new SAE from a study participant or receives updated 
data on a previously reported SAE after the electronic data collection tool has been 
taken off-line, then the site can report this information on a paper SAE form (see 
next section) or to the medical monitor or SAE coordinator by telephone.

Contacts for SAE reporting can be found in SRM.
SAE Reporting to GSK via Paper CRF

The site will use the paper SAE data collection tool in order to report the event 


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within 24 hours, only if the electronic system is unavailable.

Facsimile transmission of the SAE paper CRF is the preferred method to transmit 
this information to the medical monitor or the SAE coordinator.

In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable with a copy of the SAE data collection tool sent by overnight 
mail or courier service.

Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE CRF pages within the designated reporting time frames.

Contacts for SAE reporting can be found in SRM.


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12.4.
Appendix 4: Contraceptive Guidance and Collection of 
Pregnancy Information
Definitions
Woman of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming post-menopausal 
unless permanently sterile (see below)
Women in the following categories are not considered WOCBP
1.
Premenarchal
2.
Premenopausal female with ONE of the following:

Documented hysterectomy

Documented bilateral salpingectomy

Documented bilateral oophorectomy
Note:  Documentation can come from the site personnel’s: review of participant’s 
medical records, medical examination, or medical history interview.
3.
Postmenopausal female

A postmenopausal state is defined as no menses for 12 months without an 
alternative medical cause. A high follicle stimulating hormone (FSH) level in 
the postmenopausal range may be used to confirm a postmenopausal state in 
women not using hormonal contraception or hormonal replacement therapy 
(HRT). However, in the absence of 12 months of amenorrhea, a single FSH 
measurement is insufficient. 

Females on HRT and whose menopausal status is in doubt will be required to 
use one of the non-hormonal highly effective contraception methods if they wish 
to continue their HRT during the study. Otherwise, they must discontinue HRT 
to allow confirmation of postmenopausal status before study enrollment.
Contraception Guidance
Female participants
Female participants of childbearing potential are eligible to participate if they agree to 
use a highly effective method of contraception consistently and correctly as described in  
Table 10, from at least 28 days prior to the first dose of study treatment and until at least 
28 days after the last dose of study treatment and completion of the Follow-up visit (4 to 
6 weeks after the end of study treatment); those who permanently discontinue study 
treatment prior to the end of study should continue contraceptive methods following the 
Early Treatment Discontinuation Visit until the final pregnancy test assessment at a 
subsequent study visit (at least 4 weeks after the end of study treatment) as described in 
the SoA in Section 2.


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Table 10
Highly Effective Contraceptive Methods
Highly Effective Contraceptive Methods That Are User Dependent a
Failure rate of <1% per year when used consistently and correctly. 
Combined (estrogen- and progestogen-containing) hormonal contraception associated with 
inhibition of ovulationb

oral

intravaginal 

transdermal 
Progestogen-only hormonal contraception associated with inhibition of ovulationb

injectable 
Highly Effective Methods That Are User Independent 

Implantable progestogen-only hormonal contraception associated with inhibition of 
ovulationb

Intrauterine device (IUD)

Intrauterine hormone-releasing system (IUS)

bilateral tubal occlusion
Vasectomized partner 
(A vasectomized partner is a highly effective contraception method provided that the partner is 
the sole male sexual partner of the WOCBP and the absence of sperm has been confirmed. If 
not, an additional highly effective method of contraception should be used.)
Sexual abstinence 
(Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study drug. The 
reliability of sexual abstinence needs to be evaluated in relation to the duration of the study and 
the preferred and usual lifestyle of the participant.)
NOTES: 
a.
Typical use failure rates may differ from those when used consistently and correctly. Use should be consistent 
with local regulations regarding the use of contraceptive methods for participants in clinical studies. 
b.
Hormonal contraception may be susceptible to interaction with the study drug, which may reduce the efficacy of 
the contraceptive method. In this case two highly effective methods of contraception should be utilized during the 
treatment period and for at least 4 weeks after the last dose of study treatment, and until the follow-up visit is 
performed or until the final pregnancy test assessment at a subsequent study visit for participants who 
permanently discontinued study treatment.
Pregnancy Testing

WOCBP should only be included after a confirmed negative highly sensitive serum 
pregnancy test during screening (Week -4).


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
Additional pregnancy testing should be performed as specified in the SoA (Section 
2), and as required locally.

Pregnancy testing will be assayed in the central laboratory.
Collection of Pregnancy Information
Female Participants who become pregnant

Investigator will collect pregnancy information on any female participant, who 
becomes pregnant while participating in this study. 

Information will be recorded on the appropriate form and submitted to GSK within 
24 hours of learning of a participant's pregnancy. 

Participant will be followed to determine the outcome of the pregnancy. The 
investigator will collect follow up information on participant and neonate, which will 
be forwarded to GSK. Generally, follow-up will not be required for longer than 6 to 
8 weeks beyond the estimated delivery date.  

Any termination of pregnancy will be reported, regardless of fetal status (presence or 
absence of anomalies) or indication for procedure. 

While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy will be reported as an AE or 
SAE. 

A spontaneous abortion is always considered to be an SAE and will be reported as 
such.  

Any SAE occurring as a result of a post-study pregnancy which is considered 
reasonably related to the study treatment by the investigator, will be reported to GSK
as described in Appendix 3. While the investigator is not obligated to actively seek 
this information in former study participants, he or she may learn of an SAE through 
spontaneous reporting. 
Any female participant who becomes pregnant while participating will discontinue 
study treatment.


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12.5.
Appendix 5: Genetics
USE/ANALYSIS OF DNA

Genetic variation may impact a participant’s response to therapy, susceptibility, 
severity and progression of disease. Variable response to therapy may be due to 
genetic determinants that impact drug absorption, distribution, metabolism, and 
excretion; mechanism of action of the drug; disease etiology; and/or molecular 
subtype of the disease being treated. Therefore, where local regulations and IRB/IEC 
allow, a blood sample will be collected for DNA analysis

DNA samples will be used for research related to daprodustat or anemia of chronic 
kidney disease and related diseases. They may also be used to develop tests/assays 
including diagnostic tests) related to daprodustat or PHIs, and anemia of chronic 
kidney disease. Genetic research may consist of the analysis of one or more 
candidate genes or the analysis of genetic markers throughout the genome or analysis 
of the entire genome, as appropriate.

DNA samples will be analyzed if it is hypothesized that this may help further 
understand the clinical data. 

The samples may be analyzed as part of a multi-study assessment of genetic factors 
involved in the response to daprodustat or study treatments of this class. The results 
of genetic analyses may be reported in the clinical study report or in a separate study 
summary.

The sponsor will store the DNA samples in a secure storage space with adequate 
measures to protect confidentiality. 

The samples will be retained while research on daprodustat (or study treatments of 
this class) or anemia of chronic kidney disease continues but no longer than 15 years 
after the last participant’s last visit or other period as per local requirements.


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12.6.
Appendix 6: Liver Safety Required Actions and Follow-up 
Assessments and Study Treatment Restart Guidelines
12.6.1.
Liver Safety Required Actions and Follow-up Assessments
Phase III-IV liver chemistry stopping and increased monitoring criteria have been 
designed to assure participant safety and evaluate liver event etiology.
Phase III-IV liver chemistry stopping criteria and required follow up assessments 
Liver Chemistry Stopping Criteria - Liver Stopping Event
ALT-absolute
ALT 8xULN
ALT Increase
ALT 5xULN but <8xULN persists for 2 weeks
ALT 3xULN but <5xULN persists for 4 weeks
Bilirubin1, 2
ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin) 
INR2
ALT 3xULN and INR>1.5, if INR measured
Cannot 
Monitor
ALT 5xULN but <8xULN and cannot be monitored weekly for 2 weeks
ALT 3xULN but <5xULN and cannot be monitored weekly for 4 weeks
Symptomatic3
ALT  3xULN associated with symptoms (new or worsening) believed to be 
related to liver injury or hypersensitivity
Required Actions and Follow up Assessments 
Actions
Follow Up Assessments

Immediately discontinue study treatment 

Report the event to GSK within 24 hours

Complete the liver event eCRF and complete 
an SAE data collection tool if the event also 
meets the criteria for an SAE2

Perform liver event follow up assessments 

Monitor the participant until liver chemistries 
resolve, stabilize, or return to within baseline 
(see MONITORING below)

Do not restart participant with study 
treatment unless allowed per protocol and 
GSK Medical Governance approval is 
granted (refer to Section 12.6.2)

Viral hepatitis serology4

Obtain INR and recheck with each liver 
chemistry assessment until the 
transaminases values show downward 
trend

Only in those with underlying chronic 
hepatitis B at study entry (identified by 
positive hepatitis B surface antigen) 
quantitative hepatitis B DNA and hepatitis 
delta antibody5.

Obtain blood sample for pharmacokinetic 
(PK) analysis, within 24 hours after last 
dose6

Serum creatine phosphokinase (CPK) and 


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
If restart is not allowed or not granted, 
permanently discontinue study treatment and 
may continue participant in the study for any 
protocol specified follow up assessments
MONITORING:
For bilirubin or INR criteria:

Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin) and perform 
liver event follow up assessments within 24 
hrs

Monitor participants twice weekly until liver 
chemistries resolve, stabilize or return to 
within baseline

A specialist or hepatology consultation is 
recommended
For All other criteria:

Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin) and perform 
liver event follow up assessments within 24 
to 72 hrs 

Monitor participants weekly until liver 
chemistries resolve, stabilize or return to 
within baseline
lactate dehydrogenase (LDH).

Fractionate bilirubin, if total 
bilirubin2xULN

Obtain complete blood count with 
differential to assess eosinophilia

Record the appearance or worsening of 
clinical symptoms of liver injury, or 
hypersensitivity, on the AE report form

Record use of concomitant medications on 
the concomitant medications case report 
formincluding acetaminophen, herbal 
remedies, other over the counter 
medications.

Record alcohol use on the liver event 
alcohol intake case report form
For bilirubin or INR criteria:

Anti-nuclear antibody, anti-smooth muscle 
antibody, Type 1 anti-liver kidney 
microsomal antibodies, and quantitative 
total immunoglobulin G (IgG or gamma 
globulins).

Serum acetaminophen adduct high 
performance liquid chromatography 
(HPLC) assay (quantifies potential 
acetaminophen contribution to liver injury 
in participants with definite or likely 
acetaminophen use in the preceding week
[James, 2009]). 

Liver imaging (ultrasound, magnetic 
resonance, or computerized tomography) 
and /or liver biopsy to evaluate liver 
disease; complete Liver Imaging and/or 
Liver Biopsy CRF forms.
1.
Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin fractionation is not 
immediately available, discontinue study treatment for that participant if ALT 3xULN and bilirubin 2xULN. 
Additionally, if serum bilirubin fractionation testing is unavailable, record presence of detectable urinary 
bilirubin on dipstick, indicating direct bilirubin elevations and suggesting liver injury. 
2.
All events of ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin) or ALT 3xULN and INR>1.5, if INR 
measured which may indicate severe liver injury (possible ‘Hy’s Law’), must be reported as an SAE (excluding 
studies of hepatic impairment or cirrhosis); INR measurement is not required and the threshold value stated 
will not apply to participants receiving anticoagulants


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3.
New or worsening symptoms believed to be related to liver injury (such as fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, or jaundice) or believed to be related to hypersensitivity (such as fever, rash or 
eosinophilia)   
4.
Includes: Hepatitis A IgM antibody; Hepatitis B surface antigen and Hepatitis B Core Antibody (IgM); Hepatitis C 
RNA; Cytomegalovirus IgM antibody; Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, obtain 
heterophile antibody or monospot testing); Hepatitis E IgM antibody 
5.
If hepatitis delta antibody assay cannot be performed, it can be replaced with a PCR of hepatitis D RNA virus 
(where needed) [Le Gal, 2005].
6.
Record the date/time of the PK blood sample draw and the date/time of the last dose of study treatment prior to 
blood sample draw on the CRF. If the date or time of the last dose is unclear, provide the participant’s best 
approximation. If the date/time of the last dose cannot be approximated OR a PK sample cannot be collected in 
the time period indicated above, do not obtain a PK sample. Instructions for sample handling and shipping are in 
the SRM.  
Phase III-IV liver chemistry increased monitoring criteria with continued therapy
Liver Chemistry Increased Monitoring Criteria – Liver Monitoring Event
Criteria
Actions
ALT 5xULN and <8xULN and
bilirubin <2xULN without symptoms 
believed to be related to liver injury or 
hypersensitivity, and who can be 
monitored weekly for 2 weeks.
OR
ALT 3xULN and <5xULN and
bilirubin <2xULN without symptoms 
believed to be related to liver injury or 
hypersensitivity, and who can be 
monitored weekly for 4 weeks.

Notify the GSK medical monitor within 24 hours
of learning of the abnormality to discuss 
participant safety. 

Participant can continue study treatment  

Participant must return weekly for repeat liver 
chemistries (ALT, AST, alkaline phosphatase, 
bilirubin) until they resolve, stabilise or return to 
within baseline 

If at any time participant meets the liver chemistry 
stopping criteria, proceed as described above

If ALT decreases from ALT 5xULN and <8xULN 
to ≥3xULN but <5xULN, continue to monitor liver 
chemistries weekly. 

If, after 4 weeks of monitoring, ALT <3xULN and 
bilirubin <2xULN, monitor participants twice 
monthly until liver chemistries normalize or return 
to within baseline.
References
James LP, Letzig L, Simpson PM, Capparelli E, Roberts DW, Hinson JA, et al. 
Pharmacokinetics of Acetaminophen-Adduct in Adults with Acetaminophen Overdose 
and Acute Liver Failure. Drug Metab Dispos 2009; 37:1779-1784.


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Le Gal F, Gordien E, Affolabi D, Hanslik T, Alloui C, Dény P, et al.  Quantification of 
Hepatitis Delta Virus RNA in Serum by Consensus Real-Time PCR Indicates Different 
Patterns of Virological Response to Interferon Therapy in Chronically Infected Patients.  
J Clin Microbiol. 2005;43(5):2363–2369. 
12.6.2.
Liver Safety Study Treatment Restart Guidelines
Restart Following Transient Resolving Liver Stopping Events Not Related 
to Study Treatment
Restart refers to resuming study treatment following liver stopping events in which there 
is a clear underlying cause (other than DILI) of the liver event (e.g., biliary obstruction, 
pancreatic events, hypotension, acute viral hepatitis). Furthermore, restart is not permitted 
following liver stopping event when the underlying cause was alcoholic hepatitis.
Approval by GSK for study treatment restart can be considered where:

Investigator requests consideration for study treatment restart if liver chemistries 
have a clear underlying cause (e.g., biliary obstruction, hypotension and liver 
chemistries have improved to normal or are within 1.5 x baseline and ALT 
<3xULN).

Possible study treatment-induced liver injury has been excluded by the investigator 
and the study team. This includes the absence of markers of hypersensitivity 
(otherwise unexplained fever, rash, eosinophilia). Where a study treatment has a 
confirmed genetic marker associated with liver injury, the presence of the marker 
should be excluded. If study treatment-related liver injury cannot be excluded, the 
guidance on study treatment restart in Section 8.1.3 will apply.

There is no evidence of alcoholic hepatitis.

IRB/IEC approval of study treatment restart has been obtained.
If restart of study treatment is approved by GSK in writing: 

The participant must be provided with a clear description of the possible benefits and 
risks of study treatment administration including the possibility of recurrent, more 
severe liver injury or death. 

The participant must also provide signed informed consent specifically for the restart 
of study treatment. Documentation of informed consent must be recorded in the 
study file. 

Study treatment must be administered at the dose specified by GSK

Participants approved by GSK for restart of study treatment must return to the clinic 
twice a week for liver function tests until stable liver function tests have been 
demonstrated and then standard laboratory monitoring may resume as per protocol.

If the participant meets protocol-defined liver function stopping criteria after study 
treatment restart, study treatment should be permanently discontinued. 


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
GSK Medical Monitor, and the IRB/IEC, must be informed of the outcome for the 
participant following study treatment restart. 

GSK must be notified of any adverse events, as per Appendix 3. 


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12.7.
Appendix 7: Stratification by Region - Region Groupings
Region
Countries1
1

Republic of 
Korea
2

Poland

Russian 
Federation
3

Australia

France

Germany

Spain
4

Argentina

Brazil
5

US
1.
Countries that do not participate or do not randomize any participants will be removed 
from the regional grouping. If any additional countries are added during the course of the 
study, they will be added to the regional grouping consistent with study 200807, and such 
changes will be detailed in the RAP.


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12.8.
Appendix 8: Country-specific requirements
12.8.1.
French Administrative Considerations and Specifics
Requirements
This appendix includes all the requirements of the French law (n2004-806 of 9th August 
2004), and identifies, item per item, the mandatory modifications or additional 
information to the study protocol and includes specific GSK requirements.
1. Concerning the « STUDY POPULATION»
In line with the local regulatory requirements, the following text in section «OTHER 
STUDY ELIGIBILITY CRITERIA CONSIDERATIONS » is added: A participant
will be eligible for inclusion in this study if he /she is either affiliated to or beneficiary of 
a social security category.
It is the investigator’s responsibility to ensure and to document (in source document -
patient notes) that the patient is either affiliated to or beneficiary of a social security 
category.
2. Concerning the “DATA ANALYSIS AND STATISTICAL 
CONSIDERATIONS” and specially in the “SAMPLE SIZE ASSUMPTION”
The expected number of patients to be recruited in France is declared to the French 
regulatory authority.
3.
Concerning the “STUDY CONDUCT CONSIDERATIONS” 
In section “Regulatory and Ethical Considerations, Including the Informed Consent 
Process”
Concerning the process for informing the patient or his/her legally authorized 
representative, the following text is added: 
French Patient Informed Consent form is a document which summarizes the main 
features of the study and allows collection of the patient's written consent in duplicate. It 
also contains a reference to the authorization of L'Agence nationale de sécurité du 
médicament et des produits de santé (ANSM) and the approval from the French Ethics 
committee.
Concerning the management of the Patient Informed Consent forms, the following 
text is added:
The first copy of the Patient Informed Consent form is kept by the investigator. The 
second is given to the patient or his/her legally authorized representative

In section concerning the “NOTIFICATION TO THE HOSPITAL DIRECTOR”
the following text is added:
In accordance with Article L1123-13 of the Public Health Code, the Hospital 
Director is informed of the commitment to the trial in his establishment. The 


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Hospital Director is supplied with the protocol and any information needed for the 
financial disposition, the name of the investigator(s), the number of sites involved in 
his establishment and the estimated time schedule of the trial (R.1123-63).

In section concerning the “INFORMATION TO THE HOSPITAL 
PHARMACIST” the following text is added:
In accordance with Article R.1123-64 of the Public Health Code, the Hospital 
Pharmacist is informed of the commitment to the trial in his establishment. The 
Pharmacist is supplied with a copy of the protocol (which allows him to dispense the 
drug(s) of the trial according to the trial methodology), all information concerning 
the product(s) of the trial (e.g. included in the CIB), the name of the investigator(s), 
the number of sites involved in his establishment and the estimated time schedule of 
the trial.

In section “DATA MANAGEMENT” the following text is added:
Within the framework of this clinical trial, data regarding the identity of the 
investigators and/or co-investigators and/or the pharmacist if applicable, involved in 
this clinical trial, and data regarding the patients recruited in this clinical trial (patient 
number, treatment number, patient status with respect to the clinical trial, dates of 
visit, medical data) will be collected and computerized in GSK data bases by 
GlaxoSmithKline Laboratory or on its behalf, for reasons of follow up, clinical trial 
management and using the results of said clinical trial. According to the Act n° 78-17 
of 6th January 1978 further modified, each of these people aforesaid has a right of 
access, correction and opposition on their own data through GlaxoSmithKline 
Laboratory (Clinical Operations Department).
4.
Monitoring visits
The Health Institution and the Investigator agree to receive on a regular basis a Clinical 
Research Assistant of GLAXOSMITHKLINE or of a service provider designated by 
GLAXOSMITHKLINE. The Health Institution and the Investigator agree to be available 
for any phone call and to systematically answer to all correspondence regarding the Study 
from GLAXOSMITHKLINE or from a service provider designated by 
GLAXOSMITHKLINE. In addition, the Health Institution and the Investigator agree that 
the CRA or the service provider designated by GLAXOSMITHKLINE have direct access 
to all the data concerning the Study (test results, medical record, etc.). This consultation 
of the information by GLAXOSMITHKLINE is required to validate the data registered in 
the eCRF, in particular by comparing them directly to the source data. In accordance with 
the legal and regulatory requirements, the strictest confidentiality will be respected.
5.
Data entry into the eCRF
The Health Institution and the Investigator agree to meet deadlines, terms and conditions 
of the study’s eCRF use here below:
The Health Institution and the Investigator undertake:
1) That the Investigator and the staff of the investigator center make themselves 
available to attend the training concerning the computer system dedicated to the 


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eCRF of the Study provided by GLAXOSMITHKLINE or by a company 
designated by GLAXOSMITHKLINE.
2) That the Investigator and the staff of the investigator center use the IT Equipment 
loaned and/or the access codes only for the purpose of which they are intended 
and for which they have been entrusted to them, namely for the Study 
achievement, to the exclusion of any other use.
3) That the Investigator and the staff of the investigator center use the IT Equipment 
loaned according to the specifications and manufacturer’s recommendations 
which will have been provided by GLAXOSMITHKLINE.
4) To keep the IT Equipment and/or access codes in a safe and secure place and to 
only authorize the use of this IT Equipment by investigator center staff designated 
by the principal investigator to enter the data of the Study.
5) That the Investigator and the staff of the investigator center enter the data of the 
eCRF related to a patient visit in the 3 days following the date of the patient visit 
or, for the patient test results, in the 3 days following the reception of the results 
of such tests.
6) That the Investigator resolves and returns to GLAXOSMITHKLINE the data 
queries issued by GLAXOSMITHKLINE or a service provider designated by 
GLAXOSMITHKLINE within 7 days after the reception of the request of 
clarification or in a period of one (1) day during the final stage of clarification of 
the data base or in such other period as provided by GLAXOSMITHKLINE 
and/or a company designated by GLAXOSMITHKLINE.
7) To be responsible for the installation and payment of the required Internet 
connections needed for the use of the IT Equipment, Computer systems and/or 
access codes.
8) To return at the end of the Study the IT Equipment and/or access codes to 
GLAXOSMITHKLINE or to any company designated by GLAXOSMITHKLINE 
and any training material and documentation. The IT Equipment cannot under any 
circumstances be kept by the Health Institution or the Investigator for any reason 
whatsoever. 
6.
CTR publication
It is expressly specified that GLAXOSMITHKLINE and/or the Sponsor can make 
available to the public the results of the Study by the posting of the said results on a 
website of the GLAXOSMITHKLINE GROUP named Clinical Trial Register (CTR) 
including the registration of all the clinical trials conduct by the GLAXOSMITHKLINE 
Group and this before or after the publication of such results by any other process.
7.
Data Protection French Law of 6 January 1978 (CNIL)
In accordance with the Data Protection French Law of 6 January 1978 as modified, 
computer files used by GLAXOSMITHKLINE to monitor and follow the implementation 
and the progress of the Study are declared with the Commission Nationale de 
I'Informatique et des Libertés (CNIL) by GLAXOSMITHKLINE. The Investigator has 
regarding the processing data related to him a right of access, of rectification and of 


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opposition with GLAXOSMITHKLINE in accordance with the legal provisions. This 
information can be transferred or be accessed to other entities of GLAXOSMITHKLINE 
Group in France, Britain or United States, what the Investigator agrees by the signature of 
the present Protocol.
12.8.2.
Country-Specific Requirements for Korea
The following information pertains to all sites in Korea.
Inclusion Criteria – Age Range
In Korea, an adult is considered to be any individual who is ≥19 years old. 
In regards to Inclusion Criterion #1, in Korea per local laws, only adult participants, who 
are between 19 and 99 years of age, inclusive, at the time of signing the informed consent 
will be eligible for inclusion in this study.
Clinical Laboratory Assessments – Point-of-Care Hemoglobin Analyzer
The following point-of-care HemoCue hemoglobin analyzer, or similar device, will be 
supplied to each study site. Any changes to the details of the device listed below will be 
provided in the SRM, and will not constitute a protocol amendment.

Name of device: HemoCue Hb201+ hemoglobin analyzer

Model number: 121704

Manufacturer: HemoCue AB: SE-262 23 Angelholm, Sweden

SAP_001.pdf: 
 
CONFIDENTIAL 
 
The GlaxoSmithKline group of companies 
 
204837 
 
1 
 
Division 
: Worldwide Development 
Information Type 
: Reporting and Analysis Plan (RAP)  
 
Title 
: Reporting and Analysis Plan for A Phase 3 randomized, 
double-blind, active-controlled, parallel-group, multi-center 
study in hemodialysis participants with anemia of chronic 
kidney disease to evaluate the efficacy, safety and 
pharmacokinetics of three-times weekly dosing of 
daprodustat compared to recombinant human 
erythropoietin, following a switch from recombinant human 
erythropoietin or its analogs.   
Compound Number  : GSK1278863 
Effective Date  
: 02-SEP-2020 
 
Description: 
• 
The purpose of this RAP is to describe the planned analyses and output to be 
included in the Clinical Study Report for Protocol 204837 (GSK Document 
Number 2016N279035_00) 
 
Author(s) 
 
Author 
Date 
Lead 
 
Statistics Leader, (Speciality, Clinical Statistics) 
01-SEP-2020 
Co-Author 
 
Director (Clinical Pharmacology Modelling & Simulation) 
01-SEP-2020 
Copyright 2020 the GlaxoSmithKline group of companies. All rights reserved.  
Unauthorised copying or use of this information is prohibited 
204837 | Statistical Analysis Plan   02 Sep 2020 | TMF-2094919 | 2.0
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CONFIDENTIAL 
 
The GlaxoSmithKline group of companies 
 
204837 
 
2 
 
RAP Team Review Confirmations 
(Method: E-mail) 
 
Reviewer 
Date 
 
Lead Programmer (Speciality, Clinical Programming) 
27-AUG-2020 
 
Director (Clinical Pharmacology Modelling & Simulation) 
21-AUG-2020 
 
Clinical Development Director (Clinical Science Lead) 
24-AUG-2020 
 
Medical Director (Study Physician) 
22-AUG-2020 
  
Global Clinical Development Manager (Study Delivery Lead) 
28-AUG-2020 
  
Sr. Clinical Development Director (Clinical Development Lead) 
26-AUG-2020 
 
Principal Clinical Data Manager (Data Manager) 
20-AUG-2020 
 
SERM Director (Daprodustat Safety Lead) 
26-AUG-2020 
  
Medical Director (Daprodustat Safety Physician) 
26-AUG-2020 
 
Senior Director (Medical Writing & Clinical Submission 
Planning, Global Clinical Sciences & Delivery) 
31-AUG-2020 
 
Senior Director (Value Evidence Leader) 
28-AUG-2020 
 
Director (Value Evidence) 
28-AUG-2020 
 
Senior Director (Global Regulatory Affairs) 
31-AUG-2020 
 
Clinical Statistics & Clinical Programming Line Approvals 
(Method: Pharma TMF eSignature) 
 
Approver 
Date 
 
Statistics Director (Speciality, Clinical Statistics)  
02-SEP-2020 
 
Programming Manager (Speciality, Clinical Programming) 
02-SEP-2020 
 
 
204837 | Statistical Analysis Plan   02 Sep 2020 | TMF-2094919 | 2.0
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CONFIDENTIAL 
 
 
204837 
3 
 
TABLE OF CONTENTS 
PAGE 
1. 
INTRODUCTION ...................................................................................................... 7 
2. 
SUMMARY OF KEY PROTOCOL INFORMATION .................................................. 7 
2.1. 
Changes to the Protocol Defined Statistical Analysis Plan ............................ 7 
2.2. 
Study Objective(s) and Endpoint(s)............................................................... 8 
2.3. 
Study Design .............................................................................................. 12 
2.4. 
Statistical Hypotheses................................................................................. 13 
3. 
PLANNED ANALYSES .......................................................................................... 15 
3.1. 
Interim Analyses ......................................................................................... 15 
3.2. 
Final Analyses ............................................................................................ 15 
4. 
ANALYSIS POPULATIONS ................................................................................... 15 
4.1. 
Protocol Deviations ..................................................................................... 16 
5. 
CONSIDERATIONS FOR DATA ANALYSES AND DATA HANDLING 
CONVENTIONS ..................................................................................................... 18 
5.1. 
Study Treatment & Sub-group Display Descriptors ..................................... 18 
5.2. 
Baseline Definitions and Derivations ........................................................... 18 
5.2.1. 
Baseline Definitions ..................................................................... 18 
5.2.2. 
Derivations and Handling of Missing Baseline Data ..................... 19 
5.3. 
Multicentre Studies ..................................................................................... 21 
5.4. 
Examination of Covariates, Other Strata and Subgroups ............................ 21 
5.4.1. 
Covariates and Other Strata ........................................................ 21 
5.4.2. 
Examination of Subgroups ........................................................... 21 
5.5. 
Multiple Comparisons and Multiplicity ......................................................... 32 
5.6. 
Other Considerations for Data Analyses and Data Handling 
Conventions ................................................................................................ 32 
6. 
STUDY POPULATION ANALYSES ....................................................................... 33 
6.1. 
Overview of Planned Study Population Analyses ........................................ 33 
6.2. 
Display Details ............................................................................................ 33 
6.2.1. 
Subject Disposition ...................................................................... 33 
6.2.2. 
Protocol Deviations ...................................................................... 35 
6.2.3. 
Population Analysed .................................................................... 35 
6.2.4. 
Demographic and Baseline Characteristics .................................. 35 
6.2.5. 
Medical Conditions, Prior and Concomitant Medications .............. 36 
6.2.6. 
Exposure and Treatment Compliance .......................................... 37 
6.2.7. 
COVID-19 Impacted Visits ........................................................... 37 
7. 
EFFICACY ANALYSES .......................................................................................... 38 
7.1. 
Primary Efficacy Analyses .......................................................................... 38 
7.1.1. 
Endpoint / Variables ..................................................................... 38 
7.1.2. 
Summary Measure ...................................................................... 38 
7.1.3. 
Population of Interest ................................................................... 38 
7.1.4. 
Strategy for Intercurrent (Post-Randomization) Events ................ 38 
7.1.5. 
Statistical Analyses / Methods ..................................................... 39 
7.1.5.1. 
Statistical Methodology Specification .......................... 39 
7.2. 
Principal Secondary Efficacy Analyses ....................................................... 44 
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7.2.1. 
Endpoint / Variables ..................................................................... 44 
7.2.2. 
Summary Measure ...................................................................... 44 
7.2.3. 
Population of Interest ................................................................... 44 
7.2.4. 
Strategy for Intercurrent (Post-Randomization) Events ................ 44 
7.2.5. 
Statistical Analyses / Methods ..................................................... 44 
7.2.5.1. 
Statistical Methodology Specification .......................... 45 
7.3. 
Additional Secondary Efficacy Analyses ..................................................... 46 
7.3.1. 
Planned Secondary Efficacy Statistical Analyses ......................... 46 
7.4. 
Exploratory Efficacy Analyses ..................................................................... 49 
7.4.1. 
Planned Exploratory Efficacy Display Details ............................... 49 
8. 
SAFETY ANALYSES ............................................................................................. 56 
8.1. 
Secondary Safety Analyses ........................................................................ 56 
8.2. 
Exploratory Safety Analyses ....................................................................... 58 
8.3. 
Adverse Events Analyses ........................................................................... 63 
8.3.1. 
Analysis of Adverse Event of Special Interest (AESI) ................... 64 
8.3.2. 
Adverse Events............................................................................ 65 
8.3.3. 
Serious and Other Significant Adverse Events ............................. 66 
8.3.4. 
Other CV Events .......................................................................... 67 
8.4. 
Clinical Laboratory Analyses ....................................................................... 67 
8.4.1. 
Planned Clinical Laboratory Safety Displays ................................ 69 
8.5. 
Other Safety Analyses ................................................................................ 71 
8.5.1. 
Electrocardiograms ...................................................................... 71 
8.5.2. 
Vital Signs .................................................................................... 71 
8.5.3. 
Pregnancy ................................................................................... 72 
8.5.4. 
COVID-19 Analyses ..................................................................... 72 
9. 
PATIENT REPORTED OUTCOMES ANALYSIS .................................................... 73 
10. PHARMACOKINETIC ANALYSES ......................................................................... 75 
10.1. 
Secondary Pharmacokinetic Analyses ........................................................ 75 
10.1.1. 
Endpoint / Variables ..................................................................... 75 
10.1.1.1. Drug Concentration Measures .................................... 75 
10.1.1.2. Derived Pharmacokinetic Parameters......................... 75 
10.1.2. 
Population of Interest ................................................................... 75 
11. PHARMACODYNAMIC ANALYSES....................................................................... 76 
11.1. 
Exploratory Pharmacodynamic Analyses .................................................... 76 
12. PHARMACOKINETIC / PHARMACODYNAMIC ANALYSES ................................. 77 
13. REFERENCES ....................................................................................................... 78 
14. APPENDICES ........................................................................................................ 79 
14.1. 
Appendix 1: Protocol Deviation Management and Definitions for Per 
Protocol Population ..................................................................................... 79 
14.1.1. 
Exclusions from Per Protocol Population ..................................... 79 
14.2. 
Appendix 2: Schedule of Activities .............................................................. 80 
14.2.1. 
Protocol Defined Schedule of Events ........................................... 80 
14.2.1.1. Schedule of Activities for Participants on 
Randomized Study Treatment .................................... 80 
14.2.1.2. Schedules of Activities for Participants Who 
Permanently Discontinue Study Treatment ................. 83 
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14.3. 
Appendix 3: Assessment Windows ............................................................. 84 
14.4. 
Appendix 4: Study Phases and Treatment Emergent Adverse 
Events ........................................................................................................ 85 
14.4.1. 
Study Phases .............................................................................. 85 
14.4.1.1. Study Phases for Hgb, Iron Parameters, IV Iron 
Dose Endpoints, Iron Use Summaries, 
Transfusion and PRO Data ......................................... 85 
14.4.1.2. Study Phases for CV Endpoint Data ........................... 85 
14.4.1.3. Study Phases for BP, Lipid Parameters, 
Clinical Chemistry, Hematology, Other 
Laboratory Tests, Hepatobiliary (Liver), ECG 
and Vital Signs Data ................................................... 85 
14.4.1.4. Study Phase for AE Data ............................................ 86 
14.4.1.5. Study Phases for Concomitant Medication 
(Other Than IV Iron Dose Endpoints and Iron 
Use Summaries) ......................................................... 87 
14.5. 
Appendix 5: Data Display Standards & Handling Conventions .................... 89 
14.5.1. 
Reporting Process ....................................................................... 89 
14.5.2. 
Reporting Standards .................................................................... 89 
14.5.3. 
Reporting Standards for Pharmacokinetic .................................... 90 
14.6. 
Appendix 6: Derived and Transformed Data ............................................... 92 
14.6.1. 
General ........................................................................................ 92 
14.6.2. 
Study Population .......................................................................... 94 
14.6.2.1. Demographics & Baseline Characteristics .................. 94 
14.6.2.2. Study Treatment Discontinuation and Study 
Withdrawal ............................................................... 101 
14.6.2.3. Prior and Concomitant Medications .......................... 101 
14.6.2.4. Exposure and Compliance ........................................ 102 
14.6.3. 
Efficacy ...................................................................................... 103 
14.6.3.1. Hemoglobin Endpoints ............................................. 103 
14.6.3.2. Iron Endpoints .......................................................... 105 
14.6.3.3. Time to Rescue ........................................................ 112 
14.6.3.4. RBC and Whole Blood Transfusion Endpoints .......... 113 
14.6.3.5. Dose Adjustment Scheme Endpoints ....................... 118 
14.6.4. 
Safety ........................................................................................ 121 
14.6.4.1. CV Safety Endpoints ................................................ 121 
14.6.4.2. Blood Pressure Endpoints ........................................ 127 
14.6.4.3. Adverse Events ........................................................ 128 
14.6.4.4. Laboratory Parameters ............................................. 133 
14.6.4.5. Vital Signs ................................................................ 134 
14.6.4.6. COVID-19 ................................................................. 134 
14.6.5. 
Pharmacokinetic ........................................................................ 135 
14.6.6. 
Pharmacodynamic (and / or Biomarker) ..................................... 135 
14.6.7. 
Patient Reported Outcomes ....................................................... 135 
14.7. 
Appendix 7: Premature Withdrawals & Handling of Missing Data ............. 137 
14.7.1. 
Premature Withdrawals .............................................................. 137 
14.7.2. 
Handling of Missing Data ........................................................... 137 
14.7.2.1. Handling of Missing and Partial Dates ...................... 137 
14.8. 
Appendix 8: Values of Potential Clinical Importance ................................. 138 
14.8.1. 
Laboratory Values ...................................................................... 138 
14.8.2. 
ECG ........................................................................................... 139 
14.8.3. 
Vital Signs .................................................................................. 139 
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14.9. 
Appendix 9: Abbreviations & Trade Marks ................................................ 140 
14.9.1. 
Abbreviations ............................................................................. 140 
14.9.2. 
Trademarks ............................................................................... 142 
14.10. Appendix 10: List of Data Displays............................................................ 143 
14.10.1. Data Display Numbering ............................................................ 143 
14.10.2. Mock Example Shell Referencing .............................................. 143 
14.10.3. Deliverables ............................................................................... 143 
14.10.4. Study Population Tables ............................................................ 144 
14.10.5. Study Population Figures ........................................................... 153 
14.10.6. Efficacy Tables .......................................................................... 154 
14.10.7. Efficacy Figures ......................................................................... 168 
14.10.8. Safety Tables ............................................................................. 173 
14.10.9. Safety Figures ........................................................................... 192 
14.10.10. Patient Reported Outcome Tables ............................................. 198 
14.10.11. Patient Reported Outcome Figures ............................................ 199 
14.10.12. Pharmacokinetic Tables ............................................................. 200 
14.10.13. Pharmacodynamic Tables ......................................................... 201 
14.10.14. ICH Listings ............................................................................... 202 
14.10.15. Non-ICH Listing ......................................................................... 208 
 
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1. 
INTRODUCTION 
The purpose of this reporting and analysis plan (RAP) is to describe the analyses to be 
included in the Clinical Study Report for Protocol: 204837 (GSK Document Number 
2016N279035_00) 
2. 
SUMMARY OF KEY PROTOCOL INFORMATION 
2.1. 
Changes to the Protocol Defined Statistical Analysis Plan 
Changes from the originally planned statistical analysis specified in the protocol are 
outlined in Table 1. 
Table 1 
Changes to Protocol Defined Analysis Plan 
Protocol 
Reporting & Analysis Plan 
Statistical Analysis Plan 
Statistical Analysis Plan 
Rationale for Changes 
• 
None 
• 
New displays related to 
COVID-19 pandemic have 
been added 
• 
Assessing the impact of the 
COVID-19 pandemic 
• 
Only include randomized 
subjects who have both baseline 
and at least one Hgb 
assessment during the EP in the 
primary Hgb analysis 
• 
All randomized subjects will 
be included in the primary 
Hgb analysis by imputing 
missing post-baseline Hgb 
data using pre-specified 
multiple imputation 
approach 
• 
Addressing the feedback 
from FDA 
• 
None 
• 
Worsening of Hypertension 
has been added to the list 
of AESI and is included in 
the summary and analysis 
of AESI 
• 
Worsening of Hypertension 
added to the listing of AESI  
across the daprodustat 
program following review of 
data supporting Japan NDA 
• 
None 
• 
Number of RBC 
transfusions, whole blood 
transfusions, and 
transfusion events are 
included in the exploratory 
efficacy analysis of RBC 
and Whole Blood 
Transfusions 
• 
Number of RBC 
transfusions, whole blood 
transfusions, and 
transfusion events have 
been defined and included 
in the exploratory endpoints 
• 
None 
• 
Time to first RBC 
transfusion and/or whole 
blood transfusion is 
included in the exploratory 
efficacy analysis of RBC 
and Whole Blood 
Transfusions 
• 
Time to first RBC 
transfusion and/or whole 
blood transfusion has been 
included in the exploratory 
endpoints 
• 
Subgroup: Weight: < 75kg, 
≥75kg 
• 
Baseline post-dialysis 
weight quartiles 
• 
Subgroup update prior to 
unblinding the trial 
• 
Baseline hsCRP: ≤3 mg/L, >3 
mg/L 
• 
Baseline hsCRP quartiles 
• 
Subgroup update prior to 
unblinding the trial 
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Protocol 
Reporting & Analysis Plan 
Statistical Analysis Plan 
Statistical Analysis Plan 
Rationale for Changes 
• 
PK endpoint: pre-dose trough 
(Ctau)   
• 
“Pre-dose trough (Ctau)” 
has been replaced with 
“Pre-dose trough (Ctrough) 
• 
Ctrough is more accurate 
for TIW dosing regimen 
• 
None 
• 
New PK-related parameters 
(Dapro Efficacy Dose 
Parameters, Dapro Efficacy 
Special Parameters, Dapro 
Safety Dose Parameters, 
Dapro Safety Special 
Parameters)  
• 
Provides transparency to 
the intermediate endpoints 
required for figure creation 
at individual and population 
level. 
• 
Explore the graphical 
relationship between Dapro 
exposure and Mean Hgb 
• 
Explore the graphical 
relationship between Dapro 
exposure and Mean Hgb 
change from baseline 
• 
Mean Hgb change from 
baseline is a better 
assessment of daprodustat 
efficacy than absolute Hgb. 
2.2. 
Study Objective(s) and Endpoint(s) 
 
Objectives 
Endpoints 
Primary Objectives 
Primary Endpoints 
• 
To compare the effect of daprodustat 
to epoetin alfa on Hgb efficacy when 
administered three-times weekly to 
hemodialysis-dependent participants 
(non-inferiority) 
• 
Mean change in Hgb between baseline and over the 
evaluation period (EP, mean over Weeks 28 to 52) 
Principal Secondary Objectives  
Principal Secondary Endpoints (tested for superiority, 
adjusted for multiplicity) 
• 
To compare daprodustat administered 
three-times weekly to epoetin alfa on 
the use of intravenous (IV) iron 
• 
Average monthly IV iron dose (mg)/participant to Week 
52 
Safety Objectives 
Safety Endpoints 
• 
To compare the safety and tolerability 
of daprodustat administered three-
times weekly to epoetin alfa 
• 
Incidence and severity of AEs and serious adverse 
events (SAEs) including AEs of special interest and 
MACE 
• 
Reasons for discontinuation of study treatment 
• 
Absolute values and changes from baseline in laboratory 
parameters, BP and heart rate (HR) 
Secondary Objectives  
Secondary Endpoints (Non-PK endpoints tested for 
superiority1, with no multiplicity adjustment) 
• 
To compare the effect of daprodustat 
administered three-times weekly to 
epoetin alfa on Hgb variability  
• 
Hgb change from baseline to Week 52 1 
• 
% time Hgb in analysis range (10 to 11.5 g/dL) during the 
EP 1 
• 
N (%) responders, defined as mean Hgb within the Hgb 
analysis range 10 to 11.5 g/dL during the EP 
• 
To compare daprodustat administered 
three-times weekly to epoetin alfa on 
the time to rescue 
• 
Time to stopping study treatment due to meeting rescue 
criteria 
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Objectives 
Endpoints 
• 
To compare the effect of daprodustat 
administered three-times weekly to 
epoetin alfa on BP 
• 
Change from baseline in SBP, DBP and mean arterial 
pressure (MAP) at Week 52 and at the end of study 
treatment 
• 
Number of BP exacerbation events per 100 patient years  
• 
N (%) with at least one BP exacerbation event during 
study 
• 
To generate pharmacokinetic 
parameters of daprodustat and 
predominant metabolites following 
three-times weekly dosing 
• 
Plasma daprodustat, M2, M3, M4, M5, M6 and M13 PK 
parameters pre-dose trough (Ctau) and Cmax 
• 
To compare daprodustat administered 
three-times weekly to epoetin alfa on 
global symptom severity and change 
• 
Change from Baseline at Weeks 8,12, 28, and 52 in PGI-
S 
Exploratory Objectives (no statistical 
testing planned) 
Exploratory Endpoints 
• 
To evaluate graphical relationships 
between exposure parameters and 
selected efficacy endpoints of 
daprodustat administered three-times 
weekly 
• 
Extrapolated Cmax of daprodustat vs. the percent time 
within the Hgb target range during the EP 
• 
Extrapolated Cmax of daprodustat vs. mean Hgb over the 
52-week treatment period 
• 
Mean weekly daprodustat dose over 52 weeks vs. the 
percent time within the Hgb target range during the EP 
• 
Mean weekly daprodustat dose over 52 weeks vs. mean 
Hgb over the 52-week treatment period 
• 
To evaluate graphical relationships 
between daprodustat administered 
three-times weekly against MACE and 
the combined safety endpoint of 
MACE + thromboembolic event + 
hospitalization for Congestive Heart 
Failure (CHF) 
• 
Extrapolated Cmax of daprodustat in participants without 
MACE compared to those with MACE (as well as for the 
combined safety endpoint of MACE + thromboembolic 
event + hospitalization for CHF)  
• 
Mean weekly daprodustat dose in participants without 
MACE compared to those with MACE (as well as for the 
combined safety endpoint of MACE + thromboembolic 
event + hospitalization for CHF) 
• 
To compare the effect of daprodustat 
administered three-times weekly to 
epoetin alfa on BP and BP medication 
changes 
• 
Observed and change from baseline in SBP, DBP and 
MAP by visit 
• 
Number of BP medications per participant by visit 
• 
Change from baseline in the number or dose of BP 
medications per participant by visit 
• 
N (%) of participants who had no change in the number or 
dose of BP medications from baseline by visit 
• 
N (%) of participants who had an increase in the number 
or dose of BP medications from baseline by visit  
• 
N (%) of participants who had a decrease in the number 
or dose of BP medications from baseline by visit 
• 
To further compare the effect of 
daprodustat administered three-times 
weekly to epoetin alfa on Hgb 
variability 
• 
Hgb observed and change from baseline across all visits  
• 
% of time Hgb is above, within and below the analysis 
range of 10 to 11.5 g/dL during the EP 
• 
Number (%) of participants with mean Hgb above, within 
and below the Hgb analysis range during the EP  
• 
Number (%) of participants with a Hgb <7.5 g/dL during 
the EP 
• 
Number of times Hgb <7.5 g/dL during the EP 
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Objectives 
Endpoints 
• 
Number (%) of participants with a >1 g/dL increase in Hgb 
within any 2-week period (assessed at Week 2 through 
Week 8), or with a >2 g/dL increase in Hgb within any 4-
week period up to Week 52 
• 
Number (%) of participants with a >1 g/dL decrease in 
Hgb within any 2-week period (assessed at Week 2 
through Week 8), or with a >2 g/dL decrease in Hgb 
within any 4-week period up to Week 52 
• 
N (%) of participants with a Hgb value 12 g/dL during 
the EP 
• 
Number of times Hgb 12 g/dL during the EP 
• 
% of time Hgb 12 g/dL during the EP 
• 
To compare the effect of daprodustat 
administered three-times weekly to 
epoetin alfa on measures of iron 
parameters 
• 
Observed and change from baseline in hepcidin, ferritin, 
transferrin saturation (TSAT), total iron, total iron binding 
capacity (TIBC) across all visits  
• 
Average quarterly ferritin 
• 
Average quarterly TSAT 
• 
Average quarterly IV iron dose/participant 
• 
N (%) of participants who met iron management criteria 
• 
N (%) of participants who reduced IV iron 
supplementation relative to baseline [defined as total iron 
(mg) over 4 weeks prior to randomization] during EP 
[defined as average monthly IV iron dose (mg) over 
Weeks 28 to 52] 
• 
To compare the effect of daprodustat 
administered three-times weekly to 
epoetin alfa on the need for red blood 
cell (RBC) and whole blood 
transfusions 
• 
Number (%) of participants who receive at least one RBC 
or whole blood transfusion by Week 52 
• 
Number of RBC and whole blood transfusions per 100 
patient years  
• 
Number of RBC and whole blood units per 100 patient 
years 
• 
Characterize the pharmacodynamic 
(PD) effect of daprodustat 
administered three-times weekly on 
EPO, vascular endothelial growth 
factor (VEGF) and RBC 
• 
Maximum observed change from baseline in EPO  
• 
Maximum observed % change from baseline in VEGF 
• 
Change from baseline in hematocrit, RBC count, and 
reticulocyte count 
• 
To compare the effect of daprodustat 
administered three-times weekly to 
epoetin alfa on lipid parameters. 
• 
Observed and % change from baseline in lipid 
parameters by visit [total cholesterol, direct low density 
lipoprotein cholesterol (LDL-C), high density lipoprotein 
cholesterol (HDL-C)] 
• 
To evaluate the dose adjustment 
scheme 
• 
Assigned dose by visit and at Day 1, Week 28, and Week 
52 
• 
Most recent dose prior to Week 28, Week 52 and end of 
study treatment 
• 
Number (%) of participants with 0, 1, 2, or >2 dose 
adjustments during the following periods: 
o Day 1 to < Week 28 
o Week 28 to < Week 52 
o Day 1 to < Week 52 
• 
Number of dose adjustments during the following periods: 
o Day 1 to < Week 28 
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Objectives 
Endpoints 
o Week 28 to < Week 52 
o Day 1 to < Week 52 
• 
Number of dose adjustments per year during Day 1 to < 
Week 52 
• 
Time dose held for Hgb 12 g/dL 
• 
To further compare daprodustat 
administered three-times weekly to 
epoetin alfa on global symptom 
severity and change 
• 
Shift tables (Baseline to Weeks 8, 12, 28, and 52) in PGI-
S 
• 
N (%) of participants within each PGI-C symptom change 
level at Weeks 8, 12, 28, and 52 
1. Hgb change from baseline to Week 52 is tested for non-inferiority, using the -0.75 g/dL margin used in the primary 
analysis. % time in range is tested first for non-inferiority, then for superiority. The non-inferiority margin for % time 
in range is defined in Section 7.3.1. 
 
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2.3. 
Study Design 
 
Overview of Study Design and Key Features 
Design 
Features 
• 
This is a randomized, double-blind, active-controlled, parallel-group, multi-center 
study in hemodialysis-dependent participants, including combination methods such 
as hemodiafiltration or hemofiltration with HD, who have anemia of CKD and are 
currently treated with rhEPO or its analogs. 
• 
This study includes a 4-week Screening Period, a 52-week Treatment Period and a 
Follow-up Period 
• 
The 52-week Treatment Period consists of: 
o The Stabilization Period (SP), defined as the period from Day 1 to Week 
28 (up to but excluding the Week 28 visit), during which study treatment 
will be dose-titrated to achieve and maintain Hgb in the target range.   
o The Evaluation Period (EP), defined as the period from Week 28 to Week 
52, to assess long-term efficacy and safety. The study treatment may be 
dose-titrated, if needed, during this period to achieve or maintain Hgb level 
in the target range. 
• 
Each participant will remain in the study for up to 62 weeks, including screening 
through the follow-up period. Participants who permanently discontinue study 
treatment will remain in the study. 
Treatment 
Assignment 
• 
The randomization schedule will be computer generated by Pharmaceutical 
Product Development, LLC (PPD) prior to the start of the study, using the validated 
randomization system Prism. Participants will be randomized centrally using an 
Interactive Response Technology (IRT) system. 
• 
Randomization will be stratified by region. Following stratification, participants will 
be randomized 2:1 to daprodustat or epoetin alfa. Daprodustat will be administered 
three-times weekly and epoetin alfa will be administered once weekly or three-times 
weekly, depending on dose level. 
• 
Due to the difference in formulations between the investigational product and the 
active control (tablets versus IV injection), and in order to maintain the study blind, 
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Overview of Study Design and Key Features 
each participant will receive a tablet and an IV study treatment; one will be active 
and one will be inactive. Participants randomized to receive daprodustat will also 
receive saline IV injection. Participants randomized to receive epoetin alfa will also 
receive placebo tablets. 
Dosing 
• 
The dose of both study treatments will be adjusted in order to maintain Hgb 
concentration in the target range (10.0 to 11.0 g/dL). Adjustment of both study 
treatments (tablets and IV injection formulation) will follow a protocol-specified 
study treatment dose adjustment algorithm to achieve and maintain Hgb within the 
target range of 10.0 to 11.0 g/dL, inclusive. Dose changes will be made 
programmatically by the Interactive Response Technology (IRT) system for both 
study treatment arms. Please refer to the protocol for starting doses, dose steps, 
dose adjustment algorithm, and temporary study treatment interruption.  
Time & 
Events 
• 
Refer to Section 14.2. Appendix 2: Schedule of Activities 
Interim 
Analysis 
• 
There are no plans to evaluate interim data for the purposes of stopping based on 
Hgb efficacy data. 
• 
The IDMC will periodically receive unblinded safety reports containing clinical 
endpoints (whether adjudicated or pending adjudication) and SAEs, from an 
independent Statistical Data Analysis Center (SDAC) while Phase 3 studies with 
daprodustat are ongoing. The IDMC may recommend stopping this study for safety 
at any time. 
 
