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
Phase: PHASE3
Conditions: Anaemia
Sponsor: GlaxoSmithKline

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GlaxoSmithKline group of companies
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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.
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evaluate the efficacy, safety and pharmacokinetics of three-times weekly dosing of 
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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