A Phase 3 Randomized, Open-label (Sponsor-blind), Active-controlled, Parallel-group, Multi-center, Event Driven Study in Dialysis Subjects With Anemia Associated With Chronic Kidney Disease to Evaluate the Safety and Efficacy of Daprodustat Compared to Recombinant Human Erythropoietin, Following a Switch From Erythropoietin-stimulating Agents
Phase: PHASE3
Conditions: Anaemia, Aspergillosis, Allergic Bronchopulmonary
Sponsor: GlaxoSmithKline

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CONFIDENTIAL
The GlaxoSmithKline group of companies
200807
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TITLE PAGE
Division: Worldwide Development
Information Type: Protocol Amendment
Title:
A phase 3 randomized, open-label (sponsor-blind), active-
controlled, parallel-group, multi-center, event driven study in 
dialysis subjects with anemia associated with chronic kidney 
disease to evaluate the safety and efficacy of daprodustat 
compared to recombinant human erythropoietin, following a 
switch from erythropoietin-stimulating agents.
Short Title:
Anemia Studies in CKD: Erythropoiesis via a Novel PHI 
Daprodustat-Dialysis (ASCEND-D)
Compound Number:
GSK1278863
Development Phase:
IIIA
Effective Date:
30-JUL-2020
Protocol Amendment Number:  04
Copyright 2020 the GlaxoSmithKline group of companies.  All rights reserved.  
Unauthorised copying or use of this information is prohibited.

2015N226659_07
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Revision Chronology
GlaxoSmithKline
Document Number
Date
Version
2015N226659_00
2016-MAY-27
Original
2015N226659_01
2016-JUN-09
Republishing
2015N226659_02
2016-SEP-20
Amendment No. 1
Amendment 1 applies only to Austria, Belgium, Czech Republic, Denmark, Estonia, 
Germany, Hungary, Italy, Norway, Poland, Portugal, Romania, Spain, Sweden and the 
United Kingdom.

Text added to clarify when the end of the study will occur.

Removal of requirement to reduce ESA dose if Week -8 Hgb is >11.5 g/dL (study 
rationale and inclusion criteria).

Additional guidance added to iron management criteria

New exploratory objective to compare the effect of daprodustat to rhEPO on delayed 
graft function (DGF) after deceased donor kidney transplantation added.
2015N226659_03
2016-OCT-12
Amendment No. 2

Changes from country-specific Amendment 1 applied to global amendment

Country-specific requirements for France and Czech Republic added.

Section and 6 relating to darbepoetin alfa pre-filled syringe incidents, malfunctions 
and user errors. Section deleted as darbepoetin alfa pre-filled syringes are not subject 
to device reporting requirements.

Time and events Table 7 ‘Schedule of Assessments Year 1 to End of Study’
modified. Main changes include new timepoints at Run-in (Week -4) and Week 2 for 
collection of information related to iron therapy; new timepoint at Week 52 for 
Kt/Vurea assessment; and transfusions and kidney transplant added to prompt 
completion of page in eCRF.

Time and Events Table 8 ‘Schedule of Assessments for Patient Reported Outcomes, 
Genetics and Sub-studies’ modified. Main changes are changes to the ABPM sub-
study assessments including prompts for the end of the 44hr ABPM assessments and 
prompts for recording the times the subject awakens and goes to sleep during this 44 
hour ABPM period.

Time and events Table 9 ‘Schedule of Assessments for Subjects Permanently 
Discontinuing Randomized Treatment’ modified. Main changes include IRT system 
call removed at all visits except Early Treatment Discontinuation Visit and End of 
Study Visit; new timepoints for collection of information related to iron therapy, 
transfusions; and kidney transplant added to prompt completion of page in eCRF.

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
Text added to clarify those randomized to rhEPO who transition from HD to PD will 
change from epoetin alfa to darbepoetin alfa.  

Text relating to the timing of dialysis in relation to the study visit has been amended. 
The original text ‘For subjects receiving PD or home HD >3x/week, study visits 
must occur within 48 hours of their last dialysis session’ was inaccurate as PD is a 
daily treatment.

For the negatively adjudicated events in 200807, the reporting process has been 
updated and the investigator-reported term (not the adjudicator-reported term) will 
be used.

In addition to allowing a historical (last 6 months) kidney ultrasound to be used to 
assess entry criteria, a provision was added for a more sensitive imaging study (e.g., 
MRI, CT) to be used to assess entry criteria.

Other changes include minor wording changes for clarity, updating of section 
numbering and cross referencing, formatting changes and administrative changes. 
2015N226659_05
2017-OCT-05
Amendment No. 3

Added retest values for Hgb and TSAT to determine eligibility at Week -8.

Broadened exclusion to include participation in an interventional study with an 
investigational agent or device.

Removed option to have Early Treatment Discontinuation visit supersede the 
scheduled study visit.  

Provided guidance for those receiving HD two times a week who are randomized to 
the epoetin alfa arm and require three times a week epoetin alfa dosing.

Added a provision that in unexpected circumstances where the supply to the site is 
interrupted, then local standard of care for anemia management during this time 
period may be considered.  

Added new darbepoetin alfa dose strengths (not available in all countries).

Added direction regarding randomized treatment and study continuation for subjects 
who will be away from the research site for an extended period of time.

Clarified timeframe for iron management criteria.

Clarified “frequency of dialysis” inclusion criterion and valid study visit days by 
dialysis type. 

Clarified baseline dose for the purposes of the rescue algorithm for subjects switching 
from HD to PD who are randomized to rhEPO.

Shortened visit window for the Week 2 and 4 visits and clarified visit window for 
Week -4 and Day 1 visits.

Modified Time and Events Table 7 ‘Schedule of Assessments Year 1 to End of 
Study’.  Main changes include addition of Informed Consent activity; revised 
footnotes to remove Kt/V and URR measurement for daily HHD and allowance of 
extended timing to do Day 1 ECG and to do ultrasound and/or additional testing; 
more clarity around randomized treatment dispensing and compliance, including 
provisions for deferring dose changes till the next HD treatment; removed capture of 
rescue medications from unscheduled and early termination visits as rescue 
evaluation is triggered at scheduled visits; added footnote to clarify biomarkers will 
be stored for future analyses except if not permitted by IRB/EC or refused by subject; 

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addition of Argentina only pregnancy requirement; and removal of footnote at Week -
4 visit for only collecting SAEs related to study participation or a GSK product as it 
did not apply.

Modified Time and Events Table 8 ‘Schedule for Assessments for Patient Reported
Outcomes, Genetics and Sub-studies’ modified to add healthcare resource utilization 
data collection, to streamline ABPM assessments and to add timing for informed 
consent and additional eligible collection visits for PK sub-study.

Modified Time and Events Table 9 “Schedule of Assessments for Subjects 
Permanently Discontinuing Randomized Treatment” to remove capture of rescue 
medications (rescue evaluation is triggered at on-treatment scheduled visits), to add 
healthcare resource utilization data collection, and to complete ABPM assessments.

Added direction to see CEC Site Manual for full scope of reporting requirements.

Add clarifications for PD subjects as to how weight, blood pressure, and laboratory 
assessments are to be done.  

Clarified timing of assessments relative to dialysis for SBP, DBP, HR and laboratory 
assessments.

Added reminder for the ordering of assessments for blood pressure and that the over-
read of the Day 1 ECG is required to confirm eligibility. 

Updated PRO section to add healthcare resource utilization data being collected for 
completeness and updated endpoint labels for EQ-5D-5L & EQ-VAS.

Revised statistical section to change from two-sided testing at the 5% level to one-
sided testing at the 2.5% level; correct the comparator for the Null and Alternative 
hypotheses; to change significance levels to p-values; to add a more complete 
description of the adjustments to statistical model; to update hyporesponder analyses; 
and to add additional text regarding the interim analysis process.

Added exploratory endpoints around Hgb variability, iron parameters, transfusions, 
and dose adjustment scheme.

Edited Risk Assessment information to align with version 8 of the Investigator’s 
Brochure. 

Updated FSH level to confirm menopause.

Provision for possible adjustment to the Dose Adjustment Algorithm triggers for Hgb 
values 7.5 g/dL to <9.5 g//dL based on the review of blinded instream aggregate Hgb 
data.

Changes to ABPM sub-study to add atrial fibrillation/flutter screening, remove home 
BP monitoring, change from 44- to 24-hour APBM, change in time-point for 
assessment (from Week 28 to Week 16), and adjustments to objectives, endpoints and 
analysis. 

Clarified additional inclusion and added additional eligible visits to collect PK 
samples in PK sub-studies.

Other changes include spelling corrections or minor wording changes for clarity, 
formatting changes, a missing reference (epoetin alfa IV:SC conversion), and 
administrative changes.

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2015N226659_07
30-JUL-2020
Amendment No. 4

Revised MACE NI margin in order to align the NI margin with similar studies that 
have already compared the effects of HIF-PHIs on MACE versus rhEPO.

Revised target MACE as a result of the change to the non-inferiority margin.

Updated the analysis of the hemoglobin co-primary endpoint based on FDA feedback.

Updated terminology (i.e., use of ‘supportive’) to be consistent with ICH-E9 
addendum.

Multiplicity adjustment strategy updated from Hommel to Holm-Bonferroni based on 
FDA feedback.

Added AESI of worsening of hypertension to footnote (included in IB, version 10).

Edited Risk Assessment information to include worsening of hypertension.

Updated pregnancy reporting timelines to align with revised Sponsor timings.

1
From:
Sent:
Thursday, July 30, 2020 6:25 PM
To:
Subject:
FW: 200807-sponsign
 
 
From: Alex Cobitz 
  
Sent: Thursday, July 30, 2020 8:21 AM 
To:
Subject: RE: 200807-sponsign 
 
, 
 
                I approve the protocol amendment. 
 
                                Alex 
 
 
From:
 
Sent: Thursday, July 30, 2020 6:55 AM 
To: Alex Cobitz 
 
Subject: 200807-sponsign 
 
Dear Alex,  
 
To approve the clinical protocol indicated below, reply to this email and state your approval.  
 
PROTOCOL NUMBER: 200807  
DOCUMENT IDENTIFIER:  2015N226659_07 
AMENDMENT NUMBER: 04 
PROTOCOL TITLE: A phase 3 randomized, open-label (sponsor-blind), active-controlled, parallel-group, 
multi-center, event driven study in dialysis subjects with anemia associated with chronic kidney disease to 
evaluate the safety and efficacy of daprodustat compared to recombinant human erythropoietin, following a 
switch from erythropoietin-stimulating agents 
 
Name of Sponsor Signatory:  Alexander R. Cobitz, M.D., PhD 
 
Title of Sponsor Signatory: Clinical Development Lead  
  
 
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD

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MEDICAL MONITOR/SPONSOR INFORMATION PAGE
Medical Monitor/SAE Contact Information: 
As this is a multinational study medical monitor/SAE contact information will be 
provided as a separate document.
Sponsor Legal Registered Address: 
GlaxoSmithKline Research & Development Limited
980 Great West Road
Brentford
Middlesex, TW8 9GS
UK
PPD is the contract research organization for this study.
In some countries, the clinical trial sponsor may be the local GlaxoSmithKline Affiliate 
Company (or designee). If applicable, the details of the alternative sponsor and contact 
person in the territory will be provided to the relevant regulatory authority as part of the 
clinical trial application.   
IND Number:  101,291 
EudraCT: 2016-000541-31

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INVESTIGATOR PROTOCOL AGREEMENT PAGE
For protocol 200807 
I confirm agreement to conduct the study in compliance with the protocol, as amended by 
this protocol amendment.
I acknowledge that I am responsible for overall study conduct. I agree to personally 
conduct or supervise the described study.
I agree to ensure that all associates, colleagues and employees assisting in the conduct of 
the study are informed about their obligations. Mechanisms are in place to ensure that site 
staff receives the appropriate information throughout the study. 
Investigator Name:
Investigator Address:
Investigator Phone Number:
Investigator Signature
Date

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TABLE OF CONTENTS
PAGE
1.
PROTOCOL SYNOPSIS FOR STUDY 200807......................................................13
2.
INTRODUCTION....................................................................................................15
2.1.
Brief Background ........................................................................................15
2.2.
Study Rationale ..........................................................................................15
3.
OBJECTIVE(S) AND ENDPOINT(S) ......................................................................16
4.
STUDY DESIGN ....................................................................................................16
4.1.
Overall Design ............................................................................................16
4.2.
Type and Number of Subjects.....................................................................18
4.3.
Design Rationale ........................................................................................18
4.4.
Dose Justification........................................................................................19
4.4.1.
Daprodustat.................................................................................19
4.4.2.
Randomized Treatment Dose Adjustment Scheme......................19
4.5.
Benefit:Risk Assessment ............................................................................20
4.5.1.
Risk Assessment .........................................................................20
4.5.2.
Benefit Assessment.....................................................................20
4.5.3.
Overall Benefit:Risk Conclusion...................................................20
5.
SELECTION OF STUDY POPULATION AND WITHDRAWAL CRITERIA .............20
5.1.
Inclusion Criteria.........................................................................................21
5.2.
Exclusion Criteria........................................................................................22
5.3.
Screening/ Run-in Failures .........................................................................24
5.4.
Subject Retention .......................................................................................24
5.5.
Permanent Discontinuation of Randomized Treatment ...............................24
5.5.1.
Procedures for Subject Follow-up ................................................25
5.6.
Withdrawal from Study................................................................................25
5.6.1.
Withdrawal of Consent for Contact...............................................25
5.6.2.
Subjects Deemed Lost to Follow-up.............................................26
5.7.
Subject and Study Completion....................................................................26
6.
PLACEBO RUN-IN AND RANDOMIZED TREATMENT .........................................26
6.1.
Placebo Run-in and Randomized Treatment ..............................................26
6.2.
Randomized Treatment Assignment...........................................................27
6.3.
Randomized Treatment Starting Dose and Dose Adjustment .....................28
6.3.1.
Daprodustat Dosing Information ..................................................28
6.3.2.
rhEPO Dosing Information ...........................................................28
6.3.3.
Daprodustat and rhEPO Dose Adjustment Algorithm...................30
6.3.4.
Randomized Treatment Temporary Interruption...........................31
6.3.5.
Randomized Treatment Discontinuation ......................................31
6.4.
Blinding.......................................................................................................31
6.5.
Packaging and Labeling..............................................................................32
6.6.
Preparation/Handling/Storage/Accountability..............................................32
6.7.
Compliance with Randomized Treatment Administration ............................32
6.8.
Treatment of Randomized Treatment Overdose .........................................33
6.9.
Treatment after the End of the Study ..........................................................33
6.10.
Concomitant Medications and Non-Drug Therapies....................................33

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6.10.1.
Permitted Medications and Non-Drug Therapies..........................33
6.10.2.
Prohibited Medications and Non-Drug Therapies.........................33
6.11.
Standard of Care ........................................................................................34
6.11.1.
Iron Management Criteria ............................................................34
6.12.
Rescue Therapy .........................................................................................34
6.13.
Subjects Changing Dialysis Modality ..........................................................35
7.
STUDY ASSESSMENTS AND PROCEDURES .....................................................36
7.1.
Time and Events Table...............................................................................37
7.2.
Screening and Critical Baseline Assessments ............................................46
7.3.
Efficacy.......................................................................................................46
7.4.
Safety .........................................................................................................46
7.4.1.
Events Referred to the Clinical Events Committee.......................46
7.4.2.
Other CV Events..........................................................................47
7.4.3.
Adverse Events (AE) and Serious Adverse Events (SAEs)..........47
7.4.3.1.
Time period and Frequency for collecting AE 
and SAE information...................................................48
7.4.3.2.
Method of Detecting AEs and SAEs ...........................48
7.4.3.3.
Follow-up of AEs and SAEs........................................48
7.4.3.4.
Regulatory Reporting Requirements for SAEs............49
7.4.4.
Adverse Events of Special Interest ..............................................49
7.4.5.
Possible Suicidality Related Adverse Events ...............................49
7.4.6.
Pregnancy ...................................................................................50
7.4.7.
Height and Weight .......................................................................50
7.4.8.
Blood Pressure and Heart Rate ...................................................50
7.4.9.
Electrocardiogram (ECG).............................................................50
7.4.10.
Ultrasound ...................................................................................51
7.4.11.
Clinical Laboratory Assessments .................................................51
7.4.12.
Liver Chemistry Stopping Criteria ................................................52
7.4.12.1.
Randomized Treatment Restart..................................54
7.5.
Genetics .....................................................................................................54
7.6.
Storage Biomarkers....................................................................................55
7.7.
Patient Reported Outcomes........................................................................55
7.7.1.
Patient Global Impression of Severity (PGI-S) and Patient 
Global Impression of Change (PGI-C) .........................................55
7.7.2.
Health Related Quality of Life (SF-36) .........................................55
7.7.3.
Health Status (EQ-5D-5L & EQ-VAS) ..........................................56
8.
DATA MANAGEMENT ...........................................................................................56
9.
STATISTICAL CONSIDERATIONS AND DATA ANALYSES .................................56
9.1.
Hypotheses.................................................................................................57
9.1.1.
CV Safety (MACE) Co-Primary Hypothesis..................................57
9.1.2.
Hgb efficacy Co-Primary Hypothesis............................................57
9.2.
Sample Size Considerations.......................................................................58
9.2.1.
Sample Size Assumptions ...........................................................58
9.2.2.
Sample Size Sensitivity................................................................59
9.2.3.
Sample Size Re-estimation or Adjustment...................................60
9.3.
Data Analysis Considerations .....................................................................60
9.3.1.
Analysis Populations....................................................................60
9.4.
Key Elements of Analysis Plan ...................................................................60
9.4.1.
Primary Analyses.........................................................................60

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9.4.1.1.
Primary CV Safety Analysis (co-primary)....................60
9.4.1.2.
Primary Efficacy Analysis (co-primary) .......................61
9.4.2.
Secondary Analyses ....................................................................62
9.4.2.1.
Principal Secondary Analyses ....................................62
9.4.2.2.
Analysis Patient Reported Outcomes .........................62
9.4.2.3.
Safety Analyses..........................................................62
9.4.3.
Multiplicity Strategy......................................................................63
9.4.4.
Covariates and Subgroups of Interest..........................................63
9.4.5.
Interim Analysis ...........................................................................65
10. STUDY GOVERNANCE CONSIDERATIONS........................................................66
10.1.
Posting of Information on Publicly Available Clinical Trial Registers............66
10.2.
Regulatory and Ethical Considerations, Including the Informed 
Consent Process ........................................................................................66
10.3.
Quality Control (Study Monitoring) ..............................................................67
10.4.
Quality Assurance.......................................................................................67
10.5.
Study and Site Closure ...............................................................................67
10.6.
Records Retention......................................................................................68
10.7.
Provision of Study Results to Investigators, Posting of Information 
on Publically Available Clinical Trials Registers and Publication .................68
10.8.
Review Committees....................................................................................69
10.8.1.
Independent Data Monitoring Committee.....................................69
10.8.2.
Clinical Events Committee ...........................................................69
10.8.3.
Executive Steering Committee.....................................................69
10.8.4.
Steering Committee.....................................................................69
10.8.5.
National Leader Committee .........................................................70
11. REFERENCES.......................................................................................................71
12. APPENDICES........................................................................................................72
12.1.
Appendix 1: Abbreviations and Trademarks................................................72
12.2.
Appendix 2: Secondary and Exploratory Objectives/ Endpoints..................75
12.3.
Appendix 3: Stratification by Region- Region Groupings.............................78
12.4.
Appendix 4: Risk Assessment.....................................................................79
12.5.
Appendix 5: Female Eligibility Criteria.........................................................90
12.6.
Appendix 6: Randomized Treatment Dose Adjustment Schemes ...............92
12.7.
Appendix 7: Definition of and Procedures for Recording, Evaluating, 
Follow-Up and Reporting of Adverse Events...............................................93
12.7.1.
Definition of Adverse Events........................................................93
12.7.2.
Definition of Serious Adverse Events...........................................94
12.7.3.
Recording of AEs and SAEs ........................................................95
12.7.4.
Evaluating AEs and SAEs............................................................96
12.7.5.
Reporting of SAEs to PPD...........................................................97
12.8.
Appendix 8: Liver Safety Required Actions and Follow up 
Assessments ..............................................................................................98
12.9.
Appendix 9: Liver Safety Drug Restart Guidelines ....................................102
12.10. Appendix 10: Collection of Pregnancy Information....................................104
12.11. Appendix 11: Genetic Research ...............................................................105
12.12. Appendix 12: A Sub-study of the Effect of Daprodustat Compared to 
rhEPO on BP in Hemodialysis Dependent Subjects with Anemia 
Associated with Chronic Kidney Disease who Switch from ESAs .............108
12.12.1. Introduction and Rationale .........................................................108

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12.12.2. Objectives and Endpoints ..........................................................108
12.12.3. Study Design .............................................................................110
12.12.3.1. ABPM Quality Control Criteria ..................................110
12.12.3.2. Eligibility Criteria – Screening ...................................110
12.12.3.3. Study Assessments..................................................111
12.12.3.4. Permanent Discontinuation of Randomized 
Treatment.................................................................112
12.12.3.5. Estimated Dry Weight and Antihypertensive 
Medication Changes.................................................112
12.12.3.6. Withdrawal from ABPM Sub-Study...........................113
12.12.4. Sample Size and Power Calculations ........................................113
12.12.5. Statistical Analysis.....................................................................113
12.13. Appendix 13: A Sub-study to Collect PK Samples in Dialysis 
Subjects with Anemia Associated with CKD..............................................116
12.13.1. Rationale ...................................................................................116
12.13.2. Objectives and Endpoints ..........................................................116
12.13.3. Study Design .............................................................................116
12.13.4. Additional Inclusion Criteria .......................................................117
12.13.5. Study Assessments ...................................................................117
12.13.6. Sample Size ..............................................................................117
12.13.7. PK/PD Analyses ........................................................................118
12.14. Appendix 14: Country Specific Requirements...........................................119
12.14.1. French Administrative Considerations and Specifics
Requirements ............................................................................119
12.14.2. Country-Specific Requirements for Czech Republic for 
Acceptable Contraceptive Methods............................................122
12.15. Appendix 15: Protocol Changes................................................................123
12.15.1. Changes Resulting from Protocol Amendment 1........................123
12.15.1.1. Summary of Changes...............................................123
12.15.1.2. List of Specific Changes ...........................................123
12.15.2. Changes Resulting from Protocol Amendment 2........................125
12.15.2.1. Summary of Changes...............................................125
12.15.2.2. List of Specific Changes ...........................................126
12.15.3. Changes Resulting from Protocol Amendment 3........................146
12.15.3.1. Summary of Changes...............................................146
12.15.3.2. List of Specific Changes ...........................................147
12.15.4. Changes Resulting from Protocol Amendment 4........................194
12.15.4.1. Summary of Changes...............................................194
12.15.4.2. List of Specific Changes ...........................................194

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1.
PROTOCOL SYNOPSIS FOR STUDY 200807
This Phase 3 study will evaluate the safety and efficacy of daprodustat (GSK1278863) 
compared to recombinant human erythropoietin (rhEPO) in the treatment of anemia 
associated with chronic kidney disease (CKD) in subjects on dialysis. 
Primary Objective(s)/Endpoint(s)
Objectives
Endpoints
Co-primary (tested in parallel for non-inferiority)

To compare daprodustat to rhEPO for 
cardiovascular (CV) safety (non-inferiority)

Time to first occurrence of adjudicated major 
adverse cardiovascular event (MACE) 
[composite of all-cause mortality, non-fatal 
myocardial infarction (MI) and non-fatal stroke]

To compare daprodustat to rhEPO for 
hemoglobin (Hgb) efficacy (non-inferiority)

Mean change in Hgb between baseline and 
evaluation period (EP, mean over Weeks 28 to 
52)
Overall Design

This is a randomized, open-label (sponsor blind), active-controlled, parallel-group, 
multi-center, event-driven study in dialysis subjects with anemia associated with 
CKD who are currently treated with erythropoiesis-stimulating agents (ESAs1).

This study will comprise four study periods:  a 4-week screening period, a 4-week 
placebo run-in period, a treatment period and a follow-up period. Prior ESA therapy 
continues during the screening and run-in periods.

The total duration of the study is dependent upon the accumulation of 664 adjudicated 
first MACE (i.e., it is event-driven) unless review of interim data by the Independent 
Data Monitoring Committee (IDMC) recommends bringing the study to an earlier 
close.

Subjects will be stratified by dialysis type, by region, and by participation in the 
ambulatory blood pressure monitoring (ABPM) sub-study. 

Following stratification, subjects will be randomized 1:1 to receive oral daprodustat 
or rhEPO [intravenous (IV) epoetin alfa or subcutaneous (SC) darbepoetin alfa]. 

Both treatment arms (daprodustat and rhEPO) will follow a protocol-specified 
randomized treatment dose adjustment algorithm to achieve and/or maintain Hgb 
within the target range of 10-11g/dL. Dose changes will be made programmatically 
by the Interactive Response Technology (IRT) system for both randomized treatment 
arms.

To ensure subjects remain iron replete and to minimize the potential for iron 
overload during the study, the investigator will follow the iron management criteria 
from randomization through the end of the study treatment period.
                                                
1 ESAs refer to any rhEPO or methoxy PEG-epoetin beta.

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
A rescue algorithm is provided to minimize subjects 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.

GSK will provide randomized treatment: daprodustat or rhEPO (epoetin alfa or 
darbepoetin alfa).  
Type and Number of Subjects

This study will randomize approximately 3000 dialysis subjects (1500 per treatment 
arm) with anemia associated with CKD currently receiving an ESA and with a 
baseline HemoCue Hgb 8-11.5 g/dL. 

Subjects may be on hemodialysis (HD) or peritoneal dialysis (PD). PD subjects will 
be restricted to no more than 15% of the overall study population.  
Analysis
The study’s co-primary endpoints will each be tested for non-inferiority using a one-sided
2.5% significance level and the relevant confidence bound from a two-sided 95% 
confidence interval (CI) (upper bound for MACE and lower bound for the Hgb co-
primary endpoint). 
For CV safety, the primary question is whether daprodustat is non-inferior to rhEPO for 
adjudicated MACE. An Intent-to-Treat (ITT) analysis of time to the first occurrence of 
adjudicated MACE using a margin of 1.25 and a Cox Proportional Hazards regression 
model adjusting for treatment and prognostic randomization stratification factors (dialysis 
type and region), will be used. 
For Hgb efficacy, the primary question is whether daprodustat is non-inferior to rhEPO 
for change from baseline in central laboratory Hgb. The analysis will be based on the 
mean change in Hgb between baseline and the efficacy EP (defined as Weeks 28 to 52) 
using a non-inferiority margin of -0.75 g/dL. An analysis of the ITT Population and an 
analysis of covariance (ANCOVA) model will be used. The model will include 
prognostic randomization stratification factors (dialysis type and region), and factors for 
baseline Hgb and treatment.
Non-inferiority needs to be met for both co-primary endpoints for the study to be 
considered successful.