2.4. 
Statistical Hypotheses  
The primary Hgb efficacy objective will assess the estimand defined as the effect of 
daprodustat treatment relative to rhEPO on the change in Hgb from baseline to the 
average of all values in the EP, regardless of adherence to treatment including 
interruptions and discontinuations, the use of non-randomized ESA medication for any 
reason including rescue therapy, or the use of blood transfusions, in subjects on dialysis 
currently treated with an ESA with anemia secondary to CKD and assuming subjects do 
not die before the end of the EP. The analysis will test whether daprodustat is non-
inferior to rhEPO according to the following statistical hypotheses: 
• 
Null: The difference in mean change in Hgb between baseline and EP, between 
treatment arms (daprodustat-epoetin alfa), is less than or equal to -0.75 g/dL. 
• 
Alternative: The difference in mean change in Hgb between baseline and EP, 
between treatment arms (daprodustat-epoetin alfa), is greater than -0.75 g/dL 
The non-inferiority margin is pre-defined as -0.75 g/dL. This margin was selected to be 
consistent across all clinical trials in the daprodustat Phase 3 clinical development 
program in participants with anemia of chronic kidney disease, and it was determined 
based upon a combination of clinical judgment, statistical reasoning and regulatory 
guidance for designing non-inferiority trials. 
Statistical significance of non-inferiority will be assessed at the one-sided 2.5% level. An 
analysis of covariance (ANCOVA) model including randomization stratification factor, 
baseline hemoglobin and treatment will be used to obtain a point estimate and the two-
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sided 95% confidence interval (CI) for the treatment difference (daprodustat-rhEPO) and 
generate the p-value for the non-inferiority test. The non-inferiority p-value will show 
strength of evidence against the null hypothesis. Non-inferiority will be established if the 
lower limit of the two-sided 95% CI for the treatment difference is greater than -0.75 
g/dL. 
 
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3. 
PLANNED ANALYSES 
3.1. 
Interim Analyses 
The IDMC will periodically receive unblinded safety reports containing, at a minimum, 
clinical endpoints (whether adjudicated or pending adjudication) and SAEs, from an 
independent Statistical Data Analysis Center (SDAC) while the study is ongoing. The 
IDMC may recommend stopping the study for safety at any time. (See IDMC charter for 
further details).   
There are no plans to evaluate interim data for the purposes of stopping based on Hgb 
efficacy data. 
3.2. 
Final Analyses 
The final planned primary analyses will be performed after the completion of the 
following sequential steps: 
1. The end of the study has been reached, as defined in the protocol.   
2. All required database cleaning activities have been completed and final database 
release (DBR) and database freeze (DBF) has been declared by Data Management. 
3. All criteria for unblinding the randomization codes have been met.  
4. Randomization codes generated by the Pharmaceutical Product Development, LLC 
(PPD) have been distributed according to GSK and PPD procedures. 
4. 
ANALYSIS POPULATIONS 
Inclusion in any analysis population is contingent on a subject signing informed consent. 
Population 
Definition / Criteria 
Analyses Evaluated 
Screened  
• 
All participants who sign the ICF 
• 
Study Population 
All Randomized 
(ITT) 
 
• 
All randomized participants.  This is the primary 
population for Hgb efficacy analyses.  Participants will 
be analysed according to the treatment to which they 
were randomized. 
• 
Any participant who receives a treatment randomization 
number will be considered to have been randomized. 
• 
Study Population 
• 
Efficacy 
• 
Selected Safety 
Enrolled 
• 
All participants who passed screening and entered the 
study. For this study, the Enrolled and All Randomized 
(ITT) populations will be identical. (Note: Use of enrolled 
population is required for some displays.) 
• 
Subjects will be analysed according to the treatment to 
which they were randomized. 
• 
Study Population 
Safety 
• 
All randomized participants who take at least 1 dose of 
study treatment. Participants will be analyzed according 
to the treatment they actually received.1 
• 
Safety 
Per-Protocol  
(PP) 
• 
All ITT participants who do not have PP population 
exclusions. This population will be the basis for a 
supportive analysis of the primary efficacy parameter.  
• 
Efficacy 
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Population 
Definition / Criteria 
Analyses Evaluated 
Participants will be analyzed according to the treatment 
to which they were randomized. 
• 
Protocol deviations that would exclude participants from 
the PP population are defined in Appendix 1: Protocol 
Deviation Management and Definitions for Per Protocol 
Population. 
• 
The PP set will not be analyzed if this population 
comprises more than 80% of the All Randomized (ITT) 
population. 
Pharmacokinetic 
(PK) 
• 
All randomized participants for whom a post-baseline PK 
sample was obtained and analyzed.  This will be the 
population used for all the PK displays. 
• 
PK 
[1]: Only subjects receiving incorrect study treatment for the duration of their study participation will be analyzed 
according to the treatment received. Otherwise, subjects will be analyzed according to the treatment to which they 
were randomized. 
 
Refer to Appendix 10: List of Data Displays which details the population used for each display. 
 
4.1. 
Protocol Deviations 
Important protocol deviations (including deviations related to eligibility criteria, conduct 
of the trial, patient management or patient assessment) will be summarised and listed. 
Exclusions from the main study populations described above will also be summarised. 
(Please refer to Appendix 1: Protocol Deviation Management and Definitions for Per 
Protocol Population). 
Protocol deviations will be tracked by the study team throughout the conduct of the study 
in accordance with the Protocol Deviation Management Plan [31OCT2019, Version 3.0] 
using the Protocol Deviation Management System (PDMS) 
• Data will be reviewed prior to unblinding and freezing the database to ensure all 
important deviations and deviations which may lead to exclusion from the 
analysis are captured. Protocol deviations related to incorrect treatment will be 
managed as described below. 
• This dataset will be the basis for the summaries and listings of protocol 
deviations. 
A separate summary and listing of all eligibility criteria deviations will also be provided. 
This summary will be based on data as recorded on the eligibility page of the eCRF. 
Handling of recording of treatment dispensing errors as protocol deviation: 
• Dispensing of incorrect container will be logged as an important PD and included 
in the PD dataset. 
• If it is recorded that the incorrect container was dispensed, it will NOT be flagged 
as a reason for exclusion from the Per Protocol population, since it is not known 
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before DBF/Unblinding if the incorrect container contained the incorrect 
treatment.  
• Decisions on whether or not the participant took incorrect treatment because of 
treatment dispensing errors have to be made after unblinding (i.e. post DBF). For 
Daprodustat/Placebo, this can be done after unblinding using the corresponding 
container number. For rhEPO/saline, to which no container numbers are assigned, 
if the incorrect treatment was given, it would be reported as an unblinded protocol 
deviation in the PDMS and be entered into the unblinded eCRF, which is 
designed specifically for capturing the wrong rhEPO dose.  
 
 
 
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5. 
CONSIDERATIONS FOR DATA ANALYSES AND DATA 
HANDLING CONVENTIONS 
5.1. 
Study Treatment & Sub-group Display Descriptors 
Treatment Group Descriptions 
PPD Randomization System 
Data Displays for Reporting  
Code 
Description 
Description 
Order in TLF  
1 
daprodustat 
Dapro 
1 
2 
rhEPO 
rhEPO 
2 
 
 
Total 
3 
NOTE: “No Treatment” and “All Treated” will be included in selected tables, when 
needed, and will be displayed in the order shown in the table shell.  
 
Treatment comparisons will be displayed as follows using the descriptors as specified: 
1. daprodustat vs rhEPO 
 
5.2. 
Baseline Definitions and Derivations 
5.2.1. 
Baseline Definitions 
For all endpoints (except as noted in baseline definitions) the baseline value will be the 
latest non-missing pre-dose assessment on or before the randomization date, including 
those from unscheduled visits. If time is not collected, Day 1 assessments are assumed to 
be taken prior to first dose and used as baseline (except as noted in the baseline 
definitions for post-dialysis SBP, DBP, MAP, HR and weight). 
Parameter 
Study Assessments Intended as Baseline 
Baseline Used in 
Data Display 
Screening 
(Week -4) 
Day 1 (Pre-Dose) 
Efficacy 
Hgb 
 
X 
Day 1 
Monthly IV iron1 
 
X 
Day 1 
Iron parameters 
 
X 
Day 1 
Safety 
Pre-dialysis SBP, DBP, 
MAP, HR, Weight 
 
X 
Day 1 
Estimated dry weight 
 
X 
Day 1 
Post-dialysis2 SBP, 
DBP, MAP, HR, 
Weight  
X 
 
Week -4 
Lipid parameters, 
clinical chemistry, 
 
X 
Day 1 
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Parameter 
Study Assessments Intended as Baseline 
Baseline Used in 
Data Display 
Screening 
(Week -4) 
Day 1 (Pre-Dose) 
hematology, other 
laboratory and 
hepatobiliary (liver) 
tests 
ECG3 
X 
 
Week -4 
PRO 
PGI-S 
 
X 
Day 1 
NOTE: Unless otherwise stated, the mean of replicate assessments at any given time point will be used as the value 
for that time point. 
[1]: Baseline monthly IV iron dose will be defined as total IV iron (mg) over the 12 weeks prior to randomization. See 
Section 14.6.3. 
[2]: Post-dialysis baseline values for SBP, DBP, MAP, HR, and weight will be defined as the latest non-missing pre-
dose assessment before the randomization date. This will most often be the value recorded at the Week -4 visit. 
However, for cases where the treatment start date falls after the randomization date, the randomization date will be 
used as the baseline measurement. 
[3]: The Week -4 (screening) ECG must be performed pre-dialysis, and may be performed on any dialysis day from the 
Week -4 visit to the Day 1 visit, except during the first dialysis session of the week. Two additional ECGs are required if 
the screening ECG indicates prolonged QTc. In this case, the average QTcB value of all three ECGs will be used as 
the baseline QTcB.  
5.2.2. 
Derivations and Handling of Missing Baseline Data 
Unless otherwise stated, if baseline data is missing no derivation will be performed and 
baseline will be set to missing. 
Change from Baseline 
Definition 
Reporting Details 
Change from Baseline 
= Post-Dose Visit Value – Baseline 
NOTES: 
• 
Unless otherwise specified, the baseline definitions specified in Section 5.2.1 Baseline Definitions will be used 
for derivations for endpoints / parameters and indicated on summaries and listings. 
• 
Unless otherwise stated, if baseline data is missing no derivation will be performed and the change from 
baseline value will be set to missing. 
• 
The baseline definition will be footnoted on all change from baseline displays. 
Percent Change from Baseline 
Lipid parameters will be log-transformed and the percent change from baseline will be 
reported. Other endpoints may also be log-transformed if deemed appropriate. 
To calculate a geometric mean for baseline measurement or at a specified timepoint, the 
following steps are used: 
1. Log-transform the data points 
2. Calculate the mean and standard error (SE) of the log-transformed data 
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3. Exponentiate the mean, (if required, the mean – SE, mean + SE) and the endpoints of 
the confidence interval back to the original scale in order to obtain the geometric 
mean, (the geometric mean – SE, the geometric mean + SE) and the confidence 
interval for the geometric mean. 
4. Coefficient of variation will be calculated as  
1
)
exp(
log
−
=
scale
Var
CV
 100% 
To calculate a geometric mean for the ratio of a specific timepoint to baseline (expressed 
as a percent change from baseline), the following steps are used: 
1. Log-transform the data at both the baseline and the specified timepoint  
2. For each subject, calculate a change from baseline using the log-transformed data 
3. Calculate the mean and standard error (SE) of the log-transformed data 
4. Exponentiate the mean, (if required, the mean – SE, the mean + SE) and the 
endpoints of the confidence interval, back to the original scale and then subtract 1, 
then multiply everything by 100% in order to express the geometric mean, (the 
geometric mean – SE, the geometric mean + SE) and the confidence interval (CI) as 
the percent change from baseline. 
So, geometric mean for percent change from baseline = 
     [ Exp(∑ {log(value at specified time point_i) – log(baseline value_i) }/n) – 1 ] x 100, 
Where i = subject, n= total number of subjects, and ∑ represents the sum over all 
subjects. 
To calculate the minimum, median and maximum for the ratio of a specific timepoint to 
baseline (expressed as a percent change from baseline), the following steps are used: 
1. Log-transform the data at both the baseline and the specified timepoint  
2. For each subject, calculate a change from baseline using the log-transformed data 
3. Calculate the minimum (median and maximum) of change from baseline using the 
log transformed data. 
4. Exponentiate the minimum (median and maximum), back to the original scale and 
then subtract 1, then multiply everything by 100% in order to express the minimum 
(median and maximum) as the percent change from baseline.  
So, minimum percent change from baseline = 
     [ Exp(min {log(value at specified time point_i) – log(baseline value_i) }) – 1 ] x 100, 
Where i = subject. 
Unless otherwise specified, the baseline definitions specified in Section 5.2.1 will be used 
for derivations for endpoints/parameters and indicated on summaries and listings. Unless 
otherwise specified, if baseline data is missing, no derivation will be performed and the 
% change from baseline value will be set to missing. The baseline definition will be 
footnoted on all change from baseline displays. 
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5.3. 
Multicentre Studies 
In this multicentre global study, enrolment will be presented by investigative site, 
country, and the regions. 
Region 
Countries 
Region 1: Asia Pacific 
Republic of Korea 
Region 2: Eastern Europe 
Poland, Romania, Russian Federation 
Region 3: Western 
Europe/Canada/Australia 
Australia, Canada, France, Italy, Spain, United Kingdom 
Region 4: Latin America 
Argentina, Brazil 
Region:5: USA 
USA 
 
For any summaries that include information related to a subject’s center or investigator, 
the most recent center and investigator at the time that the database is final will be used. 
 
5.4. 
Examination of Covariates, Other Strata and Subgroups 
5.4.1. 
Covariates and Other Strata 
The list of covariates and other strata may be used in descriptive summaries and 
statistical analyses, some of which may also be used for subgroup analyses. Additional 
covariates and other strata of clinical interest may also be considered. 
Category 
Details 
Strata 
Regions listed in Section 5.3. 
Covariates 
Baseline Hgb (For the analysis of the primary endpoint and other analyses of Hgb-
related endpoints) 
 
For subgroup analyses, statistical models will be adjusted for the covariates used in the 
original analysis (randomization stratification factor and baseline hemoglobin), subgroup, 
treatment and treatment by subgroup interaction (see Section 5.4.2 for the subgroup 
variables.). 
 
Randomization is stratified by the prognostic factor, region, which will be taken into 
account within the analysis models.    
5.4.2. 
Examination of Subgroups 
• 
The following is a non-exhaustive list of covariates that may be used in summaries 
of demographics, descriptive summaries and statistical analyses.  
• 
Additional covariates of clinical interest may also be considered.  
• 
If the percentage of subjects is small within a particular subgroup, then the subgroup 
categories may be refined prior to unblinding the trial. 
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• 
If the category cannot be refined further, then descriptive rather than statistical 
comparisons may be performed for the particular subgroup. If there are less than 25 
subjects in one of the subgroup categories with two levels (e.g., history of stroke 
(Yes/No)), then statistical comparison will not be performed for that subgroup. Due 
to small sample sizes in American Indian or Alaskan Native, Native Hawaiian or 
Other Pacific Islander, and Mixed Race categories, statistical comparison for race 
group will include Asian, Black or African American, and White categories only. For 
baseline Hgb subgroup, if there are fewer than 25 subjects in the category <9 g/dL, 
the categories <9 g/dL and 9 - <10 g/dL will be combined to < 10 g/dL. 
• 
A pre-specified strategy for prioritizing subgroups/covariates is defined below (as 
recommended in the 2015 draft Committee for Medicinal Products for Human Use 
(CHMP) guidance on the investigation of subgroups in confirmatory clinical trials) 
• 
The primary and principal secondary endpoints will be evaluated for the subgroups 
below. Although subgroup analyses are aimed to assess for consistency with the 
overall results, they may have low power, especially if the subgroup is small or has a 
low number of events. Statistical models (ANCOVA) will be adjusted for the 
covariates used in the original analysis, subgroup, treatment and treatment by 
subgroup interaction. For the subgroup Regions combined (USA vs. non-USA), the 
randomization stratification factor Region (with 5 levels, Regions 1- 5) will not be 
included in the statistical model. 
• 
For subgroup analyses of time-to-event endpoints, point estimates and confidence 
intervals for the rate per 100 person-years will be reported for each treatment group 
within a subgroup, as well as the point estimate and two-sided 95% CI for the 
difference in rates between treatments within a subgroup. For within-group rates, the 
two-sided 95% CI will be obtained using an exact Poisson method. For difference in 
rates between treatments, the two-sided 95% CI will be constructed with a Normal 
approximation using Wald’s method [Liu, 2006]. 
• 
For Hgb using mixed model repeated measures (MMRM) approach in the original 
analysis, the statistical model for the corresponding subgroup analyses will have the 
following factors: region, baseline value, baseline value by time, and subgroup by 
treatment by time interaction terms. The model will be run without main effects 
(treatment, visit, and subgroup) and two-way interaction terms (subgroup by time, 
treatment by time, and subgroup by treatment) for computational ease since in SAS, 
the main effects and two-way interaction terms are included within the three-way 
interaction term, thus giving equivalent result. If the model encounters convergence 
issues, then the following steps will be performed in this sequence: 
• 
Step 1: Use Fisher scoring method 
• 
Scoring=0 will be used as the first option, which is equivalent to no scoring, 
and if the model fails to converge, the scoring will be updated to scoring=1 
• 
The scoring will be updated each time the model fails to converge until a 
maximum of scoring=4 is reached. At this point, if the model fails to 
converge, Step 2 will be utilized. 
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• 
Step 2: If the model fails to converge, instead of unstructured, TOEPH variance-
covariance matrix will be used in conjunction with Step 1 
• 
Step 3: If the model fails to converge, denominator degrees of freedom will be 
changed from Kenward-Roger to Residual in conjunction with Steps 1 and 2.  
Please note that if the model still fails to converge after Step 3, model-adjusted 
subgroup analysis will not be performed. The associated descriptive statistics will be 
displayed.  If the original model fails to converge, but it converges after one of the 
three steps, the output will display the changes made to the original model in a 
footnote.  
• 
When a subgroup category assesses the same or a similar parameter (e.g., country is 
similar to region) as the prognostic stratification variable, the randomization 
stratification variable will be removed from the model. 
• 
Point estimates and two-sided 95% CIs will be estimated within subgroups, the 
subgroup by treatment interaction p-value will be calculated and subgroup results 
will be graphically presented (e.g. Forest Plots). Directional consistency in subgroup 
treatment effects and a non-significant interaction p-value (two-sided 10% level) 
would support that the overall treatment effect is broadly applicable to the full study 
population. Subgroup analyses will not be adjusted for multiplicity. 
• 
In addition, a nominal one-sided non-inferiority p-value using a non-inferiority 
margin of -0.75 g/dL and a nominal one-sided superiority p-value will be 
generated for the difference between treatment groups for each level of the 
hyporesponder subgroup analyses of the primary Hgb endpoint. 
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Category 
Categories and/or Subgroups  
Summary of 
Demographics & Baseline 
Characteristics 
Subgroup Analysis for 
Primary Hgb & Principal 
Secondary Endpoints 
Key Covariates/Subgroups of Regulatory/Clinical Interest or Potential Biological Plausibility for Different Subgroup Effects 
Age (years) 
Summary statistics of continuous values 
Yes 
No 
Age at randomization 
(Grouping 1) 
<65 years, 65-<75 years, ≥75 years 
Yes 
Yes 
Age at randomization 
(Grouping 2) 
≤18 years, 19-64 years, ≥65 years 
Yes 
No 
Age at randomization 
(Grouping 3) 
18-64 years, 65 - 84 years,  85 years 
No (included in stand-
alone age ranges table) 
No 
Gender 
Female, Male 
Yes 
Yes 
Ethnicity 
Hispanic or Latino, Not Hispanic or Latino 
Yes 
Yes 
High level race 
American Indian or Alaskan Native 
Asian  
Black or African American 
Native Hawaiian or Other Pacific Islander 
White 
Mixed Race 
Yes 
Yes 
Race detail 
Black or African American (African American/African Heritage)  
American Indian or Alaskan Native 
Asian - Central/South Asian Heritage 
Asian - East Asian Heritage 
Asian - Japanese Heritage 
Asian - South East Asian Heritage 
Native Hawaiian or Other Pacific Islander 
White – Arabic/North African Heritage 
White – White/Caucasian/European Heritage 
Yes 
No 
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Category 
Categories and/or Subgroups  
Summary of 
Demographics & Baseline 
Characteristics 
Subgroup Analysis for 
Primary Hgb & Principal 
Secondary Endpoints 
Mixed Asian Race 
Mixed White Race 
Mixed Race 
Region 
See Regions categories defined in Section 5.3 
Yes 
Yes 
Region combined 
US, Non-US 
Yes 
Yes 
Country 
See Countries listed in Section 5.3 
Yes 
No 
Dialysis Type at Screening 
In-center Hemodialysis 
Hemofiltration/Hemodiafiltration 
Missing 
Yes 
No 
Prior ESA type at 
Randomization  
Darbepoetin alfa only 
Epoetin only 
Pegzerepoetin alfa only 
Combination 
Yes 
No 
Standardized prior ESA dose 
(U/week) 1 
Summary statistics of continuous values 
Yes 
No 
Standardized Prior ESA  dose 
group1 
<7,000 U/week, ≥7,000 U/week, Missing 
Yes 
Yes 
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Category 
Categories and/or Subgroups  
Summary of 
Demographics & Baseline 
Characteristics 
Subgroup Analysis for 
Primary Hgb & Principal 
Secondary Endpoints 
Baseline erythropoietin 
resistance index (ERI) 
(U/kg/wk/g/L) 
Summary statistics of continuous values 
Yes 
No 
Baseline ERI quartiles 
Overall ITT Population Quartile 1: <xx U/kg/wk/g/L 
Overall ITT Population Quartile 2: xx - <xx U/kg/wk/g/L 
Overall ITT Population Quartile 3: xx - <xx U/kg/wk/g/L 
Overall ITT Population Quartile 4: >= xx U/kg/wk/g/L 
Missing 
Yes 
No 
rhEPO hyporesponder1  
No, Yes, Missing  
Yes 
Yes 
Standardized Prior ESA Dose 
(U/week) for rhEPO 
Hyporesponders 
Summary statistics of continuous values 
Yes 
No 
Standardized Prior ESA Dose 
(U/week) for rhEPO Non-
hyporesponders 
Summary statistics of continuous values 
Yes 
No 
Alternate definition of rhEPO 
hyporesponder 
Definition 21 
No, Yes, Missing  
Yes 
No 
Alternate definition of rhEPO 
hyporesponder 
Definition 31 
No, Yes, Missing  
Yes 
No 
Baseline Hgb (g/dL) 
Continuous covariate for Hgb primary analysis; summary statistics 
of continuous values 
Yes 
No 
Baseline Hgb group 
<9 g/dL, 9 - <10 g/dL, 10 - 11 g/dL, >11 g/dL, Missing 
Yes 
Yes 
Baseline post-dialysis body 
mass index (kg/m2) 
Summary statistics of continuous values 
Yes 
No 
Baseline post-dialysis body 
mass index group 
<30 kg/m2, ≥30 kg/m2, Missing 
Yes 
Yes 
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Category 
Categories and/or Subgroups  
Summary of 
Demographics & Baseline 
Characteristics 
Subgroup Analysis for 
Primary Hgb & Principal 
Secondary Endpoints 
Baseline post-dialysis Weight 
(kg) 
Summary statistics of continuous values 
Yes 
No 
Baseline post-dialysis Weight 
group 
< 75kg, ≥75kg, Missing 
Yes 
No 
Baseline post-dialysis weight 
quartiles 
Overall ITT Population Quartile 1: < xx kg  
Overall ITT Population Quartile 2: xx kg - < xx kg  
Overall ITT Population Quartile 3: xx kg - < xx kg  
Overall ITT Population Quartile 4: >= xx kg 
Missing 
Yes 
Yes 
Baseline hsCRP (mg/L) 
Summary statistics of continuous values 
Yes 
No 
Baseline hsCRP group 
≤3 mg/L, >3 mg/L, Missing 
Yes 
No 
Baseline hsCRP quartiles 
Overall ITT Population Quartile 1: < xx mg/L 
Overall ITT Population Quartile 2: xx mg/L - < xx mg/L 
Overall ITT Population Quartile 3: xx mg/L - < xx mg/L 
Overall ITT Population Quartile 4: >= xx mg/L 
Missing 
Yes 
Yes 
Standardized prior ESA 
dose (U/week) for baseline 
hsCRP Overall ITT 
Population Quartile 1: < xx 
mg/L 
Summary statistics of continuous values 
Yes 
No 
Standardized prior ESA 
dose (U/week) for baseline 
hsCRP Overall ITT 
Population Quartile 2: xx -< 
xx mg/L 
Summary statistics of continuous values 
Yes 
No 
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Category 
Categories and/or Subgroups  
Summary of 
Demographics & Baseline 
Characteristics 
Subgroup Analysis for 
Primary Hgb & Principal 
Secondary Endpoints 
Standardized prior ESA 
dose (U/week) for baseline 
hsCRP Overall ITT 
Population Quartile 3:xx - < 
xx mg/L 
Summary statistics of continuous values 
Yes 
No 
Standardized prior ESA 
dose (U/week) for baseline 
hsCRP Overall ITT 
Population Quartile 4: >= xx 
mg/L 
Summary statistics of continuous values 
Yes 
No 
Smoking History 
Never smoked, Current smoker, Former smoker 
No  
(included in stand-alone 
substance use table) 
Yes 
Other Exploratory Covariates/Subgroups where Biological Plausibility for Heterogeneous Effects Are Not Known or Anticipated 
CV risk score for hemodialysis 
patients 
Low risk (Overall ITT Population tertile 1: < xx), Medium risk 
(Overall ITT Population tertile 2: xx - < xx), High risk (Overall ITT 
Population tertile 3: ≥ xx) 
Yes 
No 
Dialysis vintage at screening  
0 - <2 years, 2 - <5 years, ≥5 years, Missing 
Yes 
Yes 
History of diabetes 
No, Yes, Missing 
Yes 
Yes 
History of stroke 
No, Yes, Missing 
Yes 
Yes 
History of MI 
No, Yes, Missing 
Yes 
Yes 
History of cancer 
No, Yes, Missing 
Yes 
Yes 
History of heart failure 
No, Yes, Missing 
Yes 
Yes 
History of thromboembolic 
events 
No, Yes, Missing 
Yes 
Yes 
Hospitalization within 6 months 
prior to screening 
No, yes, Missing 
Yes 
Yes 
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Category 
Categories and/or Subgroups  
Summary of 
Demographics & Baseline 
Characteristics 
Subgroup Analysis for 
Primary Hgb & Principal 
Secondary Endpoints 
Transfusion within 6 months 
prior to screening 
No, Yes, Missing 
Yes 
Yes 
Baseline iron use 
No iron use 
IV iron use only 
Oral iron use only 
Other iron use only 
IV and oral iron use only 
IV and other iron use only 
Oral and other iron use only 
IV, oral and other iron use  
Yes 
 
No 
Standardized Baseline IV Iron 
dose (mg/month) 
Continuous covariate for monthly IV iron dose analysis, summary 
statistics of continuous values 
Yes 
No 
Standardized baseline IV iron 
dose (mg/month) for subjects 
using IV iron at baseline 
Continuous covariate for monthly IV iron dose analysis, summary 
statistics of continuous values 
Yes 
No 
Baseline Pre-dialysis SBP 
(mmHg) 
Continuous covariate for change from baseline in SBP analysis, 
summary statistics of continuous values 
Yes 
No 
Baseline Post-dialysis SBP 
(mmHg) 
Continuous covariate for change from baseline in SBP analysis, 
summary statistics of continuous values 
Yes 
No 
Baseline Pre-dialysis DBP 
(mmHg) 
Continuous covariate for change from baseline in DBP analysis, 
summary statistics of continuous values 
Yes 
No 
Baseline Post-dialysis DBP 
(mmHg) 
Continuous covariate for change from baseline in DBP analysis, 
summary statistics of continuous values 
Yes 
No 
Baseline Pre-dialysis MAP 
(mmHg) 
Continuous covariate for change from baseline in MAP analysis, 
summary statistics of continuous values 
Yes 
No 
Baseline Post-dialysis MAP 
(mmHg) 
Continuous covariate for change from baseline in MAP analysis, 
summary statistics of continuous values 
Yes 
No 
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Category 
Categories and/or Subgroups  
Summary of 
Demographics & Baseline 
Characteristics 
Subgroup Analysis for 
Primary Hgb & Principal 
Secondary Endpoints 
Dialysis access type used at 
baseline 
Arteriovenous fistula 
Arteriovenous graft 
Central venous catheter – tunneled 
Central venous catheter – non-tunneled 
Other 
Missing 
Yes 
No 
ACEI/ARB use at 
randomization 
No, yes 
Yes 
Yes 
Phosphate binders use at 
randomization 
No, yes 
Yes 
No 
Vitamin D use at randomization 
No, yes 
Yes 
No 
Baseline Kt/V urea for HD 
subjects 
Summary statistics of continuous values 
Yes 
No 
Baseline URR for HD subjects 
(%) 
Summary statistics of continuous values 
Yes 
No 
History of cardiovascular 
disease 
No, Yes 
Yes 
No 
Beta blockers use at 
randomization 
No, Yes 
Yes 
No 
SGLT2i use at randomization 
No, Yes 
Yes 
No 
Statin use at randomization 
No, Yes 
Yes 
No 
Aspirin use at randomization 
No, Yes 
Yes 
No 
Vitamin K antagonist use at 
randomization 
No, Yes 
Yes 
No 
Insulin use at randomization 
No, Yes 
Yes 
No 
Calcimimetics use at 
randomization 
No, Yes 
Yes 
No 
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Category 
Categories and/or Subgroups  
Summary of 
Demographics & Baseline 
Characteristics 
Subgroup Analysis for 
Primary Hgb & Principal 
Secondary Endpoints 
Diabetic medication use at 
randomization 
No, Yes 
Yes 
No 
Baseline estimated dry weight 
(kg) 
Summary statistics of continuous values 
Yes 
No 
[1]: Prior ESA dose standardization and rhEPO hyporesponders are defined in Section 14.6.2. Supportive definitions of hyporesponders 
will be included in the summary of demographics and baseline characteristics, but will not be used in subgroup analyses 
Further details of subgroup analysis are provided in the corresponding analysis sections.   
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5.5. 
Multiple Comparisons and Multiplicity 
The primary endpoint will be tested first for non-inferiority, using the lower limit of the 
2-sided 95% confidence interval. Conditional on achieving statistical significance (i.e., 
passing the primary gate by establishing non-inferiority) the single principal secondary 
endpoint will be tested for superiority using a one-sided 2.5% significance level. This 
two-step hierarchical strategy will preserve the study-wise Type I error rate at a one-sided 
2.5% level. 
 
The additional secondary/exploratory endpoints, if tested, will not be adjusted for 
multiplicity. A nominal one-sided 2.5% significance level will be applied per test. 
Subgroup analyses will not be adjusted for multiplicity. 
5.6. 
Other Considerations for Data Analyses and Data Handling 
Conventions 
Other considerations for data analyses and data handling conventions are outlined in the 
appendices: 
Section 
Component 
14.3 
Appendix 3: Assessment Windows 
14.4 
Appendix 4: Study Phases and Treatment Emergent Adverse Events 
14.5 
Appendix 5: Data Display Standards & Handling Conventions 
14.6 
Appendix 6: Derived and Transformed Data 
14.7 
Appendix 7: Premature Withdrawals & Handling of Missing Data 
14.8 
Appendix 8: Values of Potential Clinical Importance 
 
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6. 
STUDY POPULATION ANALYSES 
6.1. 
Overview of Planned Study Population Analyses 
The study population analyses will be based on the All Randomized (ITT) population, 
unless otherwise specified. All summary tables will include a Total column, unless 
otherwise specified. 
 
Study population analyses including analyses of subject’s disposition, protocol 
deviations, population analysed, demographic and baseline characteristics, medical 
conditions, prior and concomitant medications, and exposure and treatment compliance 
will be based on GSK Core Data Standards.  Details of the planned displays are presented 
in Appendix 10: List of Data Displays. 
6.2. 
Display Details 
6.2.1. 
Subject Disposition 
The number and percentage of subjects who completed the study as well as subjects who 
withdrew from the study will be summarized by subject status and reason for withdrawal.  
For purpose of the disposition table, the number of subjects who completed the study will 
consist of all randomized subjects who, as documented in the eCRF, Study Conclusion 
form, have completed all study periods through the Week 52 visit. This summary table 
will be repeated by region and by country. [NOTE: Per study protocol Section 5.3, “A 
participant who dies while on study is also considered to have completed the study.”] The 
summary of subject status and reasons for study withdrawal will also be repeated by 
relationship to the COVID-19 pandemic. 
 
A listing of reasons for study withdrawal will be provided for all subjects who were 
withdrawn from the study. This listing will include treatment, site ID, unique subject ID, 
subject ID, date of withdrawal, study day of withdrawal, primary reason for withdrawal 
from study, was a follow-up phone contact attempted 3 times, and was a follow-up 
certified letter mailed. 
 
The number and percentage of subjects who passed screening (i.e. enrolled) and who 
failed screening and therefore were not entered into the study will be summarized along 
with the reasons for failure will be summarized for those subjects who failed screening.  
(Note that the reasons for rescreen subjects who initially failed but subsequently enrolled 
are not included in the display.) 
 
A summary of all screening attempts and associated reasons for screen failure will be 
provided for the screened population. This summary will count each screening attempt 
individually, regardless of whether or not there was a subsequent re-screen. 
 
A listing of the screen failure record for all subjects who failed screening and were not 
enrolled in the study will be produced. This listing will include Country, site ID, unique 
subject ID, Subject ID, date of screen failure, reason term(s) for screen failure (including 
the specify text, if any).  
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A listing of screening status will be provided for all subjects who were rescreened for the 
study. The listing will include unique subject ID, subject ID, screening status, date of 
screen failure, and reason for screen failure.  
Treatment status and reasons for discontinuation of study treatment will be summarized, 
which will include the overall number and percentage of subjects who never received 
study treatment, the overall number and percentage of subjects who prematurely 
discontinued study treatment during the study, including the breakdown of the number 
and percentage of subjects who died while taking study treatment and those that did not 
die while taking study treatment, and a summary of the reasons and subreasons for study 
treatment discontinuation overall and separately for subjects who died while taking study 
treatment and for subjects who did not die while taking study treatment, and the overall 
number and percentage of subjects who did not prematurely discontinue study treatment 
during the study summarized by treatment group and overall.(NOTE: Deaths with death 
date > Treatment End Date + 3 Days are considered “Did Not Die While Taking Study 
Treatment”. Deaths with death date ≤ Treatment End Date + 3 Days are considered “Died 
While Taking Study Treatment”) 
This summary table will be repeated by region and by country. The overall only summary 
of subject status and reasons for discontinuation of study treatment will be repeated by 
relationship to the COVID-19 pandemic. 
 
A listing of the study treatment discontinuation record will be provided for all 
subjects who prematurely discontinued study treatment. This listing will include 
treatment, site ID, unique subject ID, Subject ID, date of last dose, study day of 
discontinuation, primary reason for discontinuation, subreasons for discontinuation, and 
related to study treatment.  
 
A Kaplan-Meier plot of time to early withdrawal from the study will be produced by 
treatment group.  
 
Two Kaplan-Meier plots of time to permanent study treatment discontinuation by 
treatment group will be produced. The first plot will include all subjects who 
discontinued study treatment, and the second plot will only include subjects who 
discontinued study treatment but did not die while on study treatment. 
The number and percentage of subjects by Region, Country, Site ID and Investigator 
name will be summarized by treatment group and overall for the Enrolled population.  
A listing of participants for whom the treatment blind was broken during the study will 
be provided.  
A listing of planned and actual treatments will be provided. This listing will include 
country, site ID, investigator name, unique subject ID, Subject ID, randomization 
number, randomization date, randomized treatment, actual treatment and deviation. 
 
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The type of subject contact at the Week 52 visit will be provided by treatment group and 
overall. 
 
A summary of the subject survival status by study completion status will be provided by 
treatment group and overall. 
6.2.2. 
Protocol Deviations 
The number and percentage of subjects who had important protocol deviations (as 
defined in the protocol deviation management plan) will be summarized by category and 
by treatment group and overall. This summary table will be repeated by relationship to 
the COVID-19 pandemic. 
 
A listing of important protocol deviations will be provided. The listing will include 
treatment, site ID, unique subject ID, Subject ID, date of deviation, study day of 
deviation, protocol deviation category, protocol deviation coded term, and protocol 
deviation description. 
 
The number and percentage of subjects who had inclusion/exclusion criteria deviations 
will be summarized by inclusion/exclusion type, criteria description and by treatment 
group and overall. 
 
A listing of subjects with inclusion/exclusion criteria deviations will be provided. The 
listing will include treatment, site ID, unique subject ID, Subject ID, inclusion/exclusion 
type, and criteria description. 
6.2.3. 
Population Analysed  
The number and percentage of screened subjects in the Screened, Safety, All Randomized 
(ITT), Enrolled, Per Protocol and PK populations will be summarized by treatment group 
and overall. 
 
The number and percentage of subjects excluded from the Safety and PP populations will 
be summarized by reason, treatment group and overall in individual displays for each 
study population. 
A listing of subjects excluded from the Safety and PP populations will be provided. The 
listing will include the treatment arm, site ID, unique subject ID, Subject ID, date of 
deviation, study day of deviation, category, coded term, criteria which lead to exclusion, 
and the populations from which the subject was excluded. 
6.2.4. 
Demographic and Baseline Characteristics 
Demographic and baseline data will include all covariates/subgroup variables listed in 
Section 5.4.2. for summary of demographics and baseline characteristics.  
All the above demographic and baseline data will be summarized by treatment group and 
overall for All Randomized (ITT) and Safety populations. This table will be repeated for 
the primary definition of a hyporesponder outlined in Section 14.6.2.in the All 
Randomized (ITT) population.  
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A by-subject listing of selected demographic and baseline characteristics will also be 
produced. This listing will include treatment, site ID, unique subject ID, subject ID, year 
of birth, age, sex, ethnicity, height, weight, and BMI. 
 
A summary of age ranges will be produced based on the Enrolled population 
 
Summaries of race and racial combinations will be produced for each treatment group 
and overall.  
 
A listing of race and race detail by subject will also be produced, which will include 
treatment, site ID, unique subject ID, Subject ID, race, and race detail.  
 
A summary of substance use will be provided by treatment group and overall. 
 
A summary of dialysis modality and frequency at baseline, Week 28 and Week 52 will be 
provided by treatment group and overall. This summary will include the number and 
percentage of subjects who have temporarily or permanently stopped dialysis at these 
time points, as well as summary statistics for total residual urine volume. 
The number and percentage of subjects with dialysis modality changes at any point in the 
study will be provided by treatment group and overall. 
6.2.5. 
Medical Conditions, Prior and Concomitant Medications 
A summary of medical conditions will be provided by treatment group and overall. 
For reporting purposes, medications will be classified as prior (pre-treatment), 
concomitant (on-treatment), and/or post-treatment using the associated start and stop 
dates recorded in the eCRF and relative to the first and last dose dates of IP (see Section 
14.4.1). Medications will be coded using the GSK Drug coding dictionary (current 
version at the time of DBR). 
 
The number and percentage of subjects reporting the use of each concomitant medication 
will be summarized by treatment group and overall, anatomical therapeutic chemical 
(ATC) Level 1, 2, 3, and Ingredient. Summaries of pre-treatment, on-treatment, and 
posttreatment medication will be provided separately. See Section 14.4.1 for a summary 
of study phases for concomitant medications. 
 
A listing of all medications taken by subjects, including any which are only prior or post-
treatment, will be produced. The relationship between ATC level 1, ingredients and 
verbatim text for all medications in the study will be listed. 
The number and percentage of subjects with any non-randomized ESA use in addition to 
study treatment during the treatment period (see Section 14.6.2) will be provided by 
treatment group and overall. Similarly, the number and percentage of subjects with any 
non-randomized ESA used instead of study treatment during the treatment period (see 
Section 14.6.2) will be provided by treatment group and overall. Additionally, the 
duration of the non-randomized ESA use during the treatment period will be summarized 
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using mean, standard deviation, minimum, P25, median, P75, and maximum by treatment 
group and overall, as well as by the number and percentage of subjects in the following 
duration categories: < 5 days,  5 days - < 14 days,  14 days - < 28 days,  28 days. 
A listing of prior and concomitant ESA use will be provided with details of the ESA use. 
6.2.6. 
Exposure and Treatment Compliance 
Months of exposure (see Section 14.6.2.4) will be summarized using mean, standard 
deviation, minimum, P25, median, P75, and maximum by treatment group and overall. 
Additionally, the number and percentage of subjects with exposure ≤ 6-month and > 6-
month will be provided by treatment group and overall. 
A listing of exposure data will be provided. This listing will include treatment, site ID, 
unique subject ID, Subject ID, dose start date, dose stop date, duration of time on dose, 
dose, dose units, dose form, route of administration, and flags for missed dose, zero dose 
and dose hold. Exposure data from the unblinded eCRF will be listed separately.   
Percent compliance will be estimated by 100*(Total Cumulative Dose/Planned Dose for 
a specific time period). The number and percentage of subjects in each study treatment 
compliance category (see Section 14.6.2.4) during the study will be summarized by 
treatment group for the following time periods: Day 1 < Week 28, Week 28 - <= Week 
52, and Day 1 - <= Week 52 (Overall Compliance). 
The percentage of time that subjects spend in each of the three compliance categories, 
(i.e., under compliant, compliant and over compliant) will be summarized using mean, 
standard deviation, minimum, P25, median, P75, and maximum by treatment group for 
the following time periods: Day 1 < Week 28, Week 28 - <= Week 52, and Day 1 - <= 
Week 52 (Overall Compliance). 
6.2.7. 
COVID-19 Impacted Visits 
A summary of the number and percentage of subjects with any visit impacted by the 
COVID-19 pandemic and each visit impacted by the COVID-19 pandemic may be 
produced. The summary will include the impact and the reason for impact overall (any 
visit) and at each impacted visit. 
 
A listing of all subjects with visits and assessments impacted by the pandemic will be 
produced.  
 
A figure of COVID-19 pandemic visit impacts may be produced. The figure is a stacked 
bar chart for each impacted visit.  The stack bar is color coded by impact. 
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7. 
EFFICACY ANALYSES 
7.1. 
Primary Efficacy Analyses 
The primary efficacy estimand is the effect of daprodustat treatment relative to rhEPO on 
the change in Hgb from baseline to the average of all values in the EP, regardless of 
adherence to treatment including interruptions and discontinuations, the use of non-
randomized ESA medication for any reason including rescue therapy, or the use of blood 
transfusions, in patients defined by the inclusion/exclusion criteria and assuming patients 
do not die before the end of the EP. 
7.1.1. 
Endpoint / Variables 
Mean change in Hgb between baseline and over the evaluation period (EP, mean over 
Week 28 and 52).  
7.1.2. 
Summary Measure 
Model-adjusted mean treatment difference (LS mean difference) in Hgb change between 
baseline and over the evaluation period.  
7.1.3. 
Population of Interest  
The target population is defined by the study’s inclusion and exclusion criteria.   
The analysis population included in the primary efficacy analyses will be based on the 
All Randomized (ITT) population, unless otherwise specified. 
7.1.4. 
Strategy for Intercurrent (Post-Randomization) Events 
The following are the intercurrent events for the primary efficacy analyses: 
• Death prior to the end of the EP (i.e. before Week 52 visit) 
• Study treatment interruption or discontinuation prior to the end of the EP  
• Use of non-randomized ESA medications for any reason including rescue prior to 
the end of the EP 
• Receipt of blood transfusions prior to the end of the EP 
Except for the intercurrent event of deaths prior to the end of the EP, a treatment policy 
strategy will be used in which all Hgb data recorded during the EP (Weeks 28-52) will be 
included in the primary efficacy analysis, regardless of discontinuation or interruption of 
study medication due to any reasons, and regardless of receipt of non-randomized ESA 
medications for any reason including rescue, or blood transfusions. For deaths, a 
hypothetical strategy will be used as described in Section 7.1.5.1. 
The following are causes of missing Hgb data affecting the primary efficacy endpoint 
that are not due to intercurrent events: 
• Study withdrawal prior to the end of the EP 
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• Permanent switching from clinic visits to remote visits prior to end to EP 
• Intermittent missing Hgb values at one or more visits with the EP 
Missing data will be imputed as described in Section 7.1.5.1. 
7.1.5. 
Statistical Analyses / Methods 
Details of the planned displays are provided in Appendix 10: List of Data Displays and 
will be based on GSK data standards and statistical principles. 
Unless otherwise specified, endpoint / variable defined in Section 7.1.1 will be 
summarised using descriptive statistics, graphically presented (where appropriate) and 
listed. 
7.1.5.1. 
Statistical Methodology Specification 
Endpoint / Variables 
• Mean change in Hgb between baseline and over the evaluation period (EP, mean over 
Weeks 28 to 52) 
Model Specification 
• Hgb during the EP will be defined as the mean of all available post-randomization Hgb 
values (on and off-treatment) during the EP (Week 28-52). 
• The ANCOVA model used to quantify the difference in mean Hgb change will adjust for the 
following baseline values: 
o Treatment 
o Baseline Hgb (see Section 5.2.1) 
o Region (as randomized, see Section 5.3 & Section 5.4.1) 
Multiple Imputation Analysis 
• Multiple imputation analysis will be performed using all available Hgb values (on and off-
treatment) and conducted under a set of assumptions about missing Hgb values (see 
Section 14.6.3). 
o Intermittent missing post-baseline scheduled Hgb data in both arms through Week 
52 will be imputed using PROC MI procedure with NIMPUTE = 200 and MCMC 
IMPUTE = monotone to generate 200 datasets with only monotone missing 
patterns. Burn in iterations (NBITER) and maximum iteration (MAXITER) will both 
be set to 500. The seed for reproducibility is set to 204837. The imputations will be 
done by study treatment, and region.  
o For each of the monotone missing dataset (out of the 200 imputed as indicated 
above), the missing scheduled Hgb values through Week 52 will be imputed based 
on the MAR assumption and will be performed using PROC MI by treatment, and 
region. The monotone regression will have baseline Hgb, prior scheduled (possibly 
imputed) Hgb values, and may include region, as covariates (see Model Checking & 
Diagnostics, below).  The seed for reproducibility is set to 204837. 
o The low and high cutoffs at Hgb values of 6 g/dL and 15 g/dL will be applied to all 
imputed Hgb values. 
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o EP Hgb values will be computed and compared across treatment groups using the 
primary ANCOVA model described above. Rubin’s rules [Rubin, 1987] will be used 
to combine results of the imputed datasets using SAS PROC MIANALYZE 
procedure. As a result, a single estimated treatment difference and its standard 
error will be produced, with which a 95% CI will be calculated. 
 
Model Checking & Diagnostics 
• Distributional assumptions underlying the model used for analysis will be examined by 
obtaining a normal probability plot of the residuals and a plot of the residuals versus the 
fitted values (i.e. checking the normality assumption and constant variance assumption of 
the model respectively) to gain confidence that the model assumptions are reasonable. 
• If there are any departures from the distributional assumptions, alternative models will be 
explored using appropriate transformed data, if justified. 
• Models will be examined for treatment interactions with baseline Hgb and stratification 
factor. 
• For multiple imputation model checking and diagnostics, refer to Model Checking & 
Diagnostics for Tipping Point Analysis 
Model Results Presentation 
• All available observed Hgb values (on and off-treatment) will be summarized using mean, 
standard deviation, minimum, P25, median, P75 and maximum at each visit by treatment 
group. In addition to scheduled visits, the baseline value and mean EP, mean Alt. EP, and 
end of treatment will be included (see Section 14.6.3).  
o This summary of Hgb by visit will be repeated for central laboratory Hgb values 
only and for HemoCue Hgb values only. 
o This display will also be repeated for visits up to and including Week 52, using 
the data used for the primary Hgb analysis (i.e., including imputed values). 
• All available observed Hgb change from baseline values (on and off-treatment) will also be 
summarized using mean, standard deviation, minimum, P25, median, P75, and maximum at 
each post-baseline visit, including the mean EP, mean Alt EP and end of treatment values 
(see Section 14.6.3). 
o This display will be repeated for visits up to and including Week 52, using the 
data used for the primary Hgb analysis (i.e., including imputed values). 
• The number and percentage of subjects with imputed data in the primary Hgb analysis will 
be provided by treatment group. The number and percentage of subjects by reason for data 
imputation will be provided. Reasons include: intermittent missing Hgb values, death before 
Week 28, death during Week 28 – 52, investigator site closed before Week 28, investigator 
site closed during Weeks 28-52, lost to follow-up before Week 28, lost to follow-up during 
Week 28 – 52, consent withdrawn before Week 28, consent withdrawn during Week 28 – 
52, and other monotone missing Hgb values. Subjects will be further classified as either 
having observed all 7 scheduled EP Hgb values, having observed a partial schedule of EP 
Hgb values, having observed no scheduled EP Hgb values with at least one unscheduled 
EP Hgb value, or having observed no EP Hgb values, scheduled or unscheduled. For 
subjects with partial scheduled EP Hgb values, both the pattern of imputed data 
(intermittent, monotone) and the amount of imputed data (1 – 6 scheduled Hgb values 
missing) will be summarized. For subjects with partial scheduled EP Hgb values and a 
monotone imputed data pattern, the reason for the monotone imputed scheduled EP Hgb 
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values will be provided. Reasons include: death during Week 28-52, investigator site closed 
during Weeks 28-52, lost to follow-up during Week 28 – 52, consent withdrawn during Week 
28 – 52, and other monotone imputed Hgb values. And for summaries of the amount of 
missing scheduled EP Hgb values, the presence or absence of additional unscheduled EP 
Hgb values will be summarized. 
• The least square (LS) mean estimates and standard errors by treatment group, LS mean 
difference, two-sided 95% CI and one-sided non-inferiority p-value for the difference in the 
primary Hgb endpoint between the daprodustat and rhEPO arms from the ANCOVA model 
will be presented. The number of subjects contributing to the analysis and the associated 
mean and standard deviation of the baseline and EP Hgb values will also be displayed with 
the results of the ANCOVA model. 
• The LS mean difference and associated two-sided 95% CI will be displayed on a forest plot 
together with supportive analysis results (excluding the Tipping Point Analysis).  
• All available mean Hgb values (on and off-treatment, observed and imputed) will be 
displayed graphically for each scheduled study visit using a line plot. The line plot of mean 
values and 95% CI by time will include horizontal reference lines to depict the hemoglobin 
analysis range (10-11.5 g/dL), vertical reference lines to identify the EP (weeks 28-52), and 
the number of subjects by treatment group contributing to each mean value. 
• All available Hgb change from baseline values (on and off-treatment, observed and imputed) 
will be displayed graphically for each scheduled study visit using a line plot. The line plot of 
mean values and 95% CIs by time will include vertical reference lines to identify the EP 
(Weeks 28-52), and the number of subjects by treatment group contributing to each mean 
value. 
• A listing of all hemoglobin values will be provided, including treatment, most recent dose, 
site ID, unique subject ID, subject ID, visit, assessment date, selected demographic 
information and central laboratory and HemoCue Hgb values. 
Model Results Interpretation 
Non-inferiority will be achieved if the lower limit of the two-sided 95% CI of the treatment 
difference is greater than the pre-specified non-inferiority margin of -0.75 g/dL. 
 
Sensitivity Statistical Analyses 
Tipping Point (Multiple Imputation) Analysis 
• Tipping point analysis will be performed using all available Hgb values (on and off-treatment) 
as a sensitivity analysis for the primary estimand. 
• Tipping point analyses will be conducted under a range of missing data assumptions to 
determine how extreme assumptions need to be for non-inferiority conclusions to change. 
Assumptions about missing Hgb values on the daprodustat and rhEPO arms will vary 
independently, and will include scenarios where subjects with missing data on daprodustat 
have worse outcomes than subjects with missing data on rhEPO.  
o Intermittent missing scheduled Hgb data in both arms through Week 52 will be 
imputed using PROC MI procedure with NIMPUTE = 200 and MCMC IMPUTE = 
monotone to generate 200 datasets with only monotone missing patterns. Burn in 
iterations (NBITER) and maximum iteration (MAXITER) will both be set to 500. The 
seed for reproducibility is set to 204837. The imputations will be done by study 
treatment, and region.  
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o For each of the monotone missing dataset (out of the 200 imputed as indicated 
above), the missing scheduled Hgb values in both arms through Week 52 will be 
imputed based on the MAR assumption and will be performed using PROC MI by 
treatment, and region. The monotone regression will include baseline Hgb, prior 
scheduled (possibly imputed) Hgb values, and may have region as a covariate (see 
Model Checking & Diagnostics, below). The seed for reproducibility is set to 
204837. 
o For each treatment arm separately, the imputed monotone missing Hgb values will 
vary from the MAR scenario by a multiple of delta, where delta represents a change 
in Hgb over a 4-week interval. No delta adjustments will be done for intermittent 
missing values. Beginning with the first missed visit (which could occur before Week 
28), for every 4-weeks, the imputed Hgb value would shift an additional delta (for 
every 2-week interval, the imputed Hgb value would shift an additional 0.5 delta 
instead). For example, if the first missed visit is after Week 8, the first missed visit 
will use delta, the second missed visit will use 2*delta, etc. If the first missed visit is 
on or before Week 8, the first missed visit will use 0.5 delta, the second missed visit 
will use either (0.5+0.5)*delta, or (0.5+1)*delta depending on the 2- or 4-week 
interval in between the two visits, etc. The deltas explored for each treatment arm 
will range from -4 g/dL to 4 g/dL per 4-week interval with a 0.5 g/dL increment 
respectively. Delta scenarios which are known ahead of time not to possibly 
represent the tipping point may not be explored. 
o The low and high cutoffs at Hgb values of 6 g/dL and 15 g/dL will be applied to all 
imputed Hgb values. 
o EP Hgb values will be computed for each pair of deltas and compared across 
treatment groups using the primary ANCOVA model described above (including 
unscheduled visit). Rubin’s rules [Rubin, 1987] will be used to combine results of the 
imputed datasets using SAS PROC MIANALYZE procedure. As a result, for each 
pair of delta values, a single estimated treatment difference and its standard error 
will be produced, with which a 95% CI can be calculated. 
 
Model Checking & Diagnostics (for Multiple Imputation and Tipping Point Analyses) 
• Intermittent missing data imputation: 
o If there are error and or warning messages related to the by statement (e.g. not 
enough observations to fit regression models), try by study treatment only. 
o If convergence issue occurs, the convergence precision may be set to 1E-3. 
• Monotone missing data imputation: 
o When imputing for each of the monotone missing dataset (out of 200), if there are 
error and or warning messages related to the by statement and/or regression model 
(e.g. not enough observations with the Monotone statement), try 1) by study 
treatment with baseline Hgb and region as covariates, 2) impute by study treatment 
with baseline Hgb as covariates, until no error/warning messages. 
Model Results Presentation (for Tipping Point Analysis) 
• The delta pairs, their corresponding model-adjusted mean Hgb change from baseline to EP 
in the two treatment arms, the model-adjusted treatment difference, and two-sided 95% CI 
will be presented. The non-inferiority conclusion will be drawn if the lower confidence limit of 
the two-sided 95% CI is greater than -0.75, which will also be presented in the tables. 
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• Graphics depicting treatment difference and non-inferiority surfaces will be produced using 
an enhanced tipping point approach [Liublinska, 2014]; A colored heat map that illustrates 
the gradual change of treatment difference will be produced. Green borders will be used to 
highlight the delta combinations that result in rejecting the null hypothesis (i.e., non-inferiority 
established). 
 
Supportive Statistical Analyses 
While On-Treatment Evaluable Hgb Analysis 
• Alternative “while on-treatment” estimand using only evaluable Hgb data (see Section 
14.6.3): 
o This estimand utilizes the same endpoint, summary measure and target population 
as the primary Hgb estimand. For the intercurrent events of deaths, study treatment 
discontinuation, use of non-randomized ESA medication for any reason including 
rescue, and blood transfusions, a “while-on-treatment” strategy will be used.   
o This estimand reflects the effect of daprodustat treatment relative to rhEPO, while 
on treatment and without the use of non-randomized ESA medication or blood 
transfusions 
o For this analysis, the primary Hgb analyses and summaries described above will be 
performed using evaluable Hgb values (see Section 14.6.3). .  
o No data will be imputed in this analysis, so a summary of missing data will be 
provided instead of a summary of imputed data. 
o The LS mean treatment difference and associated two-sided 95% CI from this 
analysis will be included on a forest plot with the primary Hgb analysis results. 
o The number and percentage of subjects meeting each evaluable Hgb (see Section 
14.6.3) exclusion criteria will be summarized by scheduled visit. 
o A tipping point analysis similar to the one described above will be performed as a 
sensitivity analysis for this estimand using evaluable Hgb values only. 
 
PP Population Analysis 
• The while on treatment evaluable Hgb analysis and summaries described above (with the 
exception of the missing data summary) will also be performed using the PP population and 
evaluable Hgb values (see Section 14.6.3). 
• The LS mean treatment difference and associated two-sided 95% CI from this analysis will 
be included on a forest plot with the primary Hgb analysis results 
Alternative EP (Week 28-36) Analysis 
• The following analyses will be repeated using an alternative EP from Week 28-36: 
o The primary analysis and summaries (using on- and off-treatment, observed and 
imputed, Hgb values (see Section 14.6.3) 
o Supportive analyses and summaries of the alternative estimand that uses evaluable 
Hgb values and a while-on-treatment strategy for handling intercurrent events will be 
repeated using an alternative EP from Week 28-36. 
• Summaries of imputed/missing Hgb values will not be repeated. 
• The LS mean treatment difference and associated two-sided 95% CI from these analyses 
will be included on a forest plot with the primary Hgb analysis results. 
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Subgroup Analysis 
• Subgroup analysis will be performed using all available observed and imputed Hgb values 
(on and off-treatment), and Rubin’s rules [Rubin, 1987] will be used to combine results of the 
imputed datasets using SAS PROC MIANALYZE procedure.   
• Subgroup analysis will also be performed separately using evaluable Hgb values only (see 
Section 14.6.3). 
• Subgroup analysis details are discussed in Section 5.4.2. 
 
7.2. 
Principal Secondary Efficacy Analyses 
7.2.1. 
Endpoint / Variables 
Average monthly IV iron dose (mg)/participant to Week 52 
7.2.2. 
Summary Measure 
Model-adjusted mean treatment difference (LS mean difference) in average monthly IV 
iron dose (mg)/participant to Week 52. 
7.2.3. 
Population of Interest  
The principal secondary efficacy analyses will be based on the All Randomized (ITT) 
population, unless otherwise specified. 
7.2.4. 
Strategy for Intercurrent (Post-Randomization) Events 
The treatment effect to be estimated will be effect while the participants were on their 
initial study treatment. All IV iron use from Day 1 to Week 52 up to the time of study 
treatment discontinuation will be included in the principal secondary efficacy analyses. 
7.2.5. 
Statistical Analyses / Methods 
Details of the planned displays are provided in Appendix 10: List of Data Displays and 
will be based on GSK data standards and statistical principles. 
Unless otherwise specified, endpoints / variables defined in Section 7.2.1 will be 
summarised using descriptive statistics, graphically presented (where appropriate) and 
listed. 
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7.2.5.1. 
Statistical Methodology Specification 
Endpoint / Variables 
• Average monthly IV iron dose (mg)/participant to Week 52 
Model Specification 
• Average monthly IV iron dose (mg)/participant to Week 52 will be determined by calculating 
the total IV iron dose per subject from Day 1 to Week 52 while the participant was on study 
treatment and dividing by (the number of days the participant was on study 
treatment/30.4375 days). See Section 14.4.1 for the definition of on-treatment IV iron. 
• An ANCOVA model will be used to compare the difference in average monthly IV iron dose 
per participant between arms, adjusting for:  
o Treatment 
o Baseline monthly IV iron dose (see Section 5.2.1) 
o Region (as randomized, see Section 5.3 & Section 5.4.1) 
Model Results Presentation 
• The number and percentage of subjects with baseline IV iron use, on-treatment EP IV iron 
use, and on-treatment IV iron use to Week 52 will be summarized by treatment. Boxplots by 
study treatment will be created separately for on-treatment average monthly IV iron dose to 
week 52 and for post-randomization average monthly IV iron dose to week 52.  
• Average monthly IV iron dose at baseline, while on treatment during the EP, and while on 
treatment to Week 52 will be summarized by treatment group using mean, standard 
deviation, minimum, P25, median, P75, and maximum. 
• The least square (LS) mean estimates and standard errors by treatment group, LS mean 
difference, two-sided 95% CI and one-sided superiority p-value for the difference in average 
monthly IV iron dose/subject to Week 52 between the daprodustat and rhEPO arms from the 
ANCOVA model will be presented. The number of subjects contributing to the analysis and 
the associated mean and standard deviation of the baseline and Week 52 values will also be 
displayed with the results of the ANCOVA model. 
• A listing of average monthly IV iron dose will be provided including treatment, site ID, unique 
subject ID, subject ID, time period, and average monthly IV iron dose at Week 52. 
Model Results Interpretation 
• Conditional on the primary endpoint achieving non-inferiority at the one-sided 2.5% level, 
statistical testing will progress to the principal secondary endpoint with a focus on superiority 
using a one-sided 2.5% significance level.  
 
Supportive Statistical Analyses 
Average monthly IV iron dose (mg)/subject to Week 52 using on and off treatment IV iron 
records 
• The summaries and analysis described above for the principal secondary average monthly 
IV iron dose/subject to Week 52 will be repeated using all available IV iron records during 
the Day 1 – Week 52 visits, regardless of whether or not a subject was on treatment (i.e. 
treatment policy estimand). 
• The average monthly IV iron dose (mg)/subject to Week 52 for this analysis will be 
determined by calculating the total IV iron dose per subject from Day 1 to Week 52 and 
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Supportive Statistical Analyses 
dividing by (earliest of the (Week 52 visit date, study completion/withdrawal date) – 
Randomization date + 1 day/30.4375 days). 
Subgroup Analysis 
• Subgroup analyses will be performed for the principal secondary endpoint using ANCOVA 
model with terms for treatment group, baseline IV iron dose, region, subgroup and treatment 
by subgroup interaction. Subgroup analysis details are discussed in Section 5.4.2. 
• Subgroup analysis results will be presented graphically using a forest plot.  
 
7.3. 
Additional Secondary Efficacy Analyses 
7.3.1. 
Planned Secondary Efficacy Statistical Analyses 
Hgb Variability 
Secondary Efficacy Statistical Analyses: Hgb Variability 
Endpoint / Variables 
• Hgb change from baseline to Week 52 (Hgb change from baseline to Week 52 will be tested 
for non-inferiority using the -0.75 g/dL margin used in the primary analysis) 
• % time Hgb in analysis range (10-11.5 g/dL) during the evaluation period (EP, Week 28 to 
52) (% time Hgb in analysis range will be tested first for non-inferiority, then for superiority. 
The non-inferiority analysis will use a margin of 15% less time in range) 
• N (%) responders, defined as mean Hgb within the Hgb analysis range 10-11.5 g/dL during 
the EP 
Model Specification 
• For the secondary analysis of Hgb change from baseline to Week 52, a mixed model 
repeated measures (MMRM) approach will be used with an unstructured covariance matrix 
to compare the difference in means between arms. The model will be fitted to Hgb data 
collected after baseline up to Week 52, excluding values collected during the stabilization 
period (Day 1 to Week 28). The model will include factors for treatment, time, prognostic 
randomization stratification factor (region, see Section 5.3), baseline Hgb and the baseline 
Hgb by time and treatment by time interaction terms. Analyses will be done with the MIXED 
procedure in SAS, using the Kenward-Roger option to estimate denominator degrees of 
freedom and standard errors. This analysis will be performed using all available Hgb values 
(on and off-treatment) and separately using evaluable Hgb values only (see Section 14.6.3). 
In the analysis using all available Hgb values, subjects who withdraw from the study before 
Week 52 are considered to be missing at random and in the analysis using evaluable Hgb 
values, subjects who permanently discontinue study treatment before Week 52 are assumed 
to be missing at random. 
• For the analysis of % time in range, the method by Rosendaal [Rosendaal, 1993] will be 
used to calculate the percentage of time (days) a subject’s Hgb is below, within and above 
the Hgb analysis range of 10 to 11.5 g/dL during the EP (Weeks 28-52). A van Elteren test 
(stratified Wilcoxon rank sum test) will be used to compare the percentage of time in range 
between treatment arms, adjusting for treatment and the prognostic randomization 
stratification factor (see Section 5.3). This analysis will be performed using evaluable Hgb 
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values only. Hodges-Lehmann estimate of the treatment difference will be used to assess 
non-inferiority in % time in range. 
• For the Hgb responder analysis, mean Hgb during the EP will be defined as in the while on-
treatment evaluable Hgb supportive analysis (Section 14.6.3). Responders will be subjects 
with a mean Hgb during the EP that falls within the Hgb analysis range of 10-11.5 g/dL. A 
Cochran-Mantel-Haenszel (CMH) chi-squared test, adjusting for treatment and the 
prognostic randomization stratification factor (region as randomized, see Section 5.3), will be 
used to compare the number and % of responders between the treatment groups. 
Model Results Presentation 
• For the MMRM analysis of change from baseline in Hgb, an LSMEANS statement will 
provide adjusted treatment group means and standard errors and a point estimate and two-
sided 95% confidence interval for the adjusted mean treatment difference (daprodustat - 
rhEPO) at Week 52. The one-sided non-inferiority p-value for this test will be calculated. 
• For the responder analysis, the number and percentage of subjects with mean EP Hgb 
above, within and below the Hgb analysis range will be summarized by treatment group. 
• For the responder analysis, the number and % of responders by treatment group, difference 
in response rate (Dapro – rhEPO) and two-sided 95% CI will be provided along with the one-
sided CMH p-value for the treatment group comparison. 
• The % time Hgb is above, in and below the Hgb analysis range (10-11.5 g/dL) during the EP 
will be summarized using mean, standard deviation, minimum, P25, median, P75, and 
maximum by treatment group. 
• For the percent time Hgb in analysis range for each treatment group, the stratified Mann-
Whitey estimate of the treatment difference (daprodustat - rhEPO) and associated two-sided 
95% CI [Kawaguchi, 2011] will be presented in addition to the one-sided superiority p-value 
from the van Elteren test. Hodges-Lehmann estimate of the treatment difference 
(daprodustat-rhEPO) and associated two-sided 95% CI will be presented. 
Model Results Interpretation 
• For the MMRM analysis of change from baseline in Hgb, the NI margin used in the primary 
analysis of Hgb (-0.75 g/dL) will be used for reference in this comparison. Thus generating 
support for non-inferiority if the lower bound of the two-sided 95% CI is above -0.75 g/dL. 
• For the responder analysis, the one-sided CMH p-value will be compared to 0.025 to assess 
nominal significance. 
• For the percent time in range analysis, a NI margin of -15% will be used as a reference in 
this comparison, thus generating support for non-inferiority if the lower limit of the two-sided 
95% CI of Hodges-Lehmann estimate is above -0.15. If non-inferiority is established, 
nominal superiority will be achieved if the one-sided p-value is < 0.025 
Subgroup Analyses 
• Subgroup analyses will be performed for all Hgb variability endpoints, using the region and 
hyporesponder subgroups only (described in Section 5.3 & Section 5.4), in a method similar 
to that described for the subgroup analyses of the primary and principal secondary analyses 
 
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Time to Rescue 
Secondary Efficacy Statistical Analyses: Time to Rescue 
Endpoint / Variables 
• Time to stopping study treatment due to meeting rescue criteria 
Model Specification 
• The Cox Proportional Hazards model will adjust for the following baseline categorical values: 
o Treatment 
o Region (as randomized, see Section 5.3 & Section 5.4.1) 
• Confidence intervals for the rate per 100 person-years will also be reported. For within-group 
rates, the two-sided 95% CI will be obtained using an exact Poisson method. For difference 
in rates between treatments, the two-sided 95% CI will be constructed with a Normal 
approximation using Wald’s method [Liu, 2006]. 
• Analysis will include only those efficacy endpoints occurring within the time period for 
treatment discontinuation. Calculation of time-to-event or censoring is described in further 
detail in Section 14.6.3. 
• Time to stopping study medication due to meeting rescue criteria is defined as the time from 
Randomization until the date on which a subject permanently stops study medication due to 
meeting criteria for rescue. 
Model Results Presentation 
• Summaries will include (see Section 14.6.3):  
o the number and percentage of subjects meeting evaluation criteria for rescue 
and the number of occurrences (events),  
o the number and percentage of subjects unable to be evaluated for rescue, and  
o the number and percentage of subjects meeting rescue. 
• The analysis model results presentation: 
o Number (%) of subject permanently stopping study treatment due to meeting 
rescue criteria within each treatment arm 
o Number (%) of subject censored 
o Incidence rate per 100 person-year and the associated two-sided 95% 
confidence intervals for each treatment arm 
o Hazard ratio and the associated two-sided 95% confidence interval 
o One-sided p-value for the test of superiority of daprodustat vs rhEPO 
o Absolute rate difference per 100 person-year and the associated two-sided 95% 
confidence interval 
• A Kaplan-Meier plot of time to stopping study treatment due to meeting rescue criteria will be 
produced. 
Model Results Interpretation 
• One-sided p-values will be compared to 0.025 to assess nominal significance 
Subgroup Analyses 
• Subgroup analyses will be performed for the time to rescue endpoint using the 
hyporesponder subgroup only (described in Section 5.4). Cox Proportional Hazards model 
will be adjusted for the covariates used in the original analysis (region, treatment), 
hyporesponder subgroup, and treatment by subgroup interaction.  
 
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7.4. 
Exploratory Efficacy Analyses 
No statistical testing is planned for exploratory endpoints, unless otherwise noted.  
7.4.1. 
Planned Exploratory Efficacy Display Details 
Relationships between Daprodustat Exposure Parameters and Selected Efficacy 
Endpoints 
Endpoint / Variables 
Daprodustat Efficacy Dose Parameters 
Avg Dose EP 
TIR 
The average TIW daprodustat dose when the subject is on-treatment and in 
target Hgb range during the evaluation period (EP) Weeks 28-52. Evaluable 
Hgb values are used to determine time in range. Subjects who permanently 
stop study treatment before the beginning of the EP, and subjects who have 
0% time in range (e.g., subjects who have an evaluable Hgb below or above 
range for the entire EP) will have a missing value for this parameter 
Avg Dose EP 
The average TIW daprodustat dose when the subject is on-treatment during 
the EP. 
Avg Dose 52 
The average TIW daprodustat dose when the subject is on-treatment over 52 
weeks 
Daprodustat Efficacy Special Parameters 
Cmax/1mg 
Dose 
Cmax extrapolated to 1mg dose: Observed Cmax divided by dose 
administered on the PK day 
Cmax/Avg 
Dose EP TIR 
Cmax extrapolated to average dose during EP TIR: Cmax/1mg multiplied by 
the average TIW daprodustat dose when the subject is on-treatment and in 
target Hgb range during Weeks 28-52. Evaluable Hgb values are used to 
determine time in range. 
Cmax/Avg 
Dose EP 
Cmax extrapolated to average TIW dose during EP: Cmax/1mg multiplied by 
the average TIW daprodustat dose during the EP. 
Planned Exploratory Displays 
• Scatter plot of % Time Evaluable Hgb in Range during EP vs. Cmax/Avg Dose EP TIR 
• Scatter plot of Mean Evaluable Hgb Change from Baseline during EP vs. Cmax/Avg Dose 
EP 
• Scatter plot of % Time Evaluable Hgb in Range during EP vs. Avg Dose EP TIR 
• Scatter plot of Mean Evaluable Hgb Change from Baseline during EP vs. Avg Dose 52 
Daprodustat Efficacy Dose parameters (Avg Dose EP TIR, Avg Dose EP, Avg Dose 52) will be 
summarized using mean, standard deviation, minimum, P25, median, P75, and maximum. 
Efficacy Special parameters (Cmax/1mg Dose, Cmax/avg Dose EP TIR, Cmax/avg Dose EP,) 
will be summarized using mean, standard deviation, minimum, median, maximum, geometric 
mean, standard deviation of log-transformed data, and %CVb. A listing of the Efficacy Dose 
parameters and a listing of the Efficacy Special parameters will be provided. 
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Hgb Variability 
Endpoint/Variables 
• 
Hgb observed and change from baseline across all visits  
• 
% of time Hgb is above, within and below the analysis range of 10 to 11.5 g/dL during the 
EP 
• 
Number (%) of participants with mean Hgb above, within and below the Hgb analysis range 
during the EP  
• 
Number (%) of participants with a Hgb <7.5 g/dL during the EP 
• 
Number of times Hgb <7.5 g/dL during the EP 
• 
Number (%) of participants with a >1 g/dL increase in Hgb within any 2-week period 
(assessed at Week 2 through Week 8), or with a >2 g/dL increase in Hgb within any 4-week 
period up to Week 52 
• 
Number (%) of participants with a >1 g/dL decrease in Hgb within any 2-week period 
(assessed at Week 2 through Week 8), or with a >2 g/dL decrease in Hgb within any 4-
week period up to Week 52 
• 
N (%) of participants with a Hgb value ≥12 g/dL during the EP 
• 
Number of times Hgb ≥12 g/dL during the EP 
• 
% of time Hgb ≥12 g/dL during the EP 
Planned Exploratory Displays 
• All available Hgb values (on and off-treatment) will be summarized using mean, standard 
deviation, minimum, P25, median, P75 and maximum at each visit by treatment group (see 
Section 7.1.5). In addition to scheduled visits, the baseline value and mean EP and end of 
treatment values will be included (see Section 14.6.3). 
• All available Hgb change from baseline values (on and off-treatment) will also be 
summarized using mean, standard deviation, minimum, P25, median, P75, and maximum at 
each post-baseline visit (see Section 7.1.5), including the mean EP and end of treatment 
values (see Section 14.6.3). 
• The % time Hgb is above, within and below the Hgb analysis range (10-11.5 g/dL) during the 
EP will be summarized using mean, standard deviation, minimum, P25, median, P75, and 
maximum by treatment group (see Section 7.3.1). This summary will be presented using 
evaluable Hgb values only (see Section 14.6.3). 
• Number (%) of participants with mean Hgb above, within and below the Hgb analysis range 
during the EP will be summarized by treatment group (see Section 7.3.1). This summary will 
be presented using evaluable Hgb values only (see Section 14.6.3) 
• The number and percentage of subjects with a Hgb value < 7.5g/dL and the number of times 
a Hgb value < 7.5 g/dL occurs during the EP will be summarized by treatment group using 
central laboratory Hgb values and separately using HemoCue Hgb values. This summary 
will be presented using evaluable Hgb values only (see Section 14.6.3). The central 
laboratory summary will be considered the primary summary of this data. 
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• The number and percentage of subjects with a >1 g/dL increase in Hgb over 2 weeks 
(assessed at Week 2 through Week 8) or a >2 g/dL increase in Hgb within any 4-week 
period up to Week 52 will be summarized by visit and overall at Week 52 by treatment group 
using central laboratory Hgb values and separately using HemoCue Hgb values. This 
summary will be presented using evaluable Hgb values only (see Section 14.6.3). The 
central laboratory summary will be considered the primary summary of this data. 
• The number and percentage of subjects with a >1 g/dL decrease in Hgb over 2 weeks 
(assessed at Week 2 through Week 8) or a >2 g/dL decrease in Hgb within any 4-week 
period up to Week 52 will be summarized by visit and treatment group using central 
laboratory Hgb values and separately using HemoCue Hgb values. This summary will be 
presented using evaluable Hgb values only (see Section 14.6.3). The central laboratory 
summary will be considered the primary summary of this data. 
• The number and percentage of subjects with a Hgb value  12 g/dL and the number of 
times a Hgb value  12 g/dL occurs during the EP will be summarized by treatment group 
using central laboratory Hgb values and separately using HemoCue Hgb values. This 
summary will be presented using evaluable Hgb values only (see Section 14.6.3). The 
central laboratory summary will be considered the primary summary of this data. 
• The percentage of time Hgb is  12 g/dL during the EP will be calculated using the 
Rosendaal method as described in Section 7.3.1. The percentage of time Hgb is  12 g/dL 
during the EP will be summarized using mean, standard deviation, minimum, P25, median, 
P75, and maximum by treatment group. This summary will be presented using evaluable 
Hgb values only (see Section 14.6.3).In addition, the percentage of time Hgb is  12 g/dL for 
subjects with at least one Hgb  12 g/dL during the EP will be summarized using mean, 
standard deviation, minimum, P25, median, P75, and maximum by treatment group 
calculated using evaluable Hgb values.  
 
Iron Parameters 
Endpoint / Variables 
• 
Observed and change from baseline in hepcidin, ferritin, transferrin saturation (TSAT), total 
iron, total iron binding capacity (TIBC) across all visits  
• 
Average quarterly ferritin 
• 
Average quarterly TSAT 
• 
Average quarterly IV iron dose/participant 
• 
N (%) of participants who met iron management criteria 
• 
N (%) of participants who reduced IV iron supplementation relative to baseline [defined as 
total iron (mg) over 4 weeks prior to randomization] during EP [defined as average monthly 
IV iron dose (mg) over Weeks 28 to 52] 
Planned Exploratory Displays 
• Hepcidin, ferritin and total iron  on-treatment values will be log-transformed (see Section 
5.2.2) and summarized using geometric mean, coefficient of variation, minimum, P25, 
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median, P75, and maximum for each scheduled visit by treatment group. Graphical 
summaries will be provided. 
• TSAT, TIBC, and UIBC on-treatment values will be summarized using mean, standard 
deviation, minimum, P25, median, P75, and maximum for each scheduled visit by treatment 
group. Graphical summaries will be provided except for UIBC. 
• Percent change from baseline in log-transformed (see Section 5.2.2) hepcidin, ferritin and 
total iron on-treatment values will be summarized using geometric mean, 95% CI, minimum, 
P25, median, P75, and maximum for each scheduled visit by treatment group. Graphical 
summaries will be provided. 
• Change from baseline in TSAT, TIBC, and UIBC on-treatment values will be summarized 
using mean, standard deviation, minimum, P25, median, P75, and maximum for each 
scheduled visit by treatment group. Graphical summaries will be provided except for UIBC.. 
• Average quarterly IV iron dose/subject while on treatment will be summarized by presenting 
average monthly IV iron dose by quarter (see Section 14.6.3). Summaries will include mean, 
standard deviation, minimum, P25, median, P75, and maximum by treatment group. 
Graphical summaries will be provided. 
• The number and percentage of subjects who used IV iron, oral iron and/or other iron while 
on-treatment will be summarized by quarter.  
• Average quarterly TSAT while on treatment will be summarized by presenting average 
TSAT values for the quarters used to generate IV iron dose by quarter (see Section 14.6.3). 
Summaries will include mean, standard deviation, minimum, P25, median, P75, and 
maximum by treatment group. Graphical summaries will be provided. 
• Average quarterly ferritin while on treatment will be summarized by presenting average 
ferritin values by quarter (see Section 14.6.3). Summaries will include geometric mean, 
coefficient of variation, minimum, P25, median, P75, and maximum by treatment group. 
Graphical summaries will be provided. 
• The number and percentage of subjects that met the iron management criteria during the 
study while on treatment will be summarized by treatment group for each 3-month period of 
the study and across the entire study. There are two types of iron management thresholds: 
the first type requires that iron therapy be administered if subjects have ferritin and/or TSAT 
values that are too low; the second type requires that all iron (excluding multivitamins) must 
be stopped if ferritin and/or TSAT values are too high. It is also possible for a subject to 
meet starting and stopping criteria on the same day with a low ferritin and a high TSAT. 
These subjects will also be summarized (see Section 14.6.3). Assessment of meeting iron 
management thresholds will be made based on central laboratory data values. at the 
scheduled visits for ferritin and TSAT assessments, according to the schedule outlined in the 
Schedule of Activities table (see Section 14.2.1). Further, the subjects who met the 
threshold requiring iron administration to start or stop while on IV iron will be grouped by the 
action taken with IV iron therapy in the 8 weeks following the date the threshold was met 
(i.e., starting or increasing iron therapy, maintaining existing iron therapy, receiving no iron 
therapy, stopping or decreasing iron therapy with no increase, Section 14.6.3) according to 
concomitant medication records for IV iron. 
• The number and percentage of subjects that reduced IV iron supplementation relative to 
baseline during the EP while on treatment will be summarized by treatment group (see 
Section 14.6.3). 
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• A stacked bar chart of on-treatment iron use will be created by treatment group to show the 
percentages of subjects with different types of iron use at baseline and at each quarter post-
baseline.  
 
RBC and Whole Blood Transfusions 
Endpoint / Variables 
• 
Number (%) of participants who receive at least one RBC or whole blood transfusion by 
Week 52 
• 
Number of RBC and whole blood transfusion events per 100 patient years 
• 
Number of RBC and whole blood transfusions per 100 patient years  
• 
Number of RBC and whole blood units per 100 patient years 
• 
Time to first RBC and whole blood transfusion 
Planned Exploratory Displays 
• Summary and analysis tables will use the All Randomized (ITT) population. 
• The total number of on-treatment RBC and whole blood transfusion events, transfusions and 
units for each subject will be derived as described in Section 14.6.3 
• The number of on-treatment RBC and whole blood transfusion events per subject, the 
number of subjects with at least one RBC and whole blood transfusion event, and total 
number of RBC and whole blood transfusion events will be summarized.  
• The number of on-treatment RBC and whole blood transfusion events per 100 patient years 
will be summarized by treatment group. 
• The number of on-treatment RBC and whole blood transfusions per 100 patient years will be 
summarized by treatment group.  
• The number of on-treatment RBC and whole blood units per 100 patient years will be 
summarized by treatment group.  
• The reason for transfusion events will be summarized. 
• The above summaries will be produced for the Evaluation Period and Week 52. 
• An analysis of time to first RBC or whole blood transfusion will be performed as described in 
section 14.6.3, including a Kaplan-Meier plot. 
• All transfusion summaries will be repeated for the primary definition of ESA hyporesponder 
subgroups (see Section 14.6.2). 
 
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Dose Adjustment Scheme 
Endpoint / Variables 
• Assigned dose by visit and at Day 1, Week 28, and Week 52 
• Most recent dose prior to Week 28, Week 52 and end of study treatment 
• Number (%) of participants with 0, 1, 2, or >2 dose adjustments during the following periods: 
o Day 1 to < Week 28 
o Week 28 to  Week 52 
o Day 1 to  Week 52 
• Number of dose adjustments during the following periods: 
o Day 1 to < Week 28 
o Week 28 to  Week 52 
o Day 1 to  Week 52 
• Number of dose adjustments per year during Day 1 to  Week 52 
• Time dose held for Hgb ≥12 g/dL 
Planned Exploratory Displays 
• The assigned dose by visit will be summarized using mean, standard deviation, minimum, 
P25, median, P75, and maximum by treatment group.  
• The assigned dose by visit will also be summarized by treatment group using the number 
and percentage of subjects assigned to each dose level. Stacked bar graphs displaying 
assigned dose at all scheduled visits starting with Day 1 until Week 48 will be provided by 
treatment group. 
• The median assigned dose by treatment and visit will be displayed graphically for each 
scheduled study visit using a line plot. The line plot of median assigned dose along with the 
first and the third quartiles by time will include vertical reference lines to identify the EP as 
well as the number of subjects by treatment group contributing to each median value. 
• The number and percentage of patients with 0, 1, 2,….., 10 or > 10 dose adjustments will be 
summarized by treatment group. Summaries will be presented for the following categories of 
time: Day 1 – < Week 28, Week 28 – <= Week 52, and Day 1 – <= Week 52. This summary 
will be produced twice – the first time counting all dose adjustments, including adjustments 
related to periods of dose holds (i.e., no study treatment is given), the second time excluding 
dose adjustments related to periods of dose hold. The number and percentage of patients 
with dose adjustments by treatment group will also be summarized by Day 1 HemoCue 
Hemoglobin categories.  
• The number of dose adjustments per subject will be summarized using mean, standard 
deviation, minimum, P25, median, P75, and maximum by treatment group. Summaries will 
be presented for the following categories of time: Day 1 – < Week 28, Week 28 – <=Week 
52, and Day 1 – <= Week 52. For the period of time from Day 1 - <= Week 52, the number 
of dose adjustments per year will be summarized as well. This summary will be produced 
twice – the first time counting all dose adjustments, including adjustments related to periods 
of dose holds (i.e., no study treatment is given), the second time excluding dose 
adjustments related to periods of dose hold. 
• The time (in days) that study treatment was withheld for HemoCue Hgb values  12 g/dL per 
subject will be summarized for all subjects and for subjects who had a dose hold using 
mean, standard deviation, minimum, P25, median, P75, and maximum by treatment group. 
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Summaries will be presented for the following categories of time: Day 1 – < Week 28, Week 
28 – <=Week 52, and Day 1 – <= Week 52.  
• Summary tables for the dose adjustment scheme endpoints will also be repeated for the 
following subgroups (see Section 5.4.2 for subgroup definitions): 
o rhEPO hyporesponders (primary definition) 
o Region 
o Race group 
o Baseline weight quartiles 
• The median most recent dose by treatment and visit will be displayed graphically for each 
scheduled study visit using a line plot. The line plot of median most recent dose along with 
the first and the third quartiles by time will include vertical reference lines to identify the EP 
as well as the number of subjects by treatment group contributing to each median value. 
This plot will be created by treatment group and this plot will also be overlaid on a graph of 
corresponding Hgb values by visit. 
 
 
 
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8. 
SAFETY ANALYSES 
The safety analyses will be based on the Safety population, unless otherwise specified. 
8.1. 
Secondary Safety Analyses 
Blood Pressure 
Secondary Safety Statistical Analyses: Blood Pressure 
Endpoint(s) 
• Change from baseline in SBP, DBP and MAP at Week 52 and at the end of study treatment 
• Number of BP exacerbation events per 100 patient years  
• N (%) of subjects with at least one BP exacerbation event during study 
 
NOTE: Unless otherwise specified, for summaries and analyses of BP values, the post-dialysis BP 
values for subjects will be used.  
Model Specification 
• The difference in change from baseline in BP (SBP, DBP, and MAP) at Week 52 will be 
analyzed with a mixed model repeated measures (MMRM) approach with an unstructured 
covariance matrix to compare the difference in means between arms. The models will be fitted 
to scheduled BP data collected after baseline up to Week 52 (including Week 52 visit). Models 
will be run four times: 
o On-treatment BP values only, excluding values collected during the stabilization 
period (post-baseline up to but excluding Week 28 visit). 
o On-treatment BP values only, including values collected during the stabilization 
period. 
o On- and off-treatment BP values, excluding values collected during the 
stabilization period. 
o On- and off-treatment BP values, including values collected during the stabilization 
period. 
• The models will include factors for treatment, time, prognostic randomization stratification 
factor (Region, see Section 5.3), baseline BP parameter and the baseline BP parameter by 
time and treatment by time interaction terms. Analyses will be done with the MIXED procedure 
in SAS, using the Kenward-Roger option to estimate denominator degrees of freedom and 
standard errors. For analyses using on- and off-treatment values, subjects who withdraw from 
the study before Week 52 are considered to be missing at random and in the analysis using 
on-treatment values only, subjects who permanently discontinue study treatment before Week 
52 are assumed to be missing at random. 
• The difference in change from baseline in BP (SBP, DBP, and MAP) at the derived end of 
treatment (see Section 14.6.4) will be analyzed with an ANCOVA model including terms for 
treatment, prognostic randomization stratification factor (Region, see Section 5.3) and the 
corresponding baseline BP parameter. This analysis will be performed using on-treatment BP 
values only. 
• The number of on-treatment BP exacerbation events per 100 patient years will be calculated 
(see Section 14.6.4). Confidence intervals for the rate per 100 patient years will also be 
reported. For within group rates and the ratio of model estimated exacerbation rates, the point 
estimates. two-sided 95% confidence intervals, and one-sided p-value for the treatment group 
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Secondary Safety Statistical Analyses: Blood Pressure 
comparison will be obtained using a negative binomial model with treatment and the prognostic 
randomization strata as covariates and the logarithm of time on-treatment as an offset variable. 
Model Results Presentation 
• BP parameter values (SBP, DBP, and MAP) will be summarized using mean, standard 
deviation, minimum, P25, median, P75, and maximum at each visit by treatment group. In 
addition to scheduled visits, the derived baseline value, and end of treatment values will be 
summarized (see Section 14.6.4). Summaries of on-treatment BP values only and on- and off-
treatment BP values together will be produced for both pre- and post-dialysis BP. On-treatment 
BP parameter values will be plotted by visit using a line plot. 
• BP parameter change from baseline values (SBP, DBP, and MAP) will be summarized using 
mean, standard deviation, minimum, P25, median, P75, and maximum at each post-baseline 
visit by treatment group. In addition to scheduled visits, the derived end of treatment values will 
be summarized (see Section 14.6.4). Summaries of on-treatment BP values only and on- and 
off-treatment BP values together will be produced for both pre- and post-dialysis BP. On-
treatment BP parameter change from baseline values will be plotted by visit using a line plot. 
• For the MMRM analyses of change from baseline in BP parameters to Week 52, an LSMEANS 
statement will provide adjusted treatment group means, standard errors, a point estimate, a 
two-sided 95% confidence interval for the adjusted mean treatment difference (daprodustat - 
rhEPO), and a one-sided superiority p-value for this test. 
• For the ANCOVA analyses of change from baseline in BP parameters to the derived end of 
treatment, the adjusted mean estimates and standard errors by treatment group, adjusted 
mean difference, two-sided 95% CI and one-sided superiority p-value for the difference in BP 
parameter between the daprodustat and rhEPO arms from the ANCOVA model will be 
presented. The number of subjects contributing to the analysis and the associated mean and 
standard deviation of the baseline and end of treatment values will also be displayed with the 
results of the ANCOVA model. 
• The model estimated on-treatment BP exacerbation rates per 100 patient years and associated 
95% confidence intervals will be provided by treatment group.The ratio of model estimated on-
treatment BP exacerbation rates and associated two-sided 95% confidence interval and one-
sided p-value will also be provided for the comparison of daprodustat vs. rhEPO. 
• On-treatment BP exacerbations will be summarized as follows: The number and percent of 
subjects with 0, 1, 2, 3, 4, 5 and >5 on-treatment BP exacerbations will be provided by 
treatment group. Additionally, the number and percent of subjects with on-treatment BP 
exacerbations and number of on-treatment BP exacerbation events will be provided by 
treatment group, in total and by BP exacerbation type (see Section 14.6.4). The total treatment 
exposure in years and overall on-treatment BP exacerbation rate per 100 PY will be provided 
by treatment group. 
o The BP exacerbation summary above will be repeated for the following groups and 
BP values: 
▪ (1) All subjects, all on-treatment BP values (including both pre-dialysis and 
post-dialysis BP values) 
▪ (2) All subjects, on-treatment post-dialysis BP values only 
▪ (3) All subjects, on-treatment pre-dialysis BP values only. 
Model Results Interpretation 
• One-sided p-values will be compared to 0.025 to assess nominal significance. 
 
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8.2. 
Exploratory Safety Analyses 
Exploratory Cardiovascular Safety Analysis 
Exploratory CV Safety Analyses 
Endpoint(s)1: 
• MACE (composite of all-cause mortality, non-fatal MI, or non-fatal stroke) 
• MACE or a thromboembolic event (vascular access thrombosis, a symptomatic deep vein 
thrombosis or a symptomatic pulmonary embolism) 
• MACE or hospitalization for HF 
• All-cause mortality 
• CV mortality  
• MI (fatal and non-fatal) 
• Stroke (fatal and non-fatal) 
• CV mortality or non-fatal MI 
• All-cause hospitalization 
Model Specification 
• For all exploratory CV endpoints, confidence intervals for the rate per 100 person-years will be 
reported. For within-group rates, the 95% CI will be obtained using an exact Poisson method. 
For difference in rates between treatments, the two-sided 95% CI will be constructed with a 
normal approximation using Walds’ method [Liu 2006]. 
• For the MACE endpoint, the calculation of time-to-event or censoring is described in further 
detail in Section 14.6.4. 
• First occurrence of adjudicated MACE for a subject is defined as the first adjudicated event, 
determined by the event date, which is indicated as all-cause mortality, non-fatal MI or non-
fatal stroke with further details in Section 14.6.4. 
• For those endpoints or components of endpoints intended to go through the adjudication 
process, only the adjudicated results will be used. 
Model Results Presentation 
• A summary of the number and percentage of subjects having first-occurrence MACE will be 
provided by treatment group. The number and percentage of the types of events that make up 
the first occurrence of MACE will also be provided by treatment group. This summary table will 
be repeated for MACE plus thromboembolic events, for MACE plus hospitalization for heart 
failure and for MACE plus thromboembolic events or hospitalization for CHF. 
• A summary of all MACE including the number and percentage of subjects and number of 
events (including first and subsequent MACE) by type of event will be provided by treatment 
group. 
• A summary of the number and percentage of subjects having first-occurrence adjudicated 
COVID-19 MACE will be provided by treatment group. The number and percentage of the 
types of events that make up the first occurrence of adjudicated COVID-19 MACE will also be 
provided by treatment group. 
• Summaries of adjudication details of all-cause mortality will include the number and percentage 
of subjects by cause of death. 
• Summaries of adjudication details of MI will include the number and percentage of events by 
outcome of MI (fatal or non-fatal), type of MI, increased cardiac markers (y/n), ST segment 
classification [ST-elevation myocardial infarction (STEMI), non-ST-elevation myocardial 
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Exploratory CV Safety Analyses 
infarction (NSTEMI), ECG not interpretable, ECG not available], and Q wave classification (Q 
wave MI, Non Q wave MI, ECG not interpretable, ECG not available). 
• Summaries of adjudication details of stroke will include the number and percentage of events 
by outcome of stroke (fatal or non-fatal), type of stroke (ischemic, hemorrhagic, or 
undetermined) and ischemic details (with/without hemorrhagic transformation) and location if 
hemorrhagic (intraparenchymal, intraventricular, subarachnoid, retinal, unknown location). 
• Summaries of adjudication details of heart failure will include the number of events by type: 
hospitalization for heart failure, heart failure requiring urgent ER/ED visit, heart failure requiring 
urgent office/practice visit, and fatal heart failure events identified by cause of death only. 
• Summaries of adjudication details of thromboembolic events will include the number and 
percentage of events by type of thromboembolic event (DVT, PE, VAT).  
o Summaries of PEs will include outcome of PE (fatal or non-fatal). 
o Summaries of VATs will include type of VAT (AV fistula, AV graft, central venous 
catheter, other), method of diagnosis (ultrasound/Doppler, AV imaging, CVC 
imaging, other), and treatment (thrombolytic therapy, thrombectomy, angioplasty, 
stent, surgical intervention, not specified). 
• A summary of adjudicated supportive CV endpoints above (except all-cause hospitalization) 
will be provided to include the number and percentage of subjects and the number of events 
for each endpoint. 
• The model results presentation for the endpoints above plus MACE or Thromboembolic Events 
or Hospitalization for CHF will be provided to include within-group incidence rates per 100 
person-years (along with two-sided 95% CI) and difference in rates between treatments (along 
with two-sided 95% CI). For composite endpoints, the number and percentage of the type of 
first occurrence will be provided by treatment group. 
• A summary of all-cause hospitalization will be provided by treatment group including 
summaries of the number of hospitalizations per subject, average length of stay per 
hospitalization, and primary diagnosis at discharge by system organ class and lower level term.  
• Time from Randomization to first occurrence of adjudicated MACE event or end of trial will be 
evaluated using Kaplan-Meier (KM) methodology and displayed graphically for the comparison 
of daprodustat vs. rhEPO. 
• Summary of concordance between events referred for adjudication and adjudicated endpoint 
events (Positively Adjudicated or Negatively Adjudicated) will be presented. 
• A listing of all MACE events occurring during the study will be provided and will include 
treatment, site ID, unique subject ID, Subject ID, select demographic information, event type, 
event date, and study day. 
• A listing of all all-cause mortality events that occur during the study will be provided. This listing 
will include treatment, site ID, unique subject ID, select demographic information, event date, 
study day, and cause of death. 
[1] Adjudicated events used where available. 
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Rlationships between daprodustat Cmax/dosing and MACE/Combined MACE-related 
endpoint 
Endpoint / Variables 
Daprodustat Safety Dose Parameters 
Dose at first 
MACE 
The TIW daprodustat dose at the time of the subject’s first on-treatment 
adjudicated MACE. If the subject does not have an on-treatment adjudicated 
MACE, this value is missing. 
Final Dose 
for Subjects 
without 
MACE 
For subjects without an on-treatment adjudicated MACE, this is the subject’s final 
TIW daprodustat dose during the study. 
Dose at first 
MACE++ 
The TIW daprodustat dose at the time of the subject’s first on-treatment 
adjudicated MACE + thromboembolic event + hospitalization for CHF If the 
subject does not have an on-treatment adjudicated MACE + thromboembolic 
event + hospitalization for CHF this value is missing. 
Final Dose 
for Subjects 
without 
MACE++ 
For subjects without an on-treatment adjudicated MACE + thromboembolic event 
+ hospitalization for CHF, this is the subject’s final TIW dose during the study. 
Daprodustat Safety Special Parameters 
Cmax/Dose 
at first MACE 
Cmax extrapolated to dose at MACE: Cmax/1mg multiplied by the TIW 
daprodustat dose at the time of the subject’s first on-treatment adjudicated 
MACE. 
Cmax/Final 
Dose for 
subjects 
without 
MACE 
For subjects without an on-treatment adjudicated MACE, this is the subject’s 
Cmax/1mg multiplied by the subject’s final TIW daprodustat dose during the 
study. 
Cmax/Dose 
at first 
MACE++ 
Cmax extrapolated to dose at MACE + thromboembolic event + hospitalization 
for CHF: Cmax/1mg multiplied by the TIW daprodustat dose at the time of the 
subject’s first on-treatment adjudicated MACE + thromboembolic event + 
hospitalization for CHF. 
Cmax/Final 
Dose for 
subjects 
without 
MACE++ 
For subjects without an on-treatment adjudicated MACE + thromboembolic 
event + hospitalization for CHF, this is the subject’s Cmax/1mg multiplied by the 
subject’s final TIW daprodustat dose during the study. 
Planned Exploratory Displays 
• Boxplot of Cmax/Dose at on-treatment MACE by subjects with or without on-treatment 
MACE 
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• Boxplot of Cmax/Dose at on-treatment MACE + thromboembolic event + hospitalization for 
CHF by subjects with or without on-treatment MACE + thromboembolic event + 
hospitalization for CHF 
• Boxplot of Average TIW Dose at on-treatment MACE by subjects with or without on-
treatment MACE 
• Boxplot of Average TIW Dose at on-treatment MACE + thromboembolic event + 
hospitalization for CHF by subjects with or without on-treatment MACE + thromboembolic 
event + hospitalization for CHF 
• Average TIW daprodustat dose will be summarized using mean, standard deviation, 
minimum, P25, median, P75, and maximum by participants with and without MACE. 
• Average TIW daprodustat dose will be summarized using mean, standard deviation, 
minimum, P25, median, P75, and maximum by participants with and without MACE + 
thromboembolic event + hospitalization for CHF. 
Average TIW daprodustat dose = average TIW daprodustat dose while on study treatment for 
participants without MACE/Combined MACE-related endpoint and before the event for 
participants with MACE/Combined MACE-related endpoint. 
For the figures and summaries described above, the “On-Treatment” time window (“last non-
zero dose date +28 days”, see Section 14.4.1) will be used to decide whether a subject should 
be considered with MACE/Combined MACE.  
Daprodustat Safety Dose parameters (Dose at first MACE, Final Dose for Subjects without 
MACE, Dose at first MACE++,  Final Dose for Subjects without MACE++) will be summarized 
using mean, standard deviation, minimum, P25, median, P75, and maximum by participants with 
and without MACE and MACE ++. Daprodustat Safety Special parameters (Cmax/ Dose at first 
MACE, Cmax/ Final Dose for subjects without MACE, Cmax/ Dose at first MACE++, Cmax/ Final 
Dose for subjects without MACE++)   will be summarized using mean, standard deviation, 
minimum, median, maximum geometric mean, standard deviation of log-transformed data, 
and %CVb. A listing of the Safety Dose Parameters and a listing of the Safety Special 
Parameters will be provided. 
 
Blood Pressure and Blood Pressure Medication Change 
Endpoint / Variables 
• 
Observed and change from baseline in SBP, DBP, and MAP by visit 
• 
Number of BP medications per participant by visit 
• 
Change from baseline in the number or dose of BP medications per participant by visit 
• 
N (%) of participants who had no change in the number or dose of BP medications from 
baseline by visit 
• 
N (%) of participants who had an increase in the number or dose of BP medications from 
baseline by visit  
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• 
N (%) of participants who had a decrease in the number or dose of BP medications from 
baseline by visit 
Planned Exploratory Displays 
• Observed and change from baseline in SBP, DBP, and MAP by visit are included in the 
summary of secondary safety analyses described in Section 8.1. 
• The last on-treatment BP parameter change from baseline value (SBP, DBP, and MAP) 
recorded prior to the first change in BP medications will be summarized using mean, 
standard deviation, minimum, P25, median, P75, and maximum by treatment group. The 
first change in blood pressure medication occurs at the earliest time a new anti-hypertensive 
medication is administered or if the dose or frequency of an existing blood pressure 
medication is changed for any reason (increased, decreased, discontinued, or switched to 
another agent) in any anti-hypertensive medication, except medication records with 
frequencies of “Once only” and “PRN.” 
• Number of BP medications per subject while the subject was on treatment will be 
summarized using mean, standard deviation, minimum, P25, median, P75, and maximum 
for each scheduled visit by treatment group. Number of BP medications for each subject at 
baseline is defined as the number of medications taken on the day before study treatment 
start date.  For end of treatment, it is defined as the number of medications taken on last 
non-zero dose date + 1 day.  The number of BP medications at all other nominal visits is 
defined as the number of medications taken on the day of the visit.  Medication records with 
frequencies of “Once only” and “PRN” will be excluded from this summary. 
• Change from baseline in the number of BP medications per subject while the subject was on 
treatment will be summarized using mean, standard deviation, minimum, P25, median, P75, 
and maximum for each scheduled visit by treatment group. The number of BP medications 
at baseline, end of treatment and all other nominal visits will be defined as described in the 
previous paragraph. Medication records with frequencies of “Once only” and “PRN” will be 
excluded from this summary.  
• Additionally, the number and percentage of subjects who had no change, at least one 
change, an increase, a decrease, or a switch in the dosage or number of BP medications 
from baseline while the subject was on treatment will be summarized for each scheduled 
post-baseline visit by treatment group (see Section 14.6.4 for details of classifying BP 
medication changes). Medication records with frequencies of “Once only” and “PRN” will be 
excluded from this summary. 
• Cumulative number of changes in on-treatment BP medications from baseline to Week 52 
will be summarized by treatment group. For all records except with frequencies “Once only” 
and “PRN,” the cumulative number of changes will be summarized using mean, standard 
deviation, minimum, P25, median, P75, and maximum. The number of percentage of 
subjects with no change and at least one medication change will be displayed excluding 
“Once only” and “PRN” records.  For subjects with at least one change, the number and 
percentage of subjects for each reason (increase, decrease, and switch) will be displayed 
(see Section 14.6.4 for details of counting BP medication cumulative changes) by treatment 
group. Number and percentage of subjects for each reason of BP medication change will be 
displayed by treatment group. Cumulative number of changes in on-treatment BP 
medication from baseline to Week 52 for “Once only” records only will be summarized using 
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mean, standard deviation, minimum, P25, median, P75, and maximum (see Section 14.6.4 
for details of counting BP medication cumulative changes) by treatment group. 
• Number and percentage of subjects with at least one PRN record at baseline and on-
treatment BP medication during the period from study treatment start date to Week 52 will 
be displayed by treatment group. 
• Number and percentage of subjects with any BP medication taken at baseline (the day 
before study treatment state date) and any on-treatment BP medication during the period 
from study treatment start date to Week 52 will be displayed by treatment group. 
 