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2.
INTRODUCTION
2.1.
Brief Background
Daprodustat (GSK1278863) is a hypoxia-inducible factor prolyl hydroxylase inhibitor 
(HIF-PHI) currently being investigated as a treatment for anemia associated with CKD in 
both dialysis and non-dialysis (ND) subjects, with adequate safety and efficacy having 
been demonstrated in clinical trials up to 24 weeks’ duration. Both pre-clinical and 
clinical data show that daprodustat stimulates erythropoietin (EPO) production resulting 
in increased erythropoiesis and elevation in Hgb concentrations. These increases in Hgb 
are achieved with peak plasma EPO exposures substantially lower than those observed 
with rhEPO. Data from completed clinical and preclinical studies are provided in the 
current Investigator Brochure (IB) and IB supplement(s) (if applicable).
2.2.
Study Rationale
Based on its mechanism of action to stimulate erythropoiesis via inhibition of HIF-prolyl 
hydroxylase enzymes,
A Phase 2B clinical trial in dialysis subjects with anemia associated with CKD 
demonstrated that daprodustat can maintain Hgb up to 24 weeks, with minimal effects on 
plasma EPO concentration.  Daprodustat treatment for up to 24 weeks demonstrated an 
adverse event (AE) profile consistent with the patient population. Data from completed 
clinical studies are provided in the current IB and IB supplement(s) (if applicable).
This Phase 3 study in dialysis subjects with anemia associated with CKD will evaluate 
the safety and efficacy of daprodustat compared to rhEPO, the current standard of care, as 
co-primary endpoints, following switch from ESAs. Both co-primary endpoints must 
meet non-inferiority of daprodustat to rhEPO for the study to be successful and for 
analyses to progress to testing principal secondary endpoints. Data from this trial are 
intended to support the use of daprodustat for the treatment of anemia associated with 
CKD in patients on dialysis.
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3.
OBJECTIVE(S) AND ENDPOINT(S)
Objectives
Endpoints
Co-primary (tested in parallel for non-inferiority)

To compare daprodustat to rhEPO for CV 
safety (non-inferiority)

Time to first occurrence of adjudicated MACE 
(composite of all-cause mortality, non-fatal MI and 
non-fatal stroke)

To compare daprodustat to rhEPO for 
Hgb efficacy(non-inferiority)

Mean change in Hgb between baseline and EP 
(mean over Weeks 28 to 52)
Principal Secondary (tested for superiority, adjusted for multiplicity)

To compare daprodustat to rhEPO on CV 
safety endpoints

Time to first occurrence of adjudicated

MACE

MACEor a thromboembolic event (vascular 
access thrombosis, symptomatic deep vein 
thrombosis or symptomatic pulmonary 
embolism) 

MACE or a hospitalization for heart failure 
(HF)

To compare daprodustat to rhEPO on the 
use of intravenous (IV) iron

Average monthly IV iron dose (mg)/subject to 
Week 52 
Safety 

To compare the safety and tolerability of 
daprodustat to rhEPO

Incidence and severity of AEs and serious adverse 
events (SAEs) including AEs of special interest1

Reasons for discontinuation of randomized 
treatment

Absolute values and changes from baseline in 
laboratory parameters, BP and heart rate (HR)
1.
Defined as thrombosis and/or tissue ischemia secondary to excessive erythropoiesis; worsening of 
hypertension;cardiomyopathy; pulmonary artery hypertension; cancer-related mortality and tumor progression and 
recurrence; esophageal and gastric erosions; proliferative retinopathy, macular edema, choroidal 
neovascularization; and exacerbation of rheumatoid arthritis
Additional secondary and exploratory objectives/endpoints are listed in Appendix 2. 
4.
STUDY DESIGN
4.1.
Overall Design

This is a randomized, open-label (sponsor blind), active-controlled, parallel-group, 
multi-center, event-driven study in dialysis subjects with anemia associated with 
CKD who are currently treated with ESAs2.
                                                
2 ESAs refer to any rhEPO or methoxy PEG-epoetin beta.

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
This study will comprise four study periods (Figure 1):  a 4-week screening period, a 
4-week placebo run-in period, a treatment period and a follow-up period. Prior ESA 
therapy continues during the screening and run-in periods.  

The treatment period consists of  :
1. The stabilization period, defined as the period from Day 1 to Week 28 during 
which randomized treatment will be dose titrated to achieve the appropriate Hgb 
target 
2. The maintenance period, defined as the period from the end of the stabilization 
period (Week 28) to the end of treatment (variable per subject), to assess long 
term safety and efficacy. 
o
The efficacy evaluation period (EP) is defined as the period from Week 28 
to Week 52 during which Hgb efficacy will primarily be assessed.

The total duration of the study is dependent upon the accumulation of 664 
adjudicated first MACE (i.e., it is event-driven) unless review of interim data by the 
IDMC recommends bringing the study to an earlier close. 

All subjects will remain in the study (including subjects receiving kidney transplant), 
regardless of whether they continue with randomized treatment (unless consent for 
any further follow up is withdrawn), until the target number of first adjudicated 
MACE has occurred.  At that point, the sponsor will notify investigators to have 
subjects come in for an End of Study visit within a pre-defined time period.

The end of the study will occur after the accumulation of 664 adjudicated first 
MACE and the last subject has completed their last required study visit (Section 7.1). 

Subjects will be stratified by dialysis type [HD* or PD], by region (see Appendix 3), 
and by participation in the ABPM sub-study. Dialysis type and region are 
stratification factors considered to be potentially prognostically important, i.e., 
predictive of study endpoints while participation in the ABPM sub-study is an 
administrative stratification factor intended solely to ensure a similar number of sub-
study subjects in each of the two randomized groups.  
* HD group also includes hemodiafiltration (HDF) or hemofiltration (HF).

Following stratification, subjects will be randomized 1:1 to receive oral daprodustat 
or rhEPO (IV epoetin alfa for HD subjects and SC darbepoetin alfa for PD subjects). 
A central randomization approach will be used to protect against potential selection 
bias due to the open-label design. The sponsor is blinded to treatment assignment in 
the main study and ABPM sub-study.

Both treatment arms (daprodustat and rhEPO) will follow a protocol-specified 
randomized treatment dose adjustment algorithm to achieve and/or maintain Hgb 
within the target range of 10-11 g/dL (Section 6.3.3). Dose changes will be made 
programmatically by the Interactive Response Technology (IRT) system for both 
randomized treatment arms.

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
To ensure subjects remain iron replete and to minimize the potential for iron 
overload during the study, the investigator will follow the iron management criteria 
(Section 6.11.1) from randomization through the end of the study treatment period.

A rescue algorithm is provided to minimize subjects 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 6.12).

An overview of the study design is provided in Figure 1.
Figure 1
Study Schematic

This study will include the following sub-studies:

ABPM sub-study (Appendix 12)

Pharmacokinetic (PK) sub-study (Appendix 13)

An external independent Clinical Events Committee will conduct blinded 
adjudication of all events reported during this study that may meet the definition of 
the co-primary safety endpoint of MACE and additional endpoints as outlined in 
Section 7.4.1 and Section 10.8.2. 

An external IDMC will monitor the safety and efficacy data from the study 
(Section 10.8.1).
4.2.
Type and Number of Subjects

This study will randomize approximately 3000 dialysis subjects (1500 per treatment 
arm) with anemia associated with CKD currently receiving an ESA and with a 
baseline HemoCue Hgb 8-11.5 g/dL (Section 5.1). 

Subjects may be on HD or PD. PD subjects will be restricted to no more than 15% of 
the overall study population.  
4.3.
Design Rationale
This study includes both a 4 week screening and a 4 week placebo run-in period prior to 
randomization (Day 1). The screening period permits eligibility based on laboratory 

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assessments to be confirmed, while the run-in period will be used to establish compliance 
with placebo and study procedures in an attempt to minimize withdrawn consent post-
randomization. 
The stabilization period from Day 1 to Week 28 allows subjects to have their randomized 
treatment dose titrated to achieve the Hgb target range. This period of time provides the 
best opportunity for subjects to be titrated to their optimal dose of randomized treatment 
prior to the efficacy EP (Weeks 28 to 52). A percentage of subjects may still need dose 
titration during the EP. After Week 52, minimal dose changes may be required to 
maintain Hgb within the target range.
The selection of the rhEPO control (epoetin alfa for HD subjects; darbepoetin alfa for PD 
subjects) is based on clinical practice in the majority of participating countries. 
This study will be open-label (sponsor blind) because it would be complex to double-
blind due to the differing number of dose steps between randomized treatments, leading 
to potential dosing errors. Additionally, it is potentially unethical to blind the different 
route of administration of randomized treatment.
4.4.
Dose Justification
Starting doses, dose steps, and elements of the dose adjustment scheme are provided in 
Section 6.3 and Appendix 6.
4.4.1.
Daprodustat
Daprodustat starting doses were selected to reach the target Hgb concentration after 
approximately one red blood cell (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. 
The daprodustat starting doses and dose steps (including the highest dose level, 24 mg) 
selected for this study are consistent with those utilized in the completed 6-month Phase 
2B studies, and were based on exposure-response longitudinal modeling of Hgb data 
collected across the Phase 2 program. Covariate analyses elucidated that baseline Hgb, 
body-weight, and prior ESA dose (if applicable) were the most relevant covariates of Hgb 
response to daprodustat.  Simulations showed the effect of body-weight was not clinically 
important for dosing, but the relationship between prior ESA dose and response was used 
to determine starting doses of daprodustat relative to a subject’s prior ESA dose. 
Starting doses of 4, 6, 8 and 12 mg were selected and are estimated to maintain Hgb 
levels observed with their prior ESA therapy.
4.4.2.
Randomized Treatment Dose Adjustment Scheme
A randomized treatment (daprodustat and rhEPO) dose adjustment algorithm was 
designed to minimize unnecessary dose adjustments by allowing for visit-to-visit 

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variability, and it is informed by the change in Hgb from the previous visit when 
evaluating the need for a dose adjustment (Appendix 6).   
4.5.
Benefit:Risk Assessment
Summaries of findings from both clinical and non-clinical studies conducted with 
daprodustat can be found in the daprodustat IB and IB supplement(s) (if applicable). 
4.5.1.
Risk Assessment
The potential risks of clinical significance including AEs of special interest 
(Section 7.4.4), and the mitigation strategies for this protocol taking into account the 
results of completed clinical and nonclinical studies with daprodustat, are outlined in 
Appendix 4.  In addition to the mitigation strategies outlined, an IDMC will monitor 
accruing safety data for this trial (Section 10.8.1).
4.5.2.
Benefit Assessment
In clinical trials of up to 24 weeks in duration, in subjects with anemia associated with 
CKD, daprodustat has been shown to treat Hgb to target range. 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.  
 
.  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];
4.5.3.
Overall Benefit:Risk Conclusion
Daprodustat demonstrates a positive benefit vs. risk based on the evidence as follows. In 
clinical trials up to 24 weeks in duration, daprodustat treats Hgb to target range, and there 
are no adverse events that have been identified as related to treatment with daprodustat.
This protocol employs precautions to mitigate known and potential risks to randomized 
subjects (See Appendix 4). Given these precautions, as well as the potential benefit that 
daprodustat holds for the treatment of anemia associated with CKD compared to the 
current standard, the overall benefit risk balance is considered to be positive.
5.
SELECTION OF STUDY POPULATION AND 
WITHDRAWAL CRITERIA
Specific information regarding warnings, precautions, contraindications, AEs, and other 
pertinent information on the randomized treatment is provided in the IB, IB 
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supplement(s) (if applicable), product labels for epoetin alfa and darbepoetin alfa, and 
other pertinent documents (e.g., Study Reference Manual (SRM), informed consent).
Deviations from inclusion and exclusion criteria are not allowed because they can 
potentially jeopardize the scientific integrity of the study, regulatory acceptability or 
subject safety.
5.1.
Inclusion Criteria
A subject will be eligible for inclusion in this study only if all of the following criteria 
apply at screening (Week -8) and randomization (Day 1) unless otherwise specified.   
1.
Age (confirm at screening only): 18 to 99 years of age (inclusive).
2. ESAs:   Use of any approved ESA for at least the 6 weeks prior to screening and 
between screening and randomization.
3.
Hgb concentration measured by HemoCue (range is inclusive):
Hgb Range
Week -8

Hgb 8 to 12 g/dL1 (5 to 7.4 mmol/L).

If Hgb is 12.1 to 12.4 g/dL2 (7.5-7.7 mmol/L), up to two retests are allowed; the 
retest value must be between 8 to 12 g/dL (5 to 7.4 mmol/L).
Day 1

Hgb 8 to 11 g/dL (5 to 6.8 mmol/L) and receiving at least the minimum ESA dose3.

Hgb >11 g/dL to 11.5 g/dL (6.8 mmol/L to 7.1 mmol/L) and receiving greater than 
the minimum ESA dose3. 
1.
Conversion from g/dL to g/L is 1:10, e.g., Hgb of 8 to 10 g/dL is equivalent to 80-100g/L. 
2.
The first retest will use the original Week -8 blood sample. If this value is >12 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. For in-center HD, retests will be pre-dialysis, in between dialysis sessions for HHD 
subjects at the study visits, and at the study visits for PD subjects, as per standard of care.
3.
Minimum ESA dose:  epoetins (including biosimilars):  1500 units (U)/week intravenous (IV) or 1000 
U/week SC; darbepoetin alfa:  20 g/4 weeks SC/IV; methoxy PEG-epoetin:  30 g/month SC/IV
4.
Dialysis: On dialysis >90 days prior to screening and continuing on the same mode 
of dialysis from screening (Week -8) through to randomization (Day 1).
5.
Frequency of Dialysis:
a. HD (in-center):  ≥2 times/week 
b. PD: ≥5 times/week
c. Home HD: ≥2 times/week
6.
Compliance with placebo [randomization (Day 1) only]: ≥80% and ≤120% 
compliance with placebo during run-in period (NOTE: this is in addition to ESA 
treatment).

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7.
Informed consent (screening only): capable of giving signed informed consent 
which includes compliance with the requirements and restrictions listed in the consent 
form and in this protocol.
Note: The country-specific requirements for France ONLY for the informed consent 
process are provided in Appendix 14 (see Section 12.14.1, Item 3 for details).
8.
Other study eligibility criteria considerations: The country-specific requirements 
for France ONLY for inclusion in this study are provided in Appendix 14 (see Section 
12.14.1 Item 1 for details).
5.2.
Exclusion Criteria
A subject will not be eligible for inclusion in this study if any of the following criteria 
apply at screening (Week -8) or randomization (Day 1), unless otherwise specified. 
CKD related criteria
1.
Kidney transplant: Planned living-related or living-unrelated kidney transplant 
within 52 weeks after study start (Day 1).
Anemia related criteria
2.
Ferritin (screening only):  ≤100 ng/mL (≤100 g/L). 
3.
Transferrin saturation (TSAT) (screening only): ≤20%.  If TSAT is 18-20%, 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: Untreated pernicious anemia, thalassemia major, sickle 
cell disease or myelodysplastic syndrome.
6.
Gastrointestinal (GI) bleeding: Evidence of actively bleeding gastric, duodenal, or 
esophageal ulcer disease OR clinically significant GI bleeding ≤4 weeks prior to 
screening through to randomization (Day 1).
CV disease-related criteria
7.
MI or acute coronary syndrome:  ≤4 weeks prior to screening through to 
randomization (Day 1).
8.
Stroke or transient ischemic attack:  ≤4 weeks prior to screening through to 
randomization (Day 1).
9.
Heart failure (HF): Chronic Class IV HF, as defined by the New York Heart 
Association (NYHA) functional classification system.
10. Current uncontrolled hypertension: Current uncontrolled hypertension as 
determined by the investigator that would contraindicate the use of rhEPO.
11. QTcB (Day 1): QTcB >500 msec, or QTcB >530 msec in subjects with bundle 
branch block.  There is no QTc exclusion for subjects with a predominantly 
ventricular paced rhythm.

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Other disease-related criteria
12. Liver disease: (any one of the following):

Alanine transaminase (ALT) >2x upper limit of normal (ULN) (screening only)

Bilirubin >1.5xULN (screening only)
NOTE: Isolated bilirubin >1.5xULN 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 subject otherwise meets 
entry criteria.
13. Malignancy: History of malignancy within the 2 years prior to screening through to 
randomization (Day 1) or currently receiving treatment for cancer, or complex 
kidney cyst (e.g. Bosniak Category II F, III or IV) >3cm. Note:  The only exception 
is localized squamous cell or basal cell carcinoma of the skin that has been 
definitively treated 4 weeks prior to screening.
Concomitant medication and other randomized treatment-related criteria
14. 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 or darbepoetin alfa (refer to product labeling).  
15. Drugs and supplements: Use of strong inhibitors of CYP2C8 (e.g., gemfibrozil) or 
strong inducers of CYP2C8 (e.g., rifampin/rifampicin).
16. Other study participation:  Use of other investigational agent or device prior to 
screening through to randomization (Day 1).   

Note: at screening, this exclusion applies to use of the investigational agent within 
30 days or within five half lives (whichever is longer).  
17. Prior treatment with daprodustat:  Any prior treatment with daprodustat for 
treatment duration of >30 days.
General health-related criteria
18. Females ONLY: Subject is pregnant [as confirmed by a positive serum human 
chorionic gonadotrophin (hCG) test for females of reproductive potential (FRP) 
only], subject is breastfeeding, or subject is of reproductive potential and does not 
agree to follow one of the contraceptive options listed in the List of Highly Effective 
Methods for Avoiding Pregnancy in Appendix 5.
Note:  See Section 12.14.2 for the country-specific requirements for the Czech 
Republic ONLY relating to acceptable contraceptive methods during participation in 
this study. 
19. Other Conditions:  Any other condition, clinical or laboratory abnormality, or 
examination finding that the investigator considers would put the subject at 

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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. 
5.3.
Screening/ Run-in Failures
Screen failures are defined as subjects who consent to participate in the clinical trial but 
are not subsequently randomized. A minimum set of information must be collected from 
subjects that fail screening including Demography, Screen Failure details, Eligibility 
Criteria, and SAEs (Section 7.4.3.4).
Subjects that fail screening are eligible to be rescreened up to three additional times as 
soon as the investigator assesses they may meet study entry criteria. If subjects are 
rescreened, they must sign a new informed consent form.
5.4.
Subject Retention

Subjects will be educated on the importance of remaining in the study and attending 
scheduled study visits.

Investigators should make every effort to keep subjects in the trial. 

Should a subject fail to attend the clinic for a required study visit, the site should 
attempt to contact the subject and re-schedule the missed visit as soon as possible. 
The site should also counsel the subject on the importance of maintaining the 
assigned visit schedule. In cases where the subject 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 subject. The investigator (dependent on local 
regulations) should obtain the name and phone number of a relative or friend to assist 
in contacting the subject.
5.5.
Permanent Discontinuation of Randomized Treatment
Every effort should be made to keep subjects in the study including those who 
permanently stop randomized treatment. A subject may permanently discontinue 
randomized treatment at any time at his/her own request, or at the discretion of the 
investigator for safety or compliance reasons.  A subject must permanently discontinue 
randomized treatment for the pre-specified reasons below. 

Kidney transplant

Meets criterion to receive rescue (Section 6.12)

Becomes pregnant or intends to become pregnant during the study.

Liver chemistry abnormalities exceeding the threshold criteria (Section 7.4.12).

Diagnosis of cancer (new or recurrent), with the exception of localized squamous 
cell or basal cell carcinoma of the skin.

Need for more than 14 days use of prohibited medication (Section 6.10.2)

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In all cases, the reason for randomized treatment discontinuation and the date of the last 
dose will be recorded in the subject’s electronic case report form (eCRF) and the subject
will continue in the study as described in Section 5.5.1.  
Subjects may be reapproached about restarting randomized treatment in certain 
circumstances if the sponsor and the investigator agree.
5.5.1.
Procedures for Subject Follow-up
Subjects who permanently discontinue randomized treatment will be asked to attend an 
Early Treatment Discontinuation visit and will be expected to attend study visits through
the End of Study visit, according to the study visit schedule, unless consent is actively 
withdrawn. Complete details are provided in the Time and Events Table (Section 7.1).

Early Treatment Discontinuation visit:  This visit should occur within 2 weeks of 
stopping randomized treatment. 

Remaining in-clinic visits*:

Day 1 through Week 52:  Study visits at Weeks 4, 16, 28, 40 and 52.

Week 52 through end of study:  Study visits every 12 weeks.  

End of Study visit: as defined by the sponsor within a pre-defined time period.
*Phone visit acceptable in exceptional circumstances.  
If a subject does not agree to continue attending in-clinic or phone visits, other follow-up 
options to collect study outcomes and vital status 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 subject, then the subject will be considered to have remained in 
the study and not to have withdrawn consent.
5.6.
Withdrawal from Study
For subjects that choose to withdraw consent or are lost to follow up, the reason for not 
completing the study will be recorded in the subject’s eCRF. 
If a subject withdraws from the study, he/she may request destruction of any clinical 
samples taken, and the investigator must document this in the site study records.
5.6.1.
Withdrawal of Consent for Contact
Specific wording is included in the informed consent form which permits subjects to 
discontinue randomized treatment or study procedures, but states an expectation that 
follow up information will always be required. Subjects will agree to this at the time of 
consenting.
Withdrawal of consent from the study is expected to be a rare occurrence.  If a subject 
expresses a wish to withdraw consent from the study, the investigator will review the 
following contact options with the subject.

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
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 subject will be considered to have withdrawn consent. 
The principal investigator will be required to document that all alternative options have 
been reviewed with the subject.
For these subjects, 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.
5.6.2.
Subjects Deemed Lost to Follow-up

Investigators should make every effort to contact subjects who are deemed lost to 
follow-up and who have not withdrawn consent to follow-up contact.

As permitted by local regulations, a third party may be used to locate alternative 
subject contact information that will be provided to the investigator. All attempts to 
contact subjects will be documented in the subject’s source notes and a final status 
contact will be recorded in the eCRF. 
5.7.
Subject and Study Completion
A completed subject is one who has completed all periods of the study through the End of 
Study visit with the following exception: subjects who die while on study are also 
considered as having completed the study.
6.
PLACEBO RUN-IN AND RANDOMIZED TREATMENT
6.1.
Placebo Run-in and Randomized Treatment
Prior to randomization, oral placebo tablets will be dispensed at Week -4 with 
instructions to take one tablet daily through the run-in period.
The term ‘randomized treatment’ is used throughout the protocol to describe either study 
treatment (i.e., daprodustat, darbepoetin alfa or epoetin alfa) received by the subject 
during the treatment period as per the protocol design.  Randomized treatment will be 
provided by GSK3. 
During the treatment period, iron therapy (supplied locally) will be administered as per 
the iron management criteria (Section 6.11.1).  
                                                
3 If the supply to the site is interrupted due to unexpected circumstances (e.g., natural disaster), local 
standard of care for anemia management may be considered during that time period, without the need to 
withdraw the subject from the study or to permanently discontinue randomized treatment. 

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Daprodustat will be supplied as film coated tablets for oral administration containing 1, 2, 
4, 6, 8, and 10 mg of daprodustat.  Doses of 12, 16, and 24 mg of daprodustat will be 
provided using multiples of these tablet strengths.  The doses, tablet size, and description 
are provided in Table 1. Subjects are to take the daprodustat tablet(s) daily with water, 
and these tablets can be taken without regard to food.
Table 1
Description of Daprodustat and Placebo Tablets
Tablet 
size
Dose
Description
7 mm
Daprodustat 1 mg, 2 mg, 4 mg
7.0 mm round, compound radius, white film 
coated tablets
9 mm
Placebo 
Daprodustat 6 mg, 8 mg, 10 mg 
9.0 mm round, compound radius, white film 
coated tablets
GSK will provide randomized treatment for the rhEPO control arm:

Epoetin alfa using vials for IV administration. Doses from 1500 to 60000 U will be 
administered using the following vial strengths: 2000 U/ml, 3000 U/ml, 4000 U/ml 
and 10000 U/ml.

Darbepoetin alfa as prefilled syringes (PFS) for SC or IV (for subjects transitioning to
HD) injection.  Doses from 20 µg to 400 µg will be administered using the strengths 
below (Table 2).
Table 2
Description of Darbepoetin Alfa PFS
PFS Strengths
PFS Volume 
20 µg*
0.5 mL
30 µg* 
0.3 mL
40 µg
0.4 mL
60 µg
0.3 mL
80 µg*
0.4 mL
100 µg
0.5 mL
150 µg
0.3 mL
* Not available in all countries. 
See Section 6.3.2 for rhEPO dose steps and dosing frequency details. Additional details 
on rhEPO strengths to deliver the total dose are captured in the SRM.
6.2.
Randomized Treatment Assignment
Subjects will be stratified as outlined in Section 4.1 and randomized 1:1 to receive oral 
daprodustat or rhEPO (IV epoetin alfa or SC darbepoetin alfa). 

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Subjects will discontinue their ESA therapy prior to randomization so that the 
randomization date (Day 1) should coincide, as closely as possible, with the date of next 
scheduled ESA administration. Examples of switching are provided in the SRM. 
6.3.
Randomized Treatment Starting Dose and Dose Adjustment
6.3.1.
Daprodustat Dosing Information
Daprodustat Starting Dose:
The starting dose of daprodustat will be assigned based on prior ESA dose at 
randomization (Day 1) (Table 3).
Table 3
Daprodustat Starting Dose
ESA Dose at Randomization(Day 1)
Daprodustat
Starting Dose
epoetins (incl biosimilars)
(U/week IV) 1
darbepoetin 
(g/4week SC/IV) 2
methoxy PEG-epoetin 
beta (g/month SC/IV) 3, 4
(mg, once 
daily)
   1500 to 2000 
   20 to 30
   30 to 40 
4
>2000 to <10000 
>30-150 
>40 to 180
6
10000 to <20000 
>150-300 
>180 to 360 
8
20000  
>300   
>360   
12
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)
Daprodustat Dose Steps:
The available dose steps of daprodustat are outlined below.  Dose adjustments will result 
in the daprodustat dose being increased or decreased by one dose step at a time.  Those 
receiving the highest dose of daprodustat who require a dose increase will maintain the 
same dose, while those receiving the lowest dose of daprodustat that require a dose 
decrease will have doses withheld.  
6.3.2.
rhEPO Dosing Information
rhEPO Starting Dose:
The starting dose for subjects receiving rhEPO is as follows:

For subjects with a baseline (Day 1) Hgb ≤11 g/dL 

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-
For subjects already on epoetin alfa (HD subjects) or darbepoetin alfa (PD 
subjects), the starting dose will be the same as their currently scheduled dose, 
rounded to the nearest study dose. 
-
For subjects receiving other types of ESAs, the starting dose will be an IV epoetin 
alfa (HD subjects) or SC darbepoetin alfa (PD subjects) equivalent dose, rounded 
to the nearest study dose.