Lipid Parameters 
Endpoint / Variables 
• 
Observed and % change from baseline in lipid parameters by visit [total cholesterol, direct 
low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C)] 
Planned Exploratory Displays 
• Lipid parameter values for this study include total cholesterol, LDL-C (direct) and HDL-C. 
These values are collected according to the schedule outlined in the Schedule of Activities 
table (see Section 14.2.1). Lipid parameter values follow the derivation guidelines for 
laboratory values outlined in Section 14.6.4. The summaries described below will include 
summaries in both SI units and conventional units for each of the lipid parameters and will 
summarize log-transformed values. 
• Total cholesterol, LDL-C (direct), and HDL-C values will be log-transformed and summarized 
using geometric mean, CV, minimum, P25, median, P75, and maximum for each scheduled 
visit by treatment group.  
• Percent change from baseline in log-transformed total cholesterol, LDL-C (direct), and HDL-
C on-treatment values will be summarized using geometric mean, 95% confidence interval, 
minimum, P25, median, P75, and maximum for each scheduled visit by treatment group.  
8.3. 
Adverse Events Analyses 
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) coding dictionary. 
Adverse events analyses including the analysis of adverse events (AEs), Serious (SAEs) 
and other significant AEs will be based on GSK Core Data Standards. The details of the 
planned displays are provided in Appendix 10: List of Data Displays. 
For the purpose of AE summaries and analysis, the investigator-reported AE details will 
be used, regardless of the adjudication outcome of the event. 
See Section 14.4.1 for AE treatment-state definitions. 
The adverse event safety analyses will be based on the Safety population, unless 
otherwise specified. 
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8.3.1. 
Analysis of Adverse Event of Special Interest (AESI)  
A prespecified list of MedDRA terms will be used to identify AESIs. Changes to the 
MedDRA dictionary may occur between the start of the study and the time of reporting 
and/or emerging data from ongoing studies may highlight additional AESIs, therefore the 
list of terms to be used for each event of interest and the specific events of interest will be 
based on the safety review team (SRT) agreements in place at the time of reporting. The 
details of the planned displays are provided in Appendix 10: List of Data Displays. 
AESIs are described in Section 14.6.4. 
Summaries of AESIs will include the number, percentage, and rate per 100 person-years 
of subjects having at least one occurrence, the number of events, the number of subjects 
by number of occurrence, the characteristics of the AE (serious, drug-related, etc.), 
outcome, maximum intensity, time to first onset/worsening, and action taken summarized 
by treatment group. For each count, a subject will be summarized as follows: 
• Serious/drug-related/severe/fatal: If any specific AE falls in the respective 
category, the subject will be counted in that category. 
• Outcome: The subject will be counted within a category if there is at least one 
specific AE in that category. 
• Maximum intensity: The specific AE with the maximum intensity will be counted 
for this purpose. For example, a subject will be counted in the ‘severe’ category if 
there is at least one specific AE with severe intensity. A subject will be counted in 
the ‘moderate’ category if there is at least one specific AE with moderate intensity 
and there is no specific AE with severe intensity. 
• Time to first onset/worsening (days): The earliest of onset dates for the specific 
AE – treatment start + 1 
If the AE onset date/AE worsening and/or resolution date is missing or incomplete in the 
database for any occurrence of the specific AE, time to first onset/worsening will be left 
missing for the subject. These summaries of special interest AEs will be provided for 
those AEs classified as treatment emergent, follow-up, and post-randomization. 
The number and percentage of subjects reporting treatment emergent AESI will also be 
summarized by treatment group and by preferred term.  
Cumulative incidence function (CIF) plots may be produced for each special interest AE 
summarizing the time to first occurrence of the special interest AE by treatment group, 
with the exception of the composite endpoint AESI (death, myocardial infarction, stroke, 
heart failure, thromboembolic events, thrombosis of vascular access). This endpoint will 
use a Kaplan-Meier plot. If there are less than 20 subjects total for both the daprodustat 
and rhEPO arm, then these plots will not be created. Competing risks for the AESI 
cumulative incidence plots include: 
 
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AE of Special Interest (Event of interest) 
Competing Risk Events 
Thrombosis and/or tissue ischemia secondary 
to excessive erythropoiesis 
Death due to any cause prior to the AESI 
Cardiomyopathy 
Death due to any cause prior to the AESI 
Pulmonary artery hypertension 
Death due to any cause prior to the AESI 
Cancer-related mortality and tumor 
progression and recurrence 
All other non-cancer-related death prior to the 
AESI (use death date as the competing risk 
date) 
Esophageal and gastric erosions 
Death due to any cause prior to the AESI 
Proliferative retinopathy, macular edema, 
choroidal neovascularization 
Death due to any cause prior to the AESI 
Exacerbation of rheumatoid arthritis 
Death due to any cause prior to the AESI 
Worsening of hypertension 
Death due to any cause prior to the AESI 
 
Dot plots displaying the incidence of the treatment emergent event will be provided for 
AESIs by AESI term and treatment group. The incidence rate in each treatment group 
and corresponding two-sided 95% confidence interval for the relative risk of the 
daprodustat group compared to the rhEPO group will be provided. 
8.3.2. 
Adverse Events 
The number and percentage of subjects reporting at least one AE will be provided for 
each treatment group. These events will be summarized by treatment group, primary 
system organ class, and preferred term. Post-randomization, treatment emergent and 
follow-up AEs will be summarized separately. 
Summaries of all treatment emergent AEs will be produced for the age group, gender, 
race group and weight quartile subgroups. Summaries of treatment emergent AEs by 
subgroup will be produced twice: by system organ class and preferred term and 
separately by overall frequency. 
A listing of AE records for all subjects who reported AEs will be produced. 
Summaries of all treatment emergent AEs will be provided by maximum intensity. For 
AEs reported more than once by a subject, the most severe intensity will be included in 
summaries where applicable. Analysis will be repeated for all drug-related treatment 
emergent AEs. 
The number and percentage of subjects reporting the most common treatment emergent 
AEs (those occurring in  5% of subjects in any treatment group) will be summarized by 
preferred term and treatment group.  
Additionally, the most common treatment emergent AEs will be summarized graphically 
by preferred term and treatment group. The incidence rate in each treatment group and 
corresponding two-sided 95% confidence interval for the appropriate comparator 
estimate (relative risk) of the daprodustat group compared to the rhEPO group will be 
provided. Displays will be sorted by magnitude of risk, from largest to smallest.  
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The number and percentage of subjects reporting treatment emergent AEs assessed by the 
investigator to be related to the study drug will be summarized by treatment group, 
primary system organ class, and preferred term and separately by overall frequency.  
The number and percentage of subjects and the number of occurrences of common non-
serious treatment emergent adverse events (those occurring in  5% of subjects in any 
treatment group) will be summarized by primary system organ class, preferred term, and 
treatment group and separately by overall frequency.  
A listing of which subjects reported specific adverse events will be produced. 
The hierarchical relationship between MedDRA SOCs, PTs, and verbatim text will be 
listed for all adverse events. 
A listing of pre-treatment adverse events will be produced.  
8.3.3. 
Serious and Other Significant Adverse Events 
The number and percentage of subjects and the number of occurrences of SAEs will be 
provided for each treatment group. These events will be summarized by treatment group, 
primary system organ class, and preferred term. Pre-treatment, post-randomization, 
treatment emergent and follow-up SAEs will be summarized separately. Treatment 
emergent SAE preferred terms will also be summarized by treatment group and overall 
frequency. 
A listing of reasons for considering as a SAE will be produced for all SAEs. 
The number and percentage of subjects and the number of occurrences of treatment 
emergent drug-related SAEs, drug-related non-SAEs, fatal SAEs, non-fatal SAEs, and 
drug-related fatal SAEs will be summarized by treatment group: by primary system organ 
class and preferred term and separately by overall frequency. 
A listing of fatal SAE records and a listing of non-fatal SAE records will be provided. 
The number and percentage of subjects reporting treatment emergent SAEs will be 
summarized by treatment group, maximum intensity, primary system organ class, and 
preferred term. 
The number and percentage of subjects reporting treatment emergent AEs leading to 
discontinuation of study treatment or withdrawal from the study will be summarized by 
treatment group, primary system organ class, and preferred term. Treatment emergent 
AEs leading to discontinuation of study treatment or withdrawal from the study will also 
be summarized by treatment group and overall frequency. 
A listing of AEs leading to discontinuation of study treatment and a listing of AEs 
leading to withdrawal from study will be provided. 
BP events and BP-related SAEs are defined in Section 14.6.4. 
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The number and percentage of subjects with at least one on-treatment BP event will be 
provided for each treatment group. In addition, this summary will include the number and 
percentage of subjects with at least one on-treatment BP event that is considered 
clinically significant and the number and percentage of subjects with at least one on-
treatment BP event that is considered to be symptomatic. 
The number and percentage of subjects reporting at least one treatment emergent BP-
related SAE will be provided for each treatment group. In addition, the number of 
treatment emergent BP-related SAEs will be summarized by treatment group, primary 
system organ class, and preferred term. 
A listing of other significant adverse events will be produced. Other significant adverse 
events are events that are not reported as fatal or serious but represent ICH-defined 
‘Other significant adverse events’ (i.e., marked haematological and other laboratory 
abnormalities or led to an intervention, dose reduction, or significant additional 
concomitant therapy). For this study, other significant AEs will be defined as non-fatal 
non-serious AEs resulting in an action taken with study treatment of either ‘dose 
interrupted/delayed’ or ‘dose reduced’. 
8.3.4. 
Other CV Events 
GSK has identified other CV events of interest for all clinical studies. In this study, 
investigators will be required to fill out the specific CV event page of the eCRF for the 
following CV AEs and SAEs or any event that may potentially be one of the categories 
listed: 
• Arrhythmias 
• Pulmonary hypertension (also an adverse event of special interest [AESI]) 
• Valvulopathy 
• Revascularization 
Electronically generated patient profiles for participants reporting these events will not be 
prospectively created. 
8.4. 
Clinical Laboratory Analyses 
Laboratory evaluations including the analyses of chemistry laboratory tests, hematology 
laboratory tests, and liver function tests will be based on GSK Core Data Standards. The 
details of the planned displays are in Appendix 10: List of Data Displays. 
Clinical chemistry, hematology and other laboratory tests are assessed in this study 
according to the schedule outlined in the Schedule of Activities table (see Section 14.2.1) 
and include the following tests: 
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Laboratory 
Assessments 
Parameters 
Hematology 
Platelet count 
RBC indices: 
Leukocyte (white blood cell) 
count with Differential 
Erythrocyte (red blood 
cell) count 
Mean corpuscular volume 
(MCV) 
Neutrophils (absolute and 
segmented) 
Hemoglobin 
Mean corpuscular 
hemoglobin (MCH) 
Lymphocytes 
Hematocrit 
Mean corpuscular 
hemoglobin concentration 
(MCHC) 
Monocytes 
Reticulocyte count 
Erythrocytes (red cell) 
distribution width (RDW) 
Eosinophils 
 
 
Basophils 
Clinical 
Chemistry  
Potassium (serum) 
Aspartate 
aminotransferase  (AST) 
Albumin  
Calcium (albumin-
corrected) 
Alanine amintotransferase 
(ALT) 
Blood Urea Nitrogen (BUN) 
Phosphate 
Bilirubin (total, direct and 
indirect) 
 
Iron 
parameters 
Iron (serum) 
Ferritin  
UIBC 
Hepcidin  
TIBC 
TSAT 
Lipid 
parameters 
Total cholesterol 
LDL-C (direct) 
HDL-C 
Other 
laboratory 
tests 
Serum pregnancy test  
High-sensitivity C-reactive 
protein (hsCRP) 
HemoCue Hgb 
Estradiol  
Intact parathyroid 
hormone (iPTH) 
Stored sample (blood)  
FSH  
Erythropoietin (EPO) 
 
Hemoglobin A1c 
(HbA1c) 
Vascular Endothelial 
Growth Factor (VEGF) 
 
MCV, mean corpuscular volume; MCH, mean corpuscular hemoglobin; MCHC, mean corpuscular hemoglobin 
concentration; RDW, red blood cell distribution width; AST, aspartate transaminase; ALT, alanine transaminase; 
UIBC, unbound iron binding capacity; TIBC, total iron binding capacity; TSAT, transferring saturation; LDL-C, low 
density lipoprotein-C; HDL-C, high density lipoprotein-C;  
 
Summaries of central laboratory Hgb values, HemoCue Hgb values, iron parameter 
values (serum iron, ferritin, hepcidin, TIBC, TSAT, UIBC), PD parameters (EPO, 
VEGF), and lipid parameter values (total cholesterol, direct LDL-C, HDL-C) are 
included in the separate efficacy, safety, and pharmacodynamic sections and will not be 
included with clinical laboratory displays. However, these parameters may be included in 
PCI summaries. 
The clinical chemistry tests performed in this study include ALT, AST and bilirubin. In 
addition to being summarized with the clinical chemistry values, these laboratory values 
will be included in some of the Hepatobiliary (liver) displays. 
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In addition to the visits listed for the laboratory assessments in the Schedule of Activities 
table (see Section 14.2.1), any of these assessments may be performed at an 
unscheduled/retest visit at the discretion of the investigator. See Section 14.5.2 for 
handling of unscheduled values. The laboratory’s normal range values will be provided 
by the central laboratory, and potential clinical importance thresholds are defined in 
Section 14.8.1. 
All of the tabular summaries described below will include summaries in SI units; 
conventional units will also be provided for the following laboratory tests: MCHC, total 
calcium, albumin-corrected calcium, phosphate, albumin, BUN, total cholesterol, LDL-C, 
and HDL-C. Conversions from SI units to conventional units are included in Section 
14.6.4. Hemoglobin summaries will only use conventional mg/dL units. Summaries of 
reticulocytes will be provided for the total count and percent of total erythrocytes and 
summaries of neutrophils, lymphocytes, monocytes, eosinophils, and basophils will be 
provided for total counts and differentials (percent of total leukocytes). TSAT will be 
reported in the conventional unit (%).  
The clinical laboratory safety analyses will be based on the Safety population, unless 
otherwise specified. 
8.4.1. 
Planned Clinical Laboratory Safety Displays 
Clinical Chemistry 
Continuous on-treatment values (see Section 14.4.1) will be summarized using mean, 
standard deviation, minimum, P25, median, P75, and maximum for each scheduled visit 
and for baseline and end of treatment (see Section 14.6.4) by treatment group.  
Continuous on-treatment change from baseline values will be summarized using mean, 
standard deviation, minimum, P25, median, P75, and maximum for each scheduled visit 
and for end of treatment (see Section 14.6.4) by treatment group.  
The number and percentage of subjects with on-treatment worst case laboratory results 
relative to the normal range which are post-baseline relative to baseline will be 
summarized by laboratory test, category, and treatment group. See Section 14.6.4 for 
additional information on worst case values and normal range categories. 
The number and percentage of subjects with on-treatment worst case laboratory results 
relative to PCI criteria (see Section 14.8.1) which are post-baseline relative to baseline 
will be summarized by laboratory test, category, and treatment group. See Section 14.6.4 
for additional information on worst case values and PCI categories. 
Hematology 
The displays presented for clinical chemistry laboratory values will also be presented for 
the hematology central laboratory tests listed in Section 8.4. 
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Other Laboratory Tests 
The displays presented for clinical chemistry laboratory values will also be presented for 
the other laboratory tests listed in Section 8.4.  
The number and percentage of subjects with on-treatment worst case iron parameter 
results relative to PCI criteria (see Section 14.8.1) which are post-baseline relative to 
baseline will be summarized separately by laboratory test, category, and treatment group. 
See Section 14.6.4 for additional information on worst case values, normal range 
categories and PCI categories. 
On-treatment hsCRP values will be log-transformed (see Section 5.2.2) and summarized 
using geometric mean, coefficient of variation, minimum, P25, median, P75, and 
maximum for each scheduled visit by treatment group. 
Percent change from baseline in log-transformed (see Section 5.2.2) on-treatment hsCRP 
values will be summarized using geometric mean, 95% confidence interval, minimum, 
P25, median, P75, and maximum for each scheduled visit by treatment group. 
Hepatobiliary (Liver) 
Please refer to the protocol for details of liver chemistry increased monitoring and 
stopping criteria. 
Liver monitoring/stopping events will be summarized by treatment group. 
Hepatobiliary laboratory abnormalities will be summarized by treatment group. 
Medical conditions for subjects with liver stopping events and substance use for subjects 
with liver stopping events will be listed. 
A scatter plot of maximum on-treatment ALT values versus baseline ALT values will be 
produced. 
A scatter plot of maximum on-treatment total bilirubin (xULN) versus maximum on-
treatment ALT (xULN) values will be produced. 
All Laboratory 
A listing of all chemistry data, a listing of all hematology data, and a listing of all other 
laboratory data will be provided.  
In addition, for subjects with abnormalities of potential concern, a listing of all chemistry 
data, a listing of all hematology data, and a listing of all other laboratory data will be 
generated separately.  
A listing of laboratory data with character results will be provided. 
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8.5. 
Other Safety Analyses 
The analyses of non-laboratory safety test results including ECGs and vital signs will be 
based on GSK Core Data Standards, unless otherwise specified. The details of the 
planned displays are presented in Appendix 10: List of Data Displays. 
8.5.1. 
Electrocardiograms 
A summary of the number and percentage of subjects who had normal, abnormal and/or 
clinically significant ECG findings will be displayed by treatment group. For all ECG 
parameters, change from baseline in ECG values at week 52 will be summarized by 
treatment group. 
 
The number of subjects with maximum QTc values (i.e., worst case) post-baseline 
relative to baseline will be summarized by test (e.g., QTcB Interval, Aggregate) and 
category for each treatment group.  
 
Subjects will also be summarized by a categorization of their maximum increase in QTc 
value (e.g., QTcB Interval, Aggregate) (i.e., worst case) post-baseline relative to baseline. 
 
8.5.2. 
Vital Signs 
Vital signs are assessed in this study according to the schedule outlined in the Schedule 
of Activities table (see Section 14.2.1) and include the following assessments: 
• HR (pre- and post-dialysis) 
• Weight (pre- and post-dialysis) 
• Estimated Dry Weight (EDW, recorded in the eCRF only at Day 1, full study 
visits, and Week 52) 
Summaries and analyses of BP values are described in earlier safety sections and will not 
be included with vital signs summaries. However, BP values will be included in PCI 
summaries. 
The vital signs analyses will be based on the Safety population, unless otherwise 
specified. 
Vital sign values will be summarized using mean, standard deviation, minimum, P25, 
median, P75, and maximum for each scheduled visit and for baseline and end of 
treatment by treatment group. Separate summaries for HR and weight measured pre- and 
post-dialysis will be provided.  
Vital sign change from baseline values will be summarized using mean, standard 
deviation, minimum, P25, median, P75, and maximum for each scheduled visit and for 
end of treatment by treatment group. Separate summaries for HR and weight measured 
pre- and post-dialysis will be provided.  
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The number and percentage of subjects with on-treatment or post-treatment worst case 
vital sign results relative to PCI criteria (see Section 14.8.3) which are post-baseline 
relative to baseline will be summarized by test, category, and treatment group. See 
Section 14.6.4 for additional information on worst case values and PCI categories. Post-
dialysis BP values and heart rate outside of the PCI range will be summarized separately.  
The difference between on-treatment post-dialysis weight and estimated dry weight will 
be summarized using mean, standard deviation, minimum, P25, median, P75, and 
maximum for each scheduled visit and for baseline and end of treatment by treatment 
group. A corresponding line plot will be provided to display this data graphically. 
A listing of all vital signs data for subjects with post-dialysis vital signs values outside of 
PCI criteria will be provided. 
8.5.3. 
Pregnancy 
A listing of all subjects who became pregnant during the study will be included. 
8.5.4. 
COVID-19 Analyses 
The following COVID-19 related displays will be provided. 
A summary of the number and percentage of subjects for the following assessments will 
be produced: Case Diagnosis, COVID-19 Test performed, and Results of the COVID-19 
test. 
A summary of exposure adjusted incidence rates over time (see Section 14.6.4) will be 
produced by treatment group for any AE, any SAE, and any Severe AE, for two periods – 
pre COVID-19 pandemic and during COVID-19 pandemic. The summary will be 
produced overall, by Country, Region, Sex, and by Age at randomization (Grouping 2) 
(see Section 5.4.2). A summary of exposure adjusted incidence rates by treatment group 
will also be produced for Common (>5%) AEs for two periods – pre COVID-19 
pandemic and during COVID-19 pandemic. 
 
 
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9. 
PATIENT REPORTED OUTCOMES ANALYSIS 
This study includes the following patient reported outcomes (PROs) that are assessed 
according to the schedule in the Schedule of Activities table in Section 14.2.1: 
• Patient Global Impression of Severity (PGI-S) 
• Patient Global Impression of Change (PGI-C) 
Additional details on these questionnaires can be found in Section 14.6.7. 
Except for baseline, only on-treatment post-baseline PGI-S and PGI-C will be 
summarized/analyzed, unless otherwise specified.  
Patient Reported Outcomes Statistical Analyses: Symptom Severity & Change 
Secondary Endpoint(s) 
• Change from Baseline at Wk 8,12, 28, 52 in PGI-S 
Exploratory Endpoint(s) 
• Shift tables (Baseline to Weeks 8, 12, 28, and 52) in PGI-S 
• N (%) of patients within each PGI-C symptom change level at Weeks 8, 12, 28, 52 
Model Specification 
• Scoring for the PGI-S and PGI-C parameters is outlined in Section 14.6.7. 
• The mean change from baseline in PGI-S score will be analyzed using an MMRM approach 
with an unstructured covariance matrix to compare the difference in means between arms. The 
models will be fitted to data collected after baseline up to Week 52. The model will include 
factors for treatment, time, region, baseline PGI-S score value and the baseline PGI-S score by 
time and treatment by time interaction terms. Analyses will be done with the MIXED procedure 
in SAS, using the Kenward-Roger option to estimate denominator degrees of freedom and 
standard errors. 
Model Results Presentation 
• PGI-S scores will be summarized using mean, standard deviation, minimum, P25, median, 
P75, and maximum by treatment group at all scheduled visits. 
• Change from baseline in PGI-S values will be summarized using mean, standard deviation, 
minimum, P25, median, P75, and maximum by treatment group at all scheduled visits. 
• For the MMRM analyses of change from baseline in PGI-S, an LSMEANS statement will 
provide adjusted treatment group means and standard errors and a point estimate and two-
sided 95% confidence interval for the adjusted mean treatment difference (daprodustat - 
rhEPO) and a one-sided superiority p-value for this test at Weeks 8, 12, 28, and 52. 
• Additionally, shift tables by treatment group will be generated that display the number and 
percentage of subjects in each PGI-S category at baseline and the resulting PGI-S category at 
each scheduled visit. 
• Stacked bar charts will be produced by treatment group that display the percentage of subjects 
with each PGI-S response at baseline and Weeks 8, 12, 28 and 52. 
• The number and percentage of subjects in each PGI-C category at each scheduled visit will be 
summarized. 
Model Results Interpretation 
• One-sided p-values will be compared to 0.025 to assess nominal significance. 
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Patient Reported Outcomes Statistical Analyses: Symptom Severity & Change 
• Clinically meaningful effects for PRO assessments will be specified in a separate 
reimbursement RAP. 
 
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10. 
PHARMACOKINETIC ANALYSES 
10.1. 
Secondary Pharmacokinetic Analyses 
10.1.1. 
Endpoint / Variables 
• Plasma daprodustat, GSK2391220 (M2), GSK2506104 (M3), GSK2487818 (M4), 
GSK2506102 (M5), GSK2531398 (M6) and GSK2531401 (M13) PK parameters 
pre-dose trough (Ctrough) and Cmax 
10.1.1.1. 
Drug Concentration Measures  
Refer to Appendix 5: Data Display Standards & Handling Conventions (Section 14.5.3  
Reporting Standards for Pharmacokinetic) 
10.1.1.2. 
Derived Pharmacokinetic Parameters 
• Pharmacokinetic parameters described in Table 2 will be determined from the plasma 
concentration-time data, as data permits. 
Table 2 
Derived Pharmacokinetic Parameters for daprodustat, and/or  
GSK2391220 (M2), GSK2506104 (M3), GSK2487818 (M4), 
GSK2506102 (M5), GSK2531398 (M6) and GSK2531401 (M13) 
daprodustat, GSK2391220 (M2), GSK2506104 (M3), GSK2487818 (M4), GSK2506102 (M5), 
GSK2531398 (M6) and GSK2531401 (M13) 
Tmax 
Time to reach Cmax, determined directly from the concentration-time data. 
Ctrough 
Post-baseline sample pre-dose concentration 
Cmax 
Maximum observed concentration of all five post-baseline PK samples, determined 
directly from the concentration-time data. 
Planned Exploratory Displays  
• Plasma concentration-time data for daprodustat and its six metabolites will be summarized 
by dose level at the PK sampling using mean, standard deviation, minimum, median and 
maximum. A listing of Daprodustat and its six metabolities PK plasma concentration-time 
data will be produced. 
• Plasma PK parameters (Cmax, tmax, and Ctrough)) for daprodustat and its six metabolites will 
be summarized by dose level at the PK sampling using mean, standard deviation, 
minimum, median, maximum geometric mean, standard deviation of log-transformed data, 
and %CVb. A listing of PK parameters for daprodustat and its six metabolites will be 
provided.  
10.1.2. 
Population of Interest  
The secondary pharmacokinetic analyses will be based on the Pharmacokinetic 
population, unless otherwise specified. 
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11. 
PHARMACODYNAMIC ANALYSES 
 
11.1. 
Exploratory Pharmacodynamic Analyses 
Endpoint / Variables 
• 
Maximum observed change from baseline in EPO  
• 
Maximum observed % change from baseline in VEGF 
• 
Change from baseline in hematocrit, RBC count, and reticulocyte count 
Planned Exploratory Displays 
• Observed EPO and change from baseline in EPO will be summarized using mean, standard 
deviation, minimum, P25, median, P75, and maximum by visit, sample time, PD visit dose, 
and treatment group. Maximum observed post-baseline EPO and maximum observed 
change from baseline in EPO will be summarized using mean, standard deviation, minimum, 
P25, median, P75, and maximum by PD visit dose and treatment group. 
• Observed VEGF will be summarized using geometric mean, CV(%), 95% CI,  minimum, 
P25, median, P75, and maximum by visit, sample time, PD visit dose, and treatment group. 
Percent change from baseline in VEGF will be summarized using geometric mean, 95% CI,  
minimum, P25, median, P75, and maximum by visit, sample time, PD visit dose, and 
treatment group. Maximum observed post-baseline VEGF and maximum observed change 
from baseline in VEGF will be summarized using geometric mean, CV(%) (for maximum 
observed VEGF only), 95% CI,  minimum, P25, median, P75, and maximum by PD visit 
dose and treatment group. (Summary statistics for VEGF will be calculated based on log-
transformed values. See Section 5.2.2 for details of log-transformation.) 
• Change from baseline in hematocrit, RBC count, and reticulocyte count are included in the 
summary of clinical laboratory analyses described in Section 8.4. 
 
 
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12. 
PHARMACOKINETIC / PHARMACODYNAMIC 
ANALYSES 
• 
The primary goal of this analysis is to characterize the pharmacokinetic/ 
pharmacodynamic relationship of parent daprodustat and efficacy and safety 
endpoints in the “All Randomized (ITT)” or the “Pharmacokinetic” population from 
this study. Please refer to Section 7.4, Section 8.2, Section 10.1 and Section 11.1 for 
further details of related PK/PD analyses. Any changes to the proposed analyses 
would be described in the CSR.  
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13. 
REFERENCES 
Anker SD et al. Development and validation of cardiovascular risk scores for 
haemodialysis patients.  International Journal of Cardiology. 2016; 216:68–77. 
Iverson C, Christiansen S, Flanagin A, et al. AMA Manual of Style: A Guide for Authors 
and Editors. 10th ed. New York, NY: Oxford University Press; 2007. 
Kawaguchi A, Koch GG, Wang X. Stratified multivariate Mann-Whitey estimators for 
the comparison of two treatments with randomization based covariance adjustment. 
Statistics in Biopharmaceutical Research. 2011; 3 (2): 217-231. 
Liu GF, Wang J, Liu K, Snavely DB. Confidence intervals for an exposure adjusted 
incidence rate difference with applications to clinical trials. Statistics in Medicine 2006; 
25: 1275-1286. 
Liublinska V, Rubin DB. Sensitivity analysis for a partially missing binary outcome in a 
two-arm randomized clinical trial. Statistics in Medicine 2014; 33(24): 4170-4185. 
Rosendaal FR, Cannegieter SC, Van der Meer, FJM, and Briet, E. A Method to 
Determine the Optimal Intensity of Oral Anticoagulant Therapy. Thrombosis and 
Haemostasis. 1993; 69 (3): 236 – 239. 
Rubin DB. Multiple Imputation for Nonresponse in Surveys.  John Wiley & Sons, 1987. 
 
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14. 
APPENDICES 
14.1. 
Appendix 1: Protocol Deviation Management and Definitions 
for Per Protocol Population 
All deviations are to be tracked in GSK Protocol Deviation Management System 
(PDMS). Protocol deviations will be reviewed by the study team and important protocol 
deviations will be identified according to the Protocol Deviation Management Plan. 
14.1.1. 
Exclusions from Per Protocol Population 
Exclusions from the PP population include events that, if they should occur, might: 
• 
Directly impact the hemoglobin efficacy endpoint; or 
• 
Lead to permanent discontinuation of study treatment or study withdrawal and 
hence indirectly impact the efficacy endpoint by causing data to be missing. 
The following criteria define the events which, if they occur prior to the end of the EP, 
may lead to exclusion of a subject from the PP population. Exclusions from the PP 
Population will be subject to blinded review by the study team. Protocol deviations 
meeting the exclusion criteria and programmatically-identified exclusions, including 
those, which are not considered to be protocol deviations, will be reviewed by the study 
team. The study team will also review the listing of unique concomitant medication terms 
to identify the prohibited medications. These reviews will occur before database has been 
unblinded for analysis. 
A subject meeting any of the following criteria may be excluded from the Per-Protocol 
population: 
Number 
Exclusion Description 
01 
Baseline HemoCue Hgb value outside of Randomization (Day 1) Hgb entry criteria range 
02 
Less than 5 out of 7 scheduled evaluable2 Hgb values1 from the EP 
03 
Non-compliance with study treatment (compliance category of under compliant or over 
compliant) during the EP, based on eCRF study treatment and compliance record forms 
04 
Inadequate iron status during EP, defined as ferritin  100 ng/mL on two consecutive 
scheduled visits or TSAT  20% on two consecutive scheduled visits 
05 
Subject received prohibited medication3 for more than two weeks during EP 
NOTES: 
1. Based on central laboratory Hgb values. If central laboratory Hgb value is missing, a non-missing 
HemoCue Hgb value will be used.  
2. See Section 14.6.3. 
3. Prohibited medications include strong inhibitors of CYP2C8 (e.g., gemfibrozil) and strong inducers 
of CYP2C8 (e.g., rifampin/rifampicin). 
 
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14.2. 
Appendix 2: Schedule of Activities 
14.2.1. 
Protocol Defined Schedule of Events 
14.2.1.1. 
Schedule of Activities for Participants on Randomized Study Treatment 
Procedure 
Visit window of ±3 days for Weeks 2 to 8, and ±1 week 
for all other visits. 
All visit timings are relative to Day 1. 
All assessments will be performed pre-dialysis unless 
otherwise specified.  
Screening  
(Week -4) 
Treatment Period: Day 1 through Week 52 
Follow-up 
Visit 
(4 to 6 weeks 
after last dose) 
Day 1 1 
Full Study Visit 
Week 4, 16, 28, 40 
Abbreviated 
Study Visit Week 
2, 6, 8, 12, 20, 24, 
32, 36, 44, 48 
Week 52 
Unscheduled 2 
Informed consent 
X 
 
 
 
 
 
 
IRT system transaction 3 
X 
X 
X 
X 
X 
X 
X 
Inclusion and exclusion criteria  
X 
X 
 
 
 
 
 
Randomization 4 
 
X  
 
 
 
 
 
Study Treatment Dispensing 5, 6 
 
X 
X 
X 7 
 
X 7 
 
Study Treatment Compliance 6 
 
 
X 
X 7 
X 
X 7 
 
Participant reminder to report changes in health 8 
 
X 
 
 
 
 
 
Medical history (including past and current medical 
conditions, hospitalization and transfusion) 9 
X  
 
 
 
 
 
 
Demography, height 
X 
 
 
 
 
 
 
Weight (pre- and post-dialysis) and EDW 10 
X 
X 
X 
X 
X 
X 
X 
SBP/DBP, HR (pre- and post-dialysis) 
X 
X (triplicate) 
X 
X 
X (triplicate) 
X 
X 
Kt/Vurea 11 
 
X 
X 
 
X 
 
 
12-lead ECG 12 
X 
 
 
 
X 
 
 
Ultrasound of kidneys and adrenal glands 13 
X 
 
 
 
 
 
 
Estradiol and FSH (females only, if required) 14 
X 
 
 
 
 
 
 
Serum pregnancy test (WOCBP only) 15, 16 
X 
X 
X 
 
X 
 
X 
HemoCue Hgb 
X 
X 
X 
X 
X 
X 
 
Hematology 17 
X 
X 
X 
X (Hgb only) 
X 
X 
X 
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Procedure 
Visit window of ±3 days for Weeks 2 to 8, and ±1 week 
for all other visits. 
All visit timings are relative to Day 1. 
All assessments will be performed pre-dialysis unless 
otherwise specified.  
Screening  
(Week -4) 
Treatment Period: Day 1 through Week 52 
Follow-up 
Visit 
(4 to 6 weeks 
after last dose) 
Day 1 1 
Full Study Visit 
Week 4, 16, 28, 40 
Abbreviated 
Study Visit Week 
2, 6, 8, 12, 20, 24, 
32, 36, 44, 48 
Week 52 
Unscheduled 2 
Clinical chemistry 17 
X 
X 
X 
 
X 
X 
X 
Ferritin, total iron and UIBC 17 
X 
X 
X 
 
X 
 
X 
Lipids (non-fasting) 17 
 
X 
X 
 
X 
 
 
iPTH, hsCRP, HbA1c 17, 18 
 
X 
Wk 28 
 
X 
 
 
Hepcidin 17, 19 
 
X 
Wk 4, 16, 28 
 
X 
 
 
PD: EPO, VEGF 17 
 
X 
X (once from Wk 28 to Wk 52) 20 
 
 
PK 
 
X 
X (once from Wk 8 to Wk 52) 21 
 
 
Stored samples for biomarkers 22 
 
X 
Wk 28 
 
X 
 
 
Genetic sample 23  
 
X 
 
 
 
 
 
Patient Global Impression of Severity (PGI-S) 24 
 
X 
Wk 28 
Wk 8, 12 
X 
 
 
Patient Global Impression of Change (PGI-C) 24 
 
 
Wk 28 
Wk 8, 12 
X 
 
 
Non-serious AEs, SAEs, AEs of Special Interest, 
clinical events 
X 25 
X 
X 
X 
X 
X 
X 
Concomitant medication review 
X 
X 
X 
X 
X 
X 
X 
Iron therapy, transfusions, rescue medications 26, 27 
X 
X 
X 
X 
X 
X 
X 
Hospitalization or kidney transplant 26 
 
 
X 
X 
X 
X 
X 
DBP, diastolic blood pressure; ECG, electrocardiogram; EDW, estimated dry weight; FSH, follicle stimulating hormone; HbA1c, glycated hemoglobin; HR, heart rate; hsCRP, high 
sensitivity C-reactive protein; iPTH, intact parathyroid hormone; PD, pharmacodynamics; PK, pharmacokinetics; SBP, systolic blood pressure; UIBC, unsaturated iron binding capacity; 
VEGF, vascular endothelial growth factor; WOCBP, woman of childbearing potential. 
Note: Pre-dialysis assessments should be performed in the following order, where applicable: patient reported outcomes, ECG, BP/HR, blood sample collection. 
1. 
All assessments to be performed pre-dose. 
2. 
If additional study treatment is required prior to the next scheduled study visit, it is not necessary to perform the unscheduled visit assessments other than dispensing study 
treatment.   
3. 
Study treatment will be dispensed every 4±1 weeks, with the exception that it may be every 2 weeks ± 3 days up to the Week 6 visit. An IRT transaction will be required to 
dispense study treatment. Additional IRT transactions may occur if needed to dispense additional study treatment.  
4. 
In circumstances where randomization of an eligible participant cannot be completed at the Day 1 visit, the visit may be rescheduled up to 1 week later. Clinical laboratory 
assessments performed at the original visit, no more than 1 week prior, do not need to be repeated, except for the HemoCue hemoglobin and the Q2 hemoglobin. 
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5. 
Study treatment will be dispensed, i.e., allocated to a specific participant, and stored at the dialysis center or research site. Participant may take study treatment tablets at home in 
preparation for PD visit. See protocol Section 7 for further study treatment details. 
6. 
In circumstances where a new supply of study treatment (including a new dose) cannot be dispensed on the day of the study visit, the new supply of study treatment can be 
dispensed at the next dialysis session. Prior study treatment should be continued unless on dose interruption, e.g., Hgb ≥12 g/dL. Compliance is deferred until study treatment is 
returned.   
7. 
At the Week 2, Week 6 or unscheduled visits, if dose is not changed, new study treatment does not need to be dispensed and use of existing study treatment is continued. 
Compliance checking is required if new study treatment is dispensed. 
8. 
Participant will be instructed to promptly notify site staff in the event of any changes to his or her health. Health changes include new symptoms, medical problems (e.g., 
pregnancy, hospitalization), and medication changes. 
9. 
Medical history (including CV medical history/risk factors) will be assessed at screening (Week -4). Medical history will be re-assessed at Day 1 to confirm eligibility prior to 
randomization.    
10. Estimated Dry Weight (EDW) to be recorded in the eCRF only at Day 1, full study visits, and Week 52. 
11. A historical Kt/Vurea measurement within the last 12 weeks can be used. If a Kt/Vurea measurement is not available, then a urea reduction ratio (URR) measurement is 
acceptable. 
12. The Week -4 (screening) ECG must be performed pre-dialysis, and may be performed on any dialysis day from the Week -4 visit to the Day 1 visit, except during the first dialysis 
session of the week. The result of the screening ECG, including physician interpretation, must be available to confirm eligibility prior to randomization. All other ECG assessments 
may be performed either pre- or post-dialysis. See protocol Section 9.4.3.. 
13. Ultrasound of the kidneys and adrenal glands will be performed between the Week -4 and Day 1 visits. If the results of the kidney and adrenal ultrasound require follow-up testing, 
then the screening period may be extended by 1 additional week. A documented ultrasound of the kidneys within the 6 months prior to screening may be used to assess entry 
criteria, provided the size and cyst category has been reported. If a more sensitive imaging study [e.g., magnetic resonance imaging (MRI), computed tomography (CT)] has been 
performed within this timeframe and a report is available, this may be used in place of the ultrasound. See protocol Section 9.4.4.. 
14. Only required to confirm menopausal status if in question. 
15. Repeat pregnancy test prior to study treatment re-administration if study treatment was interrupted for >7 days and there was also a lapse in contraceptive use, regardless of the 
reason for the interruption. 
16. In Argentina only, pregnancy testing will be performed every 4 weeks for WOCBP as required by local law. 
17. See details for laboratory assessments in protocol Section 9.4.5.  
18. HbA1c assessment is applicable only for participants with diabetes on Day 1 or diagnosed during the study. 
19. At each visit specified in the table, a hepcidin sample will be collected prior to dosing with either study treatment and prior to administration of any iron supplementation. 
20. Post-baseline PD samples (i.e., EPO and VEGF) may be taken during any week from Week 28 to Week 52, inclusive, preferably at the earliest opportunity. See protocol Section 
9.6 for additional details and requirements for the collection of PD samples.  
21. Post-baseline PK samples will be taken at any one of the post-baseline visits indicated in the table, preferably at the earliest opportunity. See protocol Section 9.5 for additional 
details and requirements for the collection of PK samples. 
22. Biomarker samples will be collected and stored for potential future analysis for all participants, except if not permitted by local regulations or IRB/EC, or refused by participant. 
23. Participation in genetics research is optional. A separate informed consent signature is required for participation. See protocol Section 9.7 for additional details.  
24. Participants who are unable to or require assistance to read must not complete the questionnaires. See protocol Section 9.9 for additional details. 
25. Only SAEs, which are assessed as related to study participation or a GlaxoSmithKline (GSK) product, are collected at this visit. See protocol Section 9.2.1 for additional details.  
26. Record in the eCRF, if applicable. 
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27. See details on Rescue in protocol Section 7.9. 
 
14.2.1.2. 
Schedules of Activities for Participants Who Permanently Discontinue Study Treatment 
Procedure  
 
Early Treatment Discontinuation Visit 
(within 2 weeks of discontinuing study 
treatment) 
Day 1 through Week 52 0 
 Week 4, 16, 28, 40, 52 ± 2 weeks 
Un-scheduled 
IRT system transaction 
X 
X 
X 
SBP/DBP, HR (pre- and post-dialysis) 
X (triplicate) 
X 
X 
12-lead ECG 0 
X 
 
 
Iron therapy, transfusions 0 
X 
X 
X 
Serum pregnancy test (WOCBP only) 
X 0 
 
 
HemoCue Hgb 
X 
X 
X 
Hematology 0 
X 
X 
Clinical chemistry 0 
X 
X 
 
Ferritin, total iron, UIBC, lipids, iPTH 0 
X 
 
 
Hospitalization, kidney transplant 0 
X 
X 
X 
Non-serious AEs, SAEs, AEs of Special Interest, 
clinical events 
X 
X 
X 
Review concomitant medications 
X 
X 
X 
PGI-S and PGI-C 0 
X 
 
 
1. Participants will attend those study visits up to Week 52 which have not been completed at the time of early treatment discontinuation. Phone visits are acceptable in exceptional 
circumstances. 
2. ECG assessment may be recorded pre- or post-dialysis. 
3. Record in the eCRF, if applicable. 
4. Additional pregnancy test required at subsequent visit. Must be at least 4 weeks after the end of study treatment. 
5. See details for laboratory assessments in protocol Section 9.4.5. 
6. Participants who are unable to or require assistance to read must not complete the questionnaires. See protocol Section 9.9for additional details. 
 
 
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14.3. 
Appendix 3: Assessment Windows 
• Data for continuous variables that are not related to time-to-event will be summarized 
according to the scheduled visit time period for which they were recorded in the 
eCRF. Unscheduled assessments will not be slotted to a particular time point, but will 
remain as unscheduled if they are either summarized or listed unless otherwise 
specified (i.e. Hgb endpoints described in Section 14.6.3 and BP endpoints described 
in Section 14.6.4). 
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14.4. 
Appendix 4: Study Phases and Treatment Emergent 
Adverse Events 
14.4.1. 
Study Phases 
Assessments and events will be classified according to the time of occurrence relative to 
the treatment start and stop dates and last non-zero dose date (see Section 14.6.1). 
14.4.1.1. 
Study Phases for Hgb, Iron Parameters, IV Iron Dose Endpoints, Iron 
Use Summaries, Transfusion and PRO Data 
Study Phase 
Definition 
Pre-Treatment 
Date ≤ Study Treatment Start Date 
On-Treatment 
Study Treatment Start Date < Date ≤ Study Treatment Stop Date + 1 day 
Post-Treatment 
Date > Study Treatment Stop Date + 1 day 
Post-Randomization 
Randomization Date < Date 
NOTES:  
• 
If the treatment stop date is missing and the treatment start date is non-missing, and Date > Treatment Start 
Date, then the assessment will be considered to be On-Treatment 
 
14.4.1.2. 
Study Phases for CV Endpoint Data 
Study Phase 
Definition 
Pre-Treatment 
Date < Treatment Start Date 
On-Treatment 
Treatment Start Date  Date ≤ Last Non-Zero Dose Date + 28 days 
Post-Treatment 
Date > Last Non-Zero Dose Date + 28 days 
Post-Randomization 
Randomization Date ≤ Date 
NOTES:  
• 
If the last non-zero dose date is missing and the treatment start date is non-missing, and Date ≥ Treatment 
Start Date, then the assessment will be considered to be On-Treatment 
• 
Study phase definitions use the imputed CV endpoint date 
 
14.4.1.3. 
Study Phases for BP, Lipid Parameters, Clinical Chemistry, 
Hematology, Other Laboratory Tests, Hepatobiliary (Liver), ECG and 
Vital Signs Data 
Study Phase 
Definition 
Pre-Treatment 
Date ≤ Treatment Start Date 
On-Treatment 
Treatment Start Date < Date ≤ Last Non-Zero Dose Date + 1 day 
Post-Treatment 
Date > Last Non-Zero Dose Date + 1 day 
Post-Randomization 
Randomization Date < Date 
NOTES:  
• 
If the last non-zero dose date is missing and the treatment start date is non-missing, and Date > Treatment 
Start Date, then the assessment will be considered to be On-Treatment 
• 
Post-dialysis BP measured on treatment start date is considered on-treatment 
 
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14.4.1.4. 
Study Phase for AE Data 
All AEs (non-serious AEs and serious AEs) will be collected and recorded on the eCRF  
from the start of treatment until the follow-up visit at the time points specified in the SoA 
from Section 14.2. Serious AEs assessed as related to study participation (e.g., study 
treatment, protocol-mandated procedures, invasive tests, or change in existing therapy) or 
related to a GSK product will be recorded on the eCRF from the time a participant 
consents to participate in the study up to and including any follow-up contact. AE of 
worsening of an on-going event will be counted once in a particular study phase. 
Study Phase  
Definition 
Pre-treatment 
• 
For subjects with a non-missing screen failure date, if AE onset is on or before 
the screen failure date: AE Start Date  Screen Failure Date 
• 
For randomized subjects with a missing treatment start date, all AEs are 
considered pre-treatment 
• 
For randomized subjects with a non-missing treatment start date, if AE onset 
date is before treatment start date: AE Start Date < Treatment Start Date 
Post-
randomization 
If AE onset date or AE worsening date is on or after the randomization date 
Randomization date  AE Start Date 
Randomization date  AE Worsening Date 
AE worsening during post-randomization will be defined relative to the maximum 
intensity of AE prior to randomization date.  
AE worsening date is the first date in the post-randomization period, when AE 
intensity increased relative to the maximum intensity of the AE prior to randomization 
date. 
Treatment 
emergent 
If AE onset date or AE worsening date is on or after treatment start date & on or 
before the last non-zero dose date plus 1 day. 
Treatment Start Date ≤ AE Start Date ≤ Last Non-Zero Dose Date + 1 day 
Treatment Start Date ≤ AE Worsening Date ≤ Last Non-Zero Dose Date + 1 day 
AE worsening during treatment emergent period will be defined relative to the 
maximum intensity of AE prior to study treatment start date.  
AE worsening date is the first date in the treatment emergent period, when AE 
intensity increased relative to the maximum intensity of the AE prior to study 
treatment start date. 
Follow-up 
If AE onset date or AE worsening date is after the last non-zero dose date plus 1 
day. 
AE Start Date > Last Non-Zero Dose Date + 1 day 
AE Worsening Date > Last Non-Zero Dose Date + 1 day 
AE worsening during follow-up will be defined relative to the maximum intensity of 
AE prior to study treatment start date.  
AE worsening date is the first date in the follow-up period, when AE intensity 
increased relative to the maximum intensity of the AE prior to study treatment start 
date. 
Onset 
/Worsening Time 
Since 1st Dose 
(Days) 
If Treatment Start Date ˃  AE Onset Date: AE Onset Date - Treatment Start Date 
If Treatment Start Date ≤ AE Onset Date: AE Onset Date - Treatment Start Date +1 
If Treatment Start Date ˃  AE Worsening Date: AE Worsening Date - Treatment 
Start Date 
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Study Phase  
Definition 
If Treatment Start Date ≤ AE Worsening Date: AE Worsening Date - Treatment Start 
Date +1 
Missing otherwise. 
Onset/Worsening 
Time Since Last 
Dose (Days) 
If Last Non-Zero Dose Date ≤ AE onset date: AE onset date – last non-zero dose 
date + 1 
If Last Non-Zero Dose Date > AE onset date: AE onset date – last non-zero dose 
date 
If Last Non-Zero Dose Date ≤ AE worsening date: AE worsening date – last non-
zero dose date + 1 
If Last Non-Zero Dose Date > AE worsening date: AE worsening date – last non-
zero dose date 
Missing otherwise. 
Duration (Days)  
AE Resolution Date – AE Onset Date/AE Worsening Date + 1 
Drug-related 
If relationship is marked ‘YES’ on eCRF or if the value is missing. 
NOTES:  
• 
AEs that occur or worsen during interruptions of randomized study treatment will be classified as treatment 
emergent and post-randomization. 
• 
If the last non-zero dose date is missing and the treatment start date is non-missing and the AE onset date or 
AE worsening date is on or after the treatment start date, then the AE will be considered to be treatment 
emergent. 
• 
If AE onset date or AE worsening date is missing and AE resolution date is before the treatment start date, 
then the AE will be classified as Pre-treatment.  
• 
If AE onset date or AE worsening date is missing and AE resolution date is either missing or on or after 
treatment start date, then the AE will be classified as treatment emergent and post-randomization. 
 
14.4.1.5. 
Study Phases for Concomitant Medication (Other Than IV Iron Dose 
Endpoints and Iron Use Summaries) 
Pre-treatment medications are those taken (i.e., started) before the start date of study 
treatment. On-treatment medications are those taken (i.e., started or continued) at any 
time between the study treatment start date and the last non-zero dose date + 1 day, 
inclusive. Pre-treatment medications that were continued during this on-treatment period 
are also considered to be on-treatment medications. Post-treatment medications are those 
taken (i.e., started or continued) at any time after the last non-zero dose date + 1 day. On-
treatment medications that were continued during this post-treatment period are also 
considered to be post-treatment medications. Post-randomization medications are those 
taken (i.e., started or continued) at any time on or after the randomization date. 
It will be assumed that the medication has been taken on the date in which it is reported 
as started or stopped.  Also, for any medication starting on the same date as study 
treatment, it will be assumed that the medication was taken after the subject started taking 
study treatment. 
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Illustrations of the pre-treatment, on-treatment, and post-treatment treatment states are 
included below: 
 
Pre-
treatment 
On-treatment 
Post-
treatment 
Pre-
treatment 
medicatio
n 
On-
treatment 
medicatio
n 
Post-
treatment 
medicatio
n 
(a) 
x⎯⎯x 
Randomized Treatment Start Date 
 
Last Non-zero Dose Date + 1 Day 
Last Non-zero Dose Date + 2 Days 
 
Y 
N 
N 
(b) 
x⎯⎯ 
⎯⎯x 
 
Y 
Y 
N 
(c) 
x⎯⎯ 
⎯⎯⎯ 
⎯⎯⎯x 
Y 
Y 
Y 
(d) 
 
x⎯⎯x 
 
N 
Y 
N 
(e) 
 
x⎯⎯ 
⎯⎯⎯x 
N 
Y 
Y 
(f) 
 
 
x⎯⎯x 
N 
N 
Y 
(g) 
?⎯⎯ x 
 
 
Y 
N 
N 
(h) 
?⎯⎯⎯ 
⎯⎯x 
 
Y* 
Y 
N 
(i) 
?⎯⎯⎯ 
⎯⎯⎯ 
⎯⎯⎯x 
Y* 
Y* 
Y 
(j) 
x⎯⎯⎯ 
⎯⎯⎯ 
⎯⎯⎯? 
Y 
Y** 
Y** 
(k) 
 
x⎯⎯ 
⎯⎯⎯? 
N 
Y 
Y** 
(l) 
 
 
x⎯⎯? 
N 
N 
Y 
(m) ?⎯ ⎯⎯ 
 
⎯⎯⎯  
 
⎯⎯⎯? 
Y*** 
Y*** 
Y*** 
(n) 
x⎯⎯⎯ 
x 
 
 
 
 
Y 
Y 
N 
(o) 
?⎯ ⎯⎯ 
x 
 
 
 
 
Y* 
Y 
N 
(p) 
 
x 
⎯⎯x 
 
 
 
N 
Y 
N 
(q) 
 
x 
⎯⎯⎯ 
x 
 
 
N 
Y 
N 
(r) 
 
 
 
x 
⎯ ⎯⎯⎯x 
N 
Y 
Y 
(s) 
 
 
 
x 
⎯ ⎯⎯⎯? 
N 
Y 
Y** 
(t) 
 
 
 
 
x 
⎯⎯⎯x 
N 
N 
Y 
(u) 
 
 
 
 
x 
⎯⎯⎯? 
N 
N 
Y 
(v) 
 
 
x⎯⎯ 
⎯ 
x 
 
N 
Y 
Y 
x = start/stop date of medication 
? = missing start/stop date of medication 
* If a medication is stopped On-treatment or Post-treatment and no start date is recorded it will be 
assumed that the medication was ongoing from the Pre-treatment phase 
** If a medication is started Pre-treatment or On-treatment and no stop date is recorded then 
usage will be assumed to be ongoing for the remainder of the study 
*** If a medication has no start or stop date it will be assumed that the medication was ongoing 
from the Pre-treatment phase to the Post-treatment phase 
 
 
 
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14.5. 
Appendix 5: Data Display Standards & Handling 
Conventions 
14.5.1. 
Reporting Process 
Software 
• 
The currently supported versions of SAS software will be used. 
Reporting Area 
HARP Server 
: uk1salx00175 
HARP Compound 
: gsk1278863/mid204837 
Analysis Datasets  
• 
Analysis datasets will be created according to CDISC standards (SDTM IG Version 3.2 & ADaM IG 
Version 1.1).  
• 
For creation of ADaM datasets (ADCM/ADAE), the same version of dictionary datasets will 
be implemented for conversion from system independent (SI) to SDTM 
Generation of RTF Files 
• 
RTF files will be generated for Tables  
14.5.2. 
Reporting Standards 
General 
• 
The current GSK Integrated Data Standards Library (IDSL) will be applied for reporting, unless 
otherwise stated (IDSL Standards Location: 
https://spope.gsk.com/sites/IDSLLibrary/SitePages/Home.aspx): 
• 
4.03 to 4.23: General Principles 
• 
5.01 to 5.08: Principles Related to Data Listings 
• 
6.01 to 6.11: Principles Related to Summary Tables 
• 
7.01 to 7.13: Principles Related to Graphics  
• 
Do not include subject level listings in the main body of the GSK Clinical Study Report. All subject 
level listings should be located in the modular appendices as ICH or non-ICH listings 
• 
In all displays (TFLs) the term “Subjects”, which reflects CDISC and GSK Data Display Standards 
terminology, will be used to refer to the “Participants”. In this Reporting and Analysis Plan, “subject” 
and “participant” are used interchangeably.  
Formats 
• 
GSK IDSL Statistical Principles (5.03 & 6.06.3) for decimal places (DP’s) will be adopted for 
reporting of data based on the raw data collected, unless otherwise stated. 
• 
Numeric data will be reported at the precision collected on the eCRF. 
• 
The reported precision from non eCRF sources will follow the IDSL statistical principles but may be 
adjusted to a clinically interpretable number of DP’s. 
Planned and Actual Time 
• 
Reporting for tables, figures and formal statistical analyses: 
• 
Planned time relative to randomization will be used in figures, summaries, statistical analyses 
and calculation of any derived parameters, unless otherwise stated. 
• 
All scheduled visits, regardless of deviation from the planned assessment times and/or 
scheduled visit days, will be used in tables, figures and formal statistical analyses unless 
otherwise stated. 
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• 
The derived end of treatment value (see Section 14.6.1) will also be included in displays 
of data by visit. 
• 
Tables presenting data values by visit will also include values from scheduled visits 
occurring on or before the Day 1 visit, despite the description contained in the title (e.g., 
post-randomization, evaluable, or on-treatment). The description in the title refers to the 
post-randomization values that are included in the table. 
• For the purpose of statistical summary and analysis, unless otherwise specified, the 
data for visits after discontinuation of study treatment recorded under Early Trt Disc Wk 
xx visit will be summarized and analyzed along with the corresponding Wk xx visits for 
subjects who complete the study treatment. 
• 
Reporting for Data Listings:  
• 
Planned and actual time relative to study drug dosing will be shown in listings (Refer to IDSL 
Statistical Principle 5.05.1). 
• 
Unscheduled or unplanned readings will be presented within the subject’s listings.  
• 
Visits outside the protocol defined time-windows (i.e. recorded as protocol deviations) will be 
included in listings. 
Unscheduled Visits 
• 
Unscheduled visits will not be included in summary tables, with the following exceptions: 
• 
If the table includes a row for all post-baseline assessments, unscheduled visits will be included 
in this row. 
• 
Some Hgb endpoints will include unscheduled Hgb values (See Section 14.6.3) 
• 
Some BP endpoints will include unscheduled BP values (see Section 14.6.4) 
• 
Unscheduled visits will not be included in figures, with similar exceptions: 
• 
If the figure includes a data value for all post-baseline assessments, unscheduled visits will be 
included in this value. 
• 
Some Hgb endpoints will include unscheduled Hgb values (See Section 14.6.3) 
• 
Some BP endpoints will include unscheduled BP values (see Section 14.6.4)   
• 
All unscheduled visits will be included in listings. 
Descriptive Summary Statistics 
Continuous Data 
Refer to IDSL Statistical Principle 6.06.1 
Categorical Data 
N, n, frequency, % 
Graphical Displays 
• 
Refer to IDSL Statistical Principals 7.01 to 7.13. 
14.5.3. 
Reporting Standards for Pharmacokinetic 
Pharmacokinetic Concentration Data 
Descriptive Summary 
Statistics, Graphical 
Displays and Listings 
Refer to IDSL PK Display Standards. 
Refer to IDSL Statistical Principle 6.06.1. 
Note: Concentration values will be imputed as per GUI_51487 v5.0 for descriptive 
summary statistics/analysis and summarized graphical displays only.  
Note: PC WNL file or NONMEM/Pop PK is Not applicable for Non-compartmental 
analysis. 
Pharmacokinetic Parameter Derivation 
PK Parameter to be 
Derived by 
Programmer 
The following PK parameters will be derived by the Clinical Programmer: Ctrough, 
Cmax, tmax  
Formulas for these derivations are given in Section 14.6.5. 
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Pharmacokinetic Parameter Data 
Is NQ impacted PK 
Parameters Rule 
Being Followed 
No.  
 
Descriptive Summary 
Statistics, Graphical 
Displays and Listings 
Refer to IDSL PK Display Standards. 
 
 
 
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14.6. 
Appendix 6: Derived and Transformed Data 
14.6.1. 
General 
 
Multiple Measurements at One Time Point 
• 
Mean of the measurements will be calculated and used in any derivation of summary statistics but if 
listed, all data will be presented. 
o Triplicate BP and HR measurements are expected at certain time points (See Section 
14.2.1) 
• 
Subjects having both High and Low values for Normal Ranges at any post-baseline visits for safety 
parameters will be counted in both the High and Low categories of “Any visit post-baseline” row of 
related summary tables. This will also be applicable to relevant Potential Clinical Importance 
summary tables. 
Randomization Date 
• 
Date subject was randomized 
Treatment Start Date 
• 
First randomized treatment dose start date 
Last Non-Zero Dose Date 
• 
Date of last actual dose of active study treatment from the eCRF Study Treatment/Compliance 
Record Form. 
o The dose steps used by the dosing algorithm described in the protocol include a dose 
hold or a zero dose. If subjects are assigned by the algorithm to a zero dose, they only 
receive placebo and saline, and do not receive active study treatment for that period. 
When a dose interruption is required, both active treatment and placebo/saline will be 
interrupted. Hence, it would be possible for a subject to complete the study, while still 
following the dosing algorithm, but not actually taking any active study treatment. The 
last non-zero dose date, then captures the latest date in the study that a subject 
physically took a dose of active study treatment. 
Treatment Stop Date 
• 
Calculated as the latest study treatment dose stop date, after excluding the records for missed dose. 
End of Treatment Value 
• 
Only defined for subjects with a non-missing treatment start date 
• 
Hgb, iron, transfusion and PRO parameter: the latest value on or before the treatment stop date 
+ 1 day. 
• 
Blood pressure, central laboratory, and vital signs parameters: the latest value on or before the 
last non-zero dose date + 1 day. 
 
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Study Completion/Withdrawal Date 
• 
Date of withdrawal for subjects withdrawing (i.e., subjects who actively withdraw or are deemed lost 
to follow-up) from study or date of completion of study for subjects who complete the study. 
• 
Note: Subjects who die while on study are considered as having completed the study 
Planned/Actual Visit Dates 
• Planned/actual visit dates will be defined as follows: 
o Week 28 date: Non-missing Week 28 visit start date (from SV domain), 
otherwise randomization date + 28*7 
o Week 36 date: Non-missing Week 36 visit end date (from SV domain), 
otherwise randomization date + 36*7 
o Week 52 date: Non-missing Week 52 visit end date (from SV domain), 
otherwise randomization date + 52*7 
Stabilization Period 
Defined as the period between and including the randomization date + 1 day - <Week 28 visit, 
using planned/actual dates. 
Alternative Evaluation Period (Alt. EP) 
Defined as the period between and including Week 28 visit – Week 36 visit, using 
planned/actual dates.  
Evaluation Period (EP) 
Defined as the period between and including Week 28 visit – Week 52 visit, using 
planned/actual dates. 
Study Day 
• 
Calculated as the number of days from randomization date: 
• 
Ref Date = Missing                       → Study Day = Missing  
• 
Ref Date < Randomization Date   → Study Day = Ref Date – Randomization Date     
• 
Ref Data ≥ Randomization Date   → Study Day = Ref Date – (Randomization Date) + 1     
Treatment Day 
• 
Calculated as the number of days from treatment start date: 
• 
Treatment Start Date = Missing        → Treatment Day = Missing  
• 
Ref Date < Treatment Start Date      → Treatment Day = Ref Date – Treatment Start Date     
• 
Ref Data ≥ Treatment Start Date      → Treatment Day = Ref Date – (Treatment Start Date) + 1    
 
Last Study Contact Date 
• 
 Latest visit date from an unscheduled visit or a clinic, telephone, designated third party, 
healthcare provider or medical records, or other contact with subject (mail, email, text, social 
media, etc.) visit. 
Time Definitions (per GSK standard principles) 
• 
1 week = 7 days 
• 
1 month = 30.4375 days 
• 
1 year = 365.25 days 
Production of Two-Sided p-values 
• 
The majority of the efficacy and safety analyses in this study will use one-sided 2.5% p-values 
assess statistical significance. Should two-sided p-values be required for publication purposes after 
the study is complete, the corresponding two-sided p-values will be produced at that time. 
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14.6.2. 
Study Population 
14.6.2.1. 
Demographics & Baseline Characteristics 
Demographics & Baseline Characteristics 
Age 
• 
GSK standard IDSL algorithms will be used for calculating age where birth date will be imputed as 
follows: 
o Any subject with a missing day will have this imputed as day ‘15’.  
o Any subject with a missing date and month will have this imputed as ‘30th June’. 
• 
Birth date will be presented in listings as ‘YYYY’. 
High Level Race 
• 
Geographic ancestry data will be combined into five high level race categories: 
o American Indian or Alaskan Native 
o Asian (Asian-East Asian Heritage, Asian-Japanese Heritage, Asian-Central/South Asian 
Heritage, Asian-South East Asian Heritage, Mixed Asian Race) 
o Black or African American  
o Native Hawaiian or Other Pacific Islander 
o White (White-Arabic/North African Heritage, White-White/Caucasian/European Heritage, 
Mixed White Race) 
o Mixed Race (Multiple high level races are selected) 
Note: A subject will only be counted in one category. Mixed Asian Race includes subjects who have more 
than one Asian category selected, but no other categories. Mixed White Race includes subjects who have 
more than one White category selected, but no other categories. 
Race Detail 
• 
Geographic ancestry data will be combined into race detail categories: 
o American Indian or Alaskan Native 
o Asian-Central/South Asian Heritage 
o Asian-East Asian Heritage 
o Asian-Japanese Heritage 
o Asian-South East Asian Heritage 
o Mixed Asian Race 
o Black or African American (African American/African Heritage) 
o Native Hawaiian or Other Pacific Islander 
o White-Arabic/North African Heritage 
o White-White/Caucasian/European Heritage 
o Mixed White Race 
o Mixed Race (Multiple high level races are selected) 
Note: A subject will only be counted in one category. Mixed Asian Race includes subjects who have more 
than one Asian category selected, but no other categories. Mixed White Race includes subjects who have 
more than one White category selected, but no other categories. 
Prior ESA Type and Standardized Prior ESA Dose (U/week) at Randomization  
• 
During the screening period, subjects may be receiving ESAs in multiple ways, including: epoetin IV or 
SC, darbepoeitin IV or SC, or methoxy PEG-epoetin beta IV or SC.  
• 
A subject’s prior ESA type will be determined from the records that contribute to the subject’s 
standardized prior ESA dose. The following categories of prior ESA type will be summarized: 
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Demographics & Baseline Characteristics 
o Darbepoetin alfa only 
o Epoetin only 
▪ 
This group contains subjects using any of the following types of epoetin: epoetin 
alfa, epoetin beta, epoetin lambda, epoetin theta, and epoetin zeta. 
o Methoxy PEG-epoetin beta only 
▪ 
This group contains subjects using methoxy PEG-epoetin beta and pegzerepoetin 
alfa. 
o Multiple 
▪ 
This group contains subjects using any combination of the ESA types. 
o Missing 
 
• 
The dose of ESA will be standardized to obtain a continuous single unit prior ESA dose in terms of 
epoetin IV U/week for the period from the Week -4 visit to the day before the Randomization date. 
 
• 
All prior ESA therapy concomitant medication records from screening will be selected and ordered by 
start date and end date. 
 
• 
The standardization will be carried with the following formula: 
• 
For subjects taking epoetin IV: 
o Standardized ESA dose (U/week) = epoetin IV dose (U)*frequency 
• 
For subjects taking epoetin SC: 
o Standardized ESA dose (U/week) = (161/113)*epoetin SC dose(units)*frequency 
• 
For subjects taking darbepoetin IV or SC: 
o Standardized ESA dose (U/week) = 250* darbepoetin dose (g)*frequency 
• 
For subjects taking methoxy PEG-epoetin beta: 
o Standardized ESA dose (U/week) = 208*methoxy PEG-epoetin beta dose (g)*frequency 
 
Note: Frequency and Gap Factors defined as follows: 
 
Frequency (from eCRF) 
Frequency 
(for standardization formula) 
Gap Factor 
One time dose 
see below 
n/a 
Four times per week 
4 
0.75 day 
Three times per week 
3 
1.33 days 
Two times per week 
2 
2.5 days 
Every week 
1 
6 days 
Every 10 days 
0.70 
9 days 
Every 2 weeks 
0.50 
13 days 
Every 3 weeks 
0.33 
20 days 
Every 4 weeks 
0.25 
27 days 
Every 5 weeks 
0.20 
34 days 
Every 6 weeks 
0.167 
41 days 
Every 8 weeks 
0.125 
55 days 
 
• 
If the frequency of the record is not ‘one time dose’, then duration is calculated as follows: 
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Demographics & Baseline Characteristics 
o If the concomitant medication record start date  Randomization date, the duration of the 
record is 0. 
o If the concomitant medication record end date + gap factor < Week -4 visit date, the duration of 
the record is 0.  
o If the concomitant medication record end date + gap factor ≥ Week -4 visit date, the duration of 
a record will be calculated as Stop Date – Start Date +1 day, where: 
▪ 
Start date will be the latest of (concomitant medication record start date and the Week 
-4 visit date). 
▪ 
Stop date will be the concomitant medication record end date + gap factor. 
• 
If the frequency of the record is ‘one time dose’, then: 
o If the concomitant medication record start date  Randomization date, the duration of the 
record is 0. 
o If Week -4 visit date ≤ concomitant medication record start date, then: 
▪ 
Frequency (for standardization formula) = 1 
▪ 
Duration = 7 days 
o If concomitant medication record start date < Week -4 visit date, then: 
▪ 
Frequency (for standardization formula): 7/ [earliest of (the day before the next 
sequential prior ESA concomitant medication record start date and the day before 
randomization) – start date of record + 1 day] 
▪ 
If the earliest non-missing date of (the day before the next sequential prior ESA 
concomitant medication record start date and the day before randomization) < Week -
4 visit date, the duration of the record is 0. 
▪ 
If the earliest non-missing date of (the day before the next sequential prior ESA 
concomitant medication record start date and the day before randomization)  Week -
4 visit date, the duration of the record is calculated as Stop Date – Start Date + 1, 
where: 
• 
Start date will be the Week -4 visit date. 
• 
Stop date will be the earliest of (the day before the next sequential prior ESA 
concomitant medication record start date and the day before randomization) 
 
• 
The total dose for each prior ESA record will be: Standardized dose*duration/7days 
 
• 
A weighted mean will then be used to obtain the prior ESA dose: 
Mean prior ESA dose = [(ESA total doseRecord 1) + ... + (ESA total doseRecord n)]/[( Randomization Date – 
Week -4 Visit Date)/7days] 
Baseline Erythropoietin Resistance Index (ERI, U/kg/wk/g/L)  
• 
Calculated by dividing the standardized prior ESA dose (U/week) at randomization by the baseline 
estimated dry weight (in kg) and then dividing by the achieved Day 1 Hgb (in g/L). 
• 
Note: the central laboratory Hgb value from Day 1 should be used to calculate ERI, however if this value 
is missing and there is a corresponding non-missing HemoCue Hgb value available, the Day 1 
HemoCue Hgb value will be used. 
rhEPO Hyporesponders 
• 
A subject will be considered to be a hyporesponder if:  
o ERI ≥ 2.0 U/kg/wk/g/L  
Or 
o Prior ESA dose (U/week) at baseline divided by the baseline estimated dry weight (in kg)  
450 U/kg/week 
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Demographics & Baseline Characteristics 
• 
Note: an ERI ≥ 2.0 U/kg/wk/g/L for epoetin-treated subjects corresponds to an ERI ≥0.008μg/kg/wk/g/L 
for darbepoetin-treated subjects and 0.01 g/kg/wk/g/L for methoxy-PEG-epoetin-treated subjects.  
• 
Supportive analyses will be used in the summary of demographics and baseline characteristics and will 
use the following alternative hyporesponder definitions:  
1) an ERI cut-point of ≥ 1.5 U/kg/wk/g/L only 
2) subjects with prior ESA dose (U/week) at baseline in the top 20th percentile of the randomized study 
population. 
Baseline Post-Dialysis Body Mass Index (BMI) 
Calculated as baseline post-dialysis weight (kg) / [height (m)]2 
Cardiovascular Risk Score 
A risk score for two-year cardiovascular mortality and morbidity in a hemodialysis population has been 
developed [Anker, 2016] and will be calculated at baseline for each HD participant. 
 
The following table describes how the published risk score is calculated: 
 
 
 
It should be noted that creatinine is not routinely collected in this study and will be assumed to be the same 
in all HD participants (i.e. <436, resulting in 3 risk score points).   
 
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Demographics & Baseline Characteristics 
CVD history is defined as having a yes response to any of the following medical history conditions: angina 
pectoris, myocardial infarction , stroke, coronary artery disease, transient ischaemic attack, heart failure, 
atrial fibrillation, cardiac arrest, and/or valvular heart disease. 
 
Intradialytic weight change will be calculated using the Week -4 post-dialysis weight in kg – the Week -4 pre-
dialysis weight in kg. 
 
Baseline Hgb categories will be defined based on g/dL units (i.e. <10, 10-<12 and >12) and will use central 
laboratory Hgb values if available. If a baseline central laboratory Hgb value is not available, a baseline 
HemoCue Hgb value will be used.  
 
Risk score points for CKD aetiology will be determined based on the following approach: 
i. 
Participants with diabetic renal disease are assigned 4 points 
ii. 
All other participants who have hypertensive renal disease are assigned 1 point 
iii. 
All other participants who have interstitial nephritis are assigned -1 point 
iv. 
All other participants who have a medical history of polycystic kidney, autosomal dominant or do not 
have any of these medical history terms selected are assigned 0 points 
 
The overall CV risk score is determined by summing up the individual risk scores for the 11 risk factors. 
History of Diabetes 
• 
Subjects are considered to have a history of diabetes if they have a yes response to any of the following 
medical history conditions: diabetes, diabetic autonomic neuropathy, diabetic neuropathy peripheral, 
diabetic dermopathy, diabetic renal disease, diabetic retinopathy. 
• 
If subjects have indicated that they do not have any of the listed diabetic medical history conditions 
above, they are considered not to have a history of diabetes. 
• 
If subjects have not been classified as having or not having a history of diabetes and are missing a 
response to any of the listed medical history conditions, their diabetes history status will be missing. 
History of Stroke 
• 
Subjects are considered to have a history of stroke if they have a yes response to the stroke medical 
history condition. 
• 
Subjects who have indicated that they do not have a history of stroke will be summarized accordingly. 
• 
If a subject is missing a response to the stroke medical history condition, their stroke history status will 
be missing. 
History of MI 
• 
Subjects are considered to have a history of MI if they have a yes response to either of the following 
medical history conditions: myocardial infarction, cardiac arrest. 
• 
Subjects who have indicated that they do not have a medical history of myocardial infarction or cardiac 
arrest will be considered not to have a history of MI. 
• 
If subjects have not been classified as having or not having a history of MI, and are missing a response 
to either the myocardial infarction or cardiac arrest medical condition, their MI history status will be 
missing. 
History of Cancer 
• 
Subjects are considered to have a history of cancer if they have a yes response to either of the following 
medical history conditions: neoplasm malignant or unknown/unspecified, allogeneic bone marrow 
transplant. 
• 
Subjects who have indicated that they do not have a medical history of neoplasm malignant or 
unknown/unspecified or allogeneic bone marrow transplant will be considered not to have a history of 
cancer. 
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Demographics & Baseline Characteristics 
• 
If subjects have not been classified as having or not having a history of cancer and are missing a 
response to either the neoplasm malignant or unknown/unspecified or allogeneic bone marrow 
transplant medical condition, their cancer history status will be missing. 
History of Heart Failure 
• 
Subjects are considered to have a history of heart failure if they have a yes response to any of the 
following medical history conditions: heart failure, left ventricular systolic dysfunction, left ventricular 
diastolic dysfunction, pulmonary hypertension. 
• 
Subjects who have indicated that they do not have a medical history of all of the terms listed above will 
be considered not to have a history of heart failure. 
• 
If subjects have not been classified as having or not having a history of heart failure and are missing a 
response to any of the medical condition terms listed above, their heart failure history status will be 
missing. 
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Demographics & Baseline Characteristics 
History of Thromboembolic Events 
• 
Subjects are considered to have a history of thromboembolic events if they have a yes response to any 
of the following medical history conditions: pulmonary embolism, deep vein thrombosis, retinal vein 
occlusion, arteriovenous graft thrombosis, arteriovenous fistula thrombosis, central venous catheter 
thrombosis. 
• 
Subjects who have indicated that they do not have a medical history of all of the terms listed above will 
be considered not to have a history of thromboembolic events. 
• 
If subjects have not been classified as having or not having a history of thromboembolic events and are 
missing a response to any of the medical condition terms listed above, their thromboembolic event 
history status will be missing. 
History of Cardiovascular Disease 
• 
Subjects are considered to have a history of cardiovascular disease if they have a yes response to any 
of the following medical history conditions: angina pectoris, myocardial infarction, stroke, coronary artery 
disease, transient ischaemic attack, heart failure, atrial fibrillation, cardiac arrest, valvular heart disease. 
• 
Subjects who have indicated that they do not have a medical history of all of the terms listed above will 
be considered not to have a history of cardiovascular disease. 
• 
If subjects have not been classified as having or not having a history of cardiovascular disease and are 
missing a response to any of the medical condition terms listed above, their cardiovascular disease 
history status will be missing. 
Baseline Iron Use & Standardized Baseline IV Iron Dose 
See Section 14.6.3 
Phosphate Binder Use at Randomization 
• 
Phosphate binder use at randomization will be summarized as follows: 
o Iron-based phosphate binders 
o Calcium-based phosphate binders 
o Non-calcium and non-iron based phosphate binders 
o No phosphate binder use 
o Subjects will be counted in each applicable group, based on the concomitant medications 
they are receiving on the day of randomization. 
Concomitant Medication Use at Randomization 
• 
Concomitant medication records on the day of randomization will be used to determine the following 
classifications of concomitant medication use at randomization: 
o ACEI/ARB 
o Vitamin D 
o Beta blockers 
o SGLT2i 
o Statin 
o Aspirin 
o Vitamin K 
o Insulin 
o Calcimimetics 
o Diabetic medication 
 
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14.6.2.2. 
Study Treatment Discontinuation and Study Withdrawal 
Study Treatment Discontinuation and Study Withdrawal 
Study Treatment Discontinuation 
• 
Study Treatment Discontinuation Censored Time (days) = Treatment stop date – Treatment start date +1 
 
If the death date ≤ the treatment stop date + 3 days for a subject, the subject will be censored and 
will not be counted as an event for treatment discontinuation summaries that exclude subjects who 
die while on treatment. 
• 
Time to Study Treatment Discontinuation (days) = Treatment stop date – Treatment start date +1 
• 
Study Treatment Person Years = (Cumulative total of time to study treatment discontinuation for subjects 
who discontinued study treatment + Cumulative total of study treatment discontinuation censoring time 
for subjects who did not discontinue study treatment) / 365.25 
• 
Study Treatment Discontinuation Incidence Rate (per 100 person years) = 100* Number of subjects who 
discontinued study treatment / study treatment person years 
Study Withdrawal 
• 
Study Censored Time (days) = Study completion date – Randomization date +1 
• 
Time to Study Withdrawal (days) = Study withdrawal date – Randomization date +1 
• 
Study Person Years = (Cumulative total time to study withdrawal for subjects withdrawing from the study 
+ Cumulative total of study censoring time for subjects who did not withdraw from study) / 365.25 
• 
Study Withdrawal Incidence Rate (per 100 person years) = (100 * Number of subjects who have 
withdrawn from study) / Stud Person Years  
 
14.6.2.3. 
Prior and Concomitant Medications 
Prior and Concomitant Medications 
Non-randomized ESA use during treatment period 
• 
Subjects will be considered to have non-randomized ESA use during the treatment period if they have 
any ESA concomitant medication records with one of the following two reasons for medication: 
o Non-randomized rhEPO treatment in addition to study treatment 
o Non-randomized rhEPO treatment instead of study treatment during treatment 
period 
Duration of non-randomized ESA use during treatment period 
• 
If there is only one concomitant medication record of non-randomized ESA use during the treatment 
period, then:  
o Duration (days) = earliest of (concomitant medication record end date, last non-zero dose 
date + 1 day) – latest of (concomitant medication start date, treatment start date) + 1 
day 
• 
If there are multiple concomitant medication records of non-randomized ESA use during the 
treatment period, then the duration of non-randomized ESA use will add the durations for all records, 
subtracting any overlapping days that may exist between the multiple records. 
 
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14.6.2.4. 
Exposure and Compliance 
Exposure and Compliance 
Exposure 
• Exposure (days) = Treatment stop date – treatment start date + 1 day 
Compliance 
• Compliance will be calculated based on data recorded in the Study Treatment/Compliance 
Record eCRF pages (blinded and unblinded) and will only be calculated for subjects with a 
non-missing treatment start date, and will not be calculated after a subject’s treatment stop 
date, or study conclusion date for subjects who have a non-missing treatment start date and 
a missing treatment stop date. 
• A compliance category will be assigned to each study treatment exposure visit according to 
the following tables. Exposure records corresponding to periods of dose hold/zero-dose as 
assigned by the IRT will be categorized in the compliant category (given no active treatment 
doses are taken) and any gaps between exposure records will be categorized in the under 
compliant category. 
 
o Daprodustat and rhEPO 
Under Compliant 
Compliant 
Over Compliant 
Compliance for the 
exposure record < 
80% 
Compliance for the 
exposure record  
80% and  120% 
Compliance for the 
exposure record > 
120% 
Where compliance for each visit is calculated as  
(Total Cumulative Dose/Planned Dose)x100 
 
• Planned Dose [1] 
Visit  
Daprodustat 
TIW dose 
rhEPO 
Weekly dose 
Completed Day 1  
Assigned dose x 6 
Assigned dose x 2 
Completed Week 2 – Week 6 
Assigned dose x 6 
Assigned dose x 2 
Completed Week 8 – Week 48 
Assigned dose x 12 
Assigned dose x 4 
Uncompleted Visit. 
Expected Number of doses taken  
(dose stop date – dose start 
date+1)*0.428571428 
 
Expected Number of 
doses taken  
(dose stop date – dose 
start date+1)* 
0.1428571428 
Assigned dose * Expected 
Number of doses 
Assigned dose * 
Expected Number of 
doses 
0.428571428 is 3 divided by 7  
0.1428571428 is 1 
divided by 7 
[1] Assigned Dose:  Dose assigned by the IRT as the start of the Visit. 
 
• Actual Dose  
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Exposure and Compliance 
Duration of Exposure Record 
Daprodustat (mg) 
rhEPO (U) 
Day 1 to Week 48 individual 
dose record 
Container Dose x Number of 
tablets taken 
Dose recorded on 
eCRF [2] 
[2] DOSE entered on open eCRF or if “Did subject receive correct treatment?  is No then DOSE 
from unblinded eCRF. 
 
Each visit will fall into one of the 3 categories and the percentage of time that a subject spent in 
each of the 3 categories above or with missing compliance data will be determined using the 
duration of treatment in each visit with the total duration of treatment.  
 
• Compliance will be summarized for the following time periods: Day 1 - < Week 28, Week 28 
- ≤ Week 52, and Day 1 - ≤ Week 52 (Overall compliance). 
• Within each period, the percentage of time that a subject spent in each of the 3 categories 
above or with missing compliance data will be determined. 
 
14.6.3. 
Efficacy 
14.6.3.1. 
Hemoglobin Endpoints 
Hemoglobin Values 
Central Laboratory and HemoCue Hgb Values 
• 
When source of Hgb measurement is not specified: 
o For reporting purposes, central laboratory Hgb values will be used, unless otherwise 
specified. However, if a central laboratory Hgb value is missing, a corresponding non-
missing HemoCue Hgb value will be used. This approach will be used for the primary 
Hgb analysis. 
 
• 
Some displays may be created for either central laboratory Hgb values only or HemoCue Hgb 
values only. The central laboratory summary will be considered the primary summary in this 
case. 
Evaluable Hemoglobin Values 
• 
Evaluable Hgb values are on-treatment Hgb values (see Section 14.4.1) that are not taken within the 8 
weeks following a red blood cell transfusion, a whole blood transfusion, or a non-randomized ESA 
treatment which occurs on or after the randomization date. 
• 
Red blood cell transfusions, whole blood transfusions and non-randomized ESA treatments 
occurring on or after the randomization date are identified by comparing the start and stop date 
of the respective transfusion or ESA concomitant medication record to the randomization date. 
Imputed Hemoglobin Values 
• For each missing value between baseline to Week 52 (inclusive), 200 imputed values will be 
generated using the multiple imputation method (see Section 7.1.5). The average of these 200 
imputed values will be used as the value for this missing value in the summary tables and 
figures. 
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Hemoglobin Values 
• For primary efficacy Hgb analysis and the corresponding subgroup analyses using all available 
observed and imputed Hgb values (on and off-treatment), Rubin’s rules [Rubin, 1987] will be 
used to combine results of the imputed datasets using SAS PROC MIANALYZE procedure. 
EP Hemoglobin Value for Primary Hgb Analysis 
• 
For each subject, the mean of all available (on and off treatment) Hgb values during the EP (See Section 
14.6.1) including any imputed and unscheduled Hgb values that were taken during this time period. 
• 
Should the assessment dates for Hgb values from the Early Treatment Discontinuation visit fall 
within the EP, then these values will be included as unscheduled Hgb values. Hgb values from 
the Follow-up visit will not be included in the EP mean. 
EP Hemoglobin Value for While On-Treatment Evaluable Hgb Supportive Analysis 
• 
For each subject, the mean of all evaluable Hgb values during the EP (See Section 14.6.1), including 
any evaluable unscheduled Hgb values that were taken during this time period. 
• 
Should the assessment dates for Hgb values from the Early Treatment Discontinuation visit fall 
within the EP, then these values will be included as unscheduled Hgb values. Hgb values from 
the Follow-up visit will not be included in the EP mean. 
EP Hemoglobin Value for Alternative EP Supportive Analyses 
• 
For each subject, the mean of all Hgb values during the Alt. EP (See Section 14.6.1), including any 
imputed and unscheduled Hgb values that were taken during this time period. This analysis will be 
conducted using all available (on and off treatment) Hgb values and separately using evaluable Hgb 
values only. 
• 
Should the assessment dates for Hgb values from the Early Treatment Discontinuation visit fall 
within the Alt. EP, then these values will be included as unscheduled Hgb values. Hgb values 
from the Follow-up visit will not be included in the Alt. EP mean. 
Use of Unscheduled Hemoglobin Values and Multiple Hgb Values on the Same Date 
• The scenarios outlined below provide guidance on the use of unscheduled Hgb values and 
multiple Hgb values occurring on the same date. Each row represents a single calendar date. 
• Rows outlining scenarios where there is at least one central lab Hgb and at least one HemoCue 
Hgb on the same date apply only for the derivation of Hgb values to be used in the primary Hgb 
analysis, where central lab values are used if they are available and if the central lab value is 
missing, then a corresponding non-missing HemoCue Hgb value is used. 
• Rows outlining scenarios involving combinations of scheduled and unscheduled Hgb values of 
the same type apply to all Hgb summaries and analysis. 
Scheduled 
Central Lab 
Hgb Value 
Unscheduled 
Central Lab 
Hgb Value 
Scheduled 
HemoCue 
Hgb Value 
Unscheduled 
HemoCue 
Hgb Value 
Value to Use 
Type/Label 
x 
 
 
 
Scheduled central lab 
Hgb value 
Scheduled visit 
 
x 
 
 
Unscheduled central lab 
Hgb value 
Unscheduled 
 
 
x 
 
Scheduled HemoCue 
Hgb value 
Scheduled visit 
 
 
multiple1 
 
Average of scheduled 
HemoCue Hgb values 
Scheduled visit 
 
 
 
x 
Unscheduled HemoCue 
Hgb value 
Unscheduled 
 
multiple 
 
 
Average of unscheduled 
central lab Hgb values 
Unscheduled 
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Hemoglobin Values 
 
 
 
multiple 
Average of unscheduled 
HemoCue Hgb values 
Unscheduled 
x 
x 
 
 
Average of central lab 
Hgb values 
Scheduled visit 
x 
 
x 
 
Scheduled central lab 
Hgb value 
Scheduled visit 
x 
 
 
x 
Scheduled central lab 
Hgb value 
Scheduled visit 
 
x 
x 
 
Unscheduled central lab 
Hgb value 
Unscheduled 
 
x 
 
x 
Unscheduled central lab 
Hgb value 
Unscheduled 
 
 
x 
x 
Average of HemoCue 
Hgb values 
Scheduled visit 
1: The dose adjustment algorithm will require sites to obtain two HemoCue Hgb values at some visits. 
 
Time In Range 
Time in Range During the EP 
• Number of days that a subject’s evaluable Hgb is within the analysis range of 10-11.5 g/dL 
inclusive during the EP (See Section 14.6.1), including any unscheduled evaluable Hgb values 
that were taken during this time period. 
• Use of unscheduled Hgb values follows the scenarios for unscheduled and multiple Hgb values. 
• Linear interpolation is used to estimate Hgb between visits, accounting for any intermittent 
missing values (Rosendaal, 1993). 
Percent Time in Range During the EP 
• Time in Range During the EP / [Earlier of (Treatment Stop Date+1, Week 52 visit date) – Week 
28 visit date] 
• Note: Percent time in/below/above range during the EP is only defined for subjects with a 
Treatment Stop Date that is after their Week 28 visit date, and have at least two evaluable Hgb 
values on different days, where at least one evaluable Hgb value is contained within the EP and 
another evaluable Hgb value occurs within the range of the Week 16 visit through 4 weeks 
following the Week 52 visit, inclusive.  
 
14.6.3.2. 
Iron Endpoints 
Iron Endpoints 
 Iron Medications 
• During the study, subjects may be receiving iron in multiple routes, including: 
o IV iron 
o Oral iron  
o Other iron (including intramuscular, subcutaneous, and hemodialysis/dialysate) 
• Note: The iron route categories above will be determined using the route on the 
Prior/Concomitant Medication – Iron Therapy record. In addition, ferric citrate records recorded 
on the Prior/Concomitant Medication – Metabolic Bone Disease Therapy eCRF form will also be 
summarized as oral iron use. 
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Iron Endpoints 
Baseline Iron Use 
• The number and percentage of subjects in the following iron use categories at baseline will be 
summarized: 
o IV iron use only 
o Oral iron use only 
o Other iron use only 
o IV and oral iron use only 
o IV and other iron use only 
o Oral and other iron use only 
o IV, oral, and other iron use 
o No iron use 
• When determining baseline iron use, the gap factors mentioned below in the IV iron 
standardization algorithm will be applied to the end date for each iron record, and the baseline 
period of 12 weeks before the Randomization date until the day before the Randomization date 
will also be used. 
Standardized IV Iron Dose (mg/week) to Determine Iron Management Action 
• In order to compare between IV iron records, to determine the action taken with IV iron therapy 
in the 8 weeks following the date the IV management threshold was met, the dose of IV iron in 
each associated record will be standardized in terms of mg/month. 
• IV iron therapy concomitant medication records that occur or are ongoing during the 8 weeks 
following the date the IV management threshold was met (inclusive), will be selected and 
ordered by start and end date. 
o If there is a record has a start date on the date the IV management threshold was 
met, and a prior record has an end date on the day before the IV management 
threshold was met, this prior record will be selected and considered as well. 
• The standardization will be carried out with the following formula: 
o Standardized IV iron dose (mg/week) = IV iron drug dose (mg) * frequency 
 
Note: Frequency defined as follows: 
Frequency (from eCRF) 
Frequency 
(for standardization formula) 
2 times per week 
2 
3 times per week 
3 
4 times per week 
4 
5 times per week 
5 
BID 
14 
Once daily 
7 
One time dose 
1 
Every 12 Hours 
14 
Every 2 weeks 
0.5 
Every 4 weeks 
0.25 
Once a month 
0.23 
Once a week 
1 
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Iron Endpoints 
TID 
21 
Standardized Baseline IV Iron Dose (mg/month) 
• In order to calculate the baseline average monthly IV iron dose, the dose of IV iron will be 
standardized to obtain a continuous single unit IV iron dose in terms of mg/month for the period 
from 12 weeks before the Randomization date to the day before the Randomization date. 
• IV iron therapy concomitant medication records that occur or are ongoing during the period from 
(the Randomization date – 12 weeks) to the day before the Randomization date will be selected 
and ordered by start and end date. 
• The standardization will be carried out with the following formula: 
o Standardized IV iron dose (mg/week) = IV iron drug dose (mg) * frequency 
 
Note: Frequency and Gap Factors defined as follows: 
Frequency (from eCRF) 
Frequency 
(for standardization formula) 
Gap Factor 
2 times per week 
2 
2.5 days 
3 times per week 
3 
1.33 days 
4 times per week 
4 
0.75 day 
5 times per week 
5 
0.4 day 
BID 
14 
0 days 
Once daily 
7 
0 days 
One time dose 
1  
n/a 
Every 12 Hours 
14 
0 days 
Every 2 weeks 
0.5 
13 days 
Every 4 weeks 
0.25 
27 days 
Once a month 
0.23 
29 days 
Once a week 
1 
6 days 
TID 
21 
0 days 
 
• If the frequency of the record is not ‘one time dose’, then duration is calculated as follows: 
o If the concomitant medication record start date  Randomization date, the duration of 
the record is 0. 
o If the concomitant medication record end date + gap factor < (Randomization date – 12 
weeks), the duration of the record is 0. 
o If the concomitant medication record end date + gap factor  (Randomization date – 12 
weeks) or the record is ongoing, the duration of the record will be calculated as Stop 
Date – Start Date +1 day where: 
▪ Start date will be the latest of (concomitant medication record start date and the 
(the Randomization date – 12 weeks). 
▪ Stop date will be the earliest of (concomitant medication record stop date + gap 
factor and the day before randomization). 
• If the frequency of the record is ‘one time dose’, then: 
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Iron Endpoints 
o If concomitant medication record start date < Randomization date - 12 weeks, or if 
Randomization date  concomitant medication record start date, then duration of the 
record is 0. 
o If Randomization date -12 weeks  concomitant medication record start date < 
Randomization date, then: 
▪ Frequency (for standardization formula) = 1 
▪ Duration = 7 days 
• The total dose for each IV iron record will be: Standardized dose*duration/7 days 
• A weighted mean will then be used to obtain the baseline monthly IV iron dose: 
Mean baseline monthly IV iron dose = [(IV iron total doseRecord 1) + ... + (IV iron total doseRecord 
n)]/ [ (12* 7)/30.4375 days]. 
Standardized IV Iron Dose (mg/month) from Randomization to Week 52 
• In order to calculate the average monthly IV iron dose from Randomization to Week 52, the 
dose of IV iron will be standardized to obtain a continuous single unit IV iron dose in terms of 
mg/month for the period from the Randomization date to the Week 52 visit date while the 
subject is on treatment.  
o Note: Subjects who are randomized but never treated will not have a value for 
average monthly IV iron from Randomization to Week 52.  
• IV iron therapy concomitant medication records that occur or are ongoing during the period from 
the subject’s (Randomization date – 12 weeks) to the Week 52 visit date will be selected and 
ordered by start date and end date. 
• The standardization will be carried out with the following formula: 
o Standardized IV iron dose (mg/week) = IV iron drug dose (mg) * frequency 
 
Note: Frequency and Gap Factors defined as follows: 
Frequency (from eCRF) 
Frequency 
(for standardization formula) 
Gap Factor 
2 times per week 
2 
2.5 days 
3 times per week 
3 
1.33 days 
4 times per week 
4 
0.75 day 
5 times per week 
5 
0.4 day 
BID 
14 
0 days 
Once daily 
7 
0 days 
One time dose 
1  
n/a 
Every 12 Hours 
14 
0 days 
Every 2 weeks 
0.5 
13 days 
Every 4 weeks 
0.25 
27 days 
Once a month 
0.23 
29 days 
Once a week 
1 
6 days 
TID 
21 
0 days 
 
• If the frequency of the record is not ‘one time dose’, then duration is calculated as follows: 
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Iron Endpoints 
o If the concomitant medication record start date > earliest of (treatment stop date + 1 
and Week 52 visit date), the duration of the record is 0. 
o If the concomitant medication record end date + gap factor < Randomization date, the 
duration of the record is 0. 
o If the concomitant medication record end date + gap factor  Randomization date or 
the record is ongoing, the duration of the record will be calculated as Stop Date – Start 
Date +1 day where: 
▪ Start date will be the latest of (concomitant medication record start date, 
randomization date, treatment start date). 
▪ Stop date will be the earliest of (concomitant medication record stop date + gap 
factor, treatment stop date + 1, and the Week 52 visit date). 
• If the frequency of the record is ‘one time dose’, then: 
o If concomitant medication record start date < treatment start date, or if earliest of 
(treatment stop date + 1 and Week 52 visit date) < concomitant medication record start 
date, then duration of the record is 0. 
o If latest of (Randomization date, treatment start date)  concomitant medication record 
start date  earliest of (treatment stop date + 1 and Week 52 visit date), then: 
▪ Frequency (for standardization formula) = 1 
▪ Duration = 7 days 
• The total dose for each IV iron record will be: Standardized dose*duration/7 days 
• A weighted mean will then be used to obtain the monthly IV iron dose from Randomization to 
Week 52: 
Mean monthly IV iron dose from Randomization to Week 52 while on treatment =  
[(IV iron total doseRecord 1) + ... + (IV iron total doseRecord n)] / {[earliest of (treatment stop date 
+ 1, Week 52 Visit Date) – treatment start date + 1] / 30.4375 days}. 
Standardized Monthly IV Iron Dose (mg/month) from Week 28 to Week 52 (EP Average 
Monthly IV Iron Dose) 
• In order to calculate the average monthly IV iron dose from Week 28 to Week 52, the dose of IV 
iron will be standardized to obtain a continuous single unit IV iron dose in terms of mg/month for 
the period from the Week 28 visit date to the Week 52 visit date while the subject is on 
treatment. 
o Note: Subjects who are randomized but never treated or who permanently 
discontinue study treatment on or before the Week 28 visit date will not have a 
value for average monthly IV iron from Week 28 to Week 52.  
• IV iron therapy concomitant medication records that occur or are ongoing during the period from 
the subject’s Week 24 visit date to the Week 52 visit date will be selected and ordered by start 
date and end date. 
• The standardization will be carried out with the following formula: 
o Standardized IV iron dose (mg/week) = IV iron drug dose (mg) * frequency 
 
Note: Frequency and Gap Factors defined as follows: 
 
Frequency (from eCRF) 
Frequency 
(for standardization formula) 
Gap Factor 
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Iron Endpoints 
2 times per week 
2 
2.5 days 
3 times per week 
3 
1.33 days 
4 times per week 
4 
0.75 day 
5 times per week 
5 
0.4 day 
BID 
14 
0 days 
Once daily 
7 
0 days 
One time dose 
1  
n/a 
Every 12 Hours 
14 
0 days 
Every 2 weeks 
0.5 
13 days 
Every 4 weeks 
0.25 
27 days 
Once a month 
0.23 
29 days 
Once a week 
1 
6 days 
TID 
21 
0 days 
 
• If the frequency of the record is not ‘one time dose’, then duration is calculated as follows: 
o If the concomitant medication record start date > earliest of (treatment stop date + 1 
and Week 52 visit date), the duration of the record is 0. 
o If the concomitant medication record end date + gap factor < Week 28 visit date, the 
duration of the record is 0. 
o If the concomitant medication record end date + gap factor  Week 28 visit date or the 
record is ongoing, the duration of the record will be calculated as Stop Date – Start 
Date +1 day where: 
▪ Start date will be the latest of (concomitant medication record start date, and 
the Week 28 visit date). 
▪ Stop date will be the earliest of (concomitant medication record stop date + gap 
factor, treatment stop date + 1, and the Week 52 visit date). 
• If the frequency of the record is ‘one time dose’, then: 
o If concomitant medication record start date < Week 28 visit date, or if earliest of 
(treatment stop date + 1 and Week 52 visit date) < concomitant medication record start 
date, then duration of the record is 0. 
o If Week 28 visit date  concomitant medication record start date ≤ earliest of (treatment 
stop date + 1 and Week 52 visit date), then: 
▪ Frequency (for standardization formula) = 1 
▪ Duration = 7 days 
• The total dose for each IV iron record will be: Standardized dose*duration/7 days 
• A weighted mean will then be used to obtain the monthly IV iron dose from Week 28 to Week 
52: 
Mean monthly IV iron dose from Week 28 to Week 52 while on treatment =  
[(IV iron total doseRecord 1) + ... + (IV iron total doseRecord n)] / {[earliest of (treatment stop date 
+ 1, Week 52 Visit Date) – Week 28 Visit Date + 1]/30.4375 days}. 
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Iron Endpoints 
Iron Use by Quarter 
• The number and percentage of subjects in the following iron use categories defined by route will 
be summarized by quarters listed below for Average Quarterly IV Iron Dose: 
o IV iron use only 
o Oral iron use only 
o Other iron use only 
o IV and oral iron use only 
o IV and other iron use only 
o Oral and other iron use only 
o IV, oral, and other iron use 
o No iron use 
• When determining iron use by quarter, the gap factors mentioned in the IV iron standardization 
algorithm will also be applied to the end date for each iron record. 
• Baseline iron use will also be included in summaries of iron use by quarter. 
Average Quarterly IV Iron Dose 
• The standardized IV iron (mg/month) dose will be summarized by quarters, where quarters will 
be defined using study visits as follows: 
o Baseline 
o For summaries of on & off treatment IV iron dose: 
▪ Quarter 1 = [Randomization date – Week 12)  
o For summaries of on-treatment IV iron dose: 
▪ Quarter 1 = [Treatment start date + 1 – Week 12)  
▪ Quarter 2 = [Week 12 – Week 24) 
▪ Quarter 3 = [Week 24 – Week 36) 
▪ Etc. 
• To determine the planned start date and end date of quarters, the visit end date (from the SV 
domain) will be used. If there is not a corresponding visit, or if the subject is missing that visit, 
the planned visit date (Randomization date + 7*x) will be used, where x is the scheduled week 
(e.g., Week 24, x = 24). 
• A subject’s quarterly average IV iron dose will end at the earliest of the following: 
o For summaries of on & off treatment IV iron dose: death date, study 
completion/withdrawal date, and the planned quarter end date. 
o For summaries of on-treatment IV iron dose: death date, study 
completion/withdrawal date, treatment stop date + 1, and the planned quarter end 
date. 
• The standardization algorithm for IV iron described earlier in the table will be used to determine 
the standardized IV iron dose (mg/month) during each quarter. 
• Standardized baseline IV iron dose will also be included in summaries of average quarterly IV 
iron dose. 
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Iron Endpoints 
Reduction in IV Iron Supplementation 
• A reduction in IV iron supplementation relative to baseline occurs when Baseline average 
monthly IV iron > EP average monthly IV iron, when both baseline IV iron and EP average 
monthly IV iron are non-missing. 
TIBC 
• TIBC will be calculated automatically by the central laboratory using: 
o TIBC = UIBC + total iron 
TSAT 
• TSAT will be calculated automatically by the central laboratory using: 
o TSAT = 100 * (Serum Iron/TIBC) 
Average Quarterly TSAT and Ferritin 
• The average TSAT and Ferritin values will be summarized by quarters, where quarters will be 
defined as they are for Average Quarterly IV Iron Dose, with the following exception: 
o Baseline average quarterly ferritin and TSAT will take the average of all available 
records before or on randomization ferritin and TSAT values. 
 
Note: any unscheduled values falling within these quarters will be used in the calculation of the 
quarterly average value. 
Meeting Iron Management Criteria 
Iron therapy will be administered if at any visit: 
• Ferritin  100 ng/mL and/or TSAT  20% 
All iron must be stopped if at any visit: 
• Ferritin > 800 ng/mL and TSAT >20%, or 
• TSAT > 40% 
Subjects meeting iron management criteria requiring starting and stopping of iron administration on 
the same day: 
• Ferritin <= 100 ng/mL and TSAT > 40% 
 
14.6.3.3. 
Time to Rescue 
Time to Stopping Study Treatment Due to Meeting Rescue Criteria  
Meeting Rescue Evaluation Criteria and Rescue Criteria 
• Subjects meeting evaluation criteria for rescue are identified from the Anemia Intervention and 
Rescue eCRF. Subjects with a record on this form are considered to have met evaluation 
criteria for rescue. It is possible that a subject could be evaluated for rescue more than once, 
and in that case a subject would have multiple records on this form. 
• Subjects unable to be evaluated for rescue are subjects who met evaluation criteria for rescue, 
but were unable to be assessed at the 4 week check (e.g., subjects who died, permanently 
discontinued study treatment or withdrew from the study before the 4 week check). The 
outcome of initial intervention eCRF field on the Anemia Intervention and Rescue eCRF will be 
blank for these subjects. 
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Time to Stopping Study Treatment Due to Meeting Rescue Criteria  
• Subjects meeting rescue are identified by the response “If met rescue criteria, check all that 
apply” to the outcome of initial intervention question on the Anemia Intervention and Rescue 
eCRF. 
Event Date 
• Treatment stop date when the primary reason and subreason for study treatment stop are: 
o Primary reason: Subject reached protocol-defined stopping criteria 
o Subreason: Rescue 
General Definitions 
• Time to event (days) = date of event – randomization date +1 
• Censored time (days) = censoring date – randomization date + 1 
• Rescue person years = (cumulative total time to stopping study treatment for subjects who 
stopped study treatment due to meeting rescue criteria + cumulative total of censoring time for 
subjects who did not stop study treatment due to meeting rescue criteria) / 365.25 
• Rescue incidence rate (per 100 person years) = (100 * number of subjects who stopped study 
treatment due to meeting rescue criteria) / rescue person years 
• Rescue absolute rate difference (per 100 person years) = daprodustat rescue incidence rate 
(per 100 person years) – rhEPO rescue incidence rate (per 100 person years) 
Time Period for Treatment Discontinuation 
The period for treatment discontinuation begins at randomization. The end of this time period is 
defined as follows: 
• For subjects who did not take study treatment, use the date of randomization 
• For subjects whose treatment stop date is missing and who took study treatment, use study 
conclusion date 
• For subjects either continuing on study past treatment stop date or completing/withdrawing on 
the same day as treatment stop date, use treatment stop date 
 
Any events that occurred before the start of this time period are considered to be prior to the time 
period for treatment discontinuation, and any endpoints that occurred after the end of this time 
period are considered to be post the time period for treatment discontinuation. 
 