For subjects with a baseline (Day 1) Hgb >11 g/dL and 11.5 g/dL
-
The starting dose of IV epoetin alfa (HD subjects) or SC darbepoetin alfa (PD 
subjects) will be reduced to the next lowest starting dose with the aim of 
maintaining Hgb within the range of 10-11 g/dL.
rhEPO Dose Steps:
Dose-steps of rhEPO are pre-defined in this study (Table 4 and Table 5). The IV epoetin 
alfa dose steps consist of stepwise increase or decrease in weekly dose of 20 to 33% for 
most steps, except when weekly doses of 3000 U or when weekly doses are >21000 U 
per week when further increases are within the 10 to 15% range.  The darbepoetin alfa 
dose adjustment increases and decreases will be in similar steps as compared to epoetin 
alfa, generally within the 20 to 33% range with a few increases of 50% based on 
available dose strengths. In some cases, a partial amount of a darbepoetin alfa pre-filled 
syringe (PFS) will be used to deliver the total 4-weekly dose. 
Additional information about the delivery of the respective rhEPO doses is provided in 
the SRM. Those receiving the highest dose of rhEPO who require a dose increase will 
maintain the same dose, while those receiving the lowest dose of rhEPO that require a 
dose decrease will have doses withheld.  
For subjects who are on HD two times a week and are randomized to the epoetin alfa arm 
and require three times a week epoetin alfa dosing, the weekly dose should be split as 
close to equally, using the study-allocated dose vials of epoetin alfa, across the two
dialysis treatments.

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Table 4
Epoetin Alfa Dose Steps
Total  Weekly Dose
Dose and Frequency
1500
1500 U once a week
2000
2000 U once a week
3000
3000 U once a week
4000
4000 U once a week
5000
5000 U once a week
6000
6000 U once a week
8000
8000 U once a week
10000
10000 U once a week
12000
4000 U three times a week
15000
5000 U three times a week
18000
6000 U three times a week
21000
7000 U three times a week
24000
8000 U three times a week
27000
9000 U three times a week
30000
10000 U three times a week
36000
12000 U three times a week
42000
14000 U three times a week
48000
16000 U three times a week
60000
20000 U three times a week
Table 5
Darbepoetin Alfa Dose Steps
Total 4-Weekly Dose
PFS Dose and Frequency
20 µg
20 µg every 4 weeks
30 µg
30 µg every 4 weeks
40 µg
40 µg every 4 weeks
60 µg
60 µg every 4 weeks
80 µg
80 µg every 4 weeks
100 µg
100 µg every 4 weeks
150 µg
150 µg every 4 weeks
200 µg
100 µg every 2 weeks
300 µg
150 µg every 2 weeks
400 µg
100 µg once a week
6.3.3.
Daprodustat and rhEPO Dose Adjustment Algorithm
The protocol-specified randomized treatment (daprodustat or rhEPO) dose adjustment 
algorithm is provided in Appendix 6.  Dose adjustments (i.e., increase, decrease, 
maintain, or withheld if ≥12 g/dL) will be made programmatically for both the 
daprodustat and rhEPO arms by the IRT system to maintain Hgb concentrations within 
the range of 10-11 g/dL based on the HemoCue Hgb value measured at least every 4 

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weeks (Day 1 through Week 52) or at least every 12 weeks (post-Week 52 through end of 
treatment) disclosed to the IRT system by the investigator.
From Week 52 onwards, additional study visits to check Hgb and dispense randomized 
treatment (where directed by the IRT system) will be required under the circumstances 
outlined in Appendix 6.
In order to mitigate subjects remaining below the Hgb target range for an extended period 
of time, adjustments to the algorithm may be implemented by the sponsor as outlined in 
Appendix 6 based on the review of blinded instream aggregate Hgb data.  
6.3.4.
Randomized Treatment Temporary Interruption
Every effort must be made to continue randomized treatment and to complete study 
visits, where able; however, sites should contact PPD Remote Site Monitor-Local if a 
subject cannot return to the research site on a temporary basis for any one of the 
following situations:

Subjects who are hospitalized for any duration. 

HD or PD subjects receiving oral daprodustat or PD subjects receiving SC 
darbepoetin alfa who cannot return to the site for a period >5 weeks

HD subjects receiving IV rhEPO who cannot return to the site in time for the next 
dosing interval.
In exceptional circumstances, local standard of care for anemia management during this 
time period may be considered based on consultation with the PPD Medical Monitor.  If 
non-study ESAs are administered, doses should be recorded on the Prior/Concomitant 
Medications – ESA eCRF page.    
6.3.5.
Randomized Treatment Discontinuation
The sponsor will inform investigators when they should have subjects come in for an End 
of Study visit based on the projected occurrence of 664 first MACE.  Subjects will stop 
taking randomized treatment the day of the End of Study visit.
For those subjects who permanently discontinue randomized treatment, see Section 5.5.1
for study visit details.
Anemia therapy may recommence, as required, once randomized treatment has been 
discontinued.
6.4.
Blinding
This is an open-label study; however, the sponsor is blinded to treatment assignment for 
both the main study and ABPM sub-study.  Randomized treatment will have the dose 
strength on the label. A detailed Blinding Plan will describe the procedures that will be 
implemented in order to minimize the extent to which this blind may be compromised.

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6.5.
Packaging and Labeling
Daprodustat tablets are packed in white, opaque high density polyethylene (HDPE) 
bottles with child-resistant closures. The contents of the label will be in accordance with 
all applicable regulatory requirements.
6.6.
Preparation/Handling/Storage/Accountability
No special preparation of placebo run-in or randomized treatment is required.
Only subjects enrolled in the study may receive placebo run-in and subsequently, 
randomized treatment and only authorized site staff may supply placebo run-in and 
randomized treatment.  All placebo run-in and randomized treatment 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 the investigator and 
authorized site staff. 
The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for placebo run-in and randomized treatment accountability, reconciliation, 
and record maintenance (i.e. receipt, reconciliation and final disposition records).  
Further guidance and information for final disposition of unused placebo run-in and 
randomized treatment is provided in the SRM. 
Under normal conditions of handling and administration, placebo run-in and randomized 
treatment are not expected to pose significant safety risks to site staff.  
A Material Safety Data Sheet (MSDS)/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.
6.7.
Compliance with Randomized Treatment Administration
Randomized subjects, who administer randomized treatment (daprodustat or rhEPO 
[darbepoetin alfa or epoetin alfa]) at home, will be instructed to return all unused 
randomized treatment at each clinic visit. A record of the number of daprodustat tablets 
or rhEPO doses dispensed to and taken by each subject will be maintained and reconciled 
with randomized treatment and compliance records. Randomized treatment start and stop 
dates and dosing details, including dates for randomized treatment interruptions and/or 
dose increases or reductions, will be recorded in the eCRF. At Week 2 and for 
unscheduled visits, compliance checking will not be performed if the dose of randomized 
treatment is not changed.
For subjects randomized to rhEPO (darbepoetin alfa or epoetin alfa) who have 
randomized treatment administered in the clinic, the details of each administered rhEPO 
dose will be maintained and reconciled with randomized treatment and compliance 
records. Randomized treatment start and stop dates and dosing details, including dates for 
randomized treatment interruptions and/or dose increases/reductions, will be recorded in 
the eCRF.

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6.8.
Treatment of Randomized Treatment Overdose
There is no specific antidote for overdose with daprodustat. The expected manifestations 
of daprodustat overdosage include signs and symptoms associated with an excessive 
and/or rapid increase in Hgb concentration. Daprodustat is highly protein bound; thus, 
clearance of daprodustat by HD or PD is very low and these are not effective methods to 
enhance the elimination of daprodustat. Daprodustat metabolites are, in part, cleared via 
hemodialysis. In the event of a suspected overdose, it is recommended that the 
appropriate supportive clinical care be instituted, as dictated by the subject’s clinical 
status. Additionally, subjects should be monitored closely for CV events, increased HR 
and hematologic abnormalities.
Consult the approved product label for information on overdose for darbepoetin alfa and 
epoetin alfa.
6.9.
Treatment after the End of the Study
Subjects 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 subject’s medical condition.
6.10.
Concomitant Medications and Non-Drug Therapies
Concomitant medications, including over-the-counter medications and supplements, 
taken during the study will be recorded in the eCRF.  Start/stop dates and route of 
administration will be recorded for general concomitant medications. Additional details 
(e.g., 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).
6.10.1.
Permitted Medications and Non-Drug Therapies
Unless specified as a prohibited medication in Section 6.10.2, all concomitant 
medications should be considered permitted provided they are not contraindicated for the 
individual subject 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.
6.10.2.
Prohibited Medications and Non-Drug Therapies
Use of any of the following prescription drugs from screening (Week -8) until 7 days 
after the last dose of randomized treatment is prohibited and will constitute a protocol 
violation. 

Strong inhibitors of CYP2C8 (e.g., gemfibrozil)

Strong inducers of CYP2C8 (e.g., rifampin/rifampicin)

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No other investigational agents or devices are permitted from study entry through 
completion of the study, with the exception of the randomized treatment administered for 
this study.
6.11.
Standard of Care
During the study (from screening), investigators are expected to monitor the subject’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 
randomized treatment will apply. These were developed to reflect global clinical practice.
6.11.1.
Iron Management Criteria
Subjects must remain iron replete throughout the study.  The investigator will follow the 
iron management criteria from randomization (Day 1) through the end of the study 
treatment period for subjects receiving randomized treatment.  
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 
subject’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 subjects are maintained at a ferritin 
>100 ng/mL and TSAT >20%.
The Steering Committee (Section 10.8.4) will monitor blinded subject iron data in an 
ongoing fashion to ensure compliance.
6.12.
Rescue Therapy
A rescue algorithm is provided to minimize subjects 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 6.
This rescue algorithm does not apply to subjects 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 
vascular access).  In these cases, treatment should be directed to the specific cause and 
randomized treatment will be continued.  If a subject is transfused as part of the 
treatment, then the randomized treatment will be maintained at the current dose (unless 
Hgb is ≥12 g/dL which requires a dose hold).

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Table 6
Rescue Algorithm for Anemia Management
Evaluate Subject for Rescue if:  
HemoCue Hgb remains <9 g/dL (at a scheduled study visit, Week 4 onwards) despite three1 consecutive 
dose increases above the starting2 or post-rescue3 dose (where HemoCue Hgb is <9 g/dL prior to each 
dose increase) OR HemoCue Hgb is <7.5 g/dL despite a dose increase at the prior study visit.
Step 1:
Initial 
Intervention
While continuing randomized treatment (increase dose if HemoCue Hgb <7.5 g/dL; 
otherwise maintain current dose), intervene with one or more of the following as dictated 
by clinical comorbidities 
-
Single course of IV iron up to 1000 mg (in addition to the iron management criteria)
-
Transfusion of up to two units of packed red blood cells (PRBC) if clinically 
indicated
-
Allow additional 4 weeks on randomized treatment (NOTE:  this is a required 
choice; can be combined with either or both of the above).
Step 2: 
Rescue 
Check HemoCue Hgb4 weeks ±1 week from last study visit; earlier checks of Hgb may 
be obtained to advise further intervention as clinically indicated.
Randomized treatment should be permanently discontinued and the subject 
should be rescued according to local clinical practice if either,
-
If HemoCue Hgb remains <9 g/dL despite initial intervention based on the average 
of two HemoCue Hgb values4
OR
-
More than two units of PRBC were needed for transfusion (and was not related to 
acute bleeding).
1.
Two consecutive dose increases if starting/post-rescue dose is daprodustat 12 mg, epoetin alfa 42000 U per 
week, or darbepoetin alfa 200 µg over 4 weeks; one dose increase if starting/post-rescue dose is daprodustat 16 
mg, epoetin alfa 48000 U per week, or darbepoetin alfa 300 µg over 4 weeks; and no prior dose increase if 
starting/post-rescue dose is daprodustat 24 mg, epoetin alfa 60000 U per week, or darbepoetin alfa 400 µg over 4 
weeks (top dose).
2.
For subjects who have switched from HD to PD who are randomized to rhEPO, the baseline dose for the 
purposes of the rescue algorithm is the new darbepoetin alfa dose.
3.
For subjects who previously were evaluated for rescue and who are able to continue in the trial, “post-rescue” 
dose is the dose of randomized treatment that a subject is receiving at the study visit after initial intervention.
4.
Repeat HemoCue Hgb at the same study visit to confirm Hgb (using the same sample); take average of 2 values.
6.13.
Subjects Changing Dialysis Modality
Subjects changing dialysis modality should not be withdrawn from the study, and will 
continue in the same randomized treatment arm (daprodustat or rhEPO) they were 
originally assigned. Those subjects randomized to rhEPO who transition from PD to HD 
(in-center or home HD) will continue on darbepoetin alfa.  However, subjects 
randomized to rhEPO who transition from HD to PD will switch from epoetin alfa to 
darbepoetin alfa at their next study visit from Week 4 onwards.  If this occurs from Week 
52 onward, additional visits are required as outlined in Appendix 6.

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7.
STUDY ASSESSMENTS AND PROCEDURES
Protocol waivers or exemptions are not allowed with the exception of immediate safety 
concerns. Adherence to the study design requirements, including those specified in the 
Time and Events Table, are essential and required for study conduct.
This section lists the procedures and parameters of each planned study assessment.  The 
exact timing of each assessment is listed in the Time and Events Table Section 7.1. 
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. Study visit days should be scheduled as follows: 

For subjects on 3-5x/week HD, the designated study visit must not occur on the 
first dialysis session of the week, i.e., immediately following the longest interval 
between HD sessions.  For example, if on a Monday-Wednesday-Friday schedule, 
the study visit should be on Wednesday or Friday.

For subjects on PD, study visits can occur on any day of the week. 

For subjects on 2x/week HD, the study visit must occur on the day of the dialysis 
session that is closest to the previous session. For example, if a subject receives 
dialysis on a Monday and Thursday, the study visit should be on the Thursday (2 
days from the previous dialysis session) rather than the Monday (3 days from the 
previous dialysis session). 
The Week -4 and Day 1 visits should be completed 4 weeks ±1 week after the last visit; 
however, the total duration of the Screening and Run-In periods (from Week -8 to Day 1) 
should be 8 weeks ±1 week (i.e., 7-9 weeks).  
Post-randomization visits should be referenced back to the Randomization visit (Day 1).  
The visit window for those on randomized treatment for the Week 2 and Week 4 visits is 
±3 days.  The visit window specified for those on randomized treatment from Week 8 
onwards is ±1 week.  However, during the first 52 weeks, to ensure continuity of 
randomized treatment, 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 PPD Medical Monitor.
Study assessments should preferably be done at dialysis centers; however, in some 
circumstances (i.e., where the dialysis center and research site are not co-located) 
assessments can be performed at the research site.
Supplementary study conduct information is provided in the SRM. The SRM provides 
administrative and detailed technical information that does not impact subject safety.

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7.1.
Time and Events Table
Table 7
Schedule of Assessments Year 1 to End of Study
Protocol activity (visits ±1 week, except Weeks 2 and 4 
which are ±3 days)
All assessments pre-dialysis unless otherwise specified
(Note: All visit timings are relative to Day 1)
Day 1 through Week 52
Screen
Week -8
Run-in
Week -4
Day 113
Week 2
Full study visit
Week 4, 16, 28, 
40
Abbreviated study visit
Week 8, 12, 20, 24, 32, 36, 
44, 48  
Week 52 Unscheduled10
Informed consent (main study)
X22
IRT system transaction17
X
X
X
X
X
X
X
X
Subject reminder, inform site staff of changes in health1
X
X
Check/confirm entry criteria
X
X
History: medical, hospitalization, transfusion
demography, height
X
Weight (pre- and post-dialysis for in-center HD subjects;
between treatments for HHD; at study visits per standard of 
care for PD) and EDW
X
X
X
X
X
X
X
X
SBP/DBP, HR (pre- and post-dialysis for in-center HD 
subjects; between treatments for HHD; at study visits per 
standard of care for PD) (single readings unless otherwise 
indicated)
X
X
X (triplicate)
X
X
X
X (triplicate)
X
Kt/Vurea 18
X
X
X
ECG 2
X2
X
Ultrasound of kidneys and adrenal glands 
X16
Placebo run-in or randomized treatment dispensing (start 
administration on date treatment dispensed)19
X
(placebo)
X
X9
X
X
X
X9
Placebo run-in or randomized treatment compliance19
X (placebo)
X11
X
X
X
X11
Iron therapy, transfusions3
X
X
X
X
X
X
X
X
Rescue medication(s) for Initial Intervention3 ,4 
X
X
X
Females only: estradiol and FSH (if required) 
X
FRP only:  Serum pregnancy test 5,20
X
X
X
X
HemoCue Hgb
X
X
X
X
X
X
X
X
Hematology6  
X
X
X
X
Hgb only 
X
X
Clinical chemistry6
X
X
X
X
X

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Protocol activity (visits ±1 week, except Weeks 2 and 4 
which are ±3 days)
All assessments pre-dialysis unless otherwise specified
(Note: All visit timings are relative to Day 1)
Day 1 through Week 52
Screen
Week -8
Run-in
Week -4
Day 113
Week 2
Full study visit
Week 4, 16, 28, 
40
Abbreviated study visit
Week 8, 12, 20, 24, 32, 36, 
44, 48  
Week 52 Unscheduled10
Ferritin, total iron, UIBC 6
X
X
X
X
Hepcidin  
X
X
X
HbA1c7, lipids (non-fasting)
X
X
hsCRP, iPTH
X
Wk 28
X
Storage biomarkers21
X
Wk 28
X
Hospitalization 3, kidney transplant3
X
X
X
X
X
Non-serious AEs, SAEs, AEs of special interest, clinical 
events 
X8
X
X
X
X
X
X
X
Review concomitant medications
X
X
X
X
X
X
X
X

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Schedule of Assessments Year 1 to End of Study (Continued)
Year 2
Year 3
Year 4
Unscheduled10,12 End of 
Study15
Follow-up
(4-6 weeks after 
stopping 
randomized 
treatment)
Protocol activity (visits ±1 week)
All assessments pre-dialysis unless 
otherwise specified
(Note: All visit timings are relative to Day 
1)
Week 
64
Week 
76
Week 
88
Week 
100
Week 
112
Week 
124
Week 
136
Week 
148
Week 
160
Week 
172
Week 
184
Week 
196
Week 
20814
IRT system transaction17
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Weight (pre- and post-dialysis for in-center 
HD subjects; between treatments for 
HHD; at study visits per standard of care 
for PD) and EDW
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
SBP/DBP, HR (pre- and post-dialysis for 
in-center HD subjects; between 
treatments for HHD; at study visits per 
standard of care for PD) (single readings 
unless otherwise indicated)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X 
(triplicate)
X
Kt/Vurea 18
X
X
X
X
X
X
X
ECG 2
X
X
X
Randomized treatment dispensing (start 
administration on day of dispensing)17,19
X
X
X
X
X
X
X
X
X
X
X
X
X
X9
Randomized treatment compliance17,19
X
X
X
X
X
X
X
X
X
X
X
X
X
X11
X
Iron therapy, transfusions3
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Rescue medication(s) for Initial 
Intervention 3,4 
X
X
X
X
X
X
X
X
X
X
X
X
X
FRP only: serum pregnancy test5,20
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
HemoCue Hgb
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Hematology6
X
Hgb 
only
X
Hgb 
only
X
Hgb 
only
X
Hgb 
only
X
Hgb 
only
X
Hgb 
only
X
X
X
X
Clinical chemistry6
X
X
X
X
X
X
X
X
X
X
Ferritin, total iron, UIBC6
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Hepcidin, HbA1c7, lipids (non-fasting), 
hsCRP
X

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Year 2
Year 3
Year 4
Unscheduled10,12 End of 
Study15
Follow-up
(4-6 weeks after 
stopping 
randomized 
treatment)
Protocol activity (visits ±1 week)
All assessments pre-dialysis unless 
otherwise specified
(Note: All visit timings are relative to Day 
1)
Week 
64
Week 
76
Week 
88
Week 
100
Week 
112
Week 
124
Week 
136
Week 
148
Week 
160
Week 
172
Week 
184
Week 
196
Week 
20814
iPTH
X
X
Hospitalization3, kidney transplant3
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Non-serious AEs, SAEs, AEs of special 
interest, clinical events 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Review concomitant medications
X
X
X
X
X
X
X
X
X
X
X
X
x
X
X
X
iPTH, intact parathyroid hormone; FSH, follicle stimulating hormone; UIBC, unsaturated iron binding capacity; HbA1c, glycated hemoglobin; hsCRP, high sensitivity C-reactive 
protein; SBP, systolic blood pressure; DBP, diastolic blood pressure; ECG, electrocardiogram; EDW, estimated dry weight
1.
Health changes include new symptoms or medical problems (e.g., pregnancy, hospitalizations) and changes in medication.
2.
Day 1 ECG may be performed as early as the Week -4 visit through the Day 1 visit on a dialysis day (if 3 times/week dialysis, cannot be done on the first dialysis session of the 
week).  If performed on Day 1, it must be pre-dialysis and over-read prior to randomization. All other ECGs assessments may be recorded pre or post dialysis and require over-
reading. 
3.
Record in eCRF, if applicable.
4.
See details on Rescue in Section 6.12.
5.
Repeat pregnancy test prior to placebo run in or randomized treatment re-administration if it is disrupted for >7 days and there was also a lapse in contraceptive use, regardless of 
the reason for the disruption. If a subject becomes post menopausal (as defined in Appendix 5) during the study pregnancy tests are no longer required.
6.
See details on hematology and clinical chemistry in Section 7.4.11.
7.
HbA1c assessment only in subjects with diabetes on Day 1 or diagnosed during the study.
8.
Only SAEs assessed as related to study participation or a GSK product are collected at this visit. See Section 7.4.3.1 for additional details.
9.
If dose does not change, then randomized treatment is returned to subject.
10. If a subject lost their placebo run-in or randomized treatment, it is not necessary to perform the unscheduled visit assessments other than dispensing placebo run-in or randomized 
treatment. 
11. Required only if dose is changed or randomized treatment is dispensed.  Compliance checking will be required when a dose of randomized treatment is changed.
12. Additional visits to check Hgb and dispense randomized treatment (where directed by the IRT system) are required under the circumstances described in Appendix 6.  
Hematology and chemistry samples are not required.  
13. All assessments pre-dose.
14. Further visits every 12 weeks as required.
15. Investigator will inform subject when to attend this End of Study visit (Section 6.3.4).
16. Ultrasound of the kidneys and adrenal glands will be performed as early as 6 weeks prior to the Day 1 visit. If results of kidney and adrenal ultrasound require follow-up testing, 
then the run-in period can 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, 

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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 7.4.10.
17. Treatment will be dispensed every 4±1 weeks; an IRT transaction will be required; perform randomized treatment compliance. 
18. 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. Kt/Vurea and URR measurements are not required for daily HHD.
19. In circumstances where the new dose of randomized treatment cannot be dispensed on the day of the study visit, the new dose of randomized treatment can be dispensed at next 
HD treatment. For visits after Day 1, prior randomized treatment should be continued unless on dose hold, Hgb ≥12 g/dL. Compliance is deferred until randomized treatment is 
returned.
20. For Argentina ONLY: Pregnancy testing will be performed every 4 weeks for FRP as required by local law.
21. Biomarker samples will be stored for future analyses for all subjects, except if not permitted by IRB/EC or refused by subject.
22. Informed consent will be obtained prior to any study procedures. 

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Table 8
Schedule of Assessments for Patient Reported Outcomes, Genetics and Sub-studies
Protocol Activity
(visits ±1 week)
(Note: All visit timings are relative to 
Day 1)
Screening
Day 1 through Week 208
End of Study
Week -8
Week -4
Day 1
Week 4
Week 8 & 
12
Week 16, 20 
& 24
Week 28 
Week 32, 
36, 40, 44, 
48
Week 52
Week 100, 
148, 208
Patient Global Impression of Severity 
(PGI-S)1
X
X
X
X
X
Patient Global Impression of Change 
(PGI-C) 1
X
X
X
Short Form 36 (SF-36) 1
X
X
X
X
EuroQol 5 Dimension 5 Level Health 
Utility Index (EQ-5D-5L) and EuroQol 
Visual Analogue Scale (EQ-VAS) 1, 2
X
X
X
X
X
X
Healthcare resource utilization (subject 
reported)
X
X
X
X
X
X
X (& Follow up)
Genetics sample 3
X
ABPM sub-study (Appendix 12): 
                           Informed Consent 
X4
X4
   Atrial fibrillation/flutter screening
X5
                              24 hour ABPM
X6
X (Week 16)
    Record awake and sleep times
X7
X7 (Week 
16)
PK sub-study (Appendix 13):
          Informed Consent
X8
X8
X8
X8
X8
X8
X8
                           PK assessment
X9
X9
X9
X9
X9
X9
1. Subjects who are unable to or require assistance to read must not complete the questionnaires.
2. Only in selected countries. See Appendix 3.
3. Informed consent for optional Genetic research should be obtained before collecting a sample. To minimize potential study bias, the genetic sample should be collected on Day 1.
4. Informed consent for ABPM sub-study can be obtained at Week -8 or at the Week -4 visit prior to conducting any ABPM sub-study assessments.
5. Heart rate will be assessed prior to ABPM, subjects with irregular heart beat will undergo an ECG to assess if atrial fibrillation/flutter is present (see Section 12.12.3.3.)
6. Baseline ABPM will be performed at any mid-week dialysis visit starting at Week -4 until 1 week prior to randomization (Day 1); the device will be returned at the next visit, which 
ideally is no later than 1 week prior to randomization to allow for QC of the ABPM.
7. Subject will record sleep and awake times during the ABPM session.

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8. Informed consent for PK sub-study can be obtained anytime from Day 1 (once the subjects is confirmed to have been randomized to daprodustat) till Week 52, i.e., last study visit 
where PK sampling can be obtained.
9. Blood samples will be collected at any single study visit from the Week 4 through Week 52 visit (i.e., PK is collected at one visit only, based on convenience for the subject/site). 