14.6.3.4. 
RBC and Whole Blood Transfusion Endpoints 
Number of RBC and Whole Blood Transfusions 
• The number of transfusions associated with each RBC and Whole Blood Transfusion record is 
determined by the frequency, start date, end date and number of units, as described below 
• Only on-treatment transfusions are included. “End date” below refers to the end date defined for 
the transfusion, or the end of the on-treatment period, if sooner (see Section 14.4.1.1). 
• For records with a frequency of “Once only” or “Continuous infusion”, each record is considered 
to be a single transfusion (regardless of start and end dates or number of units) 
• For records with a frequency of “Once daily”, the number of transfusions will equal the duration 
(end date – start date +1) 
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• For records with a frequency of “PRN”, the number of transfusions for each record will be equal 
to the number of units recorded 
• For other transfusion records, the number of transfusions will equal the duration (end date – 
start date +1) times a multiplier, as defined below. The number of transfusions should be 
rounded to nearest integer. 
 
Frequency 
Multiplier 
QM 
0.033 
Every 2 weeks 
0.071 
Once a week 
0.14 
Q4D 
0.25 
2 times per week 
0.29 
Q3D 
0.33 
3 times per week 
0.43 
Every other day 
0.5 
4 times per week 
0.57 
5 times per week 
0.71 
BID 
2 
Q12H 
2 
TID 
3 
Q8H 
3 
QID 
4 
Q6H 
4 
5 times per day 
5 
Q4H 
6 
Number of RBC and Whole Blood Transfusion Events 
• RBC and Whole Blood Transfusion Events are defined by grouping together on-treatment 
transfusion records 
• Transfusion records are grouped into the same Transfusion Event if the transfusion start/end 
dates match with or are contained within an Admission/Discharge period, (based on the 
Hospitalization page in the eCRF). For example the following transfusion records would be 
grouped into a single Transfusion Event, because each transfusion is contained within the same 
hospital admission/discharge period:  
 
Dose 
Frequency 
Transfusion Dates 
Hospitalisation 
Comment 
Start Date 
End Date 
Admission 
Discharge 
1 unit 
Once only 
16FEB2019 16FEB2019 15FEB2019 26FEB2019 1 Transfusion 
Event 
1 unit 
Once only 
19FEB2019 19FEB2019 15FEB2019 26FEB2019 
 
• Transfusion records not matching with an Admission/Discharge period are considered to be the 
same Transfusion Event if the gap between transfusions is 5 days or less, with further details 
provided below. For any subject where the frequency is PRN and the transfusion start date ≠ 
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end date, the dates of individual transfusions are unknown and the number of transfusion 
events will be set to missing/unknown. 
• In the case of a sequence of more than two transfusions, transfusions are considered to be the 
same Transfusion Event if the gap between each transfusion and the first transfusion in the 
sequence (the “anchor” transfusion) is 5 days or less. The first transfusion that is greater than 5 
days after the “anchor” transfusion is not included in the Transfusion Event, and it becomes the 
new “anchor” transfusion for a new Transfusion Event. 
• In the example below, transfusion records 1 and 2 would be grouped into a single Transfusion 
Event, because the gap between the transfusions (17JAN2019 to 18JAN2019) was 5 days or 
less. Record 3 falls outside this Transfusion Event because the gap between the start date 
(22JAN2019) and the previous anchor date (16JAN2019) is more than 5 days. Therefore 
22JAN2019 becomes the new “anchor” transfusion used to define the next Transfusion Event. 
This pattern is repeated, if necessary. N.B.  “anchor” transfusions are shown in bold. 
 
# 
Dose 
Frequency 
Transfusion Dates 
Comment 
Start Date 
End Date 
1 
1 unit 
Once only 
16JAN2019 
16JAN2019 
1 Transfusion Event 
2 
1 unit 
Once only 
19JAN2019 
19JAN2019 
3 
1 unit 
Once only 
22JAN2019 
22JAN2019 
1 Transfusion Event 
4 
1 unit 
Once only 
25JAN2019 
25JAN2019 
5 
1 unit 
Once only 
28JAN2019 
28JAN2019 
1 Transfusion Event 
 
Number of Units 
• The number of RBC and whole blood units are derived from blood transfusion records. The 
number of units associated with each record is determined by the frequency, start date, end 
date and dose (i.e. number of units recorded), as described below. 
• Only units associated with on-treatment transfusions are included. “End date” below refers to 
the end date defined for the transfusion, or the end of the on-treatment period, if sooner (see 
Section 14.4.1.1). 
• For records with the frequency recorded as “Once only” or “Continuous infusion”, the total 
number of units associated with each record is the number of units recorded (regardless of start 
and end dates) 
• For records with the frequency recorded as “Once daily”, the total number of units associated 
with each record will equal the number of units recorded multiplied by the duration (end date – 
start date +1) 
• For records with the frequency recorded as “PRN”, the total number of units will be equal to the 
number of units recorded (regardless of start and end dates) 
• For other records, the number of units will equal to the number of units recorded multiplied by 
the duration (end date – start date +1) times a multiplier, as defined for Number of RBC and 
Whole Blood Transfusions above 
• The table below provides multipliers for converting various reported units to Units (which should 
be rounded to nearest integer).  For example, a transfusion of 450ml represents a single unit:  
(450 x 0.0025) = 1.125 (rounded to 1 Unit) 
 
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Reported Units 
Multiplier 
Units 
1 
Milliliters (ml or CC) 
0.0025 
Milligram (mg) 
0.0025 
Milligrams/millilitres (mg/ml) 
0.0025 
• Where a non-integer number of units has been entered on the eCRF, this will be rounded up to 
the nearest integer prior to any subsequent derivation (if necessary). 
 
Evaluation Period (Weeks 28 to 52) 
• Only transfusion events with a start date from date of week 28 visit to the date of the week 52 
visit will be included 
• Patient Years (PY) = (cumulative total time from date of week 28 visit to the date of the week 52 
visit, for subjects who did not withdraw from study treatment during the evaluation period + 
cumulative time from date of week 28 visit to the date of withdrawal from study treatment, for 
subjects who withdrew from study treatment during the evaluation period) / 365.25 
• Transfusion Events per 100 PY = (100 * number of on-treatment RBC or whole blood 
transfusion events during the evaluation period) / Patient Years (PY) 
• Transfusions per 100 PY = (100 * number of on-treatment RBC or whole blood transfusions 
during the evaluation period) / Patient Years (PY) 
• Units per 100 PY = (100 * number of on-treatment RBC or whole blood transfusion units during 
the evaluation period) / Patient Years (PY) 
 
Randomization to Week 52 
• Only transfusion events with a start date from the date of randomization to the date of the week 
52 visit will be included  
• Patient Years (PY) = (cumulative total time from date of randomization to the date of the week 
52 visit, for subjects who did not withdraw from study treatment prior to week 52 + cumulative 
time from date of randomization to the date of withdrawal from study treatment, for subjects who 
withdrew from study treatment prior to week 52) / 365.25 
• Transfusion Events per 100 PY = (100 * number of on-treatment RBC or whole blood 
transfusion events from the date of randomization to the date of the week 52 visit) / Patient 
Years (PY) 
• Transfusions per 100 PY = (100 * number of on-treatment RBC or whole blood transfusions 
from the date of randomization to the date of the week 52 visit) / Patient Years (PY) 
• Units per 100 PY = (100 * number of on-treatment RBC or whole blood transfusion units from 
the date of randomization to the date of the week 52 visit) / Patient Years (PY) 
 
Time to First On-Treatment RBC or Whole Blood Transfusion 
• Event Date = Start date for the first on-treatment RBC or whole blood transfusion received after 
treatment start date 
• Censoring Date = date of stopping study treatment for subjects who stopped study treatment, or 
date of study completion for subjects who did not stop study treatment 
• Time to event (days) = date of event – treatment start date +1 
• Censored time (days) = censoring date – treatment start date + 1 
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• Person years (PY) = (cumulative total time to event date, for subjects who received at least one 
on-treatment RBC or whole blood transfusion + cumulative total of censoring time for subjects 
who did not receive at least one on-treatment RBC or whole blood transfusion) / 365.25 
• Incidence rate per 100 PY = (100 * number of subjects who received at least one on-treatment 
RBC or whole blood transfusion) / person years 
• Absolute rate difference (per 100 person years) = daprodustat incidence rate (per 100 person 
years) – rhEPO incidence rate (per 100 person years) 
 
Time Period for On-Treatment Transfusions 
The period for capturing on-treatment transfusions begins on the treatment start date. The end of 
this time period is defined as follows: 
• For subjects whose treatment stop date is missing and who took study treatment, use date of 
study withdrawal/completion 
• For subjects continuing on study past the treatment stop date, use (treatment stop date) 
For subjects whose study withdrawal/completion date is on or before (treatment stop date), use 
date of study withdrawal/completion 
Model Specification 
• Analysis of time to first RBC or whole blood transfusion will be performed using a Cox 
proportional hazards model adjusted for treatment and region. 
• Analysis will include only transfusion occurring during the on-treatment period 
Model Results Presentation 
• The hazard ratio, two-sided 95% CI, and one-sided p-value for the superiority test will be 
presented for the comparison of daprodustat vs. rhEPO using the Cox Proportional Hazards 
model. 
• Number and percentage of subjects who received at least one on-treatment RBC or whole 
blood transfusion and the number and percentage of censored subjects will be provided by 
treatment group. The incidence rate per 100 PY (95% CI) within each treatment group and the 
absolute rate difference per 100 PY (95% CI) will be displayed with the results of the Cox 
proportional hazards regression model. For within-group rates, the two-sided 95% CI will be 
obtained using an exact Poisson method. For difference in rates between treatments, the two-
sided 95% CI will be constructed with a Normal approximation using Wald’s method [Liu, 2006]. 
• A Kaplan-Meier plot will be produced showing the survival function for time to first RBC or whole 
blood transfusion. 
 
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14.6.3.5. 
Dose Adjustment Scheme Endpoints 
Dose Adjustment Scheme Endpoints 
General 
• The IRT system assigns all study treatment doses in accordance with the dose adjustment 
scheme specified in the protocol.  
• During the study, it is possible for subjects to change study treatment doses at both scheduled 
and unscheduled visits.  
• Sites are instructed to complete an exposure record for every dose taken/planned.  
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Dose Adjustment Scheme Endpoints 
Tablet Combinations to Achieve Prescribed Daprodustat or Placebo Treatment 
Sites will enter the dose of daprodustat into exposure records. The dose steps of daprodustat are 
shown below: 
Dosage 
Level 1 
(mg) 
Total 
Number 
of 
Tablets 
Active Treatment for Daprodustat Randomized 
Participants  
Inactive (Placebo) 
Treatment for 
Epoetin Alfa 
Randomized 
Participants 
7 mm 
Placebo 
2 mg 
Dapro 
4 mg 
Dapro 
6 mg 
Dapro 
8 mg 
Dapro 
10 mg 
Dapro 
7mm 
Placebo 
9 mm 
Placebo 
0 
1 
1 
 
 
 
 
 
1 
 
2 
1 
 
1 
 
 
 
 
1 
 
4 
1 
 
 
1 
 
 
 
1 
 
8 
1 
 
 
 
 
1 
 
 
1 
12 
2 
 
 
 
2 
 
 
 
2 
16 
2 
 
 
 
 
2 
 
 
2 
20 
2 
 
 
 
 
 
2 
 
2 
24 
3 
 
 
 
 
3 
 
 
3 
32 
4 
 
 
 
 
4 
 
 
4 
48 
6 
 
 
 
 
6 
 
 
6 
1. Dose to be administered three-times weekly 
 
Number of Vials and Vial Combinations to Achieve Prescribed Epoetin Alfa or Saline 
Treatment 
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Sites will enter each dose of epoetin alfa into exposure records. The dose steps of epoetin alfa 
(including the corresponding total weekly doses) are shown below: 
 
Total 
Weekly 
Dose 
(Units) 
Dose and Frequency 
Epoetin Alfa Randomized Participants 1,2 
Inactive (Saline) 
Treatment for 
Daprodustat 
Randomized 
Participants 
Saline 3 
(1 mL) 
2000 
U/1mL 
3000 
U/1mL 
4000 
U/1mL 
10000 
U/1mL 
Saline 3  
(1 mL) 
0 
0 U once a week 
1 
 
 
 
 
1 
1500 4 
1500 U once a week 
 
0.75 
 
 
 
0.75 
2000 
2000 U once a week 
 
1 
 
 
 
1 
3000 
3000 U once a week 
 
 
1 
 
 
1 
4000 
4000 U once a week 
 
2 
 
 
 
2 
5000 
5000 U once a week 
 
1 
1 
 
 
2 
6000 
6000 U once a week 
 
1 
 
1 
 
2 
8000 
8000 U once a week 
 
 
 
2 
 
2 
10,000 
10,000 U once a week 
 
1 
 
2 
 
3 
12,000 
4000 U three times a 
week 
 
 
 
1 
 
1 
15,000 
5000 U three times a 
week 
 
1 
1 
 
 
2 
18,000 
6000 U three times a 
week 
 
1 
 
1 
 
2 
21,000 
7000 U three times a 
week 
 
 
1 
1 
 
2 
24,000 
8000 U three times a 
week 
 
 
 
2 
 
2 
27,000 
9000 U three times a 
week 
 
1 
1 
1 
 
3 
30,000 
10,000 U three times a 
week 
 
 
 
 
1 
1 
36,000 
12,000 U three times a 
week 
 
1 
 
 
1 
2 
42,000 
14,000 U three times a 
week 
 
 
 
1 
1 
2 
48,000 
16,000 U three times a 
week 
 
1 
 
1 
1 
3 
60,000 
20,000 U three times a 
week 
 
 
 
 
2 
2 
1. 
The vial combinations used to achieve a specific weekly dose of epoetin alfa (and number of saline syringes for the 
corresponding inactive dose) may be adjusted by the sponsor based on changes to the commercial availability of 
epoetin alfa or other supply considerations. Any change to the vial combinations will be made globally across the 
study in order to maintain the blind, and it will be managed centrally through the IRT system. Details of any 
changes will be detailed in the SRM. 
2. 
Each epoetin alfa vial should be administered using a separate syringe. 
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3. 
For saline doses, the number of ‘vials’ indicated in the table refers to the number of syringes containing 1 mL of 
saline that will be administered in order to maintain the blind. 
4. 
The 1500 U epoetin alfa dose will be achieved by administering 0.75 mL of a 2000 U/mL vial. The corresponding 
1500 U saline dose, for daprodustat randomized participants, will be achieved by administering 0.75 mL of saline. 
 
Assigned Dose At A Scheduled Visit 
• The assigned dose at a particular visit refers to the dose the subject assigned based on new 
IRT instruction received at that visit, as recorded in the eCRF. The assigned dose at Visit X is 
the dose from the earliest exposure record with a start date on or after the Visit X date, but 
before the Visit X+1 date. 
o For example, the assigned dose at the Week 28 visit is the dose from the earliest 
exposure record with a start date on or after the Week 28 visit date, but before the 
Week 32 visit date. 
Most Recent Dose Prior to A Scheduled Visit / End of Treatment 
• The most recent dose prior to a particular visit refers to the dose recorded in eCRF for the 
subject in the period directly preceding the visit. The most recent dose prior to Visit X is the 
dose from the latest exposure record with a start date that is on or after the Visit X-1 date and 
before the Visit X date. 
o For example, the most recent dose prior to Week 28 is the dose from the latest 
exposure record with a start date that is on or after the Week 24 visit date and 
before the Week 28 visit date. 
• If a subject permanently stops study treatment after Visit X-1 and on or before Visit X, the most 
recent dose prior to Visit X will be the dose from the subject’s final exposure record. 
Two Approaches to Dose Adjustment Summaries 
• The first approach counts all dose adjustments, including dose adjustments related to 
periods of dose holds (i.e., IRT assignment of a 0-dose). 
• The second approach does not count dose adjustments related to periods of dose holds. 
However, should the dose that a subject receives following a period of dose hold be 
different from the dose the subject received before the dose hold, this would still count as a 
dose adjustment in this approach. 
Number of Dose Adjustments per Year During Day 1 - < End of Treatment 
• The number of dose adjustments per year will be determined by dividing the total number of 
dose adjustments between Day 1 and End of Treatment by [(Treatment Stop Date – Day 1 date 
+ 1 day) / 365.25]. 
 
14.6.4. 
Safety  
14.6.4.1. 
CV Safety Endpoints 
CV Safety Endpoints 
Dates for Investigator Reported CV Safety Endpoints 
• 
All-cause hospitalization: admission date 
• 
All-cause hospital re-admission: admission date within 30 days following a discharge date 
• 
Death: date of death from the Death eCRF page 
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• 
Myocardial infarction: date of onset of Myocardial Infarction/Unstable Angina symptoms from the MI/UA 
eCRF page 
• 
Stroke: start date of neurological symptoms from the Stroke/TIA eCRF page 
• 
Hospitalization for HF: Earliest of (ER admission date, Hospital admission date) from Heart Failure eCRF 
page 
• 
Thromboembolic event: date of onset of thromboembolic event from the Thromboembolic Event eCRF 
page 
Dates for Adjudicated CV Safety Endpoints 
• 
Death: event date reported by CEC 
• 
Myocardial infarction: event date reported by CEC 
o Fatal MI events only identified through a primary cause of death, without a corresponding 
positively adjudicated MI event: death event date reported by CEC 
• 
Stroke: event date reported by CEC 
o Fatal stroke events only identified through a primary cause of death, without a 
corresponding positively adjudicated stroke event: death event date reported by CEC 
• 
Hospitalization for HF: event date reported by CEC 
o Fatal heart failure/cardiogenic shock events only identified through a primary cause of 
death, without a corresponding heart failure event: death event date reported by CEC 
• 
Thromboembolic event (DVT, PE, VAT): event date reported by CEC 
o Fatal PE events only identified through a primary cause of death, without a corresponding 
positively adjudicated PE event: death event date reported by CEC 
 
Due to the design of the CRF, a fatal MI is reported as both an MI and a death. Both of these events will go 
through the adjudication process. It is possible that the MI could be negatively adjudicated, while the death is 
positively adjudicated with a primary cause of acute MI. The rationale for this is that the definition of a 
positively adjudicated MI (contained in the CEC charter) is more explicit than the definition of acute MI as a 
primary cause of death. Therefore, in analyses that include MI events without including all-cause mortality, 
the primary approach will be to include only those fatal MI events that correspond to a positively adjudicated 
MI event. These analyses will then be repeated for supportive purposes using all fatal MI events – including 
those fatal MI events only identified through a primary cause of death (i.e., acute MI) without a corresponding 
positively adjudicated MI event. 
 
Additionally, a fatal MI event could have an event date that differs from the death date because the subject 
may have died as a result of the MI but not on the same day. For analysis of first occurrence MACE, MI or 
any other composite endpoint that includes both MI and death, if both the MI and death events are positively 
adjudicated, the MI date will be used as the event date. For analysis of CV mortality only and all-cause 
mortality only, the death date will be used. 
 
Similarly, fatal stroke events are reported as both a stroke and a death. In analyses that include stroke 
events without including all-cause mortality, the primary approach will be to include only those fatal stroke 
events that correspond to a positively adjudicated stroke event. These analyses will be repeated for 
supportive purposes using all fatal stroke events – including those fatal stroke events only identified through 
a primary cause of death (i.e., stroke) without a corresponding positively adjudicated stroke event. For 
analysis of first occurrence MACE, stroke, or any other composite endpoint that includes stroke and death, if 
both the stroke and death events are positively adjudicated, the stroke date will be used as the event date. 
For analysis of CV mortality only and all-cause mortality, the death date will be used. 
 
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Fatal heart failure events are reported as both a heart failure and a death. In analyses that include 
hospitalization for heart failure events without including all-cause mortality, a single approach which includes 
only those fatal hospitalization for heart failure events that correspond to a positively adjudicated 
hospitalization for heart failure event will be used. The definition of the hospitalization for heart failure 
endpoint includes requirements around hospitalization which are not captured in the associated primary 
cause of death (heart failure/cardiogenic shock), so identification of hospitalization for heart failure events 
through only a primary cause of death is not possible. However, supportive analyses of the hospitalization for 
heart failure endpoint may include all heart failure events. These supportive analyses would then be able to 
include fatal heart failure events from the death page (i.e. primary cause of death = heart failure/cardiogenic 
shock) that do not correspond to a positively adjudicated heart failure event. For analysis of hospitalization 
for heart failure or any composite endpoint that includes hospitalization for heart failure and death, if both the 
hospitalization for heart failure and death events are positively adjudicated, the hospitalization for heart 
failure date will be used as the event date. For analysis of CV mortality only and all-cause mortality, the 
death date will be used. 
 
Fatal pulmonary embolism events are reported as both a pulmonary embolism and a death. In analyses that 
include pulmonary embolism events (i.e., thromboembolic events) without including all-cause mortality, the 
primary approach will be to include only those fatal pulmonary embolism events that correspond to a 
positively adjudicated pulmonary embolism event. These analyses may be repeated for supportive purposes 
using all pulmonary embolism events – including those fatal pulmonary embolism events only identified 
through a primary cause of death (i.e., pulmonary embolism) without a corresponding positively adjudicated 
pulmonary embolism event. For analysis of pulmonary embolism or any composite endpoint that includes 
pulmonary embolism and death, if both the pulmonary embolism and death events are positively adjudicated, 
the pulmonary embolism date will be used as the event date. For analysis of CV mortality only and all-cause 
mortality, the death date will be used. 
 
In the situation that there is a fatal MI (or fatal stroke, hospitalization for heart failure, or pulmonary embolism) 
that does not have both an MI (or stroke, hospitalization for heart failure, or pulmonary embolism) endpoint 
and a death endpoint reported, the date of the event that is reported will be used in the analysis of all 
relevant endpoints. This would additionally apply to situations where the MI (or stroke, hospitalization for 
heart failure, or pulmonary embolism) may occur within an analysis period and the death may occur outside 
of the analysis period; the endpoint with the date in the analysis period will be used for all relevant endpoints. 
Missing or Partial Endpoint Dates 
• 
If event dates are missing or partial and there is not sufficient information to classify the time period of 
the event, the event will be classified as occurring on-treatment and post-randomization. The event will 
also be considered to have occurred during the follow-up for cardiovascular events as defined in Section 
14.6.4. 
• 
The following rules for missing or partial event dates for events other than death will be implemented as 
long as the imputed date is after the randomization date. If the imputed date is prior to the randomization 
date, then the date of randomization will be imputed for the event date. 
o If only the day of the month is missing, impute the first day of the month (e.g., --FEB2016 
would impute as 01FEB2016) 
o If the month and day of the month are missing, impute 01JAN (e.g., -----2016 would impute 
as 01JAN2016) 
o If the year, month, and day of month are missing, impute the randomization date 
• 
The following rules for missing or partial death dates will be implemented as long as the imputed date is 
after the randomization date. If the imputed date is prior to the randomization date, then the date of 
randomization will be imputed for the death date.  
o The latest clinic visit, telephone visit, other contact with subject visit, CV endpoint (other 
than death), AE or SAE date, or date last known to be alive will be determined. If the year, 
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month, and day of month of the death are missing then the death date will be imputed as 
the latest of the dates. 
o If only the day of the month of death is missing, then impute the first day of the month (e.g., 
--FEB2016 would impute as 01FEB2016). However, if this imputed date results in a date 
that is prior to the latest clinic visit, telephone visit, other contact with subject visit, CV 
endpoint (other than death), AE or SAE date, or date last known to be alive then impute the 
missing day of death as equal to this date instead. For example: 
▪ 
If –FEB2016 is given as the death date and there is a non-fatal MI on 
08FEB2016, then the imputed date of death would be 08FEB2016 rather than 
01FEB2016 such that the death is not before the non-fatal MI. 
▪ 
If –MAR2016 is given as the death date and the latest date is a non-fatal MI on 
08FEB2016 then the imputed date of death would be 01MAR2016. 
o If the month and day of the month of death are missing, then impute as 01JAN (e.g., -----
2016 would impute as 01JAN2016). However, if this imputed date results in a date that is 
prior to the latest clinic visit, telephone visit, other contact with subject visit, CV endpoint 
(other than death), AE or SAE date, or date last known to be alive then impute the missing 
month and day of death as equal to this date instead. For example: 
▪ 
If -----2016 is given as the death date and the latest date is a non-fatal MI on 
08FEB2016 then the imputed date of death would be 08FEB2016 rather than 
01JAN2016 such that the death is not before the non-fatal MI. 
▪ 
If -----2017 is given as the death date and the latest date is a non-fatal MI on 
08FEB2016 then the imputed date of death would be 01JAN2017. 
o For deaths that occur after subjects have prematurely withdrawn from the study, missing or 
partial dates will be imputed as specified above except if the imputation places the death 
prior to or on the premature withdrawal date. In this case the death date will be imputed as 
the premature withdrawal date + 1 day.  
Order of CV Safety Endpoint Events 
• 
If multiple events occur on the same day or have imputed dates that place them on the same day, 
but it is not clear which event occurred first, then the following order will be applied: 
1. MI 
2. Stroke 
3. Hospitalization for Heart Failure 
4. Thromboembolic Event: DVT 
5. Thromboembolic Event: VAT 
6. Thromboembolic Event: PE 
7. Death 
CV Mortality 
• 
CV mortality includes all deaths indicated as having a cardiovascular primary cause of death (including 
fatal MI and fatal stroke events) as well as deaths with an undetermined primary cause of death that are 
indicated to be either presumed sudden death or presumed cardiovascular death. Deaths with an 
undetermined primary cause of death that are indicated to be an unknown death will not be included as 
a CV mortality event. 
Heart Failure Events 
• The primary heart failure event of interest in this study is hospitalization for heart failure. 
However, investigators are requested to report all potential heart failure events for adjudication, 
even if there was no hospitalization associated with the event. 
• The CEC will categorize heart failure events into one of the following adjudicated event types: 
o Hospitalization for Heart Failure 
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o Urgent ER/ED Visit for Heart Failure 
o Urgent Office/Practice Visit for Heart Failure 
o Negative adjudication (i.e., not one of the heart failure events above) 
• For purposes of endpoints that contain hospitalization for heart failure as a component, only the 
events adjudicated by the CEC as Hospitalization for Heart Failure will be included. 
Investigator-reported Endpoint Events for Concordance 
• 
For purposes of concordance tables, events with an investigator-reported event date  randomization 
date during the time period for follow-up of cardiovascular events, that meet the following final diagnosis 
criteria will be considered to be investigator-reported endpoint events: 
 
Endpoint 
Investigator-reported final diagnosis (from eCRF) 
Myocardial infarction 
Myocardial infarction 
Stroke 
Primary ischemic stroke (with or without hemorrhagic transformation), 
Primary intracranial hemorrhage, Retinal/ocular hemorrhage or 
infarction, Unknown type of stroke 
Hospitalization for Heart 
Failure 
Systolic heart failure, Diastolic heart failure, Heart failure - unspecified 
type 
 
Additional criteria: 
If admission/discharge times are non-missing, at least one of the 
following must be true (1-3):  
1. Time in hospital is >=24 hours 
2. Time in ED/ER is >=24 hours 
3. Consecutive time in hospital + time in ED/ER is >=24 hours 
Or if admission/discharge times are missing, then at least one of the 
following must be true (4-6): 
4. Change in calendar date between hospital admission and discharge 
5. Change in calendar date between ED/ER admission and discharge 
6. Change in calendar date between consecutive hospital and ED/ER 
admission and discharge 
Thromboembolic Event 
(DVT, PE, VAT) 
Deep Vein Thrombosis (DVT), Pulmonary Embolism (PE), Vascular 
Access Thrombosis 
All-cause mortality 
Any death record 
CV mortality 
Any Cardiovascular primary cause of death 
Non-CV mortality 
Any Non-Cardiovascular primary cause of death 
Unknown (sub-category 
of All-cause mortality) 
Any Unknown primary cause of death 
 
Events with an adjudication record, but without an investigator reported record, will also be included in 
the concordance summaries 
All-cause Hospitalization  
• 
All-cause hospitalization events are defined to be hospital admissions recorded on the Hospitalization 
eCRF form with a hospitalization duration  24 hours. 
• 
Hospitalization rate (per year) across the study = number of all-cause hospitalization events / [follow-up 
time (days) / 365.25]. 
General Definitions 
• 
Time to event (days) = date of event – randomization date +1 
• 
Censored time (days) = censoring date – randomization date + 1 
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CV Safety Endpoints 
• 
First event person years = (cumulative total time to first event for subjects who have the event + 
cumulative total of censoring time for subjects without the event) / 365.25 
• 
First event incidence rate (per 100 person years) = (100 * number of subjects with at least 1 event) / first 
event person years 
• 
First event absolute rate difference (per 100 person years) = daprodustat incidence rate (per 100 person 
years) – rhEPO incidence rate (per 100 person years) 
 
Evaluation Time Periods for CV Endpoints 
Time Period for Follow-up of Cardiovascular Endpoints 
The period for capturing CV safety endpoints begins at randomization. The end of this time period is 
the date of study completion/withdrawal, with the exception that if a death has been reported in the 
clinical database after this time, then the death will be included in the analysis. 
 
Any endpoints that occurred before the start of this time period are considered to be prior to the time 
period for follow-up of cardiovascular safety events, and any endpoints that occurred after the end 
of this time period are considered to be post the time period for follow-up of cardiovascular safety 
endpoints. 
Time Period for Vital Status 
The period for capturing vital status begins at the date of randomization. The end of this time period 
is defined as follows: 
• For all subjects known to have died, use the date of death 
• For all subjects who complete the study, use the study completion date (see Section 14.6.1) 
• For all subjects who withdraw from the study, but vital status has been ascertained, and are 
known to have not died – use the latest date last known to be alive. If vital status has not been 
ascertained following study withdrawal, use the study withdrawal date 
 
Any endpoints that occurred before the start of this time period are considered to be prior to the time 
period for vital status, and any endpoints that occurred after the end of this time period are 
considered to be post the time period for vital status. 
Time Period for On-treatment Cardiovascular Endpoints 
The period for capturing on-treatment CV safety endpoint events begins at the treatment start date. 
The end of this time period is defined as follows: 
• For subjects whose last non-zero dose date is missing and who took study treatment, use date 
of study withdrawal/completion 
• For subjects continuing on study past the last non-zero dose date +28 days, use (last non-zero 
dose date + 28) 
• For subjects whose study withdrawal/completion date is on or before (last non-zero dose date 
+28), use date of study withdrawal/completion 
 
If the censoring date as defined above for on-treatment CV safety endpoints is after the censoring 
date as defined for the analysis during the time period for follow-up of CV safety endpoints, then use 
the censoring date for the analysis during the time period for follow-up of cardiovascular endpoints. 
 
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Evaluation Time Periods for CV Endpoints 
Any endpoints that occurred before the start of this time period are considered to be prior to the time 
period for on-treatment cardiovascular safety endpoints, and any endpoints that occurred after the 
end of this time period are considered to be post the time period for on-treatment cardiovascular 
safety endpoints. 
 
14.6.4.2. 
Blood Pressure Endpoints 
Blood Pressure Endpoints 
Pre- and Post- Dialysis BP 
• 
Unless otherwise specified, for summaries and analyses of BP values, the post-dialysis BP values will 
be used.  
End of Treatment BP Value 
• 
See Section 14.6.1 
Mean Arterial Pressure (MAP) 
• 
MAP = [(2*DBP)+SBP]/3 
Blood Pressure Exacerbations 
• 
BP exacerbations will be defined as (SBP  25 mmHg increase from baseline or SBP  180 mmHg or 
DBP  15 mmHg increase from baseline or DBP  110 mmHg) and grouped by type as follows: 
o BP exacerbations 
▪ 
SBP exacerbations 
• 
SBP  25 mmHg increase from baseline or  
• 
SBP  180 mmHg 
o SBP  180 mmHg and baseline SBP < 180 mmHg (including 
subjects with a missing baseline SBP) 
o SBP  180 mmHg and baseline SBP  180 mmHg 
▪ 
DBP exacerbations 
• 
DBP  15 mmHg increase from baseline or  
• 
DBP  110 mmHg 
o DBP  110 mmHg and baseline DBP < 110 mmHg (including 
subjects with a missing baseline DBP) 
o DBP  110 mmHg and baseline DBP  110 mmHg 
 
Notes:  
• 
BP values used to assess BP exacerbations must be on-treatment (see Section 14.4.1), unless 
otherwise specified. 
• 
BP values used to assess BP exacerbations can be scheduled or unscheduled. 
• 
For visits where BP is measured in triplicate, the average of the 3 BP values will be used to assess BP 
exacerbations. 
• 
BP exacerbations identified using post-dialysis BP values will be used in summaries and analyses of BP 
exacerbations, unless otherwise specified. 
• 
Subjects with multiple exacerbation events on the same calendar date for each type defined above are 
considered to have one exacerbation event for event counts by type. For example, a subject with a SBP 
and a DBP exacerbation on the same date would count in each of the SBP and DBP types, but would 
only count as one BP exacerbation event in the total BP exacerbation type. 
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Blood Pressure Endpoints 
Blood Pressure Exacerbation Event Date 
• 
Date of BP exacerbation 
On-Treatment BP Medication 
• 
See Section 14.4.1 for treatment states for concomitant medications. 
General 
• 
Censored time (days) =  last non-zero dose date– treatment start date + 1 
• 
BP exacerbation person years = (cumulative total of censoring time for all subjects) / 365.25 
• 
BP exacerbation event incidence rate (per 100 person years) = (100 * number of BP exacerbations) / BP 
exacerbation person years 
Changes in Blood Pressure Medications 
• 
No change: no new anti-hypertensive records since baseline (day before study treatment start date) 
and no change to anti-hypertensive records from baseline until date of visit while on study 
treatment. 
• 
Increase: addition of new anti-hypertensive records for any reason or a change with a primary 
reason for changing dose/frequency or stopping of ‘increased to…’ since baseline until date of visit 
while on study treatment 
• 
Decrease: discontinuation of an anti-hypertensive record with primary reason for change starting 
with “discontinued” or a change with a reason of ‘Decreased due to…’ since baseline until date of 
visit while on study treatment 
• 
Switch = change with a reason of ‘switched to another agent.’ since baseline until date of visit while 
on study treatment 
Cumulative Changes in Blood Pressure Medications 
• 
For the summary of cumulative changes excluding “Once only” and “PRN” records, cumulative 
change will be counted from the date of first study treatment to the Week 52 visit date while on 
study treatment. If a new anti-hypertensive medication is added during this time, it will be counted 
as one change. If the medication also stops during this period, then it will count as two changes 
(one change due to starting, and one change due to stopping). The cumulative number of changes 
will be calculated by adding up the changes for all records during this time period. The same steps 
will be repeated for the period starting from the date of first study treatment to End of Treatment 
• 
For the summary of cumulative changes for “Once only” records only, cumulative change will be 
counted from the date of first study treatment to the Week 52 visit date while on study treatment. 
Since “Once only” doses will have same start and stop dates, a new anti-hypertensive medication 
record during this period will be counted as one change. As “once only” doses are likely 
administered to control BP during dialysis, so they are considered part of a single titration regimen, 
hence multiple “once only” records on the same date will be counted as one change. The same 
steps will be repeated for the period starting from the date of first study treatment to End of 
Treatment 
 
14.6.4.3. 
Adverse Events 
Adverse Events 
AEs of Special Interest 
Adverse events of special interest are classified as follows: 
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Adverse Events 
• 
Death, myocardial infarction (MI), stroke, heart failure, thromboembolic events, thrombosis of vascular 
access 
• 
Thrombosis and/or tissue ischemia secondary to excessive erythropoiesis  
• 
Cardiomyopathy   
• 
Pulmonary artery hypertension 
• 
Cancer-related mortality and tumor progression and recurrence  
• 
Esophageal and gastric erosions 
• 
Proliferative retinopathy, macular edema, choroidal neovascularization  
• 
Exacerbation of rheumatoid arthritis 
 
• 
Worsening of hypertension 
 
Potential AESIs will be identified through a pre-defined terms of interest process in which pre-defined lists of 
AE preferred terms corresponding with each AESI will be used to identify events considered to be potential 
AESIs. Sites will be prompted via query to complete any necessary additional information for these AESIs in 
the eCRF. 
 
For the category of thrombosis and/or tissue ischemia secondary to excessive erythropoiesis, after the terms 
of interest list has been applied, the additional Hgb criteria described below will be applied to identify only 
those events that are considered to be secondary to excessive erythropoiesis as meeting the AESI definition 
for thrombosis and/or tissue ischemia secondary to excessive erythropoiesis. 
 
Thrombosis and tissue ischemia events will be considered to be secondary to excessive erythropoiesis if 
during the window of [AE start date – 30 days, AE start date +15 days] any one of the following 3 events 
occurs: 
• 
Any Hgb value  13 g/dL (measured pre-dialysis) 
• 
Hgb increase > 2 g/dL over 2 weeks (+1 week) 
o Note: for programming purposes, a +1 week window is applied, corresponding to 
the allowable visit window, to look for increases > 2 g/dL over 3 weeks 
• 
Hgb increase > 4 g/dL over 4 weeks (+1 week) 
o Note: for programming purposes, a +1 week window is applied, corresponding to 
the allowable visit window, to look for increases > 4 g/dL over 5 weeks. 
To identify Hgb increases that meet the increase criterion above, all Hgb values taken within [AE start date – 
58 days, AE start date + 15 days] will be identified. This corresponds to identifying Hgb values that occurred 
4 weeks before the [AE start date – 30 days, AE start date +15 days] window of interest. HemoCue Hgb and 
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central laboratory Hgb values will then be evaluated separately to identify increases, so that HemoCue and 
central laboratory Hgb values are not compared to each other to identify an increase. 
For HemoCue Hgb and separately for central laboratory Hgb values, if there is a Hgb value (or daily Hgb 
average) within the [AE start date – 30 days, AE start date +15 days] window and an earlier Hgb value (or 
daily Hgb average) that is within the larger [AE start date – 58 days, AE start date + 15 days] window, and 
the amount of time between the two Hgb values is: 
• 
Between 1 day and 3 weeks, inclusive, then the Hgb values will be compared to determine if there 
has been a Hgb increase > 2g/dL. 
• 
Between 15 days and 5 weeks, inclusive, then the Hgb values will be compared to determine if 
there has been a Hgb increase > 4g/dL. 
Unscheduled Hgb values will also be used in the assessment of secondary to excessive erythropoiesis 
following the guidance specified in Section 14.6.3 for unscheduled Hgb values and multiple Hgb values on 
the same date. 
Pre-defined Lists of AE Preferred Terms Corresponding with Each AESI 
Thrombosis and/or tissue ischemia secondary to excessive erythropoiesis 
• 
Narrow SMQ: Embolic and thrombotic events, arterial 
• 
Narrow SMQ: Embolic and thrombotic events, venous 
• 
Narrow SMQ: Embolic and thrombotic events, vessel type unspecified and mixed arterial and venous 
• 
Broad SMQ: Thrombophlebitis 
• 
Additional Preferred Terms:  
o Vascular access site occlusion 
o Stoma site ischaemia 
o Vascular access site complication 
o Subendocardial ischaemia 
o Retinal vascular occlusion 
o Uterine ischaemia 
o Administration site ischaemia 
o Vaccination site ischaemia 
o Anterior segment ischaemia 
o Vestibular ischaemia 
o Application site ischaemia 
o Cerebral small vessel ischaemic disease 
o Biliary ischaemia 
o Colitis ischaemic 
o Bone marrow ischaemia 
o Delayed ischaemic neurological deficit 
o Brain stem ischaemia 
o Hypoxic-ischeaemic encephalopathy 
o Catheter site ischaemia 
o Ischaemic cardiomyopathy 
o Cerebellar ischaemia 
o Ischaemic cerebral infarction 
o Cerebral ischaemia 
o Ischaemic contracture of the left ventricle 
o ECG signs of myocardial ischaemia 
o Ischaemic enteritis 
o Gastrointestinal ischaemia 
o Ischaemic gastritis 
o Graft ischaemia 
o Ischaemic heart disease prophylaxis 
o Hepatic ischaemia 
o Ischaemic hepatitis 
o Implant site ischaemia 
o Ischaemic limb pain 
o Infusion site ischaemia 
o Ischaemic mitral regurgitation 
o Injection site ischaemia 
o Ischaemic nephropathy 
o Intestinal ischaemia 
o Ischaemic neuropathy 
o Ischaemia 
o Ischaemic pancreatitis 
o Macular ischaemia 
o Ischaemic skin ulcer 
o Medical device site ischaemia 
o Ischaemic stroke 
o Myocardial ischaemia 
o Necrosis ischaemic 
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Adverse Events 
o Peripheral ischaemia 
o Ocular ischaemic syndrome 
o Renal ischaemia 
o Optic ischaemic neuropathy 
o Retinal ischaemia 
o Reversible ischaemic neurological deficit 
o Spinal cord ischaemia 
o Transient ischaemic attack 
 
Cardiomyopathy 
• 
Narrow SMQ: Cardiomyopathy 
Pulmonary artery hypertension 
• 
High Level Term: Pulmonary hypertensions 
• 
Additional Preferred Terms: 
o Right ventricular dilatation 
o Right ventricular enlargement 
o Right ventricular dysfunction 
o Right ventricular failure 
o Right ventricular ejection fraction decreased 
o Right ventricular hypertrophy 
 
Cancer-related mortality and tumor progression and recurrence 
• 
Narrow SMQs: 
o Biliary malignant tumours 
o Myelodysplastic syndrome 
o Biliary tumours of unspecified malignancy 
o Oropharyngeal neoplasms 
o Breast malignant tumours 
o Ovarian malignant tumours 
o Breast tumours of unspecified malignancy 
o Ovarian tumours of unspecified malignancy 
o Liver malignant tumours 
o Prostate malignant tumours 
o Liver tumours of unspecified malignancy 
o Prostate tumours of unspecified malignancy 
o Malignancy related conditions 
o Tumour lysis syndrome 
o Haematological malignant tumours 
o Skin malignant tumours 
o Non-haematolgoical malignant tumours 
o Skin tumours of unspecified malignancy 
o Haematological tumours of unspecified 
malignancy 
o Uterine and fallopian tube malignant tumours 
o Non-haematological tumours of unspecified 
malignancy 
o Uterine and fallopian tube tumours of 
unspecified malignancy 
o Malignant lymphomas 
 
 
• 
Additional Preferred Terms: 
o Aplastic anaemia 
o Pancytopenia 
o Cytopenia 
o Aplasia pure red cell 
 
Esophageal and gastric erosions 
• 
High Level Terms: 
o Duodenal ulcers and perforation 
o Oesophageal ulcers and perforation 
o Gastric ulcers and perforation 
o Peptic ulcers and perforation 
o Gastrointestinal ulcers and perforation, site 
unspecified 
 
• 
Additional Preferred Terms: 
o Haematemesis 
o Helicobacter duodenitis 
o Gastrointestinal haemorrhage 
o Helicobacter gastritis 
o Upper gastrointestinal haemorrhage 
o Melaena 
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Adverse Events 
 
Proliferative retinopathy, macular edema, choroidal neovascularization 
• 
Broad SMQ: Retinal disorders 
Exacerbation of rheumatoid arthritis 
• 
High Level Term: Rheumatoid arthropathies 
• 
Additional Preferred Terms: 
o Rheumatoid factor increased 
o Rheumatoid factor quantatative increased 
o Rheumatoid factor positive 
 
 
Worsening of hypertension 
• 
Narrow SMQ: Hypertension 
Blood Pressure Events 
BP events will be identified during the study via programmatic sweeps of AE and SAE terms entered into the 
eCRF (using the narrow SMQ for hypertension). AEs identified this way will require an additional BP 
Exacerbation eCRF page to be completed that characterizes the event as clinically significant and/or 
symptomatic.  
In addition, subjects that experience BP values that meet the following criteria at any visit will also be 
considered to have a BP event and be required to complete the Blood Pressure Exacerbation eCRF page: 
• 
SBP: an increase from baseline of  25 mmHg or SBP  180 mmHg 
• 
DBP: an increase from baseline of  15 mmHg or DBP  110 mmHg 
BP-related SAEs are those SAEs that have been identified via the BP Exacerbation eCRF page. 
General Definitions 
• 
Post-Randomization last contact date for censoring (subjects not having AE) will be defined as the 
study completion date. 
• 
Treatment emergent last contact date for censoring (subjects not having AE) will be defined as 
follows: 
o 1 day after the last non-zero dose date (last non-zero dose date + 1) for subjects not 
having treatment emergent AE and continuing on study past (last non-zero dose date + 1) 
o Last non-zero dose date for all other subjects 
• 
AE Patient Years: (Cumulative total of time to AE for subjects who have the AE + Cumulative total 
of censoring time for subjects without the AE) / 365.25 
o For treatment emergent AEs, the start date of the patient years value for each subject 
should be the treatment start date. 
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Adverse Events 
o For post-randomization AEs, the start date of the patient years value for each subject 
should be the randomization date. 
o For follow-up AEs, the start date of the patient years value for each subject should be two 
days after the last non-zero dose date (last non-zero dose date + 2). 
• 
Incidence Rate (per 100 patient years): (100 * Number of subjects with at least 1 AE) / AE person 
years 
• 
For the analysis of the time to AE onset/worsening, if the AE onset/worsening date is missing then 
the time to AE onset/worsening will be counted as 1 day. 
 
14.6.4.4. 
Laboratory Parameters 
Laboratory Parameters 
• 
If a laboratory value which is expected to have a numeric value for summary purposes, has a non-
detectable level reported in the database, where the numeric value is missing, but typically a character 
value starting with ‘<x’ or ‘>x’ (or indicated as less than x or greater than x in the comment field) is 
present, the number of significant digits in the observed values will be used to determine how much to 
add or subtract in order to impute the corresponding numeric value.  
o Example 1: 2 Significant Digits =  ‘< x ‘ becomes x – 0.01 
o Example 2: 1 Significant Digit   =  ‘> x’ becomes x + 0.1 
o Example 3: 0 Significant Digits = ‘< x’ becomes x – 1     
• 
If there is more than one laboratory value on the same date for the same laboratory test, then the 
laboratory values associated with scheduled visits will be used. Hgb summaries and analyses are an 
exception and should use the data handling conventions outlined in Section 14.6.3. 
• 
For purposes of flagging worst-case post baseline laboratory values: 
o If there are multiple scheduled values on the same day, or only multiple unscheduled 
values on the same day, then the average of the values on that day should be used for the 
purpose of determining the worst-case value. 
• 
The following will be used to convert laboratory values from SI units to conventional units [Iverson, 
2007]: 
• 
MCHC and Albumin: Divide the g/L value by 10 to get the g/dL value. 
• 
Albumin-corrected calcium: Divide the mmol/L value by 0.25 to get the mg/dL value. 
• 
Phosphate: Divide the mmol/L value by 0.323 to get the mg/dL value. 
• 
BUN: Divide the mmol/L value by 0.357 to get the mg/dL value. 
• 
Total cholesterol, LDL-C and HDL-C: Divide the mmol/L value by 0.0259 to get the mg/dL value. 
Normal Range Categories, PCI Criteria Categories and Worst Case Values 
• 
Normal range categories are: To Low, To Normal or No Change, To High 
• 
PCI criteria categories are: To Low, To w/in Range or No Change, To High 
• 
Subjects with a missing baseline value are to be assumed to have a normal/within range baseline value. 
• 
The determination of the worst case post baseline value takes into account both planned and 
unscheduled assessments. 
• 
Worst case can be either High or Low.  
o If a subject has both a decrease ‘To Low’ and an increase ‘To High’, then the subject is 
counted in both the ‘To Low’ and ‘To High’ categories.  
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Laboratory Parameters 
o If a subject was High at baseline and decreases to Low during the time interval, then the 
subject is counted in the ‘To Low’ category. Likewise, if a subject was low at baseline and 
increases to high during the time interval, then the subject is counted in the ‘To High’ 
category. 
o Subjects are only counted in the ‘To Normal or No Change’ or ‘To w/in Range or No 
Change’ category if their values are: 
▪ 
When using normal ranges: Normal at baseline and have no high and no low 
values; When using PCI ranges: Within range at baseline and have no high and 
no low values 
▪ 
High at baseline and do not change to low 
▪ 
Low at baseline and do not change to high 
 
14.6.4.5. 
Vital Signs 
Vital Signs 
Pre- and Post- Dialysis HR & Weight 
• 
Both pre- and post- dialysis HR & weight values will be measured 
• 
Unless otherwise specified, for summaries of HR & weight values, the post-dialysis HR & weight values 
will be used.  
• 
If there is more than one vital sign value on the same date for the same vital sign value, then the vital 
sign values associated with scheduled visits will be used. 
• 
If there are multiple values from a scheduled visit on the same date (e.g., BP is collected in triplicate at 
some visits), then the average of the scheduled values will be used. 
• 
For purposes of flagging worst-case post baseline vital sign values: 
o If there are multiple scheduled values on the same day, or only multiple unscheduled 
values on the same day, then the average of the values on that day should be used for the 
purpose of determining the worst-case value. 
 
14.6.4.6. 
COVID-19 
COVID-19  
Exposure Duration 
• 
For subjects who DO NOT experience the event, the exposure duration is calculated as: 
(treatment stop date or end date of time block, whichever occurs sooner – treatment start date or start 
date of time block, whichever occurs later + 1)/365.25 
• 
For subjects who DO experience the event, the exposure duration is calculated as: 
(start date of AE – treatment start date or start date of time block, whichever occurs later + 1)/365.25 
Exposure Adjusted Incidence Rate 
• 
Exposure adjusted incidence rate (rate/100 PY) = (number of subjects with the adverse event during the 
time block / total exposure duration across all subjects) * 100 
 
Time Periods  
• Pre COVID-19 pandemic period: the date of interests is prior to the country specific start date of 
COVID-19 pandemic measures. For example, for recruitment and demographic summaries, pre 
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COVID-19  
COVID-19 period is defined as the randomization date of the subject is prior to the country 
specific start date of COVID-19 pandemic measures. 
• During COVID-19 pandemic period: the date of interests is after the country specific start date 
of COVID-19 pandemic measures. For example, for recruitment and demographic summaries, 
during COVID-19 period is defined as the randomization date of the subject is after the country 
specific start date of COVID-19 pandemic measures. 
• There is currently no post COVID-19 period. 
 
 
14.6.5. 
Pharmacokinetic 
Daprodustat, M2, M3, M4, M5, M6, M13 
Tmax 
Time to reach Cmax, determined directly from the concentration-time data. 
Ctrough 
Post-baseline sample pre-dose concentration 
Cmax 
Maximum observed concentration of all five post-baseline PK samples, determined 
directly from the concentration-time data. 
 
14.6.6. 
Pharmacodynamic (and / or Biomarker) 
Pharmacokinetic Parameters 
• 
Maximum observed change from baseline in EPO 
• Maximum observed % change from baseline in VEGF 
 
14.6.7. 
Patient Reported Outcomes 
PGI-S 
General 
• 
The PGI-S is a 1-item questionnaire designed to assess a subject’s impression of disease severity on a 
5-point disease severity scale (absent, mild, moderate, severe, or very severe). 
• 
Scores range from - as follows: 
o 
o 
o 
o 
o 
 
PGI-C 
General 
• 
The PGI-C is a 1-item questionnaire designed to assess a subject’s impression of change in their 
anemia of CKD on a 7-point Likert-type response scale (very much improved, moderately improved, 
minimally improved, no change, minimally worse, moderately worse, or very much worse). 
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PGI-C 
General 
• 
Scores range from
to
as follows: 
o 
o 
o 
o 
o 
o 
o 
 
 
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Clinical Outcome Assessment 
data collection questionnaires 
or indices, which are 
protected by third party 
copyright laws and therefore 
have been excluded.
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14.7. 
Appendix 7: Premature Withdrawals & Handling of Missing 
Data 
14.7.1. 
Premature Withdrawals 
Element 
Reporting Detail 
General 
• 
Subject study completion (i.e. as specified in the protocol) was defined as completing 
all study periods of the study through the Week 52 visit, with the following exception: A 
participant who dies while on study is also considered to have completed the study. 
• 
Withdrawn subjects will not be replaced in the study. 
• 
All available data from participants who were withdrawn from the study will be listed 
and all available planned data will be included in summary tables and figures, unless 
otherwise specified.  
• 
Per protocol, subjects may prematurely discontinue study drug but are encouraged to 
remain in the study. 
14.7.2. 
Handling of Missing Data 
Element 
Reporting Detail 
General 
• 
Missing data occurs when any requested data is not provided, leading to blank fields 
on the collection instrument: 
o These data will be indicated by the use of a “blank” in subject listing displays. 
Unless all data for a specific visit are missing in which case the data is excluded 
from the table.  
o Answers such as “Not applicable” and “Not evaluable” are not considered to be 
missing data and should be displayed as such. 
Outliers 
• 
Any participants excluded from the summaries and/or statistical analyses will be 
documented along with the reason for exclusion in the clinical study report. 
14.7.2.1. 
Handling of Missing and Partial Dates 
Element 
Reporting Detail 
General 
Partial dates will be displayed as captured in subject listing displays. 
Concomitant 
Medications 
• 
Partial dates for any concomitant medications recorded in the CRF will be imputed 
using the following convention: 
o If the partial date is a start date, a '01' will be used for the day and 'Jan' will be 
used for the month 
o If the partial date is a stop date, a '28/29/30/31' will be used for the day (dependent 
on the month and year) and 'Dec' will be used for the month. 
• 
The recorded partial date will be displayed in listings. 
CV Safety 
Endpoint 
Events 
Discussed in Section 14.6.4 
 
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14.8. 
Appendix 8: Values of Potential Clinical Importance 
14.8.1. 
Laboratory Values 
Clinical Chemistry 
Laboratory Parameter 
Units 
Clinical Concern Range 
Low Flag 
High Flag 
Albumin  
g/L 
< 30 g/L 
> 55 g/L 
Aspartate Aminotransferase 
IU/L 
 
 3x ULRR 
Alanine Aminotransferase 
IU/L 
 
 3x ULRR 
Bilirubin (total) 
mol/L 
 
 2x ULRR 
Calcium (albumin-corrected ) 
mmol/L 
< 1.87 mmol/L 
> 2.56 mmol/L 
Phosphate 
mmol/L 
< 0.81 mmol/L 
> 1.77 mmol/L 
Potassium (serum) 
mmol/L 
> 0.5 mmol/L below 
LLRR 
> 1.0 mmol/L above 
ULRR 
 
Hematology 
Laboratory Parameter 
 
Units 
Clinical Concern Range 
Low Flag 
High Flag 
Platelet Count  
GI/L 
< 80 GI/L 
> 500 GI/L 
Leukocytes (white blood cell 
count)  
GI/L 
< LLRR 
> 5x ULRR 
Neutrophils 
GI/L 
< 0.5x LLRR 
 
Lymphocytes 
GI/L 
< 0.5x LLRR 
 
 
Iron Parameters 
Laboratory Parameter 
Units 
Clinical Concern Range 
Low Flag 
High Flag 
Ferritin 
ng/mL 
< 100 ng/mL 
> 800 ng/mL 
TSAT 
% 
<15% 
> 40% 
 
Other PCI Values 
Laboratory Parameter 
Units 
Clinical Concern Range 
Low Flag 
High Flag 
iPTH 
ng/L 
 
> 9x ULRR 
 
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14.8.2. 
ECG 
ECG Parameter 
Units 
Clinical Concern Range 
Lower 
Upper 
Absolute 
Absolute QTc Interval 
msec 
<300 ms 
>500 ms 
Absolute PR Interval 
msec 
<130 ms 
>250 ms 
Absolute QRS Interval 
msec 
 
>150 ms 
Change from Baseline 
Increase from Baseline QTc 
msec 
 
>60 ms 
14.8.3. 
Vital Signs 
Vital Sign Parameter 
(Absolute) 
Units 
Clinical Concern Range 
Lower 
Upper 
Systolic Blood Pressure 
mmHg 
 85 mmHg 
 180 mmHg 
Diastolic Blood Pressure 
mmHg 
 45 mmHg 
 110 mmHg 
Heart Rate 
bpm 
 40 bpm 
 110 bpm 
Notes: 
• 
At visits where BP and HR are assessed in triplicate, the average of the 3 values will be used to assess 
PCI criteria. 
• 
The post-dialysis BP and HR values will be used to assess PCI criteria, unless otherwise specified. 
 
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14.9. 
Appendix 9: Abbreviations & Trade Marks 
14.9.1. 
Abbreviations 
Abbreviation 
Description 
ADaM 
Analysis Data Model 
AE 
Adverse Event 
AESI 
Adverse Event of Special Interest 
ALT 
Alanine Aminotransferase 
Alt EP 
Alternative Evaluation Period 
ANCOVA 
Analysis of Covariance 
AST 
Aspartate Aminotransferase 
ATC 
Anatomical Therapeutic Chemical 
BID 
Twice a Day 
BMI 
Body Mass Index 
BP 
Blood Pressure 
BUN 
Blood Urea Nitrogen 
CDISC 
Clinical Data Interchange Standards Consortium 
CEC 
Clinical Endpoint Committee 
CHF 
Congestive Heart Failure 
CHMP 
Committee for Medicinal Products for Human Use 
CI 
Confidence Interval 
CIF 
Cumulative Incidence Function 
CKD 
Chronic Kidney Disease 
COVID 
Corona Virus Disease 
CMH 
Cochran-Mantel-Haenszel 
CSR 
Clinical Study Report 
CV 
Cardiovascular, Coefficient of Variation 
DBF 
Database Freeze 
DBP 
Diastolic Blood Pressure 
DBR 
Database Release 
DP 
Decimal Places 
DVT 
Deep Vein Thrombosis (DVT) 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Record Form 
EDW 
Estimated Dry Weight 
EP 
Evaluation Period 
EPO 
Erythropoietin  
ERI 
Erythropoietin Resistance Index 
ESA 
Erythropoiesis Stimulating Agent 
FDA 
Food and Drug Administration 
GSK 
GlaxoSmithKline 
HbA1c 
Hemoglobin A1c 
HD 
Hemodialysis 
HDL-C 
High Density Lipoprotein Cholesterol 
HF 
Heart Failure 
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Abbreviation 
Description 
Hgb 
Hemoglobin 
HR 
Heart Rate 
hsCRP 
High-sensitivity C-reactive Protein 
ICH 
International Conference on Harmonization 
IDMC 
Independent Data Monitoring Committee  
IDSL 
Integrated Data Standards Library 
IG 
Implementation Guide 
IP 
Investigational Product 
iPTH 
Intact Parathyroid Hormone 
IRT 
Interactive Response Technology 
ITT 
Intent-To-Treat 
IV 
Intravenous 
LDL-C 
Low Density Lipoprotein Cholesterol 
LLRR 
Lower Limit of Reference Range 
LS 
Least Squares 
MACE 
Major Adverse Cardiovascular Event 
MAP 
Mean Arterial Pressure 
MAR 
Missing at Random 
MCH 
Mean Corpuscular Hemoglobin 
MCHC 
Mean Corpuscular Hemoglobin Concentration 
MCV 
Mean Corpuscular Volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
MI 
Myocardial Infarction 
MMRM 
Mixed Model Repeated Measures 
PCI 
Potential Clinical Importance  
PD 
Pharmacodynamic 
PE 
Pulmonary Embolism 
PGI-C 
Patient Global Impression of Change 
PGI-S 
Patient Global Impression of Severity 
PK 
Pharmacokinetic 
PP 
Per Protocol 
PPD 
Pharmaceutical Product Development 
PRN 
As Needed 
PRO 
Patient Reported Outcome 
PT 
Preferred Term 
PY 
Patient Years 
QTcF 
Frederica’s QT Interval Corrected for Heart Rate 
QTcB 
Bazett’s QT Interval Corrected for Heart Rate 
RAP 
Reporting & Analysis Plan 
RBC 
Red Blood Cell 
RDW 
Red Cell Distribution Width 
RTF 
Rich Text Format 
SAC 
Statistical Analysis Complete 
SAE 
Serious Adverse Event 
SBP 
Systolic Blood Pressure 
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Abbreviation 
Description 
SC 
Subcutaneous 
SDAC 
Statistical Data Analysis Center 
SDTM 
Study Data Tabulation Model 
SE 
Standard Error 
SI 
System Independent 
SMQ 
Standard MedDRA Query 
SOC 
System Organ Class 
SP 
Stabilization Period 
SRT 
Safety Review Team 
TFL 
Tables, Figures & Listings  
TIBC 
Total Iron Binding Capacity 
TID 
Three Times A Day 
TSAT 
Transferrin Saturation 
UIBC 
unsaturated iron binding capacity 
ULN 
Upper Limit of Normal 
ULRR 
Upper Limit of Reference Range  
US 
United States 
VAT 
Vascular Access Thrombosis 
VEGF 
Vascular Endothelial Growth Factor 
WK 
Week 
14.9.2. 
Trademarks 
Trademarks of the GlaxoSmithKline 
Group of Companies 
 
Trademarks not owned by the 
GlaxoSmithKline Group of Companies 
None 
 
SAS 
 
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14.10. 
Appendix 10: List of Data Displays 
14.10.1. 
Data Display Numbering 
The following numbering will be applied for RAP generated displays: 
Section 
Tables 
Figures 
Study Population 
1.001 to 1.00n 
1.001 to 1.00n 
Efficacy 
2.001 to 2.00n 
2.001 to 2.00n 
Safety 
3.001 to 3.00n 
3.001 to 3.00n 
Patient Reported Outcome 
4.001 to 4.00n 
4.001 to 4.00n 
Pharmacokinetic  
5.001 to 5.00n 
5.001 to 5.00n 
Pharmacodynamic 
6.001 to 6.00n 
6.001 to 6.00n 
Section 
ICH Listings 
Non-ICH Listing 
Study Population 
1.001 to 1.00n 
1.00n+1 to 1.00x 
Efficacy 
2.001 to 2.00n 
2.00n+1 to 2.00x 
Safety 
3.001 to 3.00n 
3.001+1 to 3.00x 
Patient Reported Outcome 
4.001 to 4.00n 
4.00n+1 to 4.00x 
Pharmacokinetic  
5.001 to 5.00n 
5.00n+1 to 5.00x 
Pharmacodynamic 
6.001 to 6.00n 
6.00n+1 to 6.00x 
 
14.10.2. 
Mock Example Shell Referencing 
Example mock shells for data displays are developed as a separate document.  
Unless otherwise specified in the IDSL/Example Shell or Programming Notes’ column, 
TFL shell name will follow the format shown below: 
Section 
Figure 
Table 
Listing 
Study Population 
POP_Fn 
POP_Tn 
POP_Ln 
Efficacy 
EFF_Fn 
EFF_Tn 
EFF_Ln 
Safety 
SAFE_Fn 
SAFE_Tn 
SAFE_Ln 
Patient Reported Outcome 
PRO_Fn 
PRO_Tn 
PRO_Ln 
Pharmacokinetic 
PK_Fn 
PK_Tn 
PK_Ln 
Pharmacodynamic 
PD_Fn 
PD_Tn 
PD_Ln 
 
14.10.3. 
Deliverables 
Delivery 
Description 
SAC  
Final Statistical Analysis Complete 
 
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14.10.4. 
Study Population Tables 
Study Population Tables 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
Subject Disposition 
1.001 
All 
Randomized 
(ITT) 
POP_T5 
 
Summary of Subject Status and Reasons for Study Withdrawal 
 
 
Reasons for withdrawal will be 
presented in the order they are 
displayed on the eCRF 
 
Outcome of Adverse Events Which 
Led to Study Withdrawal is 
determined by first identifying the 
subjects with reason for study 
withdrawal as adverse event in the 
disposition records.  For those 
subjects, the adverse event records 
for each subject are checked to see 
if any of the adverse events that 
lead to withdrawal from study were 
fatal in the adverse event records.  
If any of the records are fatal then 
the subject will be counted in the 
fatal category in the display. 
SAC 
1.002 
All 
Randomized 
(ITT) 
POP_T5 
 
Summary of Subject Status and Reasons for Study Withdrawal 
by Region 
 
SAC 
1.003 
All 
Randomized 
(ITT) 
POP_T5 
 
Summary of Subject Status and Reasons for Study Withdrawal 
by Country 
 
SAC 
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Study Population Tables 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
1.004 
All 
Randomized 
(ITT) 
POP_T6 
 
Summary of Study Treatment Status and Reasons for 
Discontinuation of Study Treatment  
Regarding “Treatment 
Discontinuation Related to Study 
Treatment/Primary Reason” see 
IDSL Subject Disposition core 
standard section 1.1.3 for how to 
summarize those primary reasons 
for IP discontinuation that were 
related to the treatment. Note: For 
the primary reason of Adverse 
Event, the relatedness to study 
treatment is not collected and is 
instead to be determined from the 
adverse event records. 
Deaths with death date > Treatment 
End Date + 3 Days are considered 
“Did Not Die While Taking Study 
Treatment”. Deaths with death date 
≤ Treatment End Date + 3 Days are 
considered “Died While Taking 
Study Treatment”  
SAC 
1.005 
All 
Randomized 
(ITT) 
POP_T6 
 
Summary of Study Treatment Status and Reasons for 
Discontinuation of Study Treatment by Region 
 
SAC 
1.006 
All 
Randomized 
(ITT) 
POP_T6 
 
Summary of Study Treatment Status and Reasons for 
Discontinuation of Study Treatment by Country 
 
SAC 
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Study Population Tables 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
1.007 
Screened 
POP_T2 
Summary of Screening Status and Reasons for Screen Failure 
Reason(s) for Failure: see eCRF 
SCREEN FAILURE form. 
  
Note that the reasons for 
rescreened subjects who initially 
failed but subsequently enrolled are 
not included in the display. 
 
A subject may have more than one 
reason for screen failure. 
 
Since screen failures are not 
assigned to treatment groups, the 
display has only one subject-group 
column 
 
Used with Summary of Study 
Populations and Summary of 
Subject Disposition to create 
Consort diagram. 
SAC 
1.008 
Screened 
POP_T2.1 
Summary of All Screening Attempts and Associated Reasons for 
Screen Failure 
 
SAC 
1.009 
Enrolled 
POP_T8 
Summary of Number of Subject by Region, Country and Site ID 
Sort regions in RAP order, sort 
countries alphabetically, sort 
centers by decreasing total 
frequency (if ties, sort alphabetically 
by investigator) 
SAC 
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204837 
 
147 
 
Study Population Tables 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
1.010 
All 
Randomized 
(ITT) 
POP_T9 
Summary of Subject Contact at Week 52 
 
SAC 
1.011 
All 
Randomized 
(ITT) 
POP_T14 
Summary of Subject Survival Status 
 
SAC 
Protocol Deviation 
1.012 
All 
Randomized 
(ITT) 
POP_T15 
Summary of Important Protocol Deviations 
 
SAC 
1.013 
All 
Randomized 
(ITT) 
POP_T30 
Summary of Inclusion/Exclusion Criteria Deviations 
 
 
SAC 
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CONFIDENTIAL 
 
 
 
204837 
 
148 
 
Study Population Tables 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
Population Analysed 
1.014 
Screened 
POP_T1 
Summary of Study Populations  
Include all study population defined 
in the RAP 
 
The footnote should match the 
population definitions in the RAP 
 
The column ‘No Treatment’ is 
included if there are any subjects 
that did not get assigned a 
treatment, e.g., subjects who were 
screened but did not get enrolled 
into the study which includes both 
screening failures and subjects that 
were not used, enrolled subjects 
that did not get randomized or 
assigned treatment, a subject 
passed screening but withdrew 
consent prior to randomization. 
 
SAC 
1.015 
All 
Randomized 
(ITT) 
POP_T3 
Summary of Exclusions from the Per Protocol Population  
“Reason for Exclusion”: see RAP 
Section 14.1.1 
 
SAC 
1.016 
All 
Randomized 
(ITT) 
POP_T4 
Summary of Exclusions from the Safety Population 
 
SAC 
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CONFIDENTIAL 
 
 
 
204837 
 
149 
 
Study Population Tables 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
Demographic and Baseline Characteristics 
1.017 
All 
Randomized 
(ITT) 
POP_T16 
Summary of Demographic and Baseline Characteristics for the 
All Randomized (ITT) Population 
Mode of Dialysis at Screening: 
Although only Hemodialysis is 
expected at screening, other 
dialysis modes, such as peritoneal 
dialysis (PD), should be added and 
displayed here if captured in the 
eCRF at screening. 
SAC 
1.018 
All 
Randomized 
(ITT) 
POP_T16 
 
Summary of Demographic Characteristics among Subjects Who 
are Hyporesponders 
Remove the Alternate Definitions of 
rhEPO hypo-responsiveness 
section from this table 
SAC 
1.019 
Safety 
POP_T16 
 
Summary of Demographic and Baseline Characteristics for the 
Safety Population 
 
SAC 
1.020 
Enrolled 
POP_T17 
Summary of Age Ranges 
The column ‘No Treatment’ is 
included if there are any subjects 
that did not get assigned a 
treatment, e.g. a subject passed 
screening but withdrew consent 
prior to randomization 
SAC 
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CONFIDENTIAL 
 
 
 
204837 
 
150 
 
Study Population Tables 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
1.021 
All 
Randomized 
(ITT) 
POP_T18 
Summary of Race and Racial Combinations 
All five of the high level race 
categories and the two Asian 
subcategories must be appear on 
the display even if there are no 
subjects in a particular category, but 
combinations that do not exist in the 
data do not need to be represented. 
 
A subject will only be represented in 
a single category. A subject who 
selects a combination of races will 
be counted in a row within “MIXED 
RACE” or within the “MIXED ASIAN 
RACE”, not in each of the 
constituent terms. Therefore, the 
counts will add up to the total 
number of subjects with a response, 
and the percentages will add to 
100%. 
SAC 
1.022 
 
All 
Randomized 
(ITT) 
POP_T19 
Summary of Smoking History 
 
SAC 
1.023 
All 
Randomized 
(ITT) 
POP_T21 
 
Summary of Dialysis Modality and Frequency at Baseline, Week 
28 and Week 52 
  
 
SAC 
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CONFIDENTIAL 
 
 
 
204837 
 
151 
 
Study Population Tables 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
1.024 
All 
Randomized 
(ITT) 
POP_T22 
 
Summary of Dialysis Modality Changes 
 
 
SAC 
Prior and Concomitant Medications 
1.025 
All 
Randomized 
(ITT) 
POP_T20 
Summary of Medical Conditions 
 
.  
 
SAC 
1.026 
All 
Randomized 
(ITT) 
POP_T24 
Summary of Pre-treatment Medications by ATC Level and 
Ingredient 
Medications will be sorted in 
descending order of total incidence 
across treatment groups for the 
ATC level 1 and in descending 
order of total incidence for the 
ingredient within each ATC level. If 
the total incidence for any two or 
more ingredients is equal, the 
events will be presented in 
alphabetical order. 
SAC 
1.027 
All 
Randomized 
(ITT) 
POP_T24 
Summary of On-treatment Medications by ATC Level and 
Ingredient 
See above 
 
SAC 
1.028 
All 
Randomized 
(ITT) 
POP_T24 
Summary of Post-treatment Medications by ATC Level and 
Ingredient 
See above 
 
SAC 
1.029 
Safety 
POP_T25 
Summary of On-treatment Non-randomized ESA Use Instead of 
Study Treatment 
Based on the corresponding 
“Reason for Medication” in 
CONCOMITANT MEDICATIONS – 
rhEPO form 
SAC 
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CONFIDENTIAL 
 
 
 
204837 
 
152 
 
Study Population Tables 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
1.030 
Safety 
POP_T25 
Summary of On-treatment Non-randomized ESA Use in Addition 
to Study Treatment 
Based on the corresponding 
“Reason for Medication” in 
CONCOMITANT MEDICATIONS – 
rhEPO form 
SAC 
Exposure and Treatment Compliance 
1.031 
Safety 
POP_T26 
Summary of Extent of Exposure to Study Treatment 
 
 
SAC 
1.032 
Safety 
POP_T27 
Summary of Study Treatment Compliance Categories 
 
SAC 
1.033 
Safety 
POP_T28 
Summary of Study Treatment Compliance 
 
SAC 
COVID-19 Related Tables  
1.034 
All 
Randomized 
(ITT) 
COVID19 Shell 
6.1 
Summary of Subject Status and Reasons for Study Withdrawal 
by Relationship to COVID-19 Pandemic 
 
SAC 
1.035 
All 
Randomized 
(ITT) 
COVID19 Shell 
6.2 
Summary of Study Treatment Status and Reasons for 
Discontinuation of Study Treatment 
by Relationship to COVID-19 Pandemic 
 
SAC 
1.036 
All 
Randomized 
(ITT) 
COVID19 Shell 
6.5 
Summary of Significant Protocol Deviations by Relationship to 
COVID-19 Pandemic 
 
SAC 
1.037 
All 
Randomized 
(ITT) 
PAN 4 
Summary of Visits Impacted by COVID-19 Pandemic 
 
SAC 
 
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153 
 
14.10.5. 
Study Population Figures 
Study Population: Figures 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
 
1.001 
All 
Randomized 
(ITT) 
POP_F1.1 
Kaplan-Meier Plot of Time to Withdrawal from the Study 
Note: Change y-axis label to 
“Cumulative Proportion” 
 
SAC 
1.002 
All 
Randomized 
(ITT) 
POP_F1.1 
Kaplan-Meier Plot of Time to Early Treatment Discontinuation 
 
On-treatment death is counted as 
an event. 
SAC 
1.003 
All 
Randomized 
(ITT) 
POP_F1.1 
Kaplan-Meier Plot of Time to Early Treatment Discontinuation for 
Subjects Who Did Not Die While Taking Study Treatment 
 
On-treatment death will be 
censored 
 
See Section 6.2.1 and 14.6.2.2 for 
details.  
SAC 
1.004 
All 
Randomized 
(ITT) 
PAN8 
Proportion of Subject Visits Impacted by COVID-19 Pandemic 
 
SAC 
 
 
 
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154 
 
14.10.6. 
Efficacy Tables 
 
No. 
Population 
IDSL /  
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Primary Endpoint Point 
Primary Analyses of the Primary Efficacy Endpoint 
2.001 
All 
Randomized 
(ITT) 
EFF_T1 
Summary of Post-randomization Hemoglobin (g/dL) Data 
 
Observed Hgb used to calculate the 
summary statistics may include 
imputed HemoCue Hgb 
SAC 
2.002 
All 
Randomized 
(ITT) 
EFF_T1 
Summary of Post-randomization HemoCue Hemoglobin (g/dL) 
Data 
 
SAC 
2.003 
All 
Randomized 
(ITT) 
EFF_T1 
Summary of Post-randomization Central Laboratory Hemoglobin 
(g/dL) Data 
 
SAC 
2.004 
All 
Randomized 
(ITT) 
EFF_T2 
Summary of Post-randomization Hemoglobin (g/dL) Change 
from Baseline Data 
Change from based line derived 
based on observed data 
SAC 
2.005 
All 
Randomized 
(ITT) 
EFF_T45 
Summary of Post-randomization Observed and Imputed 
Hemoglobin (g/dL) Data 
Using the data used for the primary 
Hgb Analysis 
SAC 
2.006 
All 
Randomized 
(ITT) 
EFF_T46 
Summary of Post-randomization Observed and Imputed 
Hemoglobin (g/dL) Change from Baseline Data 
Using the data used for the primary 
Hgb Analysis 
SAC 
2.007 
All 
Randomized 
(ITT) 
EFF_T3 
Summary of Primary Analysis of Post-randomization 
Hemoglobin Change from Baseline to the Evaluation 
Period 
 
 
SAC 
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CONFIDENTIAL 
 
 
 
204837 
 
155 
 
 
No. 
Population 
IDSL /  
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
2.008 
All 
Randomized 
(ITT) 
EFF_T36 
Summary of Imputed Data in the Primary Post-randomization 
Hemoglobin Analysis 
 
SAC 
Supportive Analysis of While On-Treatment Evaluable Hemoglobin Data 
2.009 
All 
Randomized 
(ITT) 
EFF_T1 
Summary of Evaluable Hemoglobin (g/dL) Data 
 
SAC 
2.010 
All 
Randomized 
(ITT) 
EFF_T2 
Summary of Evaluable Hemoglobin (g/dL) Change from 
Baseline Data 
 
SAC 
2.011 
All 
Randomized 
(ITT) 
EFF_T37 
Summary of Missing Data in the Evaluable Hemoglobin Analysis 
 
SAC 
2.012 
All 
Randomized 
(ITT) 
EFF_T3 
Supportive Analysis: Summary of Analysis of Evaluable 
Hemoglobin (g/dL) Change from Baseline to the Evaluation 
Period 
 
SAC 
2.013 
All 
Randomized 
(ITT) 
EFF_T44 
Summary of Evaluable Hgb Exclusion by Visit 
 
SAC 
Per Protocol Population Analysis 
2.014 
Per Protocol 
EFF_T1 
Summary of Evaluable Hemoglobin (g/dL) Data for Subjects in 
the Per Protocol Population 
 
SAC 
2.015 
Per Protocol 
EFF_T2 
Summary of Evaluable Hemoglobin (g/dL) Change from 
Baseline Data for Subjects in the Per Protocol Population 
 
SAC 
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CONFIDENTIAL 
 
 
 
204837 
 
156 
 
 
No. 
Population 
IDSL /  
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
2.016 
Per Protocol 
EFF_T3 
Supportive Analysis: Summary of Analysis of Evaluable 
Hemoglobin (g/dL) Change from Baseline to the Evaluation 
Period for Subjects in the Per Protocol Population 
 
SAC 
Tipping Point (Multiple Imputation) Analysis of the Primary Efficacy Endpoint 
2.017 
All 
Randomized 
(ITT) 
EFF_T5 
Sensitivity Analysis: Multiple Imputation Tipping Point Analysis 
of Post-randomization Hemoglobin (g/dL) Change from Baseline 
to the Evaluation Period 
 
SAC 
2.018 
All 
Randomized 
(ITT) 
EFF_T5 
Supportive Analyses: Multiple Imputation Tipping Point Analysis 
of Evaluable Hemoglobin (g/dL) Change from Baseline During 
the Evaluation Period 
 
SAC 
Alternative EP (Week 28 to 36) Analysis 
2.019 
All 
Randomized 
(ITT) 
EFF_T3 
Supportive Analysis: Summary of Analysis of Post-
randomization Hemoglobin (g/dL) Change from Baseline to the 
Alternative Evaluation Period 
 
SAC 
2.020 
All 
Randomized 
(ITT) 
EFF_T3 
Supportive Analysis: Summary of Analysis of Evaluable 
Hemoglobin (g/dL) Change from Baseline to the Alternative 
Evaluation Period 
 
SAC 
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CONFIDENTIAL 
 
 
 
204837 
 
157 
 
 
No. 
Population 
IDSL /  
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Subgroup Analysis 
2.021 
All 
Randomized 
(ITT) 
EFF_T4 
Summary of Analysis of Post-randomization Hemoglobin 
Change from Baseline to the Evaluation Period by Subgroup 
In addition, a nominal one-sided 
non-inferiority p-value using a non-
inferiority margin of -0.75 g/dL and a 
nominal one-sided superiority p-
value will be generated for the 
difference between treatment 
groups for each level of the 
hyporesponder subgroup analyses 
of the primary Hgb endpoint, and 
will be added to shell EFF_T4 
SAC 
2.022 
All 
Randomized 
(ITT) 
EFF_T4 
Summary of Analysis of Evaluable Hemoglobin Change from 
Baseline to the Evaluation Period by Subgroup 
In addition, a nominal one-sided 
non-inferiority p-value using a non-
inferiority margin of -0.75 g/dL and a 
nominal one-sided superiority p-
value will be generated for the 
difference between treatment 
groups for each level of the 
hyporesponder subgroup analyses 
of the primary Hgb endpoint, and 
will be added to shell EFF_T4 
SAC 
Principal Secondary Endpoint 
Analysis of the Principal Secondary Endpoint 
2.023 
All 
Randomized 
(ITT) 
EFF_T7 
Summary of On-treatment Average Monthly IV Iron Dose to 
Week 52 
 
SAC 
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CONFIDENTIAL 
 
 
 
204837 
 
158 
 
 
No. 
Population 
IDSL /  
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
2.024 
All 
Randomized 
(ITT) 
EFF_T8 
Summary of Analysis of On-treatment Average Monthly IV Iron 
Dose During Day 1 to Week 52 
 
SAC 
Subgroup Analysis 
2.025 
All 
Randomized 
(ITT) 
EFF_T9 
Summary of Analysis of On-treatment Average Monthly IV Iron 
Dose During Day 1 to Week 52 by Subgroup 
 
SAC 
Supportive Analysis 
2.026 
All 
Randomized 
(ITT) 
EFF_T7 
Summary of Post-randomization Average Monthly IV Iron Dose 
to Week 52 
 
SAC 
2.027 
All 
Randomized 
(ITT) 
EFF_T8 
Supportive Analysis: Summary of Analysis of Post-
Randomization Average Monthly IV Iron Dose During Day 1 to 
Week 52 
 
SAC 
Secondary Endpoints 
Analysis of Secondary Endpoints 
2.028 
All 
Randomized 
(ITT) 
EFF_T10 
Summary of Analysis of Post-randomization Hemoglobin 
Change from Baseline at Week 52 
 
SAC 
2.029 
All 
Randomized 
(ITT) 
EFF_T10 
Summary of Analysis of Evaluable Hemoglobin Change from 
Baseline at Week 52 
 
SAC 
2.030 
All 
Randomized 
(ITT) 
EFF_T11 
Summary of Analysis of Post-randomization Hemoglobin 
Change from Baseline to Week 52 by Subgroup 
By region and hyporesponder  
SAC 
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CONFIDENTIAL 
 
 
 
204837 
 
159 
 
 
No. 
Population 
IDSL /  
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
2.031 
All 
Randomized 
(ITT) 
EFF_T11 
Summary of Analysis of Evaluable Hemoglobin Change from 
Baseline at Week 52 by Subgroup 
By region and hyporesponder 
SAC 
2.032 
All 
Randomized 
(ITT) 
EFF_T14 
Summary of Percentage of Time Hemoglobin Below, Within and 
Above the Analysis Range During the Evaluation Period using 
Evaluable Hemoglobin Values 
“m”: Subjects who have at least one 
evaluable Hgb value during the 
evaluation period. “n” is a subset of 
“m”, because there are additional 
rules to be included in the summary 
stat calculations. Three “m”s 
corresponding to the three 
categories should be the same 
value. Three “n”s corresponding to 
the three categories should also be 
the same value, because each 
subject contributes a % of time to 
each category.  
SAC 
2.033 
All 
Randomized 
(ITT) 
EFF_T15 
Summary of Analysis of Percentage of Time Hemoglobin Within 
the Analysis Range During the Evaluation Period using 
Evaluable Hemoglobin Values 
 
SAC 
2.034 
All 
Randomized 
(ITT) 
EFF_T16 
Summary of Percentage of Time Hemoglobin Below, Within and 
Above the Analysis Range During the Evaluation Period using 
Evaluable Hemoglobin Values by Subgroup 
By region and hyporesponder 
SAC 
2.035 
All 
Randomized 
(ITT) 
EFF_T17 
Summary of Analysis of Percentage of Time Hemoglobin Within 
the Analysis Range During the Evaluation Period using 
Evaluable Hemoglobin Values by Subgroup 
By region and hyporesponder 
SAC 
2.036 
All 
Randomized 
(ITT) 
EFF_T39 
Summary of Subjects with Mean Evaluation Period and End of 
Treatment Hemoglobin Below, Within and Above the Analysis 
Range using Evaluable Hemoglobin Values 
 
SAC 
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CONFIDENTIAL 
 
 
 
204837 
 
160 
 
 
No. 
Population 
IDSL /  
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
2.037 
All 
Randomized 
(ITT) 
EFF_T12 
Summary of Analysis of Hemoglobin Responders During the 
Evaluation Period using Evaluable Hemoglobin Values 
 
SAC 
2.038 
All 
Randomized 
(ITT) 
EFF_T13 
Summary of Analysis of Hemoglobin Responders During the 
Evaluation Period using Evaluable Hemoglobin Values by 
Subgroup 
By region and hyporesponder 
SAC 
2.039 
All 
Randomized 
(ITT) 
EFF_T18 
Summary of Subjects Meeting Rescue Evaluation Criteria and 
Subjects Rescued 
 
SAC 
2.040 
All 
Randomized 
(ITT) 
EFF_T19 
Summary of Analysis of Time to Permanently Stopping Study 
Treatment Due to Meeting Rescue Criteria 
 
SAC 
2.041 
All 
Randomized 
(ITT) 
EFF_T38 
Summary of Analysis of Time to Permanently Stopping Study 
Treatment Due to Meeting Rescue Criteria by Hyporesponder 
Subgroup 
 
SAC 
Exploratory Endpoints 
2.042 
All 
Randomized 
(ITT) 
EFF_T20 
Summary of Hemoglobin Values <7.5 or >=12.0 g/dL During the 
Evaluation Period Using Evaluable Central Laboratory 
Hemoglobin Values 
 
SAC 
2.043 
All 
Randomized 
(ITT) 
EFF_T20 
Summary of Hemoglobin Values <7.5 or >=12.0 g/dL During the 
Evaluation Period Using Evaluable HemoCue Hemoglobin 
Values 
 
SAC 
2.044 
All 
Randomized 
(ITT) 
EFF_T21 
Summary of Hemoglobin Increases Using Evaluable Central 
Laboratory Hemoglobin Values 
 
SAC 
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CONFIDENTIAL 
 
 
 
204837 
 
161 
 
 
No. 
Population 
IDSL /  
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
2.045 
All 
Randomized 
(ITT) 
EFF_T21 
Summary of Hemoglobin Increases Using Evaluable HemoCue 
Hemoglobin Values 
 
SAC 
2.046 
All 
Randomized 
(ITT) 
EFF_T21 
Summary of Hemoglobin Decreases Using Evaluable Central 
Laboratory Hemoglobin Values 
 
SAC 
2.047 
All 
Randomized 
(ITT) 
EFF_T21 
Summary of Hemoglobin Decreases Using Evaluable HemoCue 
Hemoglobin Values 
 
SAC 
2.048 
All 
Randomized 
(ITT) 
EFF_T22 
Summary of On-treatment Transferrin Saturation, Total Iron 
Binding Capacity, and Unsaturated Iron Binding Capacity by 
Visit 
 
SAC 
2.049 
All 
Randomized 
(ITT) 
EFF_T23 
Summary of On-treatment Change from Baseline in Transferrin 
Saturation, Total Iron Binding Capacity, and Unsaturated Iron 
Binding Capacity by Visit 
 
SAC 
2.050 
All 
Randomized 
(ITT) 
EFF_T40 
Summary of On-treatment Hepcidin, Ferritin, and Iron by Visit 
 
SAC 
2.051 
All 
Randomized 
(ITT) 
EFF_T41 
Summary of On-treatment Percent Change from Baseline in 
Hepcidin, Ferritin, and Iron by Visit 
 
SAC 
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CONFIDENTIAL 
 
 
 
204837 
 
162 
 
 
No. 
Population 
IDSL /  
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
2.052 
All 
Randomized 
(ITT) 
EFF_T24 
Summary of On-treatment Average Quarterly IV Iron Dose 
(mg/month) 
Subjects who are not using IV iron 
will be included, but with a 0mg 
dose. 
 
(1) calculate the total iron use for 
each quarter; (2) convert to monthly 
dose for each subject; (3) calculate 
summary statistics. 
SAC 
2.053 
All 
Randomized 
(ITT) 
EFF_T24 
Summary of On-treatment Average Quarterly IV Iron Dose 
(mg/month) for Subjects Using IV Iron 
Only include subjects that are using 
IV iron 
 
(1) calculate the total iron use for 
each quarter; (2) convert to monthly 
dose for each subject; (3) calculate 
summary statistics. 
SAC 
2.054 
All 
Randomized 
(ITT) 
EFF_T42 
Summary of On-treatment Iron Use by Quarter  
 
SAC 
2.055 
All 
Randomized 
(ITT) 
EFF_T24 
Summary of On-treatment Average Quarterly TSAT (%) 
 
SAC 
2.056 
All 
Randomized 
(ITT) 
EFF_T24a 
Summary of On-treatment Average Quarterly Ferritin (ug/L) 
 
SAC 
2.057 
All 
Randomized 
(ITT) 
EFF_T25 
Summary of Subjects Meeting Iron Management Criteria 
 
SAC 
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CONFIDENTIAL 
 
 
 
204837 
 
163 
 
 
No. 
Population 
IDSL /  
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
2.058 
All 
Randomized 
(ITT) 
EFF_T26 
Summary of Subjects who Reduced On-treatment Monthly IV 
Iron During the Evaluation Period Relative to Baseline 
Subjects who discontinued study 
treatment before EP will be 
excluded 
SAC 
2.059 
All 
Randomized 
(ITT) 
EFF_T27a 
Summary of On-treatment RBC or Whole Blood Transfusions 
During the Evaluation Period and by Week 52 
 
SAC 
2.060 
All 
Randomized 
(ITT) 
EFF_T27a 
Summary of On-treatment RBC or Whole Blood Transfusions 
During the Evaluation Period and by Week 52 and by 
Hyporesponder Status 
 
SAC 
2.061 
All 
Randomized 
(ITT) 
EFF_T19 
Summary of Analysis of Time to First Occurrence of On-
Treatment RBC or Whole Blood Transfusion  
 
SAC 
2.062 
All 
Randomized 
(ITT) 
EFF_T29 
Summary of Assigned Dose by Visit 
 
SAC 
2.063 
All 
Randomized 
(ITT) 
EFF_T30 
Summary of Categories of Assigned Dose by Visit for 
Daprodustat 
 
SAC 
2.064 
All 
Randomized 
(ITT) 
EFF_T31 
Summary of Categories of Assigned Dose by Visit for rhEPO 
 
SAC 
2.065 
All 
Randomized 
(ITT) 
EFF_T33 
Summary of Subjects with Dose Adjustments 
 
SAC 
2.066 
All 
Randomized 
(ITT) 
EFF_T33.1 
Summary of Subjects with Dose Adjustments by Day 1 
HemoCue Hemoglobin Category 
 
SAC 
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CONFIDENTIAL 
 
 
 
204837 
 
164 
 
 
No. 
Population 
IDSL /  
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
2.067 
All 
Randomized 
(ITT) 
EFF_T34 
Summary of Number of Dose Adjustments per Subject 
 
SAC 
2.068 
All 
Randomized 
(ITT) 
EFF_T35 
Summary of Time Dose Held for HemoCue Hemoglobin >=12 
g/dL 
 
SAC 
2.069 
All 
Randomized 
(ITT) 
EFF_T29 
Summary of Assigned Dose by Visit by Hyporesponder Status 
 
SAC 
2.070 
All 
Randomized 
(ITT) 
EFF_T30 
Summary of Categories of Assigned Dose by Visit for 
Daprodustat by Hyporesponder Status 
 
SAC 
2.071 
All 
Randomized 
(ITT) 
EFF_T31 
Summary of Categories of Assigned Dose by Visit for rhEPO by 
Hyporesponder Status 
 
SAC 
2.072 
All 
Randomized 
(ITT) 
EFF_T33 
Summary of Subjects with Dose Adjustments by Hyporesponder 
Status 
 
SAC 
2.073 
All 
Randomized 
(ITT) 
EFF_T34 
Summary of Number of Dose Adjustments per Subject by 
Hyporesponder Status 
 
SAC 
2.074 
All 
Randomized 
(ITT) 
EFF_T35 
Summary of Time Dose Held for HemoCue Hemoglobin >=12 
g/dL by Hyporesponder Status 
 
SAC 
2.075 
All 
Randomized 
(ITT) 
EFF_T29 
Summary of Assigned Dose by Visit by Region 
 
SAC 
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CONFIDENTIAL 
 
 
 
204837 
 
165 
 
 
No. 
Population 
IDSL /  
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
2.076 
All 
Randomized 
(ITT) 
EFF_T30 
Summary of Categories of Assigned Dose by Visit for 
Daprodustat by Region 
 
SAC 
2.077 
All 
Randomized 
(ITT) 
EFF_T31 
Summary of Categories of Assigned Dose by Visit for rhEPO by 
Region 
 
SAC 
2.078 
All 
Randomized 
(ITT) 
EFF_T33 
Summary of Subjects with Dose Adjustments by Region 
 
SAC 
2.079 
All 
Randomized 
(ITT) 
EFF_T34 
Summary of Number of Dose Adjustments per Subject by 
Region 
 
SAC 
2.080 
All 
Randomized 
(ITT) 
EFF_T35 
Summary of Time Dose Held for HemoCue Hemoglobin >=12 
g/dL by Region 
 
SAC 
2.081 
All 
Randomized 
(ITT) 
EFF_T29 
Summary of Assigned Dose by Visit by Race Group 
 
SAC 
2.082 
All 
Randomized 
(ITT) 
EFF_T30 
Summary of Categories of Assigned Dose by Visit for 
Daprodustat by Race Group 
 
SAC 
2.083 
All 
Randomized 
(ITT) 
EFF_T31 
Summary of Categories of Assigned Dose by Visit for rhEPO by 
Race Group 
 
SAC 
2.084 
All 
Randomized 
(ITT) 
EFF_T33 
Summary of Subjects with Dose Adjustments by Race Group 
 
SAC 
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CONFIDENTIAL 
 
 
 
204837 
 
166 
 
 
No. 
Population 
IDSL /  
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
2.085 
All 
Randomized 
(ITT) 
EFF_T34 
Summary of Number of Dose Adjustments per Subject by Race 
Group 
 
SAC 
2.086 
All 
Randomized 
(ITT) 
EFF_T35 
Summary of Time Dose Held for HemoCue Hemoglobin >=12 
g/dL by Race Group 
 
SAC 
2.087 
All 
Randomized 
(ITT) 
EFF_T29 
Summary of Assigned Dose by Visit by Baseline Weight Quartile 
 
SAC 
2.088 
All 
Randomized 
(ITT) 
EFF_T30 
Summary of Categories of Assigned Dose by Visit for 
Daprodustat by Baseline Weight Quartile 
 
SAC 
2.089 
All 
Randomized 
(ITT) 
EFF_T31 
Summary of Categories of Assigned Dose by Visit for rhEPO by 
Baseline Weight Quartile 
 
SAC 
2.090 
All 
Randomized 
(ITT) 
EFF_T33 
Summary of Subjects with Dose Adjustments by Baseline 
Weight Quartile 
 
SAC 
2.091 
All 
Randomized 
(ITT) 
EFF_T34 
Summary of Number of Dose Adjustments per Subject by 
Baseline Weight Quartile 
 
SAC 
2.092 
All 
Randomized 
(ITT) 
EFF_T35 
Summary of Time Dose Held for HemoCue Hemoglobin >=12 
g/dL by Baseline Weight Quartile 
 
SAC 
2.093 
All 
Randomized 
(ITT) 
EFF_T33 
Summary of Subjects with Dose Adjustments Excluding Periods 
of Dose Hold 
 
SAC 
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CONFIDENTIAL 
 
 
 
204837 
 
167 
 
 
No. 
Population 
IDSL /  
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
2.094 
All 
Randomized 
(ITT) 
EFF_T34 
Summary of Number of Dose Adjustments per Subject 
Excluding Periods of Dose Hold 
 
SAC 
2.095 
Pharmacoki
netic 
EFF_TED1 
Summarized Daprodustat Efficacy Dose Parameters for 
PK Population 
 
 
2.096 
Pharmacoki
netic 
EFF_TES1 
Summarized Daprodustat Efficacy Special Parameters for 
Full PK Population 
 
 
 
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CONFIDENTIAL 
 
 
 
204837 
 
168 
 
14.10.7. 
Efficacy Figures 
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CONFIDENTIAL 
 
 
 
204837 
 
169 
 
Efficacy: Figures 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Primary Efficacy Endpoint 
2.001 
All 
Randomized 
(ITT) 
EFF_F2.1 
 
Line Plot of Post-Randomization Hemoglobin Data by Visit 
 
 
SAC 
2.002 
All 
Randomized 
(ITT) 
EFF_F2.1 
 
Line Plot of Post-Randomization Hemoglobin Change from 
Baseline by Visit 
 
SAC 
2.003 
All 
Randomized 
(ITT) 
EFF_F2.2 
Forest Plot of Adjusted Mean Difference in Hemoglobin 
Change from Baseline to the Evaluation Period 
 
Excluding tipping point; including 
on-drug analysis, PP analysis and 
alternative EP (on and off treatment 
as well as evaluable). Display LS 
mean difference, associated two-
sided 95% CI and one-sided non-
inferiority p-value 
SAC 
2.004 
All 
Randomized 
(ITT) 
EFF_F2.1 
Line Plot of Evaluable Hemoglobin Data by Visit 
 
SAC 
2.005 
All 
Randomized 
(ITT) 
EFF_F2.1 
Line Plot of Evaluable Hemoglobin Change from Baseline by 
Visit   
 
SAC 
2.006 
Per Protocol 
EFF_F2.1 
Line Plot of Evaluable Hemoglobin Data by Visit for the Per-
Protocol Population 
 
SAC 
2.007 
Per Protocol 
EFF_F2.1 
Line Plot of Evaluable Hemoglobin Change from Baseline by 
Visit for the Per-Protocol Population   
 
SAC 
2.008 
All 
Randomized 
(ITT) 
EFF_F2.3 
Sensitivity Analysis: Tipping Point Analysis of Post-
Randomization Hemoglobin Change from Baseline to the 
Evaluation Period 
 
SAC 
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CONFIDENTIAL 
 
 
 
204837 
 
170 
 
2.009 
All 
Randomized 
(ITT) 
EFF_F2.3 
Supportive Analysis: Tipping Point Analysis of Evaluable 
Hemoglobin Change from Baseline to the Evaluation Period 
 
SAC 
2.010 
All 
Randomized 
(ITT) 
EFF_F2.4 
Forest Plot of Adjusted Means from the Analysis of Post-
Randomization Hemoglobin Change from Baseline to the 
Evaluation Period by Subgroup 
 
SAC 
2.011 
All 
Randomized 
(ITT) 
EFF_F2.4 
Forest Plot of Adjusted Means from the Analysis of Evaluable 
Hemoglobin Change from Baseline to the Evaluation Period by 
Subgroup 
 
SAC 
Principal Secondary Endpoint 
2.012 
All 
Randomized 
(ITT) 
POP_F1.2 
Box Plot of Summary of On-treatment Average Monthly IV Iron 
Dose to Week 52 
POP_F1.2 is a shell for Study 
Population 
SAC 
2.013 
All 
Randomized 
(ITT) 
POP_F1.2 
Box Plot of Summary of Post-randomization Average Monthly IV 
Iron Dose to Week 52 
POP_F1.2 is a shell for Study 
Population 
SAC 
2.014 
All 
Randomized 
(ITT) 
EFF_F2.4 
Forest Plot of Adjusted Treatment Differences of On-treatment 
Average Monthly IV Iron Dose (mg) to Week 52 by Subgroup 
 
SAC 
Secondary Efficacy Endpoints 
2.015 
All 
Randomized 
(ITT) 
POP_F1.1 
Kaplan-Meier Plot of Time to Stopping Study Treatment Due to 
Meeting Rescue Criteria 
POP_F1.1 is a shell for Study 
Population 
SAC 
2.016 
All 
Randomized 
(ITT) 
EFF_F2.1 
Line Plot of On-treatment Transferrin Saturation by Visit 
 
SAC 
2.017 
All 
Randomized 
(ITT) 
EFF_F2.1 
Line Plot of On-treatment Total Iron Binding Capacity by Visit 
 
SAC 
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CONFIDENTIAL 
 
 
 
204837 
 
171 
 
2.018 
All 
Randomized 
(ITT) 
EFF_F2.1 
Line Plot of On-treatment Hepcidin by Visit 
Log-transformed parameters 
SAC 
2.019 
All 
Randomized 
(ITT) 
EFF_F2.1 
Line Plot of On-treatment Ferritin by Visit 
Log-transformed parameters 
SAC 
2.020 
All 
Randomized 
(ITT) 
EFF_F2.1 
Line Plot of On-treatment Total Iron by Visit 
Log-transformed parameters 
SAC 
2.021 
All 
Randomized 
(ITT) 
EFF_F2.1 
Line Plot of On-treatment Change from Baseline in Transferrin 
Saturation by Visit 
 
SAC 
2.022 
All 
Randomized 
(ITT) 
EFF_F2.1 
Line Plot of On-treatment Change from Baseline in Total Iron 
Binding Capacity by Visit 
 
SAC 
2.023 
All 
Randomized 
(ITT) 
EFF_F2.1 
 
Line Plot of On-treatment Percent Change from Baseline in 
Hepcidin by Visit 
Log-transformed parameters 
SAC 
2.024 
All 
Randomized 
(ITT) 
EFF_F2.1 
Line Plot of On-treatment Percent Change from Baseline in 
Ferritin by Visit 
Log-transformed parameters 
SAC 
2.025 
All 
Randomized 
(ITT) 
EFF_F2.1 
Line Plot of On-treatment Percent Change from Baseline in Total 
Iron by Visit 
Log-transformed parameters 
SAC 
2.026 
All 
Randomized 
(ITT) 
EFF_F2.1 
Line Plot of On-treatment Average Quarterly IV Iron Dose  
 
SAC 
2.027 
All 
Randomized 
(ITT) 
EFF_F2.1 
Line Plot of On-treatment Average Quarterly IV Iron Dose for 
Subjects Receiving IV Iron 
 
SAC 
204837 | Statistical Analysis Plan   02 Sep 2020 | TMF-2094919 | 2.0


CONFIDENTIAL 
 
 
 
204837 
 
172 
 
2.028 
All 
Randomized 
(ITT) 
EFF_F2.6 
Stacked Bar Chart of On-treatment Iron Use by Quarter 
 
SAC 
2.029 
All 
Randomized 
(ITT) 
EFF_F2.1 
Line Plot of On-treatment Average Quartely TSAT 
 
SAC 
2.030 
All 
Randomized 
(ITT) 
EFF_F2.1 
Line Plot of On-treatment Average Quartely Ferritin 
 
SAC 
2.031 
All 
Randomized 
(ITT) 
EFF_F2.1 
Line Plot of Median Assigned Dose by Visit: Dapro and rhEPO 
Plot median dose with two Y-axes, 
Y1 for Dapro median dose and Y2 
for rhEPO median dose.  
SAC 
2.032 
All 
Randomized 
(ITT) 
EFF_F2.7 
Line Plot of Mean Evaluable Hemoglobin and Median Most 
Recent Dose by Visit: Dapro and rhEPO 
 
SAC 
2.033 
All 
Randomized 
(ITT) 
EFF_F2.5 
Stacked Bar Chart of Assigned Daprodustat Dose by Visit 
 
SAC 
2.034 
All 
Randomized 
(ITT) 
EFF_F2.5 
Stacked Bar Chart of Assigned rhEPO Dose by Visit 
 
SAC 
Exploratory Efficacy Endpoints 
2.035 
All 
Randomized 
(ITT) 
POP_F1.1 
Kaplan-Meier Plot of Time to First Occurrence of RBC or Whole 
Blood Transfusion During the Time Period for On-Treatment 
Cardiovascular Events 
POP_F1.1 is a shell for Study 
Population 
SAC 
2.036 
Pharmacoki
netic 
EF_FSP1 
Scatter plot of % Time Evaluable Hgb in Range during EP vs. 
Cmax/Avg Dose EP TIR 
 
SAC 
2.037 
Pharmacoki
netic 
EFF_FSP2 
 
Scatter plot of Mean Evaluable Hgb Change from Baseline 
during EP vs. Cmax/Avg Dose EP  
 
SAC 
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CONFIDENTIAL 
 
 
 
204837 
 
173 
 
 
 
 
14.10.8. 
Safety Tables 
Safety: Tables 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Secondary Safety Statistical Analyses: Blood Pressure 
3.001 
All 
Randomized 
(ITT) 
SAFE_T15 
Summary of On-Treatment Pre-Dialysis Blood Pressure 
Parameters by Visit  
 
SAC 
3.002 
All 
Randomized 
(ITT) 
SAFE_T15 
Summary of On-Treatment Post-Dialysis Blood Pressure 
Parameters by Visit  
 
SAC 
3.003 
All 
Randomized 
(ITT) 
SAFE_T15 
Summary of Post-Randomization Pre-Dialysis Blood Pressure 
Parameters by Visit 
On- and off-treatment BP values 
SAC 
3.004 
All 
Randomized 
(ITT) 
SAFE_T15 
Summary of Post-Randomization Post-Dialysis Blood Pressure 
Parameters by Visit 
On- and off-treatment BP values 
SAC 
2.038 
Pharmacoki
netic 
EFF_FSP3 
Scatter plot of % Time Evaluable Hgb in Range during EP vs. 
Avg Dose EP TIR  
 
SAC 
2.039 
Pharmacoki
netic 
EFF_FSP4 
Scatter plot of Mean Evaluable Hgb Change from Baseline 
during EP vs. Avg Dose 52 
 
SAC 
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CONFIDENTIAL 
 
 
 
204837 
 
174 
 
Safety: Tables 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
3.005 
All 
Randomized 
(ITT) 
SAFE_T16 
Summary of Change from Baseline in On-Treatment Pre-
Dialysis Blood Pressure Parameters by Visit 
 
SAC 
3.006 
All 
Randomized 
(ITT) 
SAFE_T16 
Summary of Change from Baseline in On-Treatment Post-
Dialysis Blood Pressure Parameters by Visit 
 