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Table 9
Schedule of Assessments for Subjects Permanently Discontinuing Randomized Treatment
Protocol Activity
All assessments pre-dialysis unless otherwise specified
(Note: All visit timings are relative to Day 1)
Early Treatment Discontinuation 
Visit (within 2 weeks of 
discontinuing randomized 
treatment)
Day 1 through Week 527
Week 4, 16, 28, 40, 52 ± 2 weeks
Unscheduled
IRT system transaction
X
SBP/DBP, HR (pre- and post-dialysis for in-center HD subjects; 
between treatments for HHD; at study visits per standard of care 
for PD) (single readings unless otherwise indicated)
X (triplicate)
X
X
ECG
X
Iron therapy, transfusions1
X
X
X
Serum pregnancy test (FRP only)
X6
HemoCue Hgb
X
X
X
Hematology3 , 
X
X
Clinical chemistry3
X
X
Ferritin, total iron, UIBC, hepcidin, lipids, iPTH
X
Hospitalization1, kidney transplant1
X
X
X
Non-serious AEs, AEs of special interest, SAEs, clinical events
X
X
X
Review concomitant medications
X
X
X
Healthcare resource utilization (subject reported)
X
PGI-S, PGI-C4, 9
X
SF-364, 9
X
EQ-5D-5L& EQ-VAS4, 5, 9
X
ABPM sub-study (Appendix 12):                        24 hour ABPM
X (Week 16)
Record awake and sleep times
X (Week 16)2
Note: see footnotes on next page

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Schedule of Assessments for Subjects Permanently Discontinuing Randomized Treatment (Continued)
Protocol activity (visits ± 2 week)
(Note: All visit timings are relative 
to Day 1)
Year 27
Year 37
Year 47
Unscheduled
End of 
Study8
Week 
64
Week 
76
Week 
88
Week 
100
Week 
112
Week 
124
Week 
136
Week 
148
Week 
160
Week 
172
Week 
184
Week 
196
Week 
208
IRT system call
X
SBP/DBP, HR (pre- and post-
dialysis for in-center HD subjects, 
between treatments for HHD and 
PD subjects) (single readings 
unless otherwise indicated)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
HemoCue Hgb
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Hematology3  
X
Hgb 
only
X
Hgb 
only
X
Hgb 
only
X
Hgb 
only
X
Hgb 
only
X
Hgb 
only
X
X
Clinical chemistry3
X
X
X
X
X
X
X
X
Hospitalization1, kidney transplant1
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Non-serious AEs, SAEs, AEs of 
special interest, clinical events 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Review concomitant medications
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
1. Record in eCRF, if applicable.
2. Subject will record sleep and wake time during the ABPM session.
3. See details on hematology and clinical chemistry in Section 7.4.11.
4. Only completed at Early Treatment Discontinuation visit if the randomized treatment discontinuation occurs on or before Week 52
5. Only in selected countries. See Appendix 3.
6. Additional pregnancy test required at subsequent visit. Must be at least 4 weeks after the end of randomized treatment.
7. Phone visits are acceptable in exceptional circumstances.
8. Investigator will inform subject when to attend this End of Study visit.
9. Subjects who are unable to or require assistance to read must not complete the questionnaires.

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7.2.
Screening and Critical Baseline Assessments
Before any study-specific procedure is performed, valid informed consent must be 
obtained at screening.
Demography and medical history (including CV medical history/risk factors) will be 
assessed at screening (Week -8).
Randomization requires a Hgb on Day 1 in the range as defined by ESA use and region 
(Section 4.1). 
Full details of screening (Week -8) and baseline (Day 1) assessments are provided in the 
Time and Events Table Section 7.1.
7.3.
Efficacy
Planned time points for all Hgb efficacy assessments are listed in the Time and Events 
Table (Section 7.1).  
GSK will supply a point-of-care Hgb analyzer (i.e., HemoCue) to each site for rapid 
measurement of Hgb. 
Blood samples for measurement of Hgb via HemoCue and also by the central laboratory 
will be collected as specified in Time and Events Table (Section 7.1).
7.4.
Safety
Planned time points for all study safety assessments are listed in the Time and Events 
Tables (Section 7.1). 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 endpoint events including deaths 
(Section 7.4.1), other CV events (Section 7.4.2), AEs of special interest (Section 7.4.4), 
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 5.5. Liver chemistry stopping and follow-up criteria are described in 
Section 7.4.12 and Appendix 8.
7.4.1.
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 for adjudication.  See CEC Site Manual for full scope of 
reporting requirements.  

All-cause mortality (CV and non-CV mortality)

Non-fatal MI

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
Non-fatal stroke

Hospitalization for HF

Thromboembolic events (vascular access thrombosis, deep vein thrombosis, 
pulmonary embolism)
When the investigator-reported event and the Clinical Events Classification (CEC) 
assessment by the committee differ, the committee’s decision will be considered final. 
The detailed descriptions of the endpoint definitions used for adjudication are contained 
within the Clinical Events Committee Charter (available on request). 
Source documentation required to support the adjudication of the events is described in 
the CEC Site Manual.  Recording of potential endpoint events in the eCRF and 
submission of source documentation will be required.
Positively adjudicated events will be reported separately (Section 7.4.3). Negatively 
adjudicated events will be reported as AEs or SAEs using the investigator-reported event 
term.
7.4.2.
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 7.4.4 for further 
details).

Valvulopathy

Revascularization 
7.4.3.
Adverse Events (AE) and Serious Adverse Events (SAEs)
The definitions of an AE or SAE can be found in Appendix 7.
The investigator or their designees are responsible for detecting, documenting and 
reporting events that meet the definition of an AE or SAE. 
For this study, events referred to the Clinical Events Committee (Section 7.4.1) will be 
subjected to blinded adjudication using pre-specified diagnostic criteria. Positively 
adjudicated events will be reported separately. Negatively adjudicated events will be 
reported as AEs or SAEs using the investigator-reported event term.
Events should be reported as an AE or SAE according to the definitions in Appendix 7. 

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7.4.3.1.
Time period and Frequency for collecting AE and SAE information

Any SAEs assessed as related to study participation (e.g., protocol-mandated 
procedures, invasive tests, or change in existing therapy) or related to a GSK product 
will be recorded in the subject’s eCRF from the time a subject consents to participate 
in the study up to and including any follow-up contact. 

AEs and SAEs will be collected from the start of placebo run-in until the Follow-up 
visit (or the “End of Study” visit for subjects that discontinue study treatment early) 
(Section 7.4.3.2), at the time points specified in the Time and Events Table (Section 
7.1).

Medical occurrences that begin prior to the start of placebo run-in but after obtaining 
informed consent may be recorded on the Medical History/Current Medical 
Conditions Section of the eCRF.

All SAEs will be recorded in the eCRF and reported to PPD within 24 hours, as 
indicated in Appendix 7.

Investigators are not obligated to actively seek AEs or SAEs in former study 
subjects. However, if the investigator learns of any SAE, including a death, at any 
time after a subject has been discharged from the study, and he/she considers the 
event reasonably related to the randomized treatment or study participation, the 
investigator must promptly notify PPD.
NOTE: The method of recording, evaluating and assessing causality of AEs and SAEs 
plus procedures for completing and transmitting SAE reports to PPD are provided in 
Appendix 7.
7.4.3.2.
Method of Detecting AEs and SAEs
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended 
and non-leading verbal questioning of the subject is the preferred method to inquire about 
AE occurrence.  Appropriate questions include:

“How are you feeling?” 

“Have you had any (other) medical problems since your last visit/contact?” 

“Have you taken any new medicines, other than those provided in this study, since 
your last visit/contact?” 
7.4.3.3.
Follow-up of AEs and SAEs
After the initial AE/SAE report, the investigator is required to proactively follow each 
subject at subsequent visits/contacts.  All endpoint events (as defined in Section 7.4.1), 
SAEs, and non-serious AEs of special interest (as defined in Section 7.4.4) will be 
followed until resolution, until the condition stabilizes, until the event is otherwise 
explained, or until the subject is lost to follow-up (as defined in Section 5.5). Further 
information on follow-up procedures is given in Appendix 7.

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7.4.3.4.
Regulatory Reporting Requirements for SAEs
Prompt notification by the investigator to PPD of SAEs related to placebo or randomized 
treatment is essential so that legal obligations and ethical responsibilities towards the 
safety of subjects and the safety of a product under clinical investigation are met. 
GSK has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a product under clinical investigation. GSK will 
comply with country specific regulatory requirements relating to safety reporting to the 
regulatory authority, Institutional Review Board (IRB)/Independent Ethics Committee 
(IEC) and investigators.
Investigator safety reports are prepared for suspected unexpected serious adverse 
reactions according to local regulatory requirements and GSK policy and are forwarded 
to investigators as necessary.
An investigator who receives an investigator safety report describing a SAE(s) or other 
specific safety information (e.g., summary or listing of SAEs) from GSK will file it with 
the IB and will notify the IRB/IEC, if appropriate according to local requirements.
7.4.4.
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):

Thrombosis and/or tissue ischemia secondary to excessive erythropoiesis

Worsening of hypertension

Cardiomyopathy  

Pulmonary artery hypertension (see also Section 7.4.2)

Cancer-related mortality and 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 page and the relevant AE 
of special interest page of the subject’s eCRF.
7.4.5.
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).

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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.
7.4.6.
Pregnancy
Details of all pregnancies in female subjects will be collected from the start of dosing and 
until seven days after the last dose.
If a pregnancy is reported then the investigator should inform PPD within 24 hours of 
learning of the pregnancy and should follow the procedures outlined in Appendix 10.
7.4.7.
Height and Weight
Height and weight will be measured as specified in the Time and Events Table (Section 
7.1). Weight will be measured with the subject wearing indoor daytime clothing with no 
shoes. For in-center HD subjects, weight will be measured pre and post-dialysis. For 
HHD subjects, weight will be done at study visits between dialysis sessions.  For PD 
subjects, this assessment will be done at study visits, as per standard of care.
EDW will be reported at each study visit as specified in the Time and Events Table 
(Section 7.1).
7.4.8.
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 Time and Events Table Section 7.1.

One measurement each of SBP, DBP and HR will be taken, except at Day 1, 
Week 52, End of Study visit, and at the Early Treatment Discontinuation visit (if 
applicable), when SBP, DBP and HR will be measured in triplicate. 

Measurements will be taken with the subject in a semi-supine or seated position in 
the dialysis chair after at least a 5-minute rest period (pre- and post-dialysis).
For in-center HD subjects, SBP, DBP and HR will be measured pre and post-dialysis. For 
HHD subjects, these assessments will be done at study visits between dialysis sessions.  
For PD subjects, this assessment will be done at study visits, as per standard of care.
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).
7.4.9.
Electrocardiogram (ECG)
ECG measurements will be taken at the time points specified in the Time and Events 
Table (Section 7.1). Full 12-lead ECGs will be recorded with the subject in a supine 
position. HR, PR interval, QRS duration, and QT (uncorrected) interval will be measured. 
QTcB will be calculated (machine-read or manually).

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For the Day 1 ECG, two additional ECGs are required if the initial ECG indicates 
prolonged QTc (see Section 5.2) using the automated or manually calculated QTcB 
value.  The average QTcB value of all three ECGs will be used to determine eligibility 
(see Section 5.2). Additional details are provided in the SRM.
ECG data will be read locally by a physician with experience in reading and interpreting 
ECGs.  The over-read of the Day 1 ECG is required to confirm eligibility. Additional 
details are provided in the SRM.
All ECGs 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).
7.4.10.
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 from 
randomization. Further details are provided in the SRM.
A documented ultrasound of the kidneys within the 6 months prior to screening may be 
used to assess entry criteria (see Section 5.2), 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.
7.4.11.
Clinical Laboratory Assessments
All protocol required laboratory assessments, as defined in Table 10, must be conducted 
in accordance with the Laboratory Manual, and Protocol Time and Events Schedule 
(Section 7.1). Laboratory assessments will be done pre-dialysis for in-center HD 
subjects, in between dialysis sessions for HHD subjects at the study visits, and at the 
study visits for PD subjects, as per standard of care.
Laboratory requisition forms must be completed and samples must be clearly labeled 
with the subject number, protocol number, site/center number, and visit date. Details for 
the preparation and shipment of samples will be provided by the laboratory and are 
detailed in the SRM. Reference ranges for all safety parameters will be provided to the 
site by the laboratory responsible for the assessments.
If additional non-protocol specified laboratory assessments are performed at the 
institution’s local laboratory and result in a change in subject management or are 
considered clinically significant by the investigator (e.g., SAE or AE or dose 
modification) the results must be recorded in the source notes.
Refer to the SRM for appropriate processing and handling of samples.

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All study-required laboratory assessments 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 must be entered into the subject’s eCRF.
Table 10
Protocol Required Laboratory Assessments
Laboratory 
Assessments
Parameters
Hematology
Platelet count
RBC indices:
WBC count with Differential
RBC count
MCV
Neutrophils
Reticulocyte count
MCH
Lymphocytes
Hgb
MCHC
Monocytes
Hematocrit
RDW
Eosinophils
Basophils
Clinical 
Chemistry1
Potassium (serum)
AST
Albumin (serum)
Calcium (total and 
albumin-adjusted)
ALT
Urea (serum) 
Inorganic phosphate
Bilirubin (total and 
direct/indirect)
Iron 
parameters
Iron (serum)
Ferritin 
UIBC
Hepcidin
TIBC 
TSAT
Lipid 
parameters
Total cholesterol
LDL-C (direct)
HDL-C
Other 
laboratory 
tests
Serum pregnancy test2
FSH3
Estradiol3
HemoCue Hgb
HbA1c4
hsCRP
iPTH
Stored sample (blood)
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; LDL-
C, low density lipoprotein-C; HDL-C, high density lipoprotein-C; TIBC, total iron binding capacity
1.
Details of Liver Chemistry Stopping Criteria and Required Actions and Follow-Up Assessments after liver stopping 
or monitoring event are given in Section 7.4.12 and Appendix 8.
2.
For females of reproductive potential only.
3.
Screening only. As needed in postmenopausal women where their menopausal status is in doubt (see Inclusion 
Criteria Section 5.1).
4.
Only subjects with diabetes.
All laboratory tests with values that are considered clinically significantly abnormal 
during participation in the study or within seven days after the last dose of randomized 
treatment should be repeated until the values return to normal or baseline.  If such values 
do not return to normal within a period judged reasonable by the investigator the sponsor 
should be notified.
7.4.12.
Liver Chemistry Stopping Criteria
Liver chemistry stopping and increased monitoring criteria have been designed to 
assure subject safety and evaluate liver event etiology [in alignment with the Food and 
Drug Administration (FDA) premarketing clinical liver safety guidance]. 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM174090.pdf

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Phase 3-4 Liver Chemistry Stopping and Increased Monitoring Algorithm
Continue Study Treatment 
Discontinue Study Treatment 
Plus 
Bilirubin≥2x
ULN (>35% 
direct) or plus
INR>1.5, if 
measured*
Possible  
Hy’s Law
ALT≥3xULN
ALT
≥8xULN
Plus
Symptoms of 
liver injury
or 
hypersensitivity
No
Yes
Yes
Yes
No
No
No
See algorithm 
for continued 
therapy with 
increased liver 
chemistry 
monitoring
Yes
*INR value not applicable to subjects on anticoagulants 
ALT 
≥3xULN 
but 
<8xULN
Yes
Must refer to Liver Safety Required Actions and Follow up Assessments section in the Appendix
Report as an SAE if possible Hy’s Law case: ALT≥3xULN and  Bilirubin≥2xULN (>35% direct)  or 
INR>1.5, if measured*
Liver Safety Required Actions and Follow up Assessments Section can be found in 
Appendix 8.

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Phase 3-4 Liver Chemistry Increased Monitoring Algorithm with Continued 
Therapy for ALT 3xULN but <8xULN
Continue Study Treatment   and   Monitor Liver Chemistry
Discontinue Study Treatment 
ALT≥5xULN 
but <8xULN
+ bili <2xULN +
no symptoms
No
Must refer to Liver Safety Required Actions and Follow up Assessments section in the Appendix
Yes
ALT ≥3xULN 
but <5xULN
+ bili <2xULN  +
no symptoms
Able to 
monitor  
weekly 
for  ≥2 
weeks
Persists for 
≥2 weeks  
or other 
stopping 
criteria  
met
No
Yes
Yes
Yes
No
No
Able to 
monitor  
weekly 
for  ≥4 
weeks
Persists for 
≥4 weeks  
or other 
stopping 
criteria  
met
No
Yes
Yes
Yes
Yes
ALT ≥5xULN 
ALT <5xULN 
Yes
Yes
*INR value not applicable to subjects on anticoagulants 
Must refer to Liver Safety Required Actions and Follow up Assessments section in the Appendix
Report as an SAE if possible Hy’s Law case: ALT≥3xULN and  Bilirubin≥2xULN (>35% direct)  or 
INR>1.5, if measured*
Liver Safety Required Actions and Follow up Assessments Section can be found in 
Appendix 8.
7.4.12.1.
Randomized Treatment Restart
If a subject meets liver chemistry stopping criteria do not restart randomized treatment 
unless there is a clear underlying cause for the liver stopping event other than drug-
induced liver injury and:

GSK Medical Governance approval is granted in writing

Ethics and/or IRB approval is obtained, if required, and

Separate consent for treatment restart is signed by the subject
Refer to Appendix 9 for full guidance. 
7.5.
Genetics
Information regarding genetic research is included in Appendix 11.
Samples for genetic analysis will be taken at the time points specified in the Time and 
Events Table (Section 7.1).

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7.6.
Storage Biomarkers
Blood (serum and plasma) samples will be collected as outlined in the Time and Events 
Table (Section 7.1) for potential future analysis of biomarkers of CV risk and iron 
metabolism.
7.7.
Patient Reported Outcomes
The patient-reported effect of daprodustat and rhEPO on symptom, health-related quality 
of life (HR-QoL), and health status (e.g. utility) 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). Quality of life will be 
measured via SF-36 and health status via the EQ-5D-5L and EQ-5D-VAS.  In addition, 
healthcare resource utilization will be assessed including outpatient visits.
All questionnaires used in this study have been translated, and culturally adapted for use 
in local country languages and will be administered electronically. Specific instructions 
on how the subject is to complete the scales and the process for data entry is provided in 
the SRM.  If there are exceptional circumstances whereby the electronic PRO 
assessments cannot be conducted, the completion of these assessments will be discussed 
with the sponsor on a case-by-case basis.
The severity, HR-QoL and Health Status questionnaires should be completed by subjects 
at a clinic visit, in the order specified: PGI-S, PGI-C, SF-36 then EQ-5D-5L and EQ-
VAS. Subjects who are unable to or require assistance to read must not complete the 
questionnaires.
7.7.1.
Patient Global Impression of Severity (PGI-S) and Patient Global 
Impression of Change (PGI-C)
The PGI-S is a 1-item questionnaire designed to assess subject’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 subject’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. 
7.7.2.
Health Related Quality of Life (SF-36)
The SF-36 acute version is a general health status questionnaire designed to elucidate the 
subject’s self perception of their health on several domains, including physical 
functioning, role physical, bodily pain, vitality, social functioning, role emotional, mental 
health, and general health over the past seven days.  The questionnaire contains 36 
questions that ask the subject to recall how they felt during the past seven days.

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7.7.3.
Health Status (EQ-5D-5L & EQ-VAS)
The EQ-5D-5L consists of 2 concepts – the EQ-5D-5L descriptive system and the EQ 
Visual Analogue Scale (EQ VAS). The EQ-5D-5L is a self-reported descriptive system 
of health-related quality of life states consisting of five dimensions (mobility, self-care, 
usual activities, pain/discomfort, anxiety/depression) each of which can take one of five 
responses. The responses record five levels of severity (no problems/slight 
problems/moderate problems/severe problems/extreme problems) within a particular EQ-
5D dimension. Self-reported health status captured by EQ-5D-5L relates to the subject’s 
situation at the time of completion. 
The EQ VAS records the respondent’s self-rated health on a vertical, visual analogue 
scale where the endpoints are labeled ‘the best health you can imagine’ and ‘the worst 
health you can imagine’. This information is used as a quantitative measure of health 
outcome as judged by individual subjects.
The EQ-5D-5L and EQ VAS will only be completed by subjects in selected countries 
which require this data as part of their reimbursement assessment process as noted in 
Appendix 3.
8.
DATA MANAGEMENT

For this study subject data will be entered into eCRFs, transmitted electronically and 
combined with data provided from other sources in a validated data system.  

Management of clinical data will be performed in accordance with applicable GSK 
standards and data cleaning procedures to ensure the integrity of the data, e.g., 
removing errors and inconsistencies in the data.

AE and concomitant medications terms will be coded using MedDRA (Medical 
Dictionary for Regulatory Activities) and an internal validated medication dictionary, 
GSK-Drug, respectively.  

eCRFs (including queries and audit trails) will be retained by GSK, and copies will be 
sent to the investigator to maintain as the investigator copy.  Subject initials will not 
be collected or transmitted to GSK according to GSK policy.
9.
STATISTICAL CONSIDERATIONS AND DATA 
ANALYSES
The study has two co-primary objectives and endpoints:
Objectives
Endpoints
Co-primary (tested in parallel for non-inferiority)

To compare daprodustat to rhEPO for CV 
safety (non-inferiority)

Time to first occurrence of adjudicated MACE 
(composite of all-cause mortality, non-fatal 
myocardial infarction (MI) and non-fatal stroke)

To compare daprodustat to rhEPO for Hgb 
efficacy(non-inferiority)

Mean change in Hgb between baseline and EP 
(mean over Weeks 28 to 52)

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The co-primary endpoints will each be tested using a one-sided 2.5% significance level 
and the relevant confidence bound of the two-sided 95% CI (upper bound for MACE and 
lower bound for the Hgb co-primary endpoint). The type I error rate will be strictly 
controlled at the one-sided 2.5% level across the co-primary analyses as both non-
inferiority tests need to be met for the trial to be considered successful and for statistical 
analysis to proceed to evaluate MACE superiority and superiority for the principal 
secondary objectives/endpoints. 
9.1.
Hypotheses
9.1.1.
CV Safety (MACE) Co-Primary Hypothesis
The co-primary CV safety objective will assess the estimand of time to first occurrence 
(in days) of adjudicated MACE from randomization to the end of study in all randomized 
subjects regardless of what treatment(s) they go on to receive. The primary analysis will 
test for non-inferiority of treatment with daprodustat relative to rhEPO, expressed by the 
following statistical hypotheses: 

Null: daprodustat is inferior to rhEPO, with at least a 25% increased relative risk 
of first MACE (i.e. the hazard ratio is 1.25)

Alternative: daprodustat is non-inferior to rhEPO (i.e. the hazard ratio is <1.25)
The non-inferiority margin is pre-defined as the hazard ratio of 1.25; supported by a 
review of evidence reported in historical randomized trials of rhEPO in dialysis and ND 
CKD subjects and after consideration of the largest point estimate that, by design, would 
meet the statistical criterion for non-inferiority. 
Statistical significance of non-inferiority will be assessed at the one-sided 2.5% level. A 
Cox-Proportional Hazards-Regression model, adjusting for treatment and prognostic 
randomization stratification factors (dialysis type and region), will be used to estimate the 
hazard-ratio, its two-sided 95% CI and to generate the p-value for the non-inferiority test. 
Non-inferiority will be achieved if the upper limit of the two-sided 95% CI is below the 
margin of 1.25.  
9.1.2.
Hgb efficacy Co-Primary Hypothesis
The co-primary Hgb efficacy objective will assess the estimand defined as the effect of 
daprodustat treatment relative to rhEPO on the change in Hgb from baseline to the 
average of all values in the EP, regardless of adherence to treatment including 
interruptions and discontinuations, the use of non-randomized ESA medication for any 
reason including rescue therapy, or the use of blood transfusions, in subjects on dialysis 
currently treated with an ESA with anemia secondary to CKD and assuming subjects do 
not die before the end of the EP. The analysis will test whether daprodustat is non-
inferior to rhEPO according to the following statistical hypotheses: 

Null: The difference in mean change in Hgb between baseline and EP, between 
treatment arms (daprodustat -rhEPO), is less than or equal to -0.75 g/dL.

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
Alternative: The difference in mean change in Hgb between baseline and EP, 
between treatment arms (daprodustat -rhEPO), is greater than -0.75 g/dL 
The non-inferiority margin is pre-defined as -0.75 g/dL; 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 
ANCOVA model including prognostic randomization stratification factors (dialysis type 
and region), baseline Hgb and treatment will be used to obtain a point estimate and the
two-sided 95% 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.
The co-primary endpoints will be tested first. Non-inferiority needs to be established for 
both co-primary’s to proceed to evaluate MACE for superiority as well as the principal 
secondary endpoints for superiority. Principal secondary endpoints include prioritized 
composites for MACE (including thromboembolic events and hospitalizations for HF) 
and IV iron utilization (defined as the average monthly IV iron dose used to Week 52). 
Statistical testing of MACE for superiority as well as the principal secondary endpoints 
will be adjusted for multiplicity (Section 9.4.3).
9.2.
Sample Size Considerations
9.2.1.
Sample Size Assumptions
The size of this event driven trial is based on the co-primary CV safety objective and is 
determined by a fixed event target of 664 adjudicated first MACE. This provides 
approximately 90% power to establish non-inferiority assuming a true underlying 3% 
lower relative risk of MACE in favor of daprodustat compared to rhEPO (i.e., hazard 
ratio=0.97) and 82% power for non-inferiority under the assumption that the true 
underlying risk of MACE is the same in both arms (i.e., hazard ratio=1.00). Other 
assumptions behind the sample size calculation include:

Projected annual adjudicated first MACE rate of 11%. All-cause death is expected 
to be the most prevalent component, followed by non-fatal MI and then non-fatal 
stroke (projected break down of 60%, 30% and 10% respectively). 

Variance under the alternative hypothesis (i.e. hazard ratio=0.97) 

1% annual lost to follow-up without vital status

A two-sided 95% CI is used for analysis
The target of 664 adjudicated first MACE will permit a two-sided 95% CI of (0.859, 
1.164) to describe the results for an observed hazard ratio of 1. The largest hazard ratio 
point estimate (two-sided 95% CI) that would meet the statistical criterion for non-
inferiority is 1.074 (0.922, 1.250) and for superiority, the minimum observable effect 
would be a 14.1% relative risk reduction in favor of daprodustat, corresponding to a 
hazard ratio of 0.859. 