SAC 
3.007 
All 
Randomized 
(ITT) 
SAFE_T16 
Summary of Change from Baseline in Post-Randomization Pre-
Dialysis Blood Pressure Parameters by Visit 
On- and off-treatment BP values 
SAC 
3.008 
All 
Randomized 
(ITT) 
SAFE_T16 
Summary of Change from Baseline in Post-Randomization  
Post-Dialysis Blood Pressure Parameters by Visit 
On- and off-treatment BP values 
SAC 
3.009 
All 
Randomized 
(ITT) 
SAFE_T17 
Summary of Analysis of Change from Baseline to Week 52 in 
On-Treatment Blood Pressure Parameters Excluding the 
Stabilization Period 
MMRM 
Per RAP Section 8.1 the post-
dialysis BP values will be used. 
SAC 
3.010 
All 
Randomized 
(ITT) 
SAFE_T17 
Summary of Analysis of Change from Baseline to Week 52 in 
On-Treatment Blood Pressure Parameters Including the 
Stabilization Period 
MMRM 
Per RAP Section 8.1 the post-
dialysis BP values will be used. 
SAC 
3.011 
All 
Randomized 
(ITT) 
SAFE_T17 
Summary of Analysis of Change from Baseline to Week 52 in 
Post-Randomization Blood Pressure Parameters Excluding the 
Stabilization Period 
MMRM 
 
On- and off-treatment BP values 
 
Per RAP Section 8.1 the post-
dialysis BP values will be used. 
SAC 
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CONFIDENTIAL 
 
 
 
204837 
 
175 
 
Safety: Tables 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
3.012 
All 
Randomized 
(ITT) 
SAFE_T17 
Summary of Analysis of Change from Baseline to Week 52 in 
Post-Randomization Blood Pressure Parameters Including the 
Stabilization Period 
MMRM 
 
On- and off-treatment BP values 
 
Per RAP Section 8.1 the post-
dialysis BP values will be used. 
SAC 
3.013 
All 
Randomized 
(ITT) 
SAFE_T18 
Summary of Analysis of Change from Baseline to End of 
Treatment in On-Treatment Blood Pressure Parameters  
ANCOVA 
Per RAP Section 8.1 the post-
dialysis BP values will be used. 
SAC 
3.014 
All 
Randomized 
(ITT) 
SAFE_T19 
Summary of Analysis of On-Treatment Blood Pressure 
Exacerbation Events  
Based on post-dialysis BP 
SAC 
3.015 
All 
Randomized 
(ITT) 
SAFE_T21 
Summary of On-Treatment Blood Pressure Exacerbation Event 
 
SAC 
Exploratory Cardiovascular Safety Analyses 
3.016 
All 
Randomized 
(ITT) 
SAFE_T1 
Summary of First Occurrence of Adjudicated MACE during the 
Time Period for Follow-up of Cardiovascular Events 
 
SAC 
3.017 
All 
Randomized 
(ITT) 
SAFE_T2aa 
 
Summary of Analysis of First Occurrence of Adjudicated MACE 
during the Time Period for Follow-up of Cardiovascular Events 
 
SAC 
3.018 
All 
Randomized 
(ITT) 
SAFE_T3 
Summary of All Adjudicated MACE during the Time Period for 
Follow-up of Cardiovascular Events 
 
 
SAC 
204837 | Statistical Analysis Plan   02 Sep 2020 | TMF-2094919 | 2.0


CONFIDENTIAL 
 
 
 
204837 
 
176 
 
Safety: Tables 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
3.019 
All 
Randomized 
(ITT) 
SAFE_T1 
Summary of First Occurrence of Adjudicated MACE or 
Thromboembolic Events during the Time Period for Follow-up of 
Cardiovascular Events 
 
SAC 
3.020 
All 
Randomized 
(ITT) 
SAFE_T2ba 
Summary of Analysis of First Occurrence of Adjudicated MACE 
or Thromboembolic Events during the Time Period for Follow-up 
of Cardiovascular Events 
 
SAC 
3.021 
All 
Randomized 
(ITT) 
SAFE_T1 
Summary of First Occurrence of Adjudicated MACE or 
Hospitalization for Heart Failure during the Time Period for 
Follow-up of Cardiovascular Events 
 
SAC 
3.022 
All 
Randomized 
(ITT) 
SAFE_T2ba 
Summary of Analysis of First Occurrence of Adjudicated MACE 
or Hospitalization for Heart Failure during the Time Period for 
Follow-up of Cardiovascular Events 
 
SAC 
3.023 
All 
Randomized 
(ITT) 
SAFE_T1 
Summary of First Occurrence of Adjudicated MACE or 
Thromboembolic Events or Hospitalization for CHF during the 
Time Period for Follow-up of Cardiovascular Events 
 
SAC 
3.024 
All 
Randomized 
(ITT) 
SAFE_T2ba 
Summary of Analysis of First Occurrence of Adjudicated MACE 
or Thromboembolic Events or Hospitalization for CHF during the 
Time Period for Follow-up of Cardiovascular Events 
 
SAC 
3.025 
All 
Randomized 
(ITT) 
SAFE_T2ba 
Summary of Analysis of Adjudicated All-Cause Mortality during 
the Time Period for Vital Status 
 
SAC 
3.026 
All 
Randomized 
(ITT) 
SAFE_T2ba 
Summary of Analysis of Adjudicated CV Mortality during the 
Time Period for Follow-up of Cardiovascular Events 
 
SAC 
3.027 
All 
Randomized 
(ITT) 
SAFE_T2ba 
Summary of Analysis of First Occurrence of Adjudicated 
Myocardial Infarction (Fatal and Non-Fatal) during the Time 
Period for Follow-up of Cardiovascular Events 
 
SAC 
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CONFIDENTIAL 
 
 
 
204837 
 
177 
 
Safety: Tables 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
3.028 
All 
Randomized 
(ITT) 
SAFE_T2ba 
Summary of Analysis of First Occurrence of Adjudicated Stroke 
(Fatal and Non-Fatal) during the Time Period for Follow-up of 
Cardiovascular Events 
 
SAC 
3.029 
All 
Randomized 
(ITT) 
SAFE_T2ba 
Summary of Analysis of First Occurrence of Adjudicated CV 
Mortality or Non-fatal Myocardial Infarction during the Time 
Period for Follow-up of Cardiovascular Events 
 
SAC 
3.030 
All 
Randomized 
(ITT) 
SAFE_T7a 
Summary of All Adjudicated and Supportive Cardiovascular 
Safety Endpoints during the Time Period for Follow-up of 
Cardiovascular Events 
 
SAC 
3.031 
All 
Randomized 
(ITT) 
SAFE_T10 
Summary of All-cause Hospitalization during the Time Period for 
Follow-up of Cardiovascular Events 
 
SAC 
3.032 
All 
Randomized 
(ITT) 
SAFE_T58 
Summary of Primary Diagnosis at Discharge by System Organ 
Class and Lower Level Term for All-Cause Hospitalization 
During the Time Period for Follow-Up of Cardiovascular Events 
 
SAC 
3.033 
All 
Randomized 
(ITT) 
 
SAFE_T2ba 
Summary of Analysis of First Occurrence of All-cause 
Hospitalization during the Time Period for Follow-up of 
Cardiovascular Events 
 
SAC 
3.034 
All 
Randomized 
(ITT) 
SAFE_T42 
Summary of Adjudication Details of All-Cause Mortality During 
the Time Period for Vital Status 
Cause of Death: collected from 
DEATH form 
 
Based on the data from DCRI 
adjudication data transfer 
SAC 
3.035 
All 
Randomized 
(ITT) 
SAFE_T43 
Summary of Adjudication Details of All Myocardial Infarction 
Events During the Time Period for Follow-up of Cardiovascular 
Events 
Based on the data from DCRI 
adjudication data transfer 
SAC 
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CONFIDENTIAL 
 
 
 
204837 
 
178 
 
Safety: Tables 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
3.036 
All 
Randomized 
(ITT) 
SAFE_T44 
Summary of Adjudication Details of All Stroke Events During the 
Time Period for Follow-up of Cardiovascular Events 
Based on the data from DCRI 
adjudication data transfer 
SAC 
3.037 
All 
Randomized 
(ITT) 
SAFE_T45 
Summary of Adjudication Details of All Heart Failure Events 
During the Time Period for Follow-up of Cardiovascular Events 
Based on the data from DCRI 
adjudication data transfer 
SAC 
3.038 
All 
Randomized 
(ITT) 
SAFE_T46 
Summary of Adjudication Details of All Thromboembolic Events 
During the Time Period for Follow-up of Cardiovascular Events 
Based on the data from DCRI 
adjudication data transfer  
SAC 
3.039 
All 
Randomized 
(ITT) 
SAFE_T13 
Summary of Concordance Between Events Referred for 
Adjudication and Adjudicated Endpoint Events During the Time 
Period for Follow-up of Cardiovascular Events 
 
SAC 
Exploratory Safety Analyses: Relationship between Daprodustat Cmax/Dosing and MACE/Combined MACE-related Endpoint 
3.040 
Pharmacoki
netic 
 
SAFE_TSS1 
Summarized Daprodustat Safety Special Parameters for PK 
Population 
Please see RAP Section 8.2 
SAC 
3.041 
Pharmacoki
netic 
SAFE_TSD1 
Summarized Daprodustat Safety Dose Parameters for PK 
Population 
Please see RAP Section 8.2  
SAC 
3.042 
Pharmacoki
netic 
SAEF_TATD1 
Summary of Average TIW Daprodustat Dose by Subjects with 
and without On-treatment MACE 
Please see RAP Section 8.2  
SAC 
3.043 
Pharmacoki
netic 
SAEF_TATD1 
Summary of Average TIW Daprodustat Dose by Subjects with 
and without On-treatment MACE + Thromboembolic Events + 
Hospitalization for CHF 
Please see RAP Section 8.2  
SAC 
Exploratory Safety Analyses: BP and BP Medication Changes 
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CONFIDENTIAL 
 
 
 
204837 
 
179 
 
Safety: Tables 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
3.044 
All 
Randomized 
(ITT) 
SAFE_T22 
Summary of On-Treatment Blood Pressure Parameters Change 
from Baseline to Last Record Prior to First Change in Blood 
Pressure Medications  
Based on Post-dialysis BP 
SAC 
3.045 
All 
Randomized 
(ITT) 
SAFE_T23 
Summary of Number of On-Treatment Blood Pressure 
Medications per Subject per Visit 
See Section 8.2 for details about 
calculation of number of BP 
medications at baseline, end of 
treatment and other nominal visits.  
SAC 
3.046 
All 
Randomized 
(ITT) 
SAFE_T24 
Summary of Change from Baseline in Number of On-Treatment 
Blood Pressure Medications per Subject per Visit 
 
SAC 
3.047 
All 
Randomized 
(ITT) 
SAFE_T25 
Summary of Subjects with Changes from Baseline in On-
Treatment Blood Pressure Medications by Visit 
 
SAC 
3.048 
All 
Randomized 
(ITT) 
SAFE_T48 
Summary of Cumulative Changes in On-treatment Blood 
Pressure Medications at Week 52 
 
SAC 
3.049 
All 
Randomized 
(ITT) 
SAFE_T50 
Summary of Subjects with at Least One PRN Record of On-
Treatment Blood Pressure Medication Until Week 52 
 
SAC 
3.050 
All 
Randomized 
(ITT) 
SAFE_T 51 
Summary of Subjects on Any On-treatment Blood Pressure 
Medication at Any Time Until Week 52 
 
SAC 
Exploratory Safety Analyses: Lipid Parameters 
3.051 
All 
Randomized 
(ITT) 
SAFE_T26 
Summary of On-treatment Lipid Parameters by Visit  
Lipid parameters: Total Cholesterol, 
LDL-C, and HDL-C. 
SAC 
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CONFIDENTIAL 
 
 
 
204837 
 
180 
 
Safety: Tables 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
3.052 
All 
Randomized 
(ITT) 
SAFE_T27 
Summary of Percent Change from Baseline in On-treatment 
Lipid Parameters by Visit  
Lipid parameters: Total Cholesterol, 
LDL-C, and HDL-C. 
SAC 
Adverse Events (AEs) 
AESI 
3.053 
Safety 
SAFE_T29 
Summary of Characteristics of Treatment Emergent Adverse 
Event of Special Interest of Death, Myocardial Infarction, Stroke, 
Heart Failure, Thromboembolic Events, and Thrombosis of 
Vascular Access 
 
SAC 
3.054 
Safety 
SAFE_T29 
Summary of Characteristics of Treatment Emergent Adverse 
Event of Special Interest of Thrombosis and/or Tissue Ischemia 
Secondary to Excessive Erythropoiesis 
 
SAC 
3.055 
Safety 
SAFE_T29 
Summary of Characteristics of Treatment Emergent Adverse 
Event of Special Interest of Cardiomyopathy 
 
SAC 
3.056 
Safety 
SAFE_T29 
Summary of Characteristics of Treatment Emergent Adverse 
Event of Special Interest of Pulmonary Artery Hypertension 
 
SAC 
3.057 
Safety 
SAFE_T29 
Summary of Characteristics of Treatment Emergent Adverse 
Event of Special Interest of Cancer-related Mortality and Tumor 
Progression and Recurrence 
 
SAC 
3.058 
Safety 
SAFE_T29 
Summary of Characteristics of Treatment Emergent Adverse 
Event of Special Interest of Esophageal and Gastric Erosions 
 
SAC 
3.059 
Safety 
SAFE_T29 
Summary of Characteristics of Treatment Emergent Adverse 
Event of Special Interest of Proliferative Retinopathy, Macular 
Edema, Choroidal Neovascularization  
 
SAC 
3.060 
Safety 
SAFE_T29 
Summary of Characteristics of Treatment Emergent Adverse 
Event of Special Interest of Exacerbation of Rheumatoid Arthritis 
 
SAC 
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CONFIDENTIAL 
 
 
 
204837 
 
181 
 
Safety: Tables 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
3.061 
Safety 
SAFE_T29 
Summary of Characteristics of Treatment Emergent Adverse 
Event of Special Interest of Worsening of Hypertension 
 
SAC 
3.062 
Safety 
SAFE_T29 
Summary of Characteristics of Adverse Event of Special Interest 
of Death, Myocardial Infarction, Stroke, Heart Failure, 
Thromboembolic Events, and Thrombosis of Vascular Access 
during the Follow-up Period 
 
SAC 
3.063 
Safety 
SAFE_T29 
Summary of Characteristics of Adverse Event of Special Interest 
of Thrombosis and/or Tissue Ischemia Secondary to Excessive 
Erythropoiesis during the Follow-up Period 
 
SAC 
3.064 
Safety 
SAFE_T29 
Summary of Characteristics of Adverse Event of Special Interest 
of Cardiomyopathy during the Follow-up Period 
 
SAC 
3.065 
Safety 
SAFE_T29 
Summary of Characteristics of Adverse Event of Special Interest 
of Pulmonary Artery Hypertension during the Follow-up Period 
 
SAC 
3.066 
Safety 
SAFE_T29 
Summary of Characteristics of Adverse Event of Special Interest 
of Cancer-related Mortality and Tumor Progression and 
Recurrence during the Follow-up Period 
 
SAC 
3.067 
Safety 
SAFE_T29 
Summary of Characteristics of Adverse Event of Special Interest 
of Esophageal and Gastric Erosions during the Follow-up Period 
 
SAC 
3.068 
Safety 
SAFE_T29 
Summary of Characteristics of Adverse Event of Special Interest 
of Proliferative Retinopathy, Macular Edema, Choroidal 
Neovascularization during the Follow-up Period 
 
SAC 
3.069 
Safety 
SAFE_T29 
Summary of Characteristics of Adverse Event of Special Interest 
of Exacerbation of Rheumatoid Arthritis during the Follow-up 
Period 
 
SAC 
3.070 
Safety 
SAFE_T29 
Summary of Characteristics of Adverse Event of Special Interest 
of Worsening of Hypertension during the Follow-up Period 
 
SAC 
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CONFIDENTIAL 
 
 
 
204837 
 
182 
 
Safety: Tables 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
3.071 
Safety 
SAFE_T29 
Summary of Characteristics of Post-Randomization Adverse 
Event of Special Interest of Death, Myocardial Infarction, Stroke, 
Heart Failure, Thromboembolic Events, and Thrombosis of 
Vascular Access 
 
SAC 
3.072 
Safety 
SAFE_T29 
Summary of Characteristics of Post-Randomization Adverse 
Event of Special Interest of Thrombosis and/or Tissue Ischemia 
Secondary to Excessive Erythropoiesis 
 
SAC 
3.073 
Safety 
SAFE_T29 
Summary of Characteristics of Post-Randomization Adverse 
Event of Special Interest of Cardiomyopathy 
 
SAC 
3.074 
Safety 
SAFE_T29 
Summary of Characteristics of Post-Randomization Adverse 
Event of Special Interest of Pulmonary Artery Hypertension 
 
SAC 
3.075 
Safety 
SAFE_T29 
Summary of Characteristics of Post-Randomization Adverse 
Event of Special Interest of Cancer-related Mortality and Tumor 
Progression and Recurrence 
 
SAC 
3.076 
Safety 
SAFE_T29 
Summary of Characteristics of Post-Randomization Adverse 
Event of Special Interest of Esophageal and Gastric Erosions 
 
SAC 
3.077 
Safety 
SAFE_T29 
Summary of Characteristics of Post-Randomization Adverse 
Event of Special Interest of Proliferative Retinopathy, Macular 
Edema, Choroidal Neovascularization  
 
SAC 
3.078 
Safety 
SAFE_T29 
Summary of Characteristics of Post-Randomization Adverse 
Event of Special Interest of Exacerbation of Rheumatoid Arthritis 
 
SAC 
3.079 
Safety 
SAFE_T29 
Summary of Characteristics of Post-Randomization Adverse 
Event of Special Interest of Worsening of Hypertension 
 
SAC 
3.080 
Safety 
SAFE_T49 
Summary of Treatment Emergent Adverse Events of Special 
Interest by Preferred Term 
 
SAC 
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CONFIDENTIAL 
 
 
 
204837 
 
183 
 
Safety: Tables 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Adverse Events 
3.081 
Safety 
SAFE_T32 
Summary of All Treatment Emergent Adverse Events by System 
Organ Class and Preferred Term 
 
SAC 
3.082 
Safety 
SAFE_T32 
Summary of All Treatment Emergent Adverse Events by System 
Organ Class and Preferred Term by Age Group 
< 65 years, 65-<75 years, ≥75 
years. Add row on top of table to 
indicate subgroup level 
 
SAC 
3.083 
Safety 
SAFE_T32 
Summary of All Treatment Emergent Adverse Events by System 
Organ Class and Preferred Term by Gender 
Add row on top of table to indicate 
subgroup level 
SAC 
3.084 
Safety 
SAFE_T32 
Summary of All Treatment Emergent Adverse Events by System 
Organ Class and Preferred Term by Race Group 
American Indian or Alaskan Native, 
Asian, Black, Native Hawaiian or 
Other Pacific Islander, White, Mixed 
Race 
 
Add row on top of table to indicate 
subgroup level 
SAC 
3.085 
Safety 
SAFE_T32 
Summary of All Treatment Emergent Adverse Events by System 
Organ Class and Preferred Term by Weight Quartiles 
 
SAC 
3.086 
Safety 
SAFE_T33 
Summary of All Treatment Emergent Adverse Events by Overall 
Frequency by Age Group 
< 65 years, 65-<75 years, ≥75 
years. Add row on top of table to 
indicate subgroup level 
SAC 
3.087 
Safety 
SAFE_T33 
Summary of All Treatment Emergent Adverse Events by Overall 
Frequency by Gender 
Add row on top of table to indicate 
subgroup level 
SAC 
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CONFIDENTIAL 
 
 
 
204837 
 
184 
 
Safety: Tables 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
3.088 
Safety 
SAFE_T 33 
Summary of All Treatment Emergent Adverse Events by Overall 
Frequency by Race Group 
American Indian or Alaskan Native, 
Asian, Black, Native Hawaiian or 
Other Pacific Islander, White, Mixed 
Race 
Add row on top of table to indicate 
subgroup level 
SAC 
3.089 
Safety 
SAFE_T33 
Summary of All Treatment Emergent Adverse Events by Overall 
Frequency by Weight Quartiles 
 
SAC 
3.090 
Safety 
SAFE_T32 
Summary of All Post-Randomization Adverse Events by System 
Organ Class and Preferred Term 
 
SAC 
3.091 
Safety 
SAFE_T32 
Summary of All Adverse Events during the Follow-up Period by 
System Organ Class and Preferred Term 
 
SAC 
3.092 
Safety 
SAFE_T33 
Summary of Common (>=5%) Treatment Emergent Adverse 
Events by Overall Frequency 
 
SAC 
3.093 
Safety 
SAFE_T32 
Summary of All Treatment Emergent Drug-Related Adverse 
Events by System Organ Class and Preferred Term 
 
SAC 
3.094 
Safety 
SAFE_T33 
Summary of All Treatment Emergent Drug-Related Adverse 
Events by Overall Frequency 
 
SAC 
3.095 
Safety 
SAFE_T33 
Summary of Common (>=5%) Non-serious Treatment Emergent 
Adverse Events by Overall Frequency 
 
SAC 
3.096 
Safety 
SAFE_T34 
Summary of Common (>=5%) Non-serious Treatment Emergent 
Adverse Events by System Organ Class and Preferred Term 
(Number of Subjects and Occurrences) 
 
SAC 
3.097 
Safety 
SAFE_T32.1 
Summary of All Treatment Emergent Adverse Events by 
Maximum Intensity by System Organ Class and Preferred Term 
 
 
SAC 
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CONFIDENTIAL 
 
 
 
204837 
 
185 
 
Safety: Tables 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
3.098 
Safety 
SAFE_T32.1 
Summary of All Treatment Emergent Drug-Related Adverse 
Events by System Organ Class and Preferred Term and 
Maximum Intensity 
 
SAC 
Serious and Other Significant Adverse Events 
3.099 
Screened 
SAFE_T34 
Summary of Pre-Treatment Serious Adverse Events by System 
Organ Class and Preferred Term (Number of Subjects and 
Occurrences) 
 
SAC 
3.100 
Safety 
SAFE_T34 
Summary of Treatment Emergent Serious Adverse Events by 
System Organ Class and Preferred Term (Number of Subjects 
and Occurrences) 
 
SAC 
3.101 
Safety 
SAFE_T33 
Summary of Treatment Emergent Serious Adverse Events by 
Overall Frequency 
 
SAC 
3.102 
Safety 
SAFE_T34 
Summary of Serious Adverse Events during the Follow-up 
Period by System Organ Class and Preferred Term (Number of 
Subjects and Occurrences) 
 
SAC 
3.103 
Safety 
SAFE_T34 
Summary of Post-Randomization Serious Adverse Events by 
System Organ Class and Preferred Term (Number of Subjects 
and Occurrences) 
 
SAC 
3.104 
Safety 
SAFE_T34 
Summary of Treatment Emergent Drug-Related Serious 
Adverse Events by System Organ Class and Preferred Term 
(Number of Subjects and Occurrences) 
 
SAC 
3.105 
Safety 
SAFE_T33 
Summary of Treatment Emergent Drug-Related Serious 
Adverse Events by Overall Frequency 
 
SAC 
3.106 
Safety 
SAFE_T34 
Summary of Treatment Emergent Drug-Related Non-Serious 
Adverse Events by System Organ Class and Preferred Term 
(Number of Subjects and Occurrences) 
 
SAC 
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CONFIDENTIAL 
 
 
 
204837 
 
186 
 
Safety: Tables 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
3.107 
Safety 
SAFE_T33 
Summary of Treatment Emergent Drug-Related Non-Serious 
Adverse Events by Overall Frequency 
 
SAC 
3.108 
Safety 
SAFE_T32 
Summary of Treatment Emergent Adverse Events Leading to 
Permanent Discontinuation of Study Treatment or Withdrawal 
from the Study by System Organ Class and Preferred Term 
 
SAC 
3.109 
Safety 
SAFE_T33 
Summary of Treatment Emergent Adverse Events Leading to 
Permanent Discontinuation of Study Treatment or Withdrawal 
from the Study by Overall Frequency 
 
SAC 
3.110 
Safety 
SAFE_T34 
Summary of Treatment Emergent Fatal Serious Adverse Events 
by System Organ Class and Preferred Term (Number of 
Subjects and Occurrences) 
 
SAC 
3.111 
Safety 
SAFE_T33 
Summary of Treatment Emergent Fatal Serious Adverse Events 
by Overall Frequency 
 
SAC 
3.112 
Safety 
SAFE_T34 
Summary of Treatment Emergent Non-fatal Serious Adverse 
Events by System Organ Class and Preferred Term (Number of 
Subjects and Occurrences) 
 
SAC 
3.113 
Safety 
SAFE_T33 
Summary of Treatment Emergent Non-fatal Serious Adverse 
Events by Overall Frequency 
 
SAC 
3.114 
Safety 
SAFE_T34 
Summary of Treatment Emergent Drug-Related Fatal Serious 
Adverse Events by System Organ Class and Preferred Term 
(Number of Subjects and Occurrences) 
 
SAC 
3.115 
Safety 
SAFE_T60 
Summary of Treatment Emergent Serious Fatal and Non-Fatal 
Drug-Related Adverse Events by Overall Frequency 
 
SAC 
3.116 
Safety 
SAFE_T57 
Summary of Treatment Emergent Serious Adverse Events by 
System Organ Class and Preferred Term and Maximum 
Intensity 
 
SAC 
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CONFIDENTIAL 
 
 
 
204837 
 
187 
 
Safety: Tables 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
3.117 
Safety 
SAFE_T39 
Summary of On-Treatment Blood Pressure Related Events 
 
 
3.118 
Safety 
SAFE_T32 
Summary of Treatment Emergent Blood Pressure Related 
Serious Adverse Events 
 
SAC 
Laboratory: Chemistry  
3.119 
Safety 
SAFE_T15 
Summary of On-Treatment Chemistry Values by Visit 
 
SAC 
3.120 
Safety 
SAFE_T16 
Summary of On-Treatment Change from Baseline Chemistry 
Values by Visit 
 
SAC 
3.121 
Safety 
SAFE_T35 
Summary of Worst Case On-treatment Chemistry Results 
Relative to Normal Range Post-Baseline Relative to Baseline 
 
SAC 
3.122 
Safety 
SAFE_T36 
Summary of Worst Case On-treatment Chemistry Results 
Relative to Potential Clinical Importance (PCI) Criteria Post-
Baseline Relative to Baseline 
 
SAC 
Laboratory: Hematology 
3.123 
Safety 
SAFE_T15 
Summary of On-Treatment Hematology Values by Visit 
 
 
3.124 
Safety 
SAFE_T16 
Summary of On-Treatment Change from Baseline Hematology 
Values by Visit 
 
SAC 
3.125 
Safety 
SAFE_T35 
Summary of Worst Case On-treatment Hematology Results 
Relative to Normal Range Post-Baseline Relative to Baseline 
 
SAC 
3.126 
Safety 
SAFE_T36 
Summary of Worst Case On-treatment Hematology Results 
Relative to Potential Clinical Importance (PCI) Criteria Post-
Baseline Relative to Baseline 
 
SAC 
Laboratory: Other Laboratory Tests 
3.127 
Safety 
SAFE_T15 
Summary of On-treatment Other Laboratory Values by Visit 
 
 
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CONFIDENTIAL 
 
 
 
204837 
 
188 
 
Safety: Tables 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
3.128 
Safety 
SAFE_T16 
Summary of On-treatment Change from Baseline Other 
Laboratory Values by Visit 
 
SAC 
3.129 
Safety 
SAFE_T35 
Summary of Worst Case On-treatment Other Laboratory Results 
Relative to Normal Range Post-Baseline Relative to Baseline 
 
SAC 
3.130 
Safety 
SAFE_T36 
Summary of Worst Case On-treatment Other Laboratory Results 
Relative to Potential Clinical Importance (PCI) Criteria Post-
Baseline Relative to Baseline 
 
SAC 
3.131 
Safety 
SAFE_T36 
Summary of Worst Case On-treatment Iron Parameter Results 
Relative to Potential Clinical Importance (PCI) Criteria Post-
Baseline Relative to Baseline 
PCI for Ferritin and TSAT are 
provided in Section 14.8.1 
SAC 
3.132 
Safety 
SAFE_T36 
Summary of Worst Case Post-treatment Iron Parameter Results 
Relative to Potential Clinical Importance (PCI) Criteria Post-
Baseline Relative to Baseline 
PCI for Ferritin and TSAT are 
provided in Section 14.8.1 
SAC 
3.133 
Safety 
SAFE_T26 
Summary of On-treatment hsCRP by Visit  
 
SAC 
3.134 
Safety 
SAFE_T27 
Summary of Percent Change from Baseline in On-treatment 
hsCRP Parameters by Visit  
 
SAC 
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CONFIDENTIAL 
 
 
 
204837 
 
189 
 
Safety: Tables 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Laboratory: Hepatobiliary (Liver) 
3.135 
 Safety 
SAFE_T37 
Summary of Post-randomization Liver Monitoring/Stopping 
criteria Event  
 
SAC 
3.136 
 Safety 
SAFE_T38 
Summary of Post-randomization Hepatobiliary Laboratory 
Abnormalities 
 
 
SAC 
ECG 
3.137 
 Safety 
SAFE_TEG1 
Summary of ECG Findings  
“Clinically significant change from 
baseline” will be derived from eCRF 
ECG form 
SAC 
3.138 
Safety 
SAFE_TEG2 
Summary of Change from Baseline in ECG Values by Visit 
For all ECG parameters 
SAC 
3.139 
Safety 
SAFE_TEG10 
Summary of Maximum QTc Values Post-Baseline Relative to 
Baseline by Category 
Remove “QTcF Interval, Aggregate 
(msec)” if not reported 
SAC 
3.140 
Safety 
SAFE_TEG11 
Summary of Maximum Increase in QTc Values Post-Baseline 
Relative to Baseline by Category 
Remove “QTcF Interval, Aggregate 
(msec)” if not reported 
SAC 
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CONFIDENTIAL 
 
 
 
204837 
 
190 
 
Safety: Tables 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Vital Signs 
3.141 
Safety 
SAFE_T15 
Summary of Post-randomization Vital Signs by Visit 
 
Included both on-treatment and of-
treatment vital signs. 
 
Add “pre-dialysis” or “post-dialysis” 
for each vital sign parameter. For 
example: 
 
Weight (kg)  
(pre-dialysis) 
SAC 
3.142 
Safety 
SAFE_T16 
Summary of Change from Baseline in Post-randomization Vital 
Signs by Visit 
Included both on-treatment and of-
treatment vital signs. 
 
Add “pre-dialysis” or “post-dialysis” 
for each vital sign parameter. For 
example: 
 
Weight (kg)  
(pre-dialysis) 
SAC 
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CONFIDENTIAL 
 
 
 
204837 
 
191 
 
Safety: Tables 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
3.143 
Safety 
SAFE_T36 
Summary of Worst Case On-treatment Vital Sign Results 
Relative to Potential Clinical Importance (PCI) Criteria Post-
Baseline Relative to Baseline 
See IDSL Vital Sign Statistical 
Display Standards for programming 
notes. (Shell SAFE_T36 is 
equivalent to IDSL VS7) 
 
Based on post-dialysis vital signs. 
Add “post-dialysis” for each vital 
sign parameter. For example: 
 
SBP (mmHg)  
(post-dialysis) 
SAC 
3.144 
Safety 
SAFE_T36 
Summary of Worst Case Post-treatment Vital Sign Results 
Relative to Potential Clinical Importance (PCI) Criteria Post-
Baseline Relative to Baseline 
See IDSL Vital Sign Statistical 
Display Standards for programming 
notes. (Shell SAFE_T36 is 
equivalent to IDSL VS7) 
 
Based on post-dialysis vital signs. 
Add “post-dialysis” for each vital 
sign parameter. For example: 
 
SBP (mmHg)  
(post-dialysis) 
SAC 
3.145 
All 
Randomized 
(ITT) 
SAFE_T15  
Summary of Difference Between On-treatment Post-Dialysis 
Weight and Estimated Dry Weight by Visit  
 
SAC 
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CONFIDENTIAL 
 
 
 
204837 
 
192 
 
Safety: Tables 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
COVID-19 Impact on Safety Assessment 
3.146 
Safety 
PAN1 
Summary of COVID-19 Assessments for Subjects with COVID-
19 Adverse Events 
 
SAC 
3.147 
Safety 
PAN11 
Summary of Exposure Adjusted Incidence Rate for Common 
(>=5%) Adverse Events 
 
SAC 
3.148 
Safety 
PAN10 
Summary of Exposure Adjusted Incidence Rates of Adverse 
Events Over Time 
 
SAC 
3.149 
Safety 
PAN10 
Summary of Exposure Adjusted Incidence Rates of Adverse 
Events Over Time by Region 
 
SAC 
3.150 
Safety 
PAN10 
Summary of Exposure Adjusted Incidence Rates of Adverse 
Events Over Time by Country 
 
SAC 
3.151 
Safety 
PAN10 
Summary of Exposure Adjusted Incidence Rates of Adverse 
Events Over Time by Sex 
 
SAC 
3.152 
Safety 
PAN10 
Summary of Exposure Adjusted Incidence Rates of Adverse 
Events Over Time by Age 
 
SAC 
3.153 
All 
Randomized 
(ITT) 
SAFE_T1 
Summary of First Occurrence of Adjudicated COVID-19 MACE 
During the Time Period for Follow-Up of Cardiovascular Events 
 
SAC 
14.10.9. 
Safety Figures 
Safety: Figures 
No. 
Population 
IDSL / 
Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Secondary Safety Analyses 
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CONFIDENTIAL 
 
 
 
204837 
 
193 
 
Safety: Figures 
No. 
Population 
IDSL / 
Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
3.001 
All Randomized 
(ITT) 
EFF_F2.1 
Line Plot of On-treatment Pre-Dialysis Blood Pressure 
Parameters by Visit  
SBP, DPB, MAP 
EFF_F2.1 is a shell for efficacy 
SAC 
3.002 
All Randomized 
(ITT) 
EFF_F2.1 
Line Plot of On-treatment Post-Dialysis Blood Pressure 
Parameters by Visit  
SBP, DPB, MAP 
EFF_F2.1 is a shell for efficacy 
SAC 
3.003 
All Randomized 
(ITT) 
EFF_F2.1 
Line Plot of On-treatment Pre-dialysis Blood Pressure 
Parameters Change from Baseline by Visit 
SBP, DPB, MAP 
EFF_F2.1 is a shell for efficacy 
SAC 
3.004 
All Randomized 
(ITT) 
EFF_F2.1 
Line Plot of On-treatment Post-dialysis Blood Pressure 
Parameters Change from Baseline by Visit 
SBP, DPB, MAP 
EFF_F2.1 is a shell for efficacy 
SAC 
Exploratory Safety Analyses 
3.005 
All Randomized 
(ITT) 
POP_F1.1 
Kaplan-Meier Plot of Time to First Occurrence of Adjudicated 
MACE During the Time Period for Follow-up of Cardiovascular 
Events 
Please see Section 14.6.4.1 CV 
Safety Endpoints, Time Period for 
Follow-up of Cardiovascular 
Endpoints, regarding deaths 
reported after this time period 
 
POP_F1.1 is a shell for Study 
Population.  
SAC 
3.006 
Safety 
POP_F1.1 
Kaplan Meier Plot of Time to First Occurrence of Treatment 
Emergent Death, Myocardial Infarction, Stroke, Heart Failure, 
Thromboembolic Events, and Thrombosis of Vascular Access 
POP_F1.1 is a shell for Study 
Population 
SAC 
3.007 Pharmacokinetic 
SAFE_FBOX1 
Boxplot of Cmax/Dose at on-treatment MACE by subjects with 
or without on-treatment MACE 
 
SAC 
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CONFIDENTIAL 
 
 
 
204837 
 
194 
 
Safety: Figures 
No. 
Population 
IDSL / 
Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
3.008 Pharmacokinetic 
SAFE_FBOX1 
Boxplot of Cmax/Dose at on-treatment MACE + 
thromboembolic event + hospitalization for CHF by subjects 
with or without on-treatment MACE + thromboembolic event + 
hospitalization for CHF 
 
SAC 
3.009 Pharmacokinetic 
SAFE_FBOX2 
Boxplot of Average TIW Dose at on-treatment MACE by 
subjects with or without on-treatment MACE 
 
SAC 
3.010 
 
Pharmacokinetic 
SAFE_FBOX2 
Boxplot of Average TIW Dose at on-treatment MACE + 
thromboembolic event + hospitalization for CHF by subjects 
with or without on-treatment MACE + thromboembolic event + 
hospitalization for CHF 
 
SAC 
Adverse Events 
3.011 
Safety 
SAFE_F3.3 
Cumulative Incidence Function Plot of Time to First 
Occurrence of Treatment Emergent Thrombosis and/or Tissue 
Ischemia Secondary to Excessive Erythropoiesis  
 
SAC 
3.012 
Safety 
SAFE_F3.3 
Cumulative Incidence Function Plot of Time to First 
Occurrence of Treatment Emergent Cardiomyopathy 
 
SAC 
3.013 
Safety 
SAFE_F3.3 
Cumulative Incidence Function Plot of Time to First 
Occurrence of Treatment Emergent Pulmonary Artery 
Hypertension 
 
SAC 
3.014 
Safety 
SAFE_F3.3 
Cumulative Incidence Function Plot of Time to First 
Occurrence of Treatment Emergent Cancer-related Mortality 
and Tumor Progression and Recurrence 
 
SAC 
3.015 
Safety 
SAFE_F3.3 
Cumulative Incidence Function Plot of Time to First 
Occurrence of Treatment Emergent Esophageal and Gastric 
Erosions 
 
SAC 
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CONFIDENTIAL 
 
 
 
204837 
 
195 
 
Safety: Figures 
No. 
Population 
IDSL / 
Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
3.016 
Safety 
SAFE_F3.3 
Cumulative Incidence Function Plot of Time to First 
Occurrence of Treatment Emergent Proliferative Retinopathy, 
Macular Edema, Choroidal Neovascularization  
 
SAC 
3.017 
Safety 
SAFE_F3.3 
Cumulative Incidence Function Plot of Time to First 
Occurrence of Treatment Emergent Exacerbation of 
Rheumatoid Arthritis 
 
SAC 
3.018 
Safety 
SAFE_F3.3 
Cumulative Incidence Function Plot of Time to First 
Occurrence of Treatment Emergent Worsening of 
Hypertension 
 
SAC 
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CONFIDENTIAL 
 
 
 
204837 
 
196 
 
3.019 
Safety 
SAFE_F3.4 
Dot Plot for Treatment Emergent Adverse Events of Special 
Interest  
o The AESI table and 
corresponding plot should be 
consistent within a study and 
across the studies 
o Please use the order that we’re 
using for our individual AESI 
displays: 
 
0. Death, myocardial infarction, 
stroke, heart failure, 
thromboembolic events, and 
thrombosis of vascular access 
1. Thrombosis and/or tissue 
ischemia secondary to excessive 
erythropoiesis 
2. Cardiomyopathy 
3. Pulmonary artery hypertension 
4. Cancer-related mortality and 
tumor progression and recurrence 
5. Esophageal and gastric 
erosions 
6. Proliferative retinopathy, 
macular edema, choroidal 
neovascularization 
7. Exacerbation of rheumatoid 
arthritis 
8. Worsening of hypertension 
 
Relative Risk (RR) is unadjusted 
raw RR. 
SAC 
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CONFIDENTIAL 
 
 
 
204837 
 
197 
 
Safety: Figures 
No. 
Population 
IDSL / 
Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
3.020 
Safety 
SAFE_F3.4 
Dot Plot of Most Common (>=5%) Treatment Emergent 
Adverse Events 
 
SAC 
Laboratory 
3.021 
Safety 
SAFE_F3.6 
Scatter Plot of On-treatment Maximum vs. Baseline ALT 
 
 
3.022 
Safety 
SAFE_F3.7 
Scatter Plot of On-treatment Maximum ALT vs. Maximum 
Total Bilirubin 
 
SAC 
Vital Signs 
3.023 
Safety 
EFF_F2.1 
Line Plot of Difference Between On-treatment Post-dialysis 
Weight and Estimated Dry Weight by Visit 
EFF_F2.1 is a shell for efficacy 
SAC 
 
 
 
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14.10.10. Patient Reported Outcome Tables 
Patient Reported Outcome: Tables 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Patient Reported Outcome 
4.001 
All 
Randomized 
(ITT) 
PRO_T7 
Summary Statistics for On-Treatment PGI-S Scores 
 
SAC 
4.002 
All 
Randomized 
(ITT) 
PRO_T8 
Summary Statistics for the Change from Baseline in On-
Treatment PGI-S Scores 
 
SAC 
4.003 
All 
Randomized 
(ITT) 
PRO_T9 
Summary of Analysis of Change from Baseline in On-
Treatment PGI-S Scores 
 
SAC 
4.004 
All 
Randomized 
(ITT) 
PRO_T10 
Summary of Shifts from Baseline in On-Treatment PGI-S 
Categories 
 
SAC 
4.005 
All 
Randomized 
(ITT) 
PRO_T11 
Summary of On-Treatment PGI-C Categories 
 
SAC 
 
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14.10.11. Patient Reported Outcome Figures 
Patient Reported Outcome:: Figures 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Patient Reported Outcome 
4.001 
All 
Randomized 
(ITT) 
PRO_F5.3 
Stacked Bar Chart of the Percentage of Patients Reporting 
Each PGI-S Response at Baseline and On-treatment at Week 
8 
 
 
SAC 
4.002 
All 
Randomized 
(ITT) 
PRO_F5.3 
Stacked Bar Chart of the Percentage of Patients Reporting 
Each PGI-S Response at Baseline and On-treatment at Week 
12 
 
 
SAC 
4.003 
All 
Randomized 
(ITT) 
PRO_F5.3 
Stacked Bar Chart of the Percentage of Patients Reporting 
Each PGI-S Response at Baseline and On-treatment at Week 
28 
 
 
SAC 
4.004 
All 
Randomized 
(ITT) 
PRO_F5.3 
Stacked Bar Chart of the Percentage of Patients Reporting 
Each PGI-S Response at Baseline and On-treatment Week 52 
 
 
SAC 
 
 
 
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14.10.12. Pharmacokinetic Tables 
Pharmacokinetic: Tables 
No. 
Population 
IDSL /  
Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Pharmacokinetic Analysis: Drug Concentration Measures and PK Parameters 
5.001 
Pharmacokinetic 
PK_T1 
Summary of GSK1278863 and Metabolites Plasma 
Pharmacokinetic Concentration Time Data (ng/ml) by Dose 
Level 
 
SAC 
5.002 
Pharmacokinetic 
PK_T2 
Summary of GSK1278863 and Metabolites Plasma 
Pharmacokinetic Parameters by Dose Level 
 
SAC 
 
 
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14.10.13. Pharmacodynamic Tables 
Pharmacodynamic: Tables 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
6.001 
All 
Randomized 
(ITT) 
PD_T1 
Summary of Observed Erythropoietin (unit) by Visit and Sample 
Time 
 
SAC 
6.002 
All 
Randomized 
(ITT) 
PD_T2 
Summary of Erythropoietin (unit) Change from Baseline by Visit 
and Sample Time 
 
SAC 
6.003 
All 
Randomized 
(ITT) 
PD_T3 
Summary of Erythropoietin (unit) Maximum Observed Change 
from Baseline 
 
SAC 
6.004 
All 
Randomized 
(ITT) 
PD_T4 
Summary of Observed VEGF (unit) by Visit and Sample Time 
 
SAC 
6.005 
All 
Randomized 
(ITT) 
PD_T5 
Summary of VEGF (unit) Percent Change from Baseline by 
Visit and Sample Time 
 
SAC 
6.006 
All 
Randomized 
(ITT) 
PD_T6       
Summary of VEGF (unit) Maximum Observed Percent Change 
from Baseline 
 
SAC 
 
 
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14.10.14. ICH Listings 
ICH: Listings 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Subject Disposition 
1.001 
Screened 
POP_L1 
Listing of Reasons for Screen Failure 
Including the “specify” text, if any, 
associated with the reason term for 
SF 
 
SAC 
1.002 
All 
Randomize 
(ITT) 
POP_L3 
Listing of Reasons for Study Withdrawal 
Note that this listing should not 
include reasons for screen failure 
SAC 
1.003 
All 
Randomize 
(ITT) 
POP_L4 
Listing of Reasons for Study Treatment Discontinuation  
 
 
 
SAC 
1.004 
All 
Randomize 
(ITT) 
POP_L14 
Listing of Subjects for Whom the Treatment Blind was Broken 
If the reason for breaking the 
treatment blind is ‘Other’, then the 
listing should display ‘Other: text’, 
where text is the reason entered on 
the eCRF page. 
SAC 
1.005 
All 
Randomize 
(ITT) 
POP_L5 
Listing of Planned and Actual Treatments 
Data will be sorted and displayed 
by country, site ID then subject 
number. Investigator name will 
appear in the page header along 
with site ID. 
 
Please print one site per page for 
this listing so that the pages can be 
sent to each site 
SAC 
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ICH: Listings 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Protocol Deviations 
1.006 
All 
Randomized 
(ITT) 
POP_L6 
Listing of Important Protocol Deviations  
 
SAC 
1.007 
All 
Randomized 
(ITT) 
POP_L7 
Listing of Subjects with Inclusion/Exclusion Criteria Deviations 
 
SAC 
Populations Analysed 
1.008 
All 
Randomized 
(ITT) 
POP_L2 
 
Listing of Subjects Excluded from Per Protocol and Safety 
Populations 
 
SAC 
Demographic and Baseline Characteristics 
1.009 
All 
Randomized 
(ITT) 
POP_L8 
 
Listing of Selected Demographic and Baseline Characteristics 
 
SAC 
1.010 
All 
Randomized 
(ITT) 
POP_L 9 
 
Listing of Race 
 
SAC 
Prior and Concomitant Medications 
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ICH: Listings 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
1.011 
All 
Randomized 
(ITT) 
POP_L10 
Listing of Concomitant Medications  
 
This listing displays all data 
captured in the concomitant 
medications dataset, including 
medications used pre-, on- and 
post-treatment. 
 
Including anti-hypertensive, iron 
therapy, and rhEPO, which are 
collected in special conmed form 
SAC 
Exposure and Treatment Compliance 
1.012 
All 
Randomized 
(ITT) 
POP_L11 
Listing of Exposure Data 
 
SAC 
1.013 
All 
Randomized 
(ITT) 
POP_L11 
Listing of Exposure Data from Unblinded eCRF 
 
SAC 
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ICH: Listings 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Adverse Events 
3.001 
Safety 
SAFE_L3  
Listing of All Adverse Events 
 
SAC 
3.002 
Safety 
SAFE_L4 
Listing of Subject Numbers for Individual Adverse Events 
 
SAC 
3.003 
Safety 
SAFE_L5 
Listing of Relationship Between Adverse Event System Organ 
Classes, Preferred Terms, and Verbatim Term 
 
SAC 
3.004 
Screened 
SAFE_L3  
Listing of Pre-treatment Adverse Events 
 
SAC 
Serious and Other Significant Adverse Events 
3.005 
Safety 
SAFE_L6 
Listing of Reasons for Considering as a Serious AE  
 
SAC 
3.006 
Safety 
SAFE_L3 
Listing of AEs Leading to Premature Withdrawal from Study 
 
SAC 
3.007 
Safety 
SAFE_L3 
Listing of AEs Leading to Permanent Discontinuation of Study 
Treatment 
 
SAC 
3.008 
Safety 
SAFE_L3 
Listing of Fatal Serious AEs 
 
SAC 
3.009 
Safety 
SAFE_L3 
Listing of Non-fatal Serious AEs 
 
SAC 
3.010 
Safety 
SAFE_L3 
Listing of Other Significant AEs 
Please include the following 
footnote: Other significant AEs are 
non-fatal non-serious AEs resulting 
in an action taken with study 
treatment of either ‘dose 
interrupted/delayed’ or ‘dose 
reduced’. 
SAC 
Hepatobiliary (Liver) 
3.011 
Safety 
SAFE_L7 
Listing of Medical Conditions for Subjects with Liver Stopping 
Events 
 
SAC 
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ICH: Listings 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
3.012 
Safety 
SAFE_L8 
Listing of Substance Use for Subjects with Liver Stopping 
Events 
AESI shown under “Visit” is the 
eCRF form from which the 
substance use data are collected. 
For example, from the 
ESOPHAGEAL AND GASTRIC 
EROSIONS form, we can get the 
data on Average Number of 
Cigarettes/Day and Average 
Number of Units of Alcohol/week 
SAC 
All Laboratory 
3.013 
Safety 
SAFE_L9 
Listing of All Chemistry Data for Subjects with Abnormalities of 
Potential Clinical Concern 
Display “ALL” (pre-, on-, and post-
treatment) labs for a subject who 
experienced an value of potential 
clinical importance 
SAC 
3.014 
Safety 
SAFE_L9 
Listing of All Hematology Data for Subjects with Abnormalities 
of Potential Clinical Concern 
Display “ALL” (pre-, on-, and post-
treatment) labs for a subject who 
experienced an value of potential 
clinical importance 
SAC 
3.015 
Safety 
SAFE_L9 
Listing of All Other Laboratory Data for Subjects with 
Abnormalities of Potential Clinical Concern 
Display “ALL” (pre-, on-, and post-
treatment) labs for a subject who 
experienced an value of potential 
clinical importance 
SAC 
3.016 
Safety 
SAFE_L9 
Listing of All Chemistry Data 
 
SAC 
3.017 
Safety 
SAFE_L9 
Listing of All Hematology Data 
 
SAC 
3.018 
Safety 
SAFE_L9 
Listing of All Other Laboratory Data 
 
SAC 
3.019 
Safety 
 IDSL LB14 
Listing of Laboratory Data with Character Results 
 
SAC 
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ICH: Listings 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Vital Signs 
3.020 
Safety 
SAFE_L10 
Listing of All Vital Signs for Subjects with Post-Dialysis Values 
of Potential Clinical Importance 
Use post-dialysis vital signs to 
identify the subject with PCI, but 
the listing will include all vital signs 
(pre- on- or post-treatment, and 
both pre-dialysis and post-dialysis 
signs) 
SAC 
 
 
 
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14.10.15. Non-ICH Listing 
Non-ICH: Listings 
No. 
Population 
IDSL / 
Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Prior and Concomitant Medications 
1.014 All Randomized 
(ITT) 
POP_L12 
Listing of Prior and Concomitant ESA Medications  
Include all ESAs, prior and 
concomitant ESA,  
SAC 
Subject Disposition 
1.015 
Screened 
POP_L13 
Listing of Subjects Who Were Rescreened 
 
SAC 
COVID-19 Impacted Visits 
1.016 All Randomized 
(ITT) 
PAN7 
Listing of Visits Impacted by COVID-19 Pandemic 
 
SAC 
Efficacy 
2.001 
All Randomized 
(ITT) 
EFF_L1 
Listing of Hemoglobin Data 
 
SAC 
2.002 
All Randomized 
(ITT) 
EFF_L2 
Listing of On-treatment Average Monthly IV Iron Dose to 
Week 52 
 
SAC 
2.003 
Pharmacokinetic 
EFF_LED1 
Listing of Daprodustat Efficacy Dose Parameters 
 
SAC 
2.004 
Pharmacokinetic 
EFF_LES1 
Listing of Daprodustat Efficacy Special Parameters 
 
SAC 
Safety 
3.021 
All Randomized 
(ITT) 
SAFE_L1 
Listing of All Adjudicated MACE Events  
 
SAC 
3.022 
All Randomized 
(ITT) 
SAFE_L2 
Listing of Adjudicated All-Cause Mortality 
 
SAC 
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Non-ICH: Listings 
No. 
Population 
IDSL / 
Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
3.023 
All Randomized 
(ITT) 
 SAFE_L15 
Listing of Subjects Who Became Pregnant During the Study 
 
SAC 
3.024 
Pharmacokinetic 
SAFE_LSD1 
Listing of Daprodustat Safety Dose Parameters 
 
SAC 
3.025 
Pharmacokinetic 
SAFE_LSS1 
Listing of Daprodustat Safety Special Parameters 
 
SAC 
Pharmacokinetic  
5.001 
Pharmacokinetic 
PK_L1 
Listing of GSK1278863 and Metabolites Pharmacokinetic 
Plasma Concentration-Time Data 
 
SAC 
5.002 
Pharmacokinetic 
PK_L2 
Listing of GS1278863 and Metabolites Plasma 
Pharmacokinetic Parameters 
 
SAC 
 
 
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