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Conditional on both co-primary endpoints achieving non-inferiority at the one-sided 
2.5% level, statistical testing will progress to evaluate MACE and the principal secondary 
endpoints for superiority. These tests will be multiplicity adjusted, details are provided in 
Section 9.4.3. 
Based on an annual MACE rate of 11%, it is anticipated that the 664 adjudicated first 
MACE target will be reached approximately 3.3 years from when the first subject is 
randomized. All subjects will have the opportunity for a minimum of 1 year exposure to 
treatment and thus the opportunity to complete the EP (Weeks 28 to 52). Exposure to 
daprodustat is expected to be in the region of 3,500 patient years with median patient 
follow-up expected to exceed 2 years.
Note: The country-specific requirements for France ONLY for the sample size 
consideration are provided in Appendix 14 (see Section 12.14.1, Item 2 for details).
9.2.2.
Sample Size Sensitivity
The estimated 11% annual MACE rate is based on a blinded summary of ASCEND-D 
data as of April 20, 2020. Table 11 illustrates the impact on power if the true underlying 
treatment effect is not a hazard ratio of 0.97. 
Table 11
Sensitivity Based on a Different True Underlying Treatment Effect
Underlying hazard 
ratio for MACE rate
Power for non-
inferiority
0.90
99%
0.95
94%
0.97 (base case)
90%
1.00
82%
1.03
70%
1.05
61%
Impact of Sample Size for Hgb Efficacy Analysis
Subjects will be treated to achieve and maintain a Hgb between 10 and 11 g/dL. The 
expected difference in mean Hgb change from baseline between arms and the EP is 
0 g/dL and the anticipated standard deviation (SD) is 1.5 g/dL, based on historical rhEPO 
trials and daprodustat clinical trial experience to date. 
For 90% power to test the co-primary non-inferiority Hgb hypothesis, with a two-sided 
95% CI, pre-specified margin of -0.75 g/dL and a two-sample T-test, a total of 86 
evaluable subjects per treatment group are required. The planned study size far exceeds 
this requirement and provides more than 99% power for non-inferiority and a high level 
of precision to estimate the treatment effect (two-sided 95% CI half width of 0.128 g/dL, 
assuming 30% of subjects will be non-evaluable for efficacy). The largest (most 
negative) difference between arms that would meet the statistical criterion for non-
inferiority would be -0.622 g/dL. If the two-sided 95% CI is completely negative (i.e. lies 
fully within the range -0.75 to <0g/dL) non-inferiority would still be concluded.

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9.2.3.
Sample Size Re-estimation or Adjustment
At the time of this protocol amendment, the study was fully enrolled, and as such no 
sample size re-estimation was performed.  
9.3.
Data Analysis Considerations
9.3.1.
Analysis Populations
The primary population for analyses of MACE and other time to event outcomes will be 
the All Randomized (ITT) Population. Subjects will be analyzed according to the 
treatment to which they were randomized.
The primary population for the Hgb efficacy analyses will also be the ITT Population.  A 
supportive analysis of the primary efficacy endpoint will be performed in a Per-Protocol 
(PP) Population defined as all ITT subjects who are not major protocol violators. Details 
will be defined in the RAP and subjects analyzed according to the treatment received.
The primary population for safety will be based on all randomized subjects who receive 
at least one dose of randomized treatment. Subjects will be analyzed according to the 
treatment received.
Additional populations may be defined in the RAP, including sub-study populations.
9.4.
Key Elements of Analysis Plan
9.4.1.
Primary Analyses
9.4.1.1.
Primary CV Safety Analysis (co-primary)
MACE: The co-primary cardiovascular safety analysis is to assess the comparative 
treatment effect for time to first occurrence of adjudicated MACE in all randomized 
subjects. Time to the first occurrence of a primary endpoint event will be computed as 
(event date – randomization date) +1. Subjects who do not have the event during the trial 
period will be censored in the analysis, with details provided in the RAP. The statistical 
model is a Cox Proportional Hazards regression model, adjusting for treatment and the 
prognostic randomization stratification factors (dialysis type and region), to estimate the 
hazard ratio, two-sided 95% CI and one-sided p-value for the statistical non-inferiority 
test. Non-inferiority will be established if the upper limit of the two-sided 95% CI is less 
than the margin of 1.25. Cumulative time from randomization to first event or end of trial 
will be evaluated using Kaplan-Meier methodology and displayed graphically. Treatment 
comparisons from the Cox regression model will be presented as hazard ratios and two-
sided 95% CIs and displayed on forest plots. The validity of the proportional hazards 
assumption will be assessed. All adjudicated events will be used for the primary analysis 
and concordance between investigator reported and adjudicated events will be 
summarized.  
Sensitivity and Supportive Analyses: A sensitivity analysis will be performed to 
address potential effects of drop outs and to evaluate the robustness of the co-primary 

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MACE analysis. A sensitivity “tipping point” analysis utilizing multiple imputation for 
randomized subjects who have withdrawn from the study will be performed, as well as a
supportive “on-drug” analysis to evaluate the comparative treatment effect during the 
time that subjects remain on randomized treatment (plus a window of 28 days). Full 
details will be provided in the RAP.
In addition, analyses will be performed for each component of MACE (all-cause
mortality, MI and stroke) to understand individual contributions to the overall MACE 
result and to assess component directional consistency. These analyses will not be 
multiplicity adjusted. Further subgroup and covariate adjusted analyses of specific 
clinical interest are detailed in Section 9.4.4 and the RAP.
9.4.1.2.
Primary Efficacy Analysis (co-primary)
Mean change in Hgb between baseline and the EP (Weeks 28 to 52): The primary 
efficacy estimand is the effect of daprodustat relative to rhEPO on the change in Hgb 
from baseline to the average of all values in the EP, regardless of adherence to treatment 
including interruptions and discontinuation, the use of non-randomized ESA medication 
for any reason including rescue therapy, or the use of blood transfusions, in subjects on 
dialysis currently treated with an ESA with anemia secondary to CKD and assuming 
subjects do not die before the end of the EP. The analysis will use an ANCOVA model. 
For each subject, 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 and imputed Hgb values between Weeks 28 to 52 inclusive regardless of 
adherence to randomized treatment. The ANCOVA model will include prognostic 
randomization stratification factors (dialysis type and region), 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. Imputation will be used for missing Hgb data; further details will be provided in the 
RAP.
Sensitivity and Supportive 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 subjects who did not fully 
complete the EP. A supportive analysis will evaluate efficacy in those subjects who 
adhere to randomized treatment, defined as ITT subjects with at least one on-treatment 
Hgb during the EP (this approach corresponds to evaluating an efficacy estimand). A 
supportive “tipping point” analysis as that described above for the primary analysis will 
be performed for this “on-drug” analysis. In addition, a per-protocol supportive analysis 
will estimate the treatment effect in subjects who strongly adhere to the protocol, and 
supportive analyses to explore a shorter EP (Weeks 28 to 36) will be performed for the 
co-primary effectiveness estimand and “on-drug” efficacy estimand. Full details of all 
sensitivity and supportive analyses will be provided in the RAP.

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9.4.2.
Secondary Analyses
9.4.2.1.
Principal Secondary Analyses
Conditional on the co-primary endpoints achieving at least non-inferiority at the one-
sided 2.5% level, statistical testing will progress to superiority for MACE and the 
principal secondary endpoints.  The hypotheses to be tested for these endpoints are as 
follows: 

Null: daprodustat is not superior to rhEPO (i.e. the hazard ratio is greater than or 
equal to 1.0 for time-to-event endpoints, or the mean difference is greater than or 
equal to 0 for continuous endpoints)

Alternative: daprodustat is superior to rhEPO (i.e. the hazard ratio is less than 1.0 
for time-to-event endpoints, or the mean difference is less than to 0 for continuous 
endpoints)
These tests will be multiplicity adjusted based on a family-wise Type I error rate set at 
the one-sided 2.5% level, see Section 9.4.3 for further details. 
For “time to event” endpoints: The statistical modeling approach described for MACE 
in Section 9.4.1.1 will be repeated for the adjudicated composite endpoints of:

MACE or a thromboembolic event (vascular access thrombosis, symptomatic deep
vein thrombosis or symptomatic pulmonary embolism).

MACE or hospitalization for HF.
For the average monthly IV iron dose up to Week 52 endpoint: IV iron use for all 
subjects will be recorded in the eCRF and the average monthly IV iron dose up to week 
52 will be calculated. An ANCOVA model will be used to compare the difference in this 
average monthly IV iron dose per subject between arms, including factors for baseline 
dose, treatment and the prognostic randomization stratification factors.
Additional secondary endpoints are listed in Appendix 2. All analyses of secondary 
endpoints are of exploratory nature, summary statistics and nominal one-sided p-values
will be used for any treatment comparisons.
9.4.2.2.
Analysis Patient Reported Outcomes
Analysis to compare the subject reported effects of daprodustat and rhEPO on symptoms, 
health related quality of life, and health status, as discussed in Section 7.7, will be 
described in the RAP.
9.4.2.3.
Safety Analyses
Safety data, including all AEs (i.e., non-serious, serious and AEs of special interest), 
laboratory data, SBP, DBP, HR, concomitant medications and meeting protocol defined 
safety stopping criteria (e.g., liver chemistry) will be descriptively summarized by 
treatment group. Reasons for stopping randomized treatment and for early study 
withdrawal will also be descriptively summarized by treatment group and time to 
stopping treatment or study will be presented graphically and assessed. Full details of all 
safety data reporting are described in the RAP.

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9.4.3.
Multiplicity Strategy
The multiplicity strategy for this trial will use a combination of a gatekeeper approach on 
the co-primary endpoints, followed by a closed-test multiplicity procedure wrapped 
around the family of superiority hypotheses consisting of MACE and the principal 
secondary endpoints. 
Figure 2 illustrates the structure of the statistical testing plan. First, the co-primary 
endpoints will be evaluated for non-inferiority by comparing each two-sided 95% CI to 
the appropriate non-inferiority margin. Conditional on both co-primary endpoints 
achieving non-inferiority (i.e., passing the gatekeeper), the family of MACE and the 
principal secondary endpoints will be formally tested for superiority using the widely 
known Holm-Bonferroni procedure [Holm, 1979]. The procedure will be conducted 
based on a family-wise Type I error rate set at the one-sided 2.5% level. Details of the 
Holm-Bonferroni procedure will be fully described in the RAP.
Section 9.4.5 describes the planned interim analysis for the assessment of MACE futility. 
While this analysis will have a small impact on reducing the study-wise Type I error rate, 
there are no plans to adjust the alpha level used for end-of-study analyses. There are no 
prospectively defined plans to stop this study early for benefit.
Figure 2
Multiplicity controlled statistical testing plan
9.4.4.
Covariates and Subgroups of Interest
The co-primary and principal secondary endpoints will be evaluated for a set of pre-
specified subgroups to support the proposed indication. For the co-primary efficacy 
endpoint, these subgroups will be evaluated for both the primary ITT analysis of Hgb 
values during the EP regardless of adherence to treatment, as well as the sensitivity 
analysis limited to on-treatment Hgb values during the EP.

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Although subgroup analyses aim to assess for consistency with the overall results, they 
may have low power, especially if the subgroup is small or has a low number of events. 
Statistical models will be adjusted for the covariates used in the original analysis, 
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 years - <75, ≥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 
Appendix 3
Country 
Appendix 3
Dialysis type 
HD, PD (repeat using HD, HDF/HF, PD)
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 below for definition)
Baseline Hgb
<9, 9 to <10, 10 to 11, >11 g/dL
BMI 
<30, ≥30 kg/m2
Weight 
< 75kg, ≥75kg 
Baseline hsCRP
≤3 mg/L, >3 mg/L
United states
US, Non-US
rhEPO hyporesponder subgroup definition:  rhEPO hyporesponders will be identified 
either by the ESA Resistance Index (ERI) [HERO study, Johnson, 2015] or by treatment 
at baseline with a very high dose of IV epoetin alpha.  For each subject, baseline ERI will 
be calculated as the dry weight adjusted weekly mean ESA dose during the 8 week 
screening period divided by baseline Hgb concentration. Subjects with baseline ERI 
≥2 U/kg/wk/g/L for epoetin-treated subjects; ≥0.008 g/kg/wk/g/L for darbepoetin-
treated subjects and ≥0.01 g/kg/wk/g/L for methoxy-PEG-epoetin-treated subjects will 
be included in the pre-specified subgroup. In addition, subjects will be included if being 
treated at baseline with greater than or equal to the equivalent of 450 U/kg/week of IV 
epoetin alpha. This latter criterion covers subjects at higher body weight for which the 
ERI calculation is less accurate and is based on the NICE anemia guidelines of June 2015 
[NICE, 2015]. Sensitivity analyses will explore alternative subgroup definitions: an ERI 
cut-point of ≥1.5 (or equivalent depending on ESA treatment) or using baseline prior 
rhEPO dose above the top 20th percentile for the study population.
rhEPO hyporesponder subgroup analysis plan:  It is anticipated that approximately 
10-15% of subjects may be classified as rhEPO hyporesponders according to this 

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definition, thus resulting in a subgroup size of potentially 300-450 subjects. The subgroup 
efficacy analysis will follow the same structure as that defined for the full study, 
assessing the comparative treatment effect in mean Hgb change between baseline and EP 
in subjects regardless of adherence to study treatment as well as in subjects who adhere to 
randomized treatment and using the same non-inferiority margin of -0.75 g/dL. For at 
least 90% power to demonstrate non-inferiority, 86 evaluable rhEPO hyporesponders are 
required per arm.  The statistical model (ANCOVA) will include terms for prognostic 
randomization stratification factors, baseline Hgb, treatment, hyporesponder subgroup 
and treatment by subgroup interaction. Point estimates and two-sided 95% CIs will be 
generated to describe the treatment effect separately for rhEPO hyporesponders and the 
complement set of rhEPO non-hyporesponders; non-inferiority would be established if 
the lower limit of the two-sided 95% CI is greater than -0.75 g/dL. In addition, a nominal 
one-sided non-inferiority p-value and a nominal one-sided superiority p-value for the 
difference between the two groups will be generated. 
While it is unlikely, given the sample size, that a sufficient number of adjudicated first 
MACE will occur to support a robust model-based analysis, subgroup analyses are 
planned for the co-primary MACE and principal secondary CV endpoints. The statistical 
analysis model (Cox Proportional Hazards) will include terms for prognostic 
randomization stratification factors, treatment, hyporesponder subgroup and treatment by 
subgroup interaction. Point estimates and two-sided 95% CIs for the hazard ratio will be 
generated to describe the treatment effect separately for rhEPO hyporesponders and the 
complement set of rhEPO non-hyporesponders; non-inferiority would be established if 
the upper limit of the two-sided 95% CI is less than 1.25.  At a minimum, the incidence 
of MACE, its components and the principal secondary CV endpoints will be descriptively 
summarized by treatment group. 
9.4.5.
Interim Analysis
The IDMC will periodically receive unblinded safety reports containing, at a minimum, 
clinical endpoints (whether adjudicated or pending adjudication) and SAEs, from an 
independent Statistical Data Analysis Center (SDAC) while the study is ongoing.  The 
IDMC may recommend stopping the study for safety at any time. 
In addition, the IDMC will evaluate the co-primary MACE endpoint to assess for futility 
of achieving non-inferiority at study completion. Pre-specified guidelines governing the 
decision to continue or stop the study will consider signals for harm, the predictive 
probability of achieving at least non-inferiority at trial end and the risk of incorrectly 
stopping for futility.  In addition to MACE, any decisions regarding futility will take into 
account data related to: 1) components of MACE, 2) endpoints describing BP, 3) efficacy 
in rhEPO hyporesponders, 4) other safety and efficacy data across the daprodustat 
clinical program, 5) emerging data in the public domain pertaining to safety or efficacy of 
HIF-prolyl hydroxylase inhibitors, and 6) any other data considered to be relevant by the 
IDMC.  The IDMC will make a recommendation to GSK and the ESC chair as outlined 
in the IDMC charter regarding whether the study should continue unchanged, be 
modified or be terminated.  

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There are no prospectively defined interim analysis planned to stop the study early for 
benefit.  While the planned futility analysis will have a small impact on reducing study-
wise Type I error rate, there are no plans to adjust the alpha level used for the final 
analysis. 
Further details of futility rules and analysis timings will be provided in the IDMC Charter 
and RAP.
10.
STUDY GOVERNANCE CONSIDERATIONS
10.1.
Posting of Information on Publicly Available Clinical Trial 
Registers
Study information from this protocol will be posted on publicly available clinical trial 
registers before enrollment of subjects begins.
10.2.
Regulatory and Ethical Considerations, Including the 
Informed Consent Process
Prior to initiation of a site, GSK will obtain favorable opinion/approval from the 
appropriate regulatory agency to conduct the study in accordance with ICH Good Clinical 
Practice (GCP) and applicable country-specific regulatory requirements.
The study will be conducted in accordance with all applicable regulatory requirements, 
and with GSK policy.
The study will also be conducted in accordance with ICH Good Clinical Practice (GCP), 
all applicable subject privacy requirements, and the guiding principles of the current 
version of the Declaration of Helsinki.  This includes, but is not limited to, the following:

IRB/IEC review and favorable opinion/approval of the study protocol and 
amendments as applicable

Obtaining signed informed consent for each subject prior to participation in the 
study.

Investigator reporting requirements (e.g. reporting of AEs/SAEs/protocol 
deviations to IRB/IEC)

GSK will provide full details of the above procedures, either verbally, in writing, 
or both.
The IEC/IRB, and where applicable the regulatory authority, approve the clinical 
protocol and all optional assessments, including genetic research.  

Optional assessments (including those in a separate protocol and/or under separate 
informed consent) and the clinical protocol should be concurrently submitted for 
approval unless regulation requires separate submission.  

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
Approval of the optional assessments may occur after approval is granted for the 
clinical protocol where required by regulatory authorities.  In this situation, 
written approval of the clinical protocol should state that approval of optional 
assessments is being deferred and the study, with the exception of the optional 
assessments, can be initiated.
10.3.
Quality Control (Study Monitoring)

In accordance with applicable regulations including GCP, and GSK procedures, PPD 
monitors will contact the site prior to the start of the study to review with the site staff 
the protocol, study requirements, and their responsibilities to satisfy regulatory, 
ethical, and GSK requirements.  

When reviewing data collection procedures, the discussion will also include 
identification, agreement and documentation of data items for which the eCRF will 
serve as the source document.
PPD will monitor the study and site activity to verify that the:

Data are authentic, accurate, and complete.

Safety and rights of subjects are being protected.

Study is conducted in accordance with the currently approved protocol and any other 
study agreements, GCP, and all applicable regulatory requirements.
The investigator and the head of the medical institution (where applicable) agrees to 
allow the monitor direct access to all relevant documents
10.4.
Quality Assurance

To ensure compliance with GCP and all applicable regulatory requirements, PPD may 
conduct a quality assurance assessment and/or audit of the site records, and the 
regulatory agencies may conduct a regulatory inspection at any time during or after 
completion of the study. 

In the event of an assessment, audit or inspection, the investigator (and institution) 
must agree to grant the advisor(s), auditor(s) and inspector(s) direct access to all 
relevant documents and to allocate their time and the time of their staff to discuss the 
conduct of the study, any findings/relevant issues and to implement any corrective 
and/or preventative actions to address any findings/issues identified.
10.5.
Study and Site Closure

Upon completion or premature discontinuation of the study, the PPD monitor will 
conduct site closure activities with the investigator or site staff, as appropriate, in 
accordance with applicable regulations including GCP, and PPD Standard Operating 
Procedures.

GSK reserves the right to temporarily suspend or prematurely discontinue this study 
at any time for reasons including, but not limited to, safety or ethical issues or severe 
non-compliance. For multicenter studies, this can occur at one or more or at all sites.  

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
If GSK determine such action is needed, PPD will discuss the reasons for taking such 
action with the investigator or the head of the medical institution (where applicable).  
When feasible, PPD will provide advance notification to the investigator or the head 
of the medical institution, where applicable, of the impending action.

If the study is suspended or prematurely discontinued for safety reasons, PPD will 
promptly inform all investigators, heads of the medical institutions (where applicable) 
and/or institution(s) conducting the study. GSK or PPD will also promptly inform the 
relevant regulatory authorities of the suspension or premature discontinuation of the 
study and the reason(s) for the action.  

If required by applicable regulations, the investigator or the head of the medical 
institution (where applicable) must inform the IRB/IEC promptly and provide the 
reason for the suspension or premature discontinuation.
10.6.
Records Retention

Following closure of the study, the investigator or the head of the medical institution 
(where applicable) must maintain all site study records (except for those required by 
local regulations to be maintained elsewhere), in a safe and secure location.  

The records must be maintained to allow easy and timely retrieval, when needed (e.g., 
for a GSK audit or regulatory inspection) and must be available for review in 
conjunction with assessment of the facility, supporting systems, and relevant site 
staff.  

Where permitted by local laws/regulations or institutional policy, some or all of these 
records can be maintained in a format other than hard copy (e.g., microfiche, scanned, 
electronic); however, caution needs to be exercised before such action is taken.  

The investigator must ensure that all reproductions are legible and are a true and 
accurate copy of the original and meet accessibility and retrieval standards, including 
re-generating a hard copy, if required.  Furthermore, the investigator must ensure 
there is an acceptable back-up of these reproductions and that an acceptable quality 
control process exists for making these reproductions.

PPD will inform the investigator of the time period for retaining these records to 
comply with all applicable regulatory requirements.  The minimum retention time 
will meet the strictest standard applicable to that site for the study, as dictated by any 
institutional requirements or local laws or regulations, PPD standards/procedures, 
and/or institutional requirements.  

The investigator must notify PPD of any changes in the archival arrangements, 
including, but not limited to, archival at an off-site facility or transfer of ownership of 
the records in the event the investigator is no longer associated with the site.
10.7.
Provision of Study Results to Investigators, Posting of 
Information on Publically Available Clinical Trials Registers 
and Publication

Where required by applicable regulatory requirements, an investigator signatory will 
be identified for the approval of the clinical study report.  The investigator will be 

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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.

All study investigators will be provided with the full summary of the study results.  
The investigator is encouraged to share the summary results with the study subjects, 
as appropriate.

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.
10.8.
Review Committees
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.
10.8.1.
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 subjects 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.
10.8.2.
Clinical Events Committee
An external independent Clinical Events Committee blinded to treatment allocation will 
adjudicate all events reported during this study that constitute the co-primary CV safety 
endpoint of MACE [composite of all-cause mortality, non-fatal MI and non-fatal stroke], 
the principal CV secondary composite endpoints of MACE plus additional components 
including events of vascular access thrombosis, symptomatic deep vein thrombosis, 
symptomatic pulmonary embolism, CV mortality and hospitalization for HF. 
10.8.3.
Executive Steering Committee
The Executive Steering Committee is the primary external advisory group for GSK. The 
committee provides academic leadership, ensures proper study conduct and conformance 
to the protocol, advises and recommends changes to the protocol based on emerging 
scientific and/or clinical advances, advises on the selection of study sites, communicates 
with the media and external audiences when appropriate, and works with the sponsor to 
assist in patient identification strategies. 
10.8.4.
Steering Committee
The Steering Committee in collaboration with the Executive Steering Committee is 
responsible for the scientific oversight of all aspects of study conduct and will provide 
advice to the National Leader Committee.  

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10.8.5.
National Leader Committee
The National Leader Committee will provide clinical and operational leadership at the 
country and regional level to support the implementation and conduct of the studies. 

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11.
REFERENCES
Beserab A, Reyes C, Hornberger J. Meta-Analysis of Subcutaneous Versus Intravenous 
Epoetin in Maintenance Treatment of Anemia in Hemodialysis Patients. Am J of Kidney 
Dis 2002;40: 439-446.
Choi P, Farouk M, Manamley N, Addison J.Dose Conversion Ratio in Hemodialysis 
Patients Switched from Darbepoetin Alfa to PEG-Epoetin Beta: AFFIRM Study. Adv 
Ther. 2013; 30:1007–1017
Holm S. A simple sequential rejective multiple test procedure. Scandinavian Journal of 
Statistics. 1979; 6: 65-70.
Johnson DW, Pascoe EM, Badve SV et al. on behalf of the HERO Study Collaboration 
Group. A randomized, placebo-controlled trial of pentoxifylline on erythropoiesis-
stimulating agent hyporesponsiveness in anemic patients with CKD: the Handling 
Erythropoietin Resistance With Oxpentifylline (HERO) trial. Am J Kidney Dis. 2015 
65(1):49-57
NICE (National Institute for Health and Care Excellence).Chronic kidney disease: 
managing anaemia. June 2015. Available at: nice.org.uk/guidance/ng8
Sterner G, Prutz KG. Letter to Editor: Conversion from epoetin beta to darbepoetin: what 
is the equivalent dose? Nephrol Dial Transplant. 2008; 23: 4084
Szczech L.A, Barnhart HX, Inrig JK, Reddan DN, Sapp S, Califf RM, Patel UD, Singh 
AK. Secondary analysis of the CHOIR trial epoetin-alpha dose and achieved Hgb 
outcomes. Kidney Int. 2008;74:791-798.

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12.
APPENDICES
12.1.
Appendix 1: Abbreviations and Trademarks
Abbreviations
ABPM
Ambulatory blood pressure monitoring
AE
Adverse event
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 Classification
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
DGF
Delayed graft function
ECG
Electrocardiogram
eCRF
Electronic case report form
EDW
Estimated dry weight
EP
Evaluation period
EPO
Erythropoietin
EQ-5D-5L
EuroQol 5 Dimension 5 Level Health Utility Index
EQ-VAS
EuroQol Visual Analogue Scale 
ESA
Erythropoiesis-stimulating agent
FDA
Food and Drug Administration
FRP
Females of reproductive potential
FSH
Follicle stimulating hormone
GCP
Good Clinical Practice
GI
Gastrointestinal
GSK
GlaxoSmithKline
HbA1c
Glycated hemoglobin
hCG
Human chorionic gonadotrophin
HD
Hemodialysis
HDF
Hemodiafiltration
HDL-c
High density lipoprotein-C
HDPE
High density polyethylene
HF
Heart failure

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Hgb
Hemoglobin
HHD
Home hemodialysis
HIF
Hypoxia-inducible factor
HIF-PHI
Hypoxia inducible factor prolyl hydroxylase inhibitor 
HR
Heart rate
HR-QoL
Health Related Quality of Life
HRT
Hormone replacement therapy
hsCRP
High sensitivity C-reactive protein
IB
Investigator’s Brochure
ICH
International Conference on 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
MACE
Major adverse cardiovascular event
MAP
Mean arterial pressure
MCH
Mean corpuscular hemoglobin;, 
MCHC
Mean corpuscular hemoglobin concentration
MCS
Mental Component Score
MCV
Mean corpuscular volume
MedDRA
Medical Dictionary for Regulatory Activities
MI
Myocardial infarction
mITT
Modified intent-to-treat
MRI
Magnetic resonance imaging
MSDS
Material Safety Data Sheet
NYHA
New York Heart Association
PASP
Pulmonary Artery Systolic Pressure
PCS
Physical Component Score
PD
Peritoneal dialysis
PEG
Polyethylene glycol
PFS
Pre-filled syringe
PGI-C
Patient Global Impression of Change
PGI-S
Patient Global Impression of Severity
PK
Pharmacokinetic
PP
Per protocol
PPD
Pharmaceutical Product Development, LLC
PRBC
Packed red blood cells
PRS
Project specific requirement
PSRAE
Possible Suicidality Related Adverse Events 

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QC
Quality control
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
HemoCue

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12.2.
Appendix 2: Secondary and Exploratory Objectives/ 
Endpoints
Objectives
Endpoints
Secondary Objectives
Secondary Endpoints (tested for superiority1, no 
multiplicity adjustment)

To compare daprodustat to rhEPO on 
additional CV safety endpoints 

All-cause mortality, CV mortality, fatal or non-fatal 
MI, fatal or non-fatal stroke2

MACE or hospitalization for HF2 (recurrent events 
analysis)

CV mortality or non-fatal MI2

All-cause hospitalization

All cause hospital re-admission within 30 days

MACE or hospitalization for HF or thromboembolic 
events2

Hospitalization for HF2

Thromboembolic events2

To compare daprodustat to rhEPO on Hgb 
variability

Hgb change from baseline to Week 521

N (%) responders, defined as mean Hgb within the 
Hgb analysis range 10-11.5  g/dL during EP

% time Hgb in analysis range (10-11.5 g/dL) during 
the evaluation period (EP, Week 28 to 52) and 
during the maintenance period (MP; Week 28 to 
end of trial) (non-inferiority analysis that will use a 
margin of 15% less time in range) 1

To compare daprodustat to rhEPO on BP

Change from baseline in SBP, DBP and MAP at 
Week 52 and at end of treatment 

Number of BP exacerbation events per 100 patient 
years

N (%) with at least one BP exacerbation event 
during study

To compare daprodustat to rhEPO on the 
time to rescue (defined as permanently 
stopping randomized treatment due to 
meeting rescue criteria).

Time to stopping randomized treatment due to 
meeting rescue criteria

To compare daprodustat to rhEPO on 
HRQoL and Utility score

Mean change in SF-36 HRQOL scores (Physical 
Component Score (PCS), Mental Component 
Score (MCS) and 8 health domains) between 
baseline and Weeks 8, 12, 28, 52, of particular 
interest are the changes from baseline in the vitality 
and physical functioning domains at Wk 28 and 52

Change from baseline in Health Utility (EQ-5D-5L) 
score at Week 52 

Change from baseline in EQ VAS at Week 52

To compare daprodustat to rhEPO on the 
symptom severity and change
Change from Baseline at Wk 8,12, 28, 52 in PGI-S

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Objectives
Endpoints
Exploratory Objectives
Exploratory Endpoints (statistical testing not 
planned)

To further compare daprodustat and rhEPO 
on Hgb variability

Hgb observed and change from baseline across all 
visits to end of treatment

% of time Hgb is above, within and below the 
range of 10-11.5 g/dL during EP and MP

Number (%) of subjects with mean Hgb above, 
within and below the Hgb analysis range during EP 
and at the end of treatment 

Number (%) of subjects with a Hgb <7.5 g/dL
during the EP and MP

Number of times Hgb < 7.5 g/dL during the EP and 
MP

Number (%) of subjects with a >1g/dL increase in 
Hgb over 2 weeks (assessed at Week 2 and Week 
4) or a >2 g/dL increase in Hgb within any 4 week 
period from Week 4 to Week 52

Number (%) of subjects with a >1g/dL decrease in 
Hgb over 2 weeks (assessed at Week 2 and Week 
4) or a >2 g/dL decrease in Hgb within any 4 week 
period from Week 4 to Week 52

N (%) of subjects with a Hgb value ≥ 12 g/dL 
during the EP and MP

Number of times Hgb ≥ 12 g/dL during the EP and 
MP

% of time Hgb ≥ 12 g/dL during the EP and MP

To compare daprodustat to rhEPO on 
measures of iron parameters

Observed and change from baseline in hepcidin, 
ferritin, TSAT, total iron, TIBC across all visits to 
end of treatment

Average quarterly ferritin

Average quarterly TSAT

Average quarterly IV iron dose/subject

N (%) of subject who met iron management criteria

N (%) of subjects 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 further  compare daprodustat to rhEPO 
on BP and BP medication changes  

Observed and change from baseline in SBP, DBP 
and MAP by visit

Number of BP medications per subject by visit

Change from baseline in the number of BP 
medications per subject by visit

N (%) of subjects who had no change, an increase 
or a decrease in the dosage or number of BP 
medications from baseline by visit

To compare daprodustat to rhEPO on the 
need for RBC and whole blood transfusions

Number (%) of subjects who receive at least one 
RBC or whole blood transfusions by Week 52 and 
by end of treatment

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Objectives
Endpoints

Number of RBC and whole blood transfusions per 
100 patient years 

Number of RBC and whole blood units per 100 
patient years

To compare daprodustat to rhEPO 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 compare the effect of daprodustat to 
rhEPO on delayed graft function (DGF) after 
deceased donor kidney transplantation

Number (%) of subjects experiencing DGF after 
deceased donor kidney transplantation (where 
DGF is defined as the use of dialysis within 7 days 
of the transplant)

Length of time that subjects experience DGF after 
deceased donor kidney transplantation

Evaluate the dose adjustment schemes

Assigned dose by visit and at Day 1, Week 28, 
Week 52, and yearly

Most recent dose prior to Week 28, Week 52, 
yearly and End of Treatment

Number (%) of patients with 0, 1, 2, or >2 dose 
adjustments during the following periods:
o
Day 1 - < Week 28
o
Week 28 - < Week 52
o
Day 1 - < End of Treatment

Number of dose adjustments during the following 
periods:
o
Day 1 - < Week 28
o
Week 28 - < Week 52
o
Day 1 - < End of Treatment

Number of dose adjustments per year during Day 
1 - < End of Treatment

Time dose held for Hgb≥12 g/dL

To further compare daprodustat to rhEPO on 
HRQoL and Utility score

Change from baseline in Health Utility I (EQ-5D-
5L) score at Weeks 8,12, 28, 52, yearly, EOS

Change from baseline in EQ VAS at Weeks 8, 12, 
28, 52, yearly, EOS

To further compare daprodustat to rhEPO on 
the symptom severity and change

Shift tables (Baseline to Weeks 8, 12, 28, and 52) 
in PGI-S

N(%) of patients within each PGI-C symptom 
change level at Weeks 8, 12, 28, 52.
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 to 11.g/dL is 
equivalent to 100-110g/L or 6.2 to 6.8 mmol/L.
1.
Hgb change from baseline to Wk 52 is tested for non-inferiority, using the -0.75 g/dL margin used in the co-
primary analysis.  % time in range is tested first for non-inferiority, then for superiority.
2.
Events adjudicated.

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12.3.
Appendix 3: Stratification by Region- Region Groupings
Region
Countries2
1

Thailand1

India 

Malaysia1

Philippines

Republic of 
Korea1

Singapore1 
Taiwan1
2

Bulgaria

Turkey

Czech Republic 
Estonia

Hungary

Poland

Romania

Russian Federation

Ukraine

Slovakia

South Africa1
3

Australia1

Austria

Belgium

Canada1

Denmark1

France

Germany

Greece

Italy

Israel

Netherlands1

New Zealand1

Norway1

Portugal

Spain1

Sweden1

United 
Kingdom1
4

Argentina

Brazil1

Mexico
5

US1
1. Countries which will collect the EQ-5D-5L and EQ VAS
2. Countries that do not participate or do not randomize any subjects will be 
removed from the regional grouping. 

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12.4.
Appendix 4: Risk Assessment
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.
Following review of clinical data received to date, this has not been 
identified as a safety concern for daprodustat.
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.

Specific eligibility criteria related to 
requirements for entry Hgb are detailed in 
Section 5.1.

Hgb will be closely monitored throughout the 
dosing period as outlined in the Time and 
Events Table Section 7.1.

Specific guidance for dose adjustment, dose 
interruption, or discontinuation of daprodustat 
based on achieved Hgb (including rate of 
change) is provided in Section 6.3 and 
Section 6.12.

Unblinded monitoring of safety data by an 
IDMC in-stream throughout the study.
Worsening of hypertension
In a dog cardiovascular study, single oral doses of daprodustat (up to 
90 mg/kg) did not produce effects on blood pressure.
Marketed rhEPO and its analogues have been associated with risks 
related to uncontrolled hypertension, including the need for initiation of 
or increases in antihypertensive therapy when used in patients with 
anemia of CKD (i.e. 25% Epogen, 27% Mircera, and 40% Aranesp 
treated patients with renal anemia required initiation or increase in 
their anti-hypertensive medications; hypertensive encephalopathy and 
seizures have been reported. The contribution of rhEPO-associated 
hypertension to the unfavourable effects on cardiovascular outcomes 
remains uncertain).
Integrated AE data from clinical trials with daprodustat [including 2 
global phase 2b studies (24-week treatment duration) and 2 Japanese 

Blood pressure will be closely monitored 
throughout the dosing period as outlined in the 
Time and Events Table Section 7.1.

Unblinded monitoring of safety data by an 
IDMC in-stream throughout the study.

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phase 3 studies (52-week treatment duration)]: 
o
The majority (>90%) of subjects had a baseline history of 
hypertension.
o
No meaningful difference was seen between treatment groups in 
AEs (preferred term) of “hypertension” [29/688 (4%) daprodustat 
vs. 19/404 (4%) rhEPO; 0.91 relative risk (RR) (95% confidence 
interval: 0.5, 1.67)] or “blood pressure increased” [16 (2%) 
daprodustat vs. 7 (2%) rhEPO; RR 1.22 (0.48,3.11)]. Results 
were not substantively different between non-dialysis and 
haemodialysis subjects.
o
Although no clinically meaningful changes in blood pressure were 
observed, subjects in both treatment groups required increases in 
anti-HTN medications:
o
In the 24-week global phase 2b studies, 25/170 (15%) 
of ND subjects receiving daprodustat vs. 18/80 (14%) 
control and 22/177 (12%) of HD subjects receiving 
daprodustat vs. 2/39 (5%) control.
o
In the 52-week Japan phase 3 studies, 57/149 (38%) of 
ND subjects receiving daprodustat vs. 68/150 (45%) 
rhEPO and 51/136 (38%) of HD subjects receiving 
daprodustat vs. 66/135 (49%) for rhEPO.
The data received to date from completed clinical trials with 
daprodustat are insufficient to refute this risk.
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 conducted to date, 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 

Specific eligibility criteria related to CV risk are 
outlined in Section 5.2.

Hgb will be closely monitored throughout the 
dosing period as outlined in the Time and 
Events Table Section 7.1.

Unblinded monitoring of safety data by an 

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this risk.
IDMC in-stream throughout the study.

Planned formal interim analyses with stopping 
guidelines for evidence of increased CV risk 
as outlined in Section 9.4.5.

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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 some marketed 
rhEPO and its analogs.
In clinical trials to date with daprodustat, mild-moderate GI signs and 
symptoms represent the most frequently reported adverse event, 
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 in-stream 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 a 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:
Once daily administration:

In studies up to 4 weeks duration, a dose-ordered increase in 

Specific eligibility criteria related to personal 
history of malignancy or subjects with 
complex kidney cyst are outlined in Section 
5.2.

Stopping criteria for subjects with treatment 
emergent malignancy are outlined in Section 
5.5.

Unblinded monitoring of safety data by an 
IDMC in-stream throughout the study.

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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, 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 

Unblinded monitoring of safety data by an 
IDMC in-stream throughout the study.

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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 subjects not on dialysis for daprodustat. In hemodialysis 
subjects, 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 subjects 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 subjects 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 subjects meeting the 
PASP PCI criterion. Overall, there is insufficient evidence to conclude 
a relationship to treatment with daprodustat.
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 

Unblinded monitoring of safety data by an 
IDMC in-stream throughout the study.

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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.
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 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 studies.
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 

Suspected proliferative retinopathy, macular 
edema, choroidal neovascularization or
symptoms consistent with these events should 
be investigated by ophthalmologic consultation 
as clinically warranted.

Unblinded monitoring of safety data by an 
IDMC in-stream throughout the study.

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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].
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.

Unblinded monitoring of safety data by an 
IDMC in-stream throughout the study.

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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.
Even though 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 
after approximately 10-14 days of dosing with rifampin (Brodie, 2013 
and 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 (i.e., 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 

Co-administration of daprodustat with strong 
CYP2C8 inhibitors (e.g., gemfibrozil) and 
inducers (e.g., rifampin/rifampicin) is not 
permitted as outlined in Section 6.10.2.

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 6.3
and Appendix 6.

Specific guidance on the management of 
potential drug-drug interactions and 
concomitant medications is provided in 
Section 6.10.

Hgb will be closely monitored throughout the 
dosing period as outlined in the Time and 
Events Table Section 7.1.

Specific guidance for dose adjustment, dose 
interruption, or discontinuation of daprodustat 
based on achieved Hgb is provided in Section 
6.3 and Appendix 6.

Unblinded monitoring of safety data by an 
IDMC in-stream throughout the study.

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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.
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 5.2.

Specific eligibility criteria related to personal 
history of pure red cell aplasia are outlined in 
Section 5.2.

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References
Brodie MJ, Mintzer S, Pack AM, Gidal Gary E, Vecht CJ, Schmidt D. Enzyme induction 
with antiepileptic drugs: Cause for concern? Epilepsia 2013;54:11–27.
Campochiaro PA and the First ARVO/Pfizer Institute Working Group2et al., Ocular 
versus Extraocular Neovascularization: Mirror Images or Vague Resemblances. Invest 
Ophthalmol & Vis Sci.2006. 47:462-474.
Formenti F, Beer PA, Croft QPP  et al., Cardiopulmonary function in two human 
disorders of the hypoxia-inducible factor (HIF) pathway: von Hippel-Lindau disease and 
HIF-2{alpha} gain-of-function mutation. FASEB J. 2011, 25(6): 2001-2011.
Muz B, Khan MN, Kiriakidis S, Paleolog EM. The role of hypoxia and HIF-dependent 
signaling events in rheumatoid arthritis. Arthritis Research & Therapy 2009. 11:201-210.
Ohnhaus EE, Breckenridge AM, Park BK. Urinary excretion of 6-Hydroxycortisol and 
the Time Course Measurement of Enzyme Induction in Man. Eur J Clin Pharmacol
1989;36:39-46.
Smith TG, Brooks JT, Balanos GM et.al., Mutation of von Hippel–Lindau Tumour 
Suppressor and Human Cardiopulmonary Physiology. PLoS MED 2006. 3:1176-1186.
Westra, J, Molema, G and Kallenberg, CGM. Hypoxia-Inducible Factor-1 as Regulator of 
Angiogenesis in Rheumatoid Arthritis - Therapeutic Implications. Current Medicinal 
Chemistry 2010. 17(3):254-263.

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12.5.
Appendix 5: Female Eligibility Criteria
A female subject is eligible to participate if she is not pregnant (as confirmed by a 
negative serum hCG test for females of reproductive potential only), not breastfeeding, or 
at least one of the following conditions applies:

Reproductive potential and agrees to follow one of the options listed in the Modified 
List of Highly Effective Methods for Avoiding Pregnancy in FRP from 30 days 
prior to the first dose of randomized treatment and until completion of the 
Follow-up visit (4-6 weeks after the end of randomized treatment); those who 
permanently discontinue randomized treatment prior to the end of the 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 randomized treatment) as described in the Time and Events Table 
(Section 7.1).
1. Contraceptive subdermal implant that meets effectiveness criteria.
2. Intrauterine device or intrauterine system.
3. Combined estrogen and progestogen oral contraceptive 
4. Injectable progestogen [Trussell, 2011]
5. Contraceptive vaginal ring [Trussell, 2011]
6. Percutaneous contraceptive patches [Trussell, 2011]
7. Male partner sterilization prior to the female subject's entry into the study, and 
this male is the sole partner for that subject [Trussell, 2011]. The documentation 
on male sterility can come from the site personnel’s: review of subject’s medical 
records, medical examination and/or semen analysis, or medical history interview 
provided by her or her partner.
These allowed methods of contraception are only effective when used consistently, 
correctly and in accordance with the product label. The investigator is responsible for 
ensuring that subjects understand how to properly use these methods of contraception.
The list does not apply to FRP with same sex partners or for subjects who are and will 
continue to be abstinent from penile-vaginal intercourse on a long term and persistent 
basis, when this is their preferred and usual lifestyle. Periodic abstinence (e.g. calendar, 
ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable 
methods of contraception.
Note:  See Section 12.14.2 for the country-specific requirements for the Czech Republic 
ONLY relating to acceptable contraceptive methods during participation in this study. 

Non-reproductive potential defined as either:
1. Pre-menopausal with one of the following: (i) documented tubal ligation; (ii) 
documented hysteroscopic tubal occlusion procedure with follow-up confirmation 
of bilateral tubal occlusion; (iii) hysterectomy; or (iv) documented bilateral 
oophorectomy, or;

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2. Postmenopausal defined as 12 months of spontaneous amenorrhea. In 
questionable cases, a blood sample with simultaneous FSH and estradiol 
consistent with menopause is confirmatory (FSH ≥23.0 MIU/mL (≥23.0 IU/L)
and estradiol ≤10 pg/mL (or ≤37 pmol/L) is confirmatory). Females on hormone 
replacement therapy (HRT) and whose menopausal status is in doubt will be 
required to use one of the highly effective contraception methods if they wish to 
continue their HRT during the study. Otherwise, they must discontinue HRT to 
allow confirmation of post-menopausal status prior to study enrollment.
References
Trussell J, Contraceptive Efficacy. In: Hatcher RA, Trussell J, Nelson AL, Cates W, 
Kowal D, and Policar M (editors). Contraceptive Technology: Twentieth Revised 
Edition. New York: Ardent Media, 2011.Table 26-1

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12.6.
Appendix 6: Randomized Treatment Dose Adjustment 
Schemes
HemoCue Hgb (g/dL) 
at current study visit1
HemoCue Hgb change since last 
study visit1
Randomized Treatment Dose 
Adjustment5
<7.52
Any change
Repeat Hgb and average values6; if 
confirmed, increase to the next higher 
dose step
7.5 to <9.5
Decreasing or No change7
Increase to the next higher dose step   
7.5 to <9.5
Increasing8
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
123
Any change  
Repeat Hgb and average values6; if 
confirmed, temporary hold the dose and 
re-check Hgb at next study visit1; 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 weeks4)
Repeat Hgb and average values6; if 
confirmed, decrease to the next lower 
dose step
Any
>2 g/dL decrease over 4 weeks
(>1 g/dL decrease over 2 weeks4)
Repeat Hgb and average values6, if 
confirmed, increase to the next higher 
dose step
1.“Study visit” refers to mandated study visits (every 4 weeks through Week 52; then every 12 weeks).  From Week 52 
onwards, additional study visits to check Hgb and dispense randomized treatment (where directed by the IRT system)
are required under the following circumstances (additional visits have a visit window of ±1 week):

When Hgb at last study visit is outside of the target range, i.e., <10 or >11 g/dL:  Visit 4 weeks later to assess for 
dose adjustment.

When the dose of randomized treatment is changed or restarted in the previous 12 weeks ±1 week: Visits every 4 
weeks for 12 weeks. 

When a medication that is a moderate CYP2C8 inhibitor (i.e., clopidogrel, teriflunomide, deferasirox) is started, 
stopped, or the dose is changed: Visits every 4 weeks for 12 weeks.

When the investigator determines it clinically necessary to evaluate a subject sooner than 12 weeks later: Visit 4 
weeks later to assess for dose adjustment. 

For subjects changing dialysis modality from HD to PD:  Visits every 4 weeks for 12 weeks. 
2.This rule applies to any mandated visit or unscheduled visit, provided it has been at least 2 weeks from the prior 
study visit.
3.This rule applies to any mandated or unscheduled visit.
4.This rule applies to Week 2 and Week 4 visits only.
5.Those receiving the highest dose of randomized treatment who require a dose increase will maintain the same dose,
while those receiving the lowest dose of randomized treatment that require a dose decrease will have doses withheld.
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 the review of blinded instream aggregate Hgb 
data.
8.Increasing may be redefined as an increase of ≥0.5 g/dL based on the review of blinded instream aggregate Hgb 
data.

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12.7.
Appendix 7: Definition of and Procedures for Recording, 
Evaluating, Follow-Up and Reporting of Adverse Events
12.7.1.
Definition of Adverse Events
Adverse Event Definition:

An AE is any untoward medical occurrence in a patient or clinical investigation 
subject, temporally associated with the use of a medicinal product, whether or not 
considered related to the medicinal product.

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 medicinal product.
Events meeting AE definition include:

Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) 
or other safety assessments (e.g., ECGs, radiological scans, SBP, DBP or HR 
measurements), including those that worsen from baseline, and felt to be clinically 
significant in the medical and scientific judgment of the investigator.

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 placebo run-in or randomized treatment 
administration even though it may have been present prior to the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected interaction.

Signs, symptoms, or the clinical sequelae of a suspected overdose of either placebo 
run-in, randomized treatment or a concomitant medication (overdose per se will not
be reported as an AE/SAE unless this is an intentional overdose taken with possible 
suicidal/self-harming intent.  This 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.  However, the signs and symptoms and/or clinical 
sequelae resulting from lack of efficacy will be reported if they fulfill the definition 
of an AE or SAE.
Events NOT meeting definition of an AE include:

Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the subject’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 subject’s 
condition.

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
Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that 
leads to the procedure is an AE.

Situations where 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.
12.7.2.
Definition of Serious Adverse Events
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, etc).
Serious Adverse Event (SAE) is defined as any untoward medical occurrence that, 
at any dose:
a.
Results in death
b.
Is life-threatening
NOTE:
The term 'life-threatening' in the definition of 'serious' refers to an event in which the 
subject 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.
c.
Requires hospitalization or prolongation of existing hospitalization
NOTE:

In general, hospitalization signifies that the subject 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 out-patient setting.  Complications that occur during hospitalization are 
AEs.  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.
d.
Results in disability/incapacity
NOTE:

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 or prevent everyday 
life functions but do not constitute a substantial disruption
e.
Is a congenital anomaly/birth defect
f.
Other situations:

Medical or scientific judgment should be exercised in deciding whether 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 subject or may require medical or surgical intervention to prevent one of the 
other outcomes listed in the above definition.  These should also be considered 
serious.

Examples of such events are 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
g.
Is associated with liver injury and impaired liver function defined as:

ALT 3xULN and total bilirubin* 2xULN (>35% direct), or

ALT 3xULN and INR** >1.5.
* Serum bilirubin fractionation should be performed if testing is available.  If 
fractionation is unavailable and ALT 3xULN and total bilirubin 2xULN, then the 
event is still to be reported as an SAE.
** INR testing not required per protocol and the threshold value does not apply to 
subjects receiving anticoagulants.  If INR measurement is obtained, the value is to be 
recorded on the SAE form.
12.7.3.
Recording of AEs and SAEs
AEs and SAE Recording:

When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (e.g., hospital progress notes, laboratory, and diagnostics reports) 
relative to the event.

The investigator will then record all relevant information regarding an AE/SAE in 
the eCRF

It is not acceptable for the investigator to send photocopies of the subject’s medical 
records to PPD in lieu of completion of the GSK, AE/SAE eCRF page.

There may be instances when copies of medical records for certain cases are 
requested by PPD.  In this instance, all subject identifiers, with the exception of the 
subject number, will be blinded on the copies of the medical records prior to 
submission of to PPD.

The investigator will attempt to establish a diagnosis of the event based on signs, 

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symptoms, and/or other clinical information.  In such cases, the diagnosis will be 
documented as the AE/SAE and not the individual signs/symptoms.

Subject-completed Patient Reported Outcomes questionnaires and the collection of 
AE data are independent components of the study.
12.7.4.
Evaluating AEs and SAEs
Assessment of Intensity
The investigator will make an assessment of intensity for each AE and SAE reported 
during the study and will assign it to one of the following categories:

Mild:  An event that is easily tolerated by the subject, causing minimal discomfort 
and not interfering with everyday activities.

Moderate:  An event that is sufficiently discomforting to interfere with normal 
everyday activities

Severe:  An event that prevents normal everyday activities. - an AE that is assessed 
as severe will not be confused with an SAE. Severity is a category utilized for rating 
the intensity of an event; and both AEs and SAEs can be assessed as severe.

An event is defined as ‘serious’ when it meets at least one of the pre-defined 
outcomes as described in the definition of an SAE.
Assessment of Causality

The investigator is obligated to assess the relationship between placebo run-in or 
randomized treatment and the occurrence of each AE/SAE.

A "reasonable possibility" is meant to convey that there are facts/evidence 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 natural history of the underlying diseases, concomitant 
therapy, other risk factors, and the temporal relationship of the event to the placebo 
run-in or randomized treatment will be considered and investigated.

The investigator will also consult the IB and/or Product Information, for marketed 
products, in the determination of 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 when an SAE has occurred and the investigator has minimal 
information to include in the initial report to PPD.  However, it is very important 
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prior to the initial transmission of the SAE data to PPD.

The investigator may change his/her opinion of causality in light of follow-up 
information, amending the SAE data collection tool accordingly.

The causality assessment is one of the criteria used when determining regulatory 
reporting requirements.
Follow-up of AEs and SAEs

The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as may be indicated or as requested by PPD to 
elucidate as fully as possible the nature and/or causality of the AE or SAE.

The investigator is obligated to assist.  This may include additional laboratory tests 
or investigations, histopathological examinations or consultation with other health 
care professionals.

New or updated information will be recorded in the originally completed eCRF.

The investigator will submit any updated SAE data to PPD within the designated 
reporting time frames.
12.7.5.
Reporting of SAEs to PPD
SAE reporting to PPD via electronic data collection tool

Primary mechanism for reporting SAEs to PPD will be the electronic data collection 
tool

If the electronic system is unavailable for greater than 24 hours, the site will use the 
paper SAE data collection tool and fax it to the Medical Monitor

Site will enter the serious adverse event data into the electronic system as soon as it 
becomes available.

The investigator will be required to confirm review of the SAE causality by ticking 
the ‘reviewed’ box at the bottom of the eCRF page within 72 hours of submission of 
the SAE.

After the study is completed at a given site, the electronic data collection tool (e.g., 
InForm system) 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 subject or receives updated data 
on a previously reported SAE after the electronic data collection tool has been taken 
off-line, the site can report this information on a paper SAE form or to the Medical 
Monitor by telephone.

Contacts for SAE receipt can be found at the beginning of this protocol on the 
Sponsor/Medical Monitor Contact Information page.

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12.8.
Appendix 8: Liver Safety Required Actions and Follow up 
Assessments
Phase 3-4 liver chemistry stopping and increased monitoring criteria have been 
designed to assure subject safety and evaluate liver event etiology (in alignment with the 
FDA premarketing clinical liver safety guidance).  
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM174090.pdf

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Phase 3-4 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 following ANY Liver Stopping Event
Actions
Follow Up Assessments

Immediately discontinue randomized 
treatment

Report the event to PPD 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 subject until liver chemistries 
resolve , stabilize, or return to within baseline 
(see MONITORING below)

Do not restart subject with randomized 
treatment unless allowed per protocol and 
GSK Medical Governance approval is 
granted (refer to Appendix 9)

If restart not  allowed or not granted, 
permanently discontinue randomized 
treatment and may continue subject in the 
study for any protocol specified follow up 
assessments

Viral hepatitis serology4

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.

Blood 
sample for PK analysis, obtained within 24 
hour after last dose6

Serum creatine phosphokinase (CPK) and 
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 report form 

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MONITORING:
For bilirubin or INR criteria:

Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin) and perform 
liver event follow up assessments within  24 
hours

Monitor subjects 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-
72 hours 

Monitor subjects weekly until liver 
chemistries resolve, stabilize or return to 
within baseline
including 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 HPLC 
assay (quantifies potential acetaminophen 
contribution to liver injury in subjects with 
definite or likely acetaminophen use in the 
preceding week [James, 2009]). 

Liver imaging (ultrasound, magnetic 
resonance, or computerised tomography) 
and /or liver biopsy to evaluate liver 
disease; complete Liver Imaging and/or 
Liver Biopsy eCRF forms.
1.
Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin fractionation is not 
immediately available, discontinue randomized treatment for that subject if ALT 3xULN and bilirubin 2xULN. 
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 subjects receiving anticoagulants
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.
PK sample may not be required for subjects known to be receiving placebo or non-GSK comparator treatments.  
Record the date/time of the PK blood sample draw and the date/time of the last dose of randomized treatment 
prior to blood sample draw on the eCRF. If the date or time of the last dose is unclear, provide the subject’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.  

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Phase 3-4 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 PPD medical monitor within 24 hours
of learning of the abnormality to discuss subject 
safety. 

Subject can continue randomized treatment 

Subject 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 subject 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 subjects twice monthly 
until liver chemistries normalize or return to within 
baseline.
References
James LP, Letzig L, Simpson PM, Capparelli E, Roberts DW, Hinson JA, Davern TJ, Lee 
WM. Pharmacokinetics of acetaminophen-adduct in adults with acetaminophen overdose 
and acute Liver failure. Drug Metab Dispos 2009; 37:1779-1784.
Le Gal F, Gordien E, Affolabi D, Hanslik T, Alloui C, Dény P, Gault E.  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. 

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12.9.
Appendix 9: Liver Safety Drug Restart Guidelines
If subject meets liver chemistry stopping criteria do not restart randomized treatment 
unless there is a clear underlying cause for the liver stopping event other than drug-
induced liver injury and:

GSK Medical Governance approval is granted (as described below),

Ethics and/or IRB approval is obtained, if required, and

Separate consent for randomized treatment restart is signed by the subject

If GSK Medical Governance approval to restart subject with randomized treatment is 
not granted, then subject must permanently discontinue randomized treatment and 
requested to continue in the study for protocol-specified follow up assessments.
Restart Following Transient Resolving Liver Stopping Events Not Related to 
Randomized Treatment
Restart refers to resuming randomized 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, there 
should be no evidence of alcoholic hepatitis or hypersensitivity, and the randomized 
treatment should not be associated with HLA markers of liver injury.
Approval by GSK for randomized treatment restart can be considered where:

Investigator  requests consideration for randomized 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).

Restart risk factors (e.g. fever, rash, eosinophilia, or hypersensitivity, alcoholic 
hepatitis, possible randomized treatment-induced liver injury) or randomized 
treatment has an HLA genetic marker associated with liver injury (e.g. lapatinib, 
abacavir, amoxicillin/clavulanate) are reviewed and excluded.

Ethics Committee or Institutional Review Board approval of randomized treatment 
restart must be obtained, as required.

If restart of randomized treatment is approved by GSK Medical Governance in 
writing, the subject must be provided with a clear description of the possible benefits 
and risks of randomized treatment administration, including the possibility of 
recurrent, more severe liver injury or death.  

The subject must also provide signed informed consent specifically for the 
randomized treatment restart.  Documentation of informed consent must be recorded
in the study chart.  

Randomized treatment must be administered at the dose specified by GSK.

Subjects approved by GSK Medical Governance for restarting randomized treatment 
must return to the clinic once a week for liver chemistry tests until stable liver 

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chemistries have been demonstrated and then laboratory monitoring may resume as 
per protocol. 

If after randomized treatment re-start, subject meets protocol-defined liver chemistry 
stopping criteria, follow usual stopping criteria instructions.

PPD Medical Monitor, and the Ethics Committee or Institutional Review Board as 
required, must be informed of the subject’s outcome following randomized treatment 
restart. 

PPD to be notified of any AEs, as per Section 7.4 and Appendix 7.

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12.10.
Appendix 10: Collection of Pregnancy Information

Investigator will collect pregnancy information on any female subject who becomes 
pregnant while participating in this study.

Information will be recorded on the appropriate form and submitted to PPD within 
24 hours of learning of a subject's pregnancy.

The subject will be followed to determine the outcome of the pregnancy. The 
investigator will collect follow up information on mother and infant, which will be 
forwarded to PPD.  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 by the 
investigator reasonably related to the randomized treatment, will be reported to PPD 
as described in Appendix 7. 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 subject who becomes pregnant while participating must permanently 
discontinue randomized treatment. Subjects will be asked to attend an Early 
Treatment Discontinuation visit and expected to attend study visits through the End 
of Study visit, according to the study visit schedule, unless consent is actively 
withdrawn. 

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12.11.
Appendix 11: Genetic Research
Genetics – Background
Naturally occurring genetic variation may contribute to inter-individual variability in 
response to medicines, as well as an individual's risk of developing specific diseases. 
Genetic factors associated with disease characteristics may also be associated with 
response to therapy, and could help to explain some clinical study outcomes. For 
example, genetic variants associated with age-related macular degeneration (AMD) are 
reported to account for much of the risk for the condition [Gorin, 2012] with certain 
variants reported to influence treatment response [Chen, 2012]. Thus, knowledge of the 
genetic etiology of disease may better inform understanding of disease and the 
development of medicines. Additionally, genetic variability may impact the 
pharmacokinetics (absorption, distribution, metabolism, and elimination), or 
pharmacodynamics (relationship between concentration and pharmacologic effects or the 
time course of pharmacologic effects) of a specific medicine and/or clinical outcomes 
(efficacy and/or safety) observed in a clinical study.
Genetic Research Objectives and Analyses
The objectives of the genetic research are to investigate the relationship between genetic 
variants and: 

Response to medicine, including any treatment regimens under investigation in this 
study or any concomitant medicines;

Anemia associated with CKD susceptibility, severity, and progression and related 
conditions
Genetic data may be generated while the study is underway or following completion of 
the study.  Genetic evaluations may include focused candidate gene approaches and/or 
examination of a large number of genetic variants throughout the genome (whole genome 
analyses). Genetic analyses will utilize data collected in the study and will be limited to 
understanding the objectives highlighted above.  Analyses may be performed using data 
from multiple clinical studies to investigate these research objectives.
Appropriate descriptive and/or statistical analysis methods will be used. A detailed 
description of any planned analyses will be documented in a Reporting and Analysis Plan 
(RAP) prior to initiation of the analysis. Planned analyses and results of genetic 
investigations will be reported either as part of the clinical RAP and study report, or in a 
separate genetics RAP and report, as appropriate.
Study Population
Any subject who is randomized in the study can participate in genetic research.  Any 
subject who has received an allogeneic bone marrow transplant must be excluded from 
the genetic research.

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Study Assessments and Procedures
A key component of successful genetic research is the collection of samples during 
clinical studies. Collection of samples, even when no a priori hypothesis has been 
identified, may enable future genetic analyses to be conducted to help understand 
variability in disease and medicine response.  

A 6 ml blood sample will be taken for Deoxyribonucleic acid (DNA) extraction. A 
blood sample is collected at the Baseline visit, after the subject has been 
randomized and provided informed consent for genetic research. Instructions for 
collection and shipping of the genetic sample are described in the laboratory 
manual. The DNA from the blood sample may undergo quality control analyses to 
confirm the integrity of the sample. If there are concerns regarding the quality of 
the sample, then the sample may be destroyed. The blood sample is taken on a 
single occasion unless a duplicate sample is required due to an inability to utilize 
the original sample.  
The genetic sample is labelled (or “coded”) with the same study specific number used to 
label other samples and data in the study.   This number can be traced or linked back to 
the subject by the investigator or site staff. Coded samples do not carry personal 
identifiers (such as name or social security number). 
Samples will be stored securely and may be kept for up to 15 years after the last subject 
completes the study, or GSK may destroy the samples sooner.  GSK or those working 
with GSK (for example, other researchers) will only use samples collected from the study 
for the purpose stated in this protocol and in the informed consent form.  Samples may be 
used as part of the development of a companion diagnostic to support the GSK medicinal 
product.
Subjects can request their sample to be destroyed at any time.
Informed Consent
Subjects who do not wish to participate in the genetic research may still participate in the 
study.  Informed consent for genetic research consent must be obtained prior to any blood 
being taken.
Subject Withdrawal from Study
If a subject who has consented to participate in genetic research withdraws from the 
clinical study for any reason other than being lost to follow-up, the subject will be given a 
choice of one of the following options concerning the genetic sample, if already 
collected:

Continue to participate in the genetic research in which case the genetic DNA 
sample is retained

Discontinue participation in the genetic research and destroy the genetic DNA 
sample 

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If a subject withdraws consent for genetic research or requests sample destruction for any 
reason, the investigator must complete the appropriate documentation to request sample 
destruction within the timeframe specified by GSK and maintain the documentation in 
the site study records. 
Genotype data may be generated during the study or after completion of the study and 
may be analyzed during the study or stored for future analysis. 

If a subject withdraws consent for genetic research and genotype data has not been 
analyzed, it will not be analyzed or used for future research.  

Genetic data that has been analyzed at the time of withdrawn consent will continue 
to be stored and used, as appropriate. 
Screen and Baseline Failures
If a sample for genetic research has been collected and it is determined that the subject 
does not meet the entry criteria for participation in the study, then the investigator should 
instruct the subject that their genetic sample will be destroyed. No forms are required to 
complete this process as it will be completed as part of the consent and sample 
reconciliation process.  In this instance a sample destruction form will not be available to 
include in the site files.
Provision of Study Results and Confidentiality of Subject’s Genetic Data
GSK may summarize the genetic research results in the clinical study report, or 
separately and may publish the results in scientific journals. 
GSK may share genetic research data with other scientists to further scientific 
understanding in alignment with the informed consent. GSK does not inform the subject, 
family members, insurers, or employers of individual genotyping results that are not 
known to be relevant to the subject’s medical care at the time of the study, unless 
required by law. This is due to the fact that the information generated from genetic 
studies is generally preliminary in nature, and therefore the significance and scientific 
validity of the results are undetermined.  Further, data generated in a research laboratory 
may not meet regulatory requirements for inclusion in clinical care.
References
Chen H, Yu KD, Xu GZ. Association between Variant Y402H in age-related macular 
degeneration (AMD) susceptibility gene CFH and treatment response of AMD: A Meta-
Analysis. PloS ONE 2012; 7: e42464
Gorin MB. Genetic insights into age-related macular degeneration: Controversies 
addressing risk, causality, and therapeutics. Mol. Asp. Med. 2012; 33: 467-486.

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12.12.
Appendix 12: A Sub-study of the Effect of Daprodustat 
Compared to rhEPO on BP in Hemodialysis Dependent 
Subjects with Anemia Associated with Chronic Kidney 
Disease who Switch from ESAs
12.12.1.
Introduction and Rationale
Hypertension is one of the major risk factors associated with cardiovascular morbidity 
and mortality and is common in patients with advanced CKD Stages 3b through 5.
Treatment of anemia associated with CKD using ESAs has the associated risk of 
increased BP.  ESA-induced elevation of BP often necessitates initiation of, or increases 
in, antihypertensive medications in patients with CKD.  While SBP and DBP are both of 
prognostic importance, SBP is the overall best predictor of future cardiovascular risk in a 
hypertensive population [Peters, 2013].  Therefore, SBP was chosen as the primary 
endpoint in this ABPM sub-study.  ABPM is being used to measure BP in this sub-study 
because previous studies have used this BP measurement modality in dialysis subjects to 
establish an association with mortality [Agarwal, 2010].
This sub-study is intended to compare daprodustat to rhEPO on BP as assessed by ABPM 
in dialysis-dependent subjects with anemia associated with CKD who switch from ESAs.  
12.12.2.
Objectives and Endpoints
Objectives
Endpoints
Primary

To compare daprodustat to rhEPO for 
effect on SBP (superiority) by ABPM in 
subjects receiving maintenance 
hemodialysis in the ABPM ITT population

Change in 24 hour average SBP from baseline to 
end of sub-study1 between treatment groups
Secondary

To assess the effect of daprodustat and 
rhEPO independently within treatment 
group on SBP, DBP and mean arterial 
blood pressure (MAP) by ABPM in the 
ABPM ITT population

Change in 24 hour average SBP from baseline to 
end of sub-study1 within each treatment group

Change in 24 hour average DBP from baseline 
to end of sub-study1 within each treatment group

Change in 24 hour average MAP from baseline 
to end of sub-study1 within each treatment group

To compare the effect of daprodustat to 
rhEPO on DBP and MAP by ABPM in 
the ABPM ITT population

Change in 24 hour average DBP from baseline 
to end of sub-study1 between treatment groups

Change in 24 hour average MAP from baseline 
to end of sub-study1 between treatment groups

To compare the effect of daprodustat to 
rhEPO on BP parameters in the ABPM 
per-protocol population

Change in:
o 24 hour average SBP
o 24 hour average DBP
o 24 hour average mean arterial pressure
from baseline to end of sub-study1
between treatment groups

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Objectives
Endpoints

To assess the effect of daprodustat and 
rhEPO on BP parameters in the ABPM 
per-protocol population

Change in:
o 24 hour average SBP
o 24 hour average DBP
o 24 hour average mean arterial pressure
from baseline to end of sub-study1 within 
each treatment group

To compare the percentage of subjects 
in each treatment group requiring a 
change in antihypertensive medications 
in the ABPM ITT population

Difference between treatment groups in 
percentage of subjects requiring no change in 
number or dosage of antihypertensive 
medications

Difference between treatment groups in 
percentage of subjects requiring an increase in 
number or dosage of antihypertensive 
medications

Difference between treatment groups in 
percentage of subjects requiring a decrease in 
number or dosage of antihypertensive 
medications

To characterize the dipping pattern of 
sleeping BP in each treatment group in 
the ABPM ITT and ABPM per-protocol 
populations

24 hour BP profile as measured by ABPM, with 
subjects categorized according to their sleeping 
BP behaviors as:
o dippers (normal) when the reduction in the 
average SBP during the sleeping period 
was >10% to 20% of mean SBP during 
waking hours,
o extreme dippers when this reduction was 
>20%,
o non-dippers when the reduction was <10%, 
and
o reverse dippers when the mean sleep SBP 
was higher than the awake SBP [Bakris, 
2014]

To compare the percentage of subjects 
that convert from non-dipper status to 
dipper status between treatment groups 
in the ABPM ITT and ABPM per-protocol 
populations

Difference between treatment groups in 
percentage of subjects that convert from non-
dipper status at baseline to dipper status at end 
of sub-study1

To compare the percentage of subjects 
that convert from dipper status to non-
dipper status between treatment groups 
in the ABPM ITT and ABPM per-protocol 
populations

Difference between treatment groups in 
percentage of subjects that convert from dipper 
status at baseline to non-dipper status at end of 
sub-study1

To compare the effect of treatment with 
daprodustat to rhEPO on heart rate by 
ABPM in the ABPM ITT population

Change from baseline to end of sub-study1 in 
24 hour average heart rate between treatment 
groups as measured by ABPM relative to time 
since administration of medication
1. The end of the sub-study is defined as Week 16, or Week 28 for subjects completing the sub-study prior 
to Amendment 2. 

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12.12.3.
Study Design
This is a multicenter sub-study of the main ASCEND-D study.  Subjects who qualify for 
the main study will be assessed for enrolment.  Approximately 136 subjects from centers 
in selected countries that are participating in the main study will be randomized.  
Note: if the target number of randomized subjects in the ABPM sub-study is not achieved
when the main study is fully enrolled, recruitment may be extended to allow 
randomization in the ABPM sub-study to complete.
12.12.3.1. ABPM Quality Control Criteria
Subjects will need to wear the ABPM device for two 24-hour sessions during the study:
at a mid-week dialysis visit starting at Week -4 until 1 week prior to randomization 
(baseline ABPM) and then at Week 16.  The ABPM device will be placed after 
assessments for the main study have been completed. Subjects will be expected to wear 
the ABPM device for 24 hours at each session.  The ABPM device will measure BP and 
heart rate every 30 minutes during both awake and asleep hours.  The times the subject 
awakens and goes to sleep during this 24 hour period will be recorded.
For each session the ABPM Quality Control (QC) criteria as defined in the Project 
Requirement Specification (PRS) for ABPM must be met. If these criteria are not met 
the ABPM may be repeated (see Section 12.12.3.3).
12.12.3.2. Eligibility Criteria – Screening
Additional Inclusion Criteria
In addition to meeting entry criteria for the main study, a subject will be eligible for 
inclusion in this sub-study only if all of the following criteria apply.
1.
Signed written informed consent prior to beginning sub-study-related procedures.  
Note:  Consent to participate in this sub-study is separate from consent to participate 
in the main study, and will be signed either at Week -8 or at Week -4 prior to ABPM 
assessments.
2.
Use of the same antihypertensive treatment for the 6 weeks prior to the Screening 
visit, through the entire Screening period and at randomization.
3.
SBP of 170 mmHg based on the average of pre-dialysis clinic values obtained at 
Week -8 and Week -4 using the methodology described in the SRM.
4.
Willing and able to wear ABPM device for 24 hours on two separate sessions.
5.
Valid ABPM at baseline [randomization (Day 1) only].
6.
Dialysis schedule of three times per week.
7.
Average awake-time SBP of ≤150 mmHg as assessed by a valid baseline ABPM
[randomization (Day 1) only].

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Additional Exclusion Criteria
A subject will not be eligible for inclusion in this sub-study if any of the following 
criteria apply:
1.
Receiving peritoneal dialysis or home HD.
2.
Subjects who are at high risk for loss to follow-up (e.g., subjects who are known to 
not regularly attend dialysis, subjects who may require frequent hospitalizations or 
vascular access interventions).
3.
Evidence of atrial fibrillation or atrial flutter at time of baseline ABPM assessment
(see Section 12.12.3.3).
4.
Oscillometer/sphygmomanometer cuff cannot accommodate their upper arm 
circumference.
5.
BP cannot be measured in the arm opposite of current vascular access.
6.
Subjects who experience, on average, >5% increase in weight above EDW between 
mid-week dialysis treatments between Week -8 and baseline ABPM reading.
12.12.3.3. Study Assessments
Week -8 Study Visit:
Subject’s consent for ABPM is obtained (Note: if missed this may be obtained at 
Week -4 prior to ABPM assessments).  
Week -4 Study Visit:
A baseline ABPM reading must be initiated at a mid-week dialysis visit and may be 
performed following completion of the Week -4 study assessments or at a subsequent 
mid-week dialysis visit provided it occurs at least 1 week prior to randomization.
Post-dialysis and prior to ABPM, subjects will be assessed for the presence of atrial 
fibrillation/flutter as follows: subjects with an irregular heart beat detected during heart 
rate measurement will undergo an ECG and those with documented atrial fibrillation or 
atrial flutter will not be eligible for ABPM. 
The ABPM device will be placed on the arm opposite current vascular access, and will be 
removed by the subject at home after a minimum of 24 hours of wear; the device will be 
returned to the research staff at the next visit, which ideally is no later than 1 week prior 
to randomization to allow for QC of the ABPM. See SRM for guidance on placement of 
ABPM device.
If the subject fails to meet the baseline ABPM QC criteria and agrees to repeat the ABPM 
procedure, then:

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
The baseline ABPM procedure can be repeated at the next mid-week dialysis visit.
Note: the atrial fibrillation/flutter assessment should be repeated prior to device 
placement.

Day 1 (randomization) may be delayed.

If the baseline ABPM fails the QC criteria after three attempts, then the subject will 
not be enrolled in this ABPM sub-study.
Subjects will have their body weight measured and recorded in the eCRF both pre- and 
post-dialysis (see SRM for guidance on body weight measurement).
Day 1 (Randomization):
If the ABPM measurements meet the QC criteria, the subject can be randomized.
Subjects who either do not qualify for entry into the ABPM sub-study after failing QC 
criteria a third time or who do not desire to continue in the ABPM sub-study although 
they pass the QC criteria, should continue with randomization into the main study 
following the schedule of assessments as outlined in Table 7 of the main protocol if 
appropriate.
Week 16 Study Visit:
At Week 16, at the mid-week dialysis visit and after all main study assessments have 
been completed, the subject’s pre- and post-dialysis weight will be measured and the 
EDW will be recorded.  
The ABPM device will be placed on the subject’s arm by site personnel. After a 
minimum of 24 hours of wear, the device will be removed by the subject at home and 
returned to the research staff at the next visit. The time and date of study medication 
administration, before and while wearing the ABPM device, will be recorded.
If the ABPM fails the QC criteria (same as baseline), up to two additional attempts may 
be made at subsequent, mid-week dialysis visits.  No further attempts are allowed.  The 
subject will continue study visits in the main study as scheduled.
12.12.3.4. Permanent Discontinuation of Randomized Treatment
A subject who permanently discontinues randomized treatment prior to completing the 
ABPM sub-study should remain in the sub-study and complete the Week 16 ABPM 
assessment unless consent to participate in the ABPM sub-study is withdrawn (see also 
Section 5.5).
12.12.3.5. Estimated Dry Weight and Antihypertensive Medication Changes
It is preferred that no changes are made to EDW and antihypertensive medications while 
the subject is part of the sub-study.  

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If changes in EDW and/or antihypertensive medications are necessary, these must be 
documented in the eCRF along with the reasons.  Subjects will remain in the sub-study 
regardless of any changes.
12.12.3.6. Withdrawal from ABPM Sub-Study
If a subject participating in this sub-study withdraws from the sub-study, the reason for 
the withdrawal must be recorded in the eCRF. The subject will remain in the main study 
unless the subject withdraws consent from the main study.
12.12.4.
Sample Size and Power Calculations
The sample size of this sub-study has been designed based on the primary sub-study 
objective to demonstrate superiority in average SBP change from baseline to end of sub-
study between arms (daprodustat versus rhEPO), measured by ABPM over a 24 hour 
assessment period.  Assuming a one-sided 2.5% significance level, a true standard 
deviation for SBP change from baseline measured by ABPM of 11 mmHg [Peixoto, 
2000], and up to a 20% withdrawal rate from the sub-study, a sample size of 68 subjects 
per group (136 subjects in total) will provide greater than 80% power to detect a 
-6 mmHg difference in treatment groups (i.e., achieve superiority).  Under these 
assumptions, superiority will be established if there is more than a 4.2 mmHg mean 
difference observed in favor of daprodustat.
Assuming a 40% screen failure rate for the additional ABPM entry criteria, 
approximately 228 subjects that are eligible for the main study will need to be screened 
for the sub-study in order to randomize approximately 136 subjects. See Section 9.2.3 for 
more information about sample size adjustments.
Unblinded ABPM data will be reviewed by the IDMC during the conduct of the trial as 
part of their data monitoring responsibilities. No formal interim analysis is planned.
12.12.5.
Statistical Analysis
The primary sub-study estimand is to compare the treatment effect on change from 
baseline in 24 hour average SBP at end of sub-study, in all randomized sub-study 
subjects.  The statistical model for analysis will be an ANCOVA with terms for treatment 
and baseline 24 hour average SBP.  This model will provide a point estimate and two-
sided 95% CI for the treatment effect and a one-sided p-value for the superiority 
assessment.  Superiority will be established if the p-value is <0.025.  The primary 
analysis population will be the ABPM sub-study-ITT population defined as randomized 
subjects who were also entered into the ABPM sub-study.
Given the nature of ABPM measurement, a high degree of dropout unrelated to 
randomized treatment is anticipated.  The potential high level of missing data poses a 
challenge in the interpretation of the primary ABPM sub-study analysis.  The reason for 
missing ABPM data will be examined to explore the impact of missing data on the sub-
study primary efficacy conclusions.  If the majority (defined as >70%) of the missing 
data is due to either subject unwillingness to repeat the ABPM procedure or due to an un-
evaluable reading, then data will be treated as missing at random and the primary analysis 

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will be considered sufficient.  Otherwise, a sensitivity analysis may be performed that 
will use multiple imputation from the active control arm to replace data from both 
treatment groups that was missing due to reasons other than subject unwillingness or un-
evaluable readings.  Further supplementary analyses may include an ABPM per-protocol 
population (PP) analysis, utilizing all ABPM-ITT subjects who are not major protocol 
violators or who did not change BP medications during the sub-study.  Further details of 
sensitivity and supplementary analyses will be described in the RAP.
In order to contextualise the primary between-group comparison, a key secondary 
objective is to assess within-group changes from baseline over the sub-study.  
Assessment of within-group changes will support interpretation of the primary analysis 
by identifying whether there was an absence of an increase in BP in one or both treatment 
groups.  To that end, two-sided 95% confidence intervals will be calculated for change 
from baseline in each ABPM parameter separately for each treatment group.  For either 
treatment group, a lack of adverse effect on the primary endpoint of average SBP at end 
of sub-study will be concluded if the upper 95% confidence limit is no more than 4 
mmHg.  This margin was chosen as it is less than the clinically meaningful change of 5 
mmHg [Whelton, 2002] and it is half the historical increase in SBP observed with rhEPO 
[Krapf, 2009].
The mean and two-sided 95% CI will be estimated from the primary statistical model for 
within treatment arm SBP change from baseline to end of sub-study.
The change from baseline 24 hour average DBP, mean arterial pressure and heart rate at 
end of sub-study will be assessed in a similar way as the primary, using analogous 
ANCOVA models with treatment and baseline as covariates.
The differences in proportion of subjects that increase/decrease their BP medication 
(number or dose) will be assessed using Fisher’s Exact Test.  The differences between 
treatment groups in the proportion of subjects that convert from dippers/non-dippers at 
baseline to non-dippers/dippers at end of sub-study will also be assessed using Fisher’s 
Exact Test.
Plots of the mean 24 hour average values (two-sided 95% CIs) and mean changes from 
baseline in 24 hour average values (two-sided 95% CIs) for BP will be provided by 
treatment group.
Additional statistical considerations will be addressed in the RAP.

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References
Agarwal R. Blood Pressure and Mortality Among Hemodialysis Patients.  Hypertension. 
2010; 55:762-768.
Bakris GL, Townsend RR, Liu M et al., Impact of Renal Denervation on 24-Hour 
Ambulatory Blood Pressure. J Am Coll Cardiol. 2014; 64:1071-1078.
Krapf R, Hulter HN. Arterial Hypertension Induced by Erythropoietin and 
Erythropoiesis-Stimulating Agents (ESA). Clin J Am Soc Nephrol2009: 4: 470-480
Peixoto AJ ,Santos SF, Mendes RB, Crowley ST, Maldonado R , Orias M, et al. 
Reproducibility of ambulatory blood pressure monitoring in hemodialysis patients.  Am J 
Kidney Dis. 2000; 36: 983–990.
Peters SA, Huxley, RR, and Woodard M, Comparison of the Sex-Specific Associations 
Between Systolic Blood Pressure and the Risk of Cardiovascular Disease: A Systematic 
Review and Meta-analysis of 124 Cohort Studies, Including 1.2 Million Individuals. 
Stroke. 2013; 44:2394-2401.
Whelton PK, He J, Appel LJ, et al. Primary Prevention of Hypertension: Clinical and 
Public Health Advisory From the National High Blood Pressure Education Program. 
JAMA 2002; 288(15):1882-1888.

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12.13.
Appendix 13: A Sub-study to Collect PK Samples in Dialysis 
Subjects with Anemia Associated with CKD
12.13.1.
Rationale
The purpose of this sub-study is to collect PK samples in a subset of subjects (n=200) 
randomized to daprodustat in the main study to enable exploratory exposure-response and 
exposure-safety analyses.
12.13.2.
Objectives and Endpoints
Objectives
Endpoints
Primary

To summarize the PK parameters of 
daprodustat and three major metabolites 
in dialysis subjects

Plasma daprodustat, M2, M3, and M13 PK parameters 
pre-dose trough (Ctau) and Cmax
Exploratory

Evaluate graphical relationships 
between exposure parameters and 
selected efficacy endpoints

Scatter plots of daprodustat PK parameters (Ctau and 
Cmax) dose normalized to 1 mg vs. percent time in 
range during EP.

Scatter plots of average daprodustat dose during EP 
vs. percent time in range during EP.

Scatter plots of daprodustat PK parameters (Ctau and 
Cmax) dose normalized to average dose during EP vs. 
percent time in range during EP.

Scatter plots of daprodustat PK parameters (Ctau and 
Cmax) dose normalized to 1 mg vs.  change from 
baseline of Hgb during EP.

Scatter plots of average daprodustat dose during EP 
vs. change from baseline of Hgb during EP.

Scatter plots of daprodustat PK parameters (Ctau and 
Cmax) dose normalized to average dose during EP vs. 
change from baseline of Hgb during EP.

The evaluate graphical relationships 
between daprodustat exposure and 
MACE and the combined safety 
endpoint of MACE + thromboembolic 
event+ hospitalization for HF

Boxplots of daprodustat PK parameters (Ctau and Cmax) 
dose normalized to 1 mg by subjects with or without 
MACE or combined safety endpoint.

Boxplots of daprodustat PK parameters (Ctau and Cmax) 
dose normalized to dose at time of MACE or 
combined safety endpoint (or end of treatment if no 
endpoint) by subjects with or without MACE or 
combined safety endpoint.
12.13.3.
Study Design
This is a multicenter sub-study of daprodustat study 200807 (the main study).  
Approximately 200 subjects from centers in selected countries that are participating in the 
main study will be invited to participate in the PK sub-study.  

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12.13.4.
Additional Inclusion Criteria

Signed written informed consent prior to beginning sub-study-related procedures 
(subject must understand the aims, procedures, and possible consequences of the 
sub-study).  Note:  Consent to participate in the sub-study is separate from 
consent to participate in the main study.

Subject must be receiving randomized daprodustat treatment in the main study.

Only subject’s receiving in center hemodialysis are eligible.
12.13.5.
Study Assessments
Blood samples will be collected at any single study visit from the Week 4 through Week 
52 visit (i.e., PK is collected at one visit only, based on convenience for the subject/site).  
Samples will be collected at the following times with respect to dosing of randomized
treatment:

Predose, 0.5h, 1h, 2h and 3h post dose.
On the day of the scheduled PK visit:

The subject is to be instructed not to take their dose at home before the visit, but 
to take the dose in the clinic after the pre-dose sample is collected.

The dose taken in the clinic should be from the same bottle(s) the subject has 
been using prior to the PK visit, not from any newly dispensed bottle(s) at the 
PK visit (Note: a subject placed on a dose hold at the previous visit should not
have PK samples taken; PK collection should be delayed until the visit after the 
subject has restarted study treatment).

Record the date and actual time of the dose taken in the clinic and the three doses 
prior to the visit, and the date and actual time of all PK samples collected. 
Samples may be collected within 20 min of the planned collected 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-DMPK/Scinovo, 
the details of which will be included in the SRM. Concentrations of main daprodustat 
and metabolites (GSK2391220 (M2), GSK2531403 (M3), and GSK2531401 (M13)) will 
be determined in plasma samples using the currently approved bioanalytical 
methodology. Raw data will be archived at the bioanalytical site.  
12.13.6.
Sample Size
It is estimated that 150 sub-study subjects are required to have at least 80% power that 
the MACE rate in the sub-study is within 20% of the MACE rate in main study.  To 

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account for missing or non-evaluable PK samples, approximately 200 subjects will be 
randomized. See Section 9.2.3 for more information about sample size adjustments.  
Approximately 45% (n65) of subjects in this sub-study would be expected to meet the 
combined safety endpoint (and n85 subjects would not).  Based on a between subject 
variability (CVb%) estimate for Cmax and Ctau of up to 100% (as seen in a prior Phase 1 
study in CKD and from population PK analysis), 65 subjects would be sufficient to have 
>80% power that the 95% CI around the geometric mean is within 0.6 to 1.4 times the 
estimate.  This is considered sufficient precision for the descriptive analysis proposed.
12.13.7.
PK/PD Analyses
The ‘PK Population' is defined as subjects for whom a PK sample was obtained and 
analyzed.  This will be the population used for all the PK displays.
The following plasma PK parameters will be determined for daprodustat and metabolites: 
Ctau (pre-dose) and Cmax.
Plasma daprodustat and metabolites concentration data will be listed and summarized by 
planned collection time and daprodustat dose administered at 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 be summarized.
All PK data will be stored in the Archives, GlaxoSmithKline Pharmaceuticals, R & D.
Based on exploratory graphs (Section 12.13.2), and the efficacy and safety results from 
the main study, post-hoc exploratory exposure-response/safety modelling may be 
conducted, including exploratory graphics with metabolites.  Further details will be 
provided in the RAP of the main study.

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12.14.
Appendix 14: Country Specific Requirements
12.14.1.
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 subject 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 
Hospital Director is supplied with the protocol and any information needed for the 

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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 
eCRF of the Study provided by GLAXOSMITHKLINE or by a company 
designated by GLAXOSMITHKLINE.

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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 
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.

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12.14.2.
Country-Specific Requirements for Czech Republic for 
Acceptable Contraceptive Methods
Purpose and Justification:
The purpose of this Czech Republic country-specific requirement is to specify acceptable
contraceptive methods for use during participation in the study 200807. This is as a result 
of recent Czech Republic legislative requirements of CA directive KLH 22 dated 
22Mar2016 for contraception methods.
Czech Republic Specific Contraception Requirements will apply in addition to the 
list of methods stated in Appendix 5:
Men and women able to have children and sexually active, must use acceptable methods 
of birth control from 30 days prior to the first dose of randomized treatment and until 
completion of the Follow-up visit (4-6 weeks after the end of randomized treatment).

Methods of birth control include, one highly reliable method (such as intrauterine 
device, sterilisation of one of the partners, hormonal birth control methods) plus 
one supplementary barrier method (such as condom, diaphragm) with a 
spermicide. 

Two barrier methods used in combination with spermicide, are considered 
as reliable contraception methods. 
The study doctor will discuss with the subject the methods of birth control that should be 
used while he/she is in this study and will help the subject to select the methods that are 
appropriate for him/her.

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12.15.
Appendix 15: Protocol Changes
12.15.1.
Changes Resulting from Protocol Amendment 1
This is an amendment to the original protocol dated 2016-JUN-09.
Amendment 1 applies only to Austria, Belgium, Czech Republic, Denmark, Estonia, 
Germany, Hungary, Italy, Norway, Poland, Portugal, Romania, Spain, Sweden and the 
United Kingdom.
12.15.1.1. Summary of Changes

Text added to clarify when the end of the study will occur.

Removal of requirement to reduce ESA dose if Week -8 Hgb is >11.5 g/dL (study 
rationale and inclusion criteria).

Additional guidance added to iron management criteria

New exploratory objective to compare the effect of daprodustat to rhEPO on DGF 
after deceased donor kidney transplantation added.
12.15.1.2. List of Specific Changes
Section 4.1 Overall Design; new text; bullet point 6

The end of the study will occur after the accumulation of 945 adjudicated first MACE 
and the last subject has completed their last required study visit (Section 7.1). 
Section 4.3 Design Rationale; paragraph 1; sentence number 3
This study includes both a 4 week screening and a 4 week placebo run-in period prior to 
randomization (Day 1). The screening period permits eligibility based on laboratory 
assessments to be confirmed, while the run-in period will be used to establish compliance 
with placebo and study procedures in an attempt to minimize withdrawn consent post-
randomization. This 8-week period also provides an opportunity for ESA users whose 
screening Hgb is above the Hgb required at randomization (i.e., >11.5 to 12 g/dL) to have 
their ESA dose reduced (but not stopped) to allow the Hgb to decrease in order to 
potentially be eligible for randomization and to approach the Hgb target range (10 to 
11g/dL).
Section 5.1 Inclusion Criteria; criteria number 3
3   Hgb concentration measured by HemoCue (range is inclusive): 
Hgb Range
Week -8

Hgb 8 to 12 g/dL1 (5 to 7.5 mmol/L) If Hgb is >11.5 g/dL (7.1 mmol/L), decrease ESA dose 
aiming to achieve Hgb 11.5 g/dL by Day 1.

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Section 6.11.1 Iron Management Criteria; paragraph 4; new text
Investigators should be guided by local/regional guidelines and may stop administration 
of iron at a lower ferritin or TSAT level as long as subjects are maintained at a ferritin 
>100 ng/mL and TSAT >20%.
Section 12.1 Appendix 1 Abbreviations and Trademarks; new abbreviation added
DGF
Delayed graft function 
Section 12.2 Appendix 2: Secondary and Exploratory Objectives/ Endpoints; new 
exploratory objective added.

To compare the effect of daprodustat to 
rhEPO on delayed graft function (DGF) 
after deceased donor kidney 
transplantation

Number (%) of subjects experiencing DGF 
after deceased donor kidney transplantation 
(where DGF is defined as the use of dialysis 
within 7 days of the transplant)

Length of time that subjects experience DGF 
after deceased donor kidney transplantation

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12.15.2.
Changes Resulting from Protocol Amendment 2
This is an amendment to the original protocol dated 2016-JUN-09.
This amendment applies to all countries
12.15.2.1. Summary of Changes

Changes from country-specific Amendment 1 applied to global amendment

Country-specific requirements for France and Czech Republic added.

Section and appendix relating to darbepoetin alfa pre-filled syringe incidents, 
malfunctions and user errors. Section deleted as darbepoetin alfa pre-filled syringes 
are not subject to device reporting requirements.

Time and events Table 7 ‘Schedule of Assessments Year 1 to End of Study’
modified. Main changes include new timepoints at Run-in (Week -4) and Week 2 for 
collection of information related to iron therapy; new timepoint at Week 52 for 
Kt/Vurea assessment; and transfusions and kidney transplant added to prompt 
completion of page in eCRF.

Time and Events Table 8 ‘Schedule of Assessments for Patient Reported Outcomes, 
Genetics and Sub-studies’ modified. Main changes are changes to the ABPM sub-
study assessments including prompts for the end of the 44hour ABPM assessments 
and prompts for recording the times the subject awakens and goes to sleep during 
this 44 hour ABPM period.

Time and events Table 9 ‘Schedule of Assessments for Subjects Permanently 
Discontinuing Randomized Treatment’ modified. Main changes include  IRT system 
call removed at all visits except Early Treatment Discontinuation Visit and End of 
Study Visit; new timepoints for collection of information related to iron therapy, 
transfusions; and kidney transplant added to prompt completion of page in eCRF.

Text added to clarify those randomized to rhEPO who transition from HD to PD will 
change from epoetin alfa to darbepoetin alfa.  

Text relating to the timing of dialysis in relation to the study visit has been amended. 
The original text ‘For subjects receiving PD or home HD >3x/week, study visits 
must occur within 48 hours of their last dialysis session’ was inaccurate as PD is 
daily treatment.

For the negatively adjudicated events in 200807, the reporting process has been 
updated and the investigator-reported term (not the adjudicator-reported term) will 
be used.

In addition to allowing a historical (last 6 months) kidney ultrasound to be used to 
assess entry criteria, a provision was added for a more sensitive imaging study (e.g., 
MRI, CT) to be used to assess entry criteria.

Other changes include minor wording changes for clarity, updating of section 
numbering and cross referencing, formatting changes (for consistency) and 
administrative changes.

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12.15.2.2. List of Specific Changes
Section 3 Objectives and Endpoints; first principal secondary endpoint; sub-bullet 2. 
Addition of the word symptomatic prior to deep vein thrombosis and pulmonary 
embolism.

To compare daprodustat to rhEPO on CV 
safety endpoints

Time to first occurrence of adjudicated

MACE

MACEor a thromboembolic event (vascular 
access thrombosis, symptomatic deep vein 
thrombosis or symptomatic pulmonary 
embolism) 

MACE or a hospitalization for heart failure 
(HF)
Section 4.1 Overall Design; new text; bullet point 6. Text added to clarify when the end of 
the study will occur.

The end of the study will occur after the accumulation of 945 adjudicated first 
MACE and the last subject has completed their last required study visit (Section 
7.1). 
Section 4.1 Overall Design; bullet point 8. Cross reference updated.

To ensure subjects remain iron replete and to minimize the potential for iron overload 
during the study, the investigator will follow the iron management criteria (Section
6.12 6.11.1) from randomization through the end of the study treatment period.
Section 4.3 Design Rationale; paragraph 1; sentence number 3. Text deleted as 
requirement to reduce ESA dose if Week -8 Hgb is >11.5 g/dL removed.
This study includes both a 4 week screening and a 4 week placebo run-in period prior to 
randomization (Day 1). The screening period permits eligibility based on laboratory 
assessments to be confirmed, while the run-in period will be used to establish compliance 
with placebo and study procedures in an attempt to minimize withdrawn consent post-
randomization. This 8-week period also provides an opportunity for ESA users whose 
screening Hgb is above the Hgb required at randomization (i.e., >11.5 to 12 g/dL) to have 
their ESA dose reduced (but not stopped) to allow the Hgb to decrease in order to 
potentially be eligible for randomization and to approach the Hgb target range (10 to 
11g/dL).
Section 5 Selection of Study Population and Withdrawal Criteria; paragraph 1. Text 
added for clarity.
Specific information regarding warnings, precautions, contraindications, AEs, and other 
pertinent information on the randomized treatment is provided in the IB, IB 

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supplement(s) (if applicable), product labels for epoetin alfa and darbepoetin alfa and 
other pertinent documents (e.g., Study Reference Manual (SRM), informed consent).
Section 5.1 Inclusion Criteria; criteria number 3. Text deleted as requirement to reduce 
ESA dose if Week -8 Hgb is >11.5 g/dL removed.
3 Hgb concentration measured by HemoCue (range is inclusive): 
Hgb Range
Week -8

Hgb 8 to 12 g/dL1 (5 to 7.5 mmol/L) If Hgb is >11.5 g/dL (7.1 mmol/L), decrease 
ESA dose aiming to achieve Hgb 11.5 g/dL by Day 1.
Section 5.1 Inclusion Criteria; criteria number 7; paragraph 2. New text relating to 
country-specific amendment for France added.
Note: The country-specific requirements for France ONLY for the informed 
consent process are provided in Appendix 14 (see Section 12.14.1, Item 3 for details).
Section 5.1 Inclusion Criteria; criteria number 8. New criteria relating to country-
specific amendment for France.
8    Other study eligibility criteria considerations: The country-specific
      requirements for France ONLY for inclusion in this study are
      provided in Appendix 14 (see Section 12.14.1, Item 1 for details).
Section 5.2 Exclusion Criteria; criteria number 18. New text added relating to the Czech 
Republic.
18   Females ONLY: Subject is pregnant [as confirmed by a positive serum human 
chorionic gonadotrophin (hCG) test for females of reproductive potential (FRP) 
only], subject is breastfeeding, or subject is of reproductive potential and does not 
agree to follow one of the contraceptive options listed in the List of Highly Effective 
Methods for Avoiding Pregnancy in Appendix 5.
Note:  See Section 12.14.2 for the country-specific requirements for the Czech 
Republic ONLY relating to acceptable contraceptive methods during 
participation in this study.
Section 6.2 Randomized Treatment Assignment; paragraph 1; sentence 2. Text deleted to 
avoid confusion. The randomization number is stored in the IRT database and will only 
be used at the very end of the study for the final data reconciliation. It is not ever used to 
identify the subject and not displayed on any notifications or reports.
Once a randomization number has been assigned by the IRT system, it must not be re-
assigned.

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Section 6.3.3 Daprodustat and rhEPO Dose Adjustment Algorithm; Paragraph 1; 
sentence 2. Words ‘at least’ added for clarity.
Dose adjustments (i.e., increase, decrease, maintain, or withheld if ≥12 g/dL) will be 
made programmatically for both the daprodustat and rhEPO arms by the IRT system to 
maintain Hgb concentrations within the range of 10-11 g/dL based on the HemoCue Hgb 
value measured at least every 4 weeks (Day 1 through Week 52) or at least every 12 
weeks (post-Week 52 through end of treatment) disclosed to the IRT system by the 
investigator.
Section 6.11.1 Iron Management Criteria; paragraph 4. Additional guidance added to 
iron management criteria.
Investigators should be guided by local/regional guidelines and may stop 
administration of iron at a lower ferritin or TSAT level as long as subjects are 
maintained at a ferritin >100 ng/mL and TSAT >20%.
Section 6.12 Rescue Therapy; paragraph 2; sentence 2. New text added.
This rescue algorithm does not apply to subjects with a decrease in Hgb as a result of an 
acute or subacute event with an identifiable cause (e.g., GI bleed, blood loss due to 
surgery or vascular access).  In these cases, treatment should be directed to the specific 
cause and randomized treatment will be continued.  If a subject is transfused as part of 
the treatment, then the randomized treatment will be maintained at the current dose 
(unless Hgb is ≥12 g/dL which requires a dose hold).
Section 6.12 Rescue Therapy; Table 6; Step 1 Initial Intervention; bullet point 3. Text 
added for clarity
Step 1:
Initial 
Intervention
While continuing randomized treatment (increase dose if HemoCue Hgb <7.5 g/dL; 
otherwise maintain current dose), intervene with one or more of the following as dictated 
by clinical comorbidities 
-
Single course of IV iron up to 1000 mg (in addition to the iron management criteria)
-
Transfusion of up to two units of packed red blood cells (PRBC) if clinically indicated
-
Allow additional 4 weeks on randomized treatment (NOTE:  this is a required 
choice; can be combined with either or both of the above).
Section 6.13 Subjects changing dialysis modality; paragraph 1; sentences 2 and 3. New 
text added to clarify those randomized to rhEPO who transition from HD to PD will 
change from epoetin alfa to darbepoetin alfa.  
Subjects changing dialysis modality should not be withdrawn from the study, and should 
continue on the same randomized treatment (daprodustat or rhEPO). Those subjects 
randomized to rhEPO who transition from PD to HD (in-center or home HD) will 
continue on darbepoetin alfa.  However, subjects randomized to rhEPO who 
transition from HD to PD will switch from epoetin alfa to darbepoetin alfa at their 
next study visit (from Week 4 onwards).  If this occurs from Week 52 onward, 
additional visits are required as outlined in Appendix 6.

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Section 7 Study Assessments and Procedures; bullet points 2 and 3 following 
paragraph 3. Text relating to the timing of dialysis in relation to study visit amended. 
Original text was inaccurate as PD is daily treatment.

For subjects on PD or home HD >3x/week, study visits can occur on any day of 
the week. 

For subjects receiving PD or home HD 3x/week, study visits must occur within 
48 hours of their last dialysis session. 

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Section 7.1 Time and Events Table; Table 7 Schedule of Assessments Year 1 to End of Study; iron therapy, transfusions assessment line, 
new timepoints at Run-in (Week -4) and Week 2.
Protocol activity (visits ±1 week)
All assessments pre-dialysis unless otherwise specified
(Note: All visit timings are relative to Day 1)
Day 1 through Week 52
Screen
Week -8
Run-in
Week -4
Day 113
Week 2
Full study visit
Week 4, 16, 28, 
40
Abbreviated study visit
Week 8, 12, 20, 24, 32, 36, 
44, 48  
Week 52
Unscheduled10
Iron therapy, transfusions3
X
X
X
X
X
X
X
X
Section 7.1 Time and Events Table; Table 7 Schedule of Assessments Year 1 to End of Study; Kt/Vurea assessment line, new timepoint at 
Week 52 and footnote for Kt/Vurea  (footnote 18) added
Protocol activity (visits ±1 week)
All assessments pre-dialysis unless otherwise specified
(Note: All visit timings are relative to Day 1)
Day 1 through Week 52
Screen
Week -8
Run-in
Week -4
Day 113
Week 2
Full study visit
Week 4, 16, 28, 
40
Abbreviated study visit
Week 8, 12, 20, 24, 32, 36, 
44, 48  
Week 52
Unscheduled10
Kt/Vurea 18
X
X
X
Year 2
Year 3
Year 4
Unscheduled10
End of 
Study15
Follow-up
(4-6 weeks after 
stopping 
randomized 
treatment)
Protocol activity (visits ±1 week)
All assessments pre-dialysis unless 
otherwise specified
(Note: All visit timings are relative to Day 
1)
Week 
64
Week 
76
Week 
88
Week 
100
Week 
112
Week 
124
Week 
136
Week 
148
Week 
160
Week 
172
Week 
184
Week 
196
Week 
20814
Kt/Vurea 18
X
X
X
X
X
X
X

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Section 7.1 Time and Events Table; Table 7 Schedule of Assessments Year 1 to End of Study; hospitalization line; kidney transplant 
added.
Protocol activity (visits ±1 week)
All assessments pre-dialysis unless otherwise specified
(Note: All visit timings are relative to Day 1)
Day 1 through Week 52
Screen
Week -8
Run-in
Week -4
Day 113
Week 2
Full study visit
Week 4, 16, 28, 
40
Abbreviated study visit
Week 8, 12, 20, 24, 32, 36, 
44, 48  
Week 52
Unscheduled10
Hospitalization 3 , kidney transplant3
X
X
X
X
X
Year 2
Year 3
Year 4
Unscheduled10
End of 
Study15
Follow-up
(4-6 weeks after 
stopping 
randomized 
treatment)
Protocol activity (visits ±1 week)
All assessments pre-dialysis unless 
otherwise specified
(Note: All visit timings are relative to Day 
1)
Week 
64
Week 
76
Week 
88
Week 
100
Week 
112
Week 
124
Week 
136
Week 
148
Week 
160
Week 
172
Week 
184
Week 
196
Week 
20814
Hospitalization3 , kidney transplant3
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Section 7.1 Time and Events Table; Table 7 Schedule of Assessments Year 1 to End of Study; footnote16.
16.  Ultrasound of the kidneys and adrenal glands will be performed between the Week -4 and Day 1 visits. 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 7.4.10.
Section 7.1 Time and Events Table; Table 7 Schedule of Assessments Year 1 to End of Study; footnote17.
17  Treatment will be dispensed every 41 weeks. IRT call will be required every 4 weeks. 

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Section 7.1 Time and Events Table; Table 7 Schedule of Assessments Year 1 to End of Study; new footnote, footnote18.
18  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.
Section 7.1 Time and Events Table; Table 8 Schedule of Assessments for Patient Reported Outcomes, Genetics and Sub-studies; VEO 
assessments; reference to footnote 5 added.
Protocol Activity
(visits ±1 week)
(Note: All visit timings are 
relative to Day 1)
Screening
Day 1 through Week 208
Post-
Week 52 
through 
End of 
Study
Week -8 Week -4 Day -211 Day -141
Day -12
Day 1
Week 4 Week 8 & 
12
Week 16, 
20 & 24
Week 28
Week 28 
(End of 
week 
visit)
Week 52
Week 
100, 148, 
208
End of 
Study
Patient Global Impression of 
Severity (PGI-S)5
X
X
X
X
X
Patient Global Impression of 
Change (PGI-C) 5
X
X
X
Short Form 36 (SF-36) 5
X
X
X
X
EuroQol 5 Dimension 5 Level 
Health Utility Index (EQ-5D-5L) 
and EuroQol Visual Analogue 
Scale (EQ-VAS)2, 5
X
X
X
X
X
X
Section 7.1 Time and Events Table; Table 8 Schedule of Assessments for Patient Reported Outcomes, Genetics and Sub-studies; VEO 
assessments; new footnote added; footnote 5.
5  Subjects who are unable to or require assistance to read must not complete the questionnaires.

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Section 7.1 Time and Events Table; Table 8 Schedule of Assessments for Patient Reported Outcomes, Genetics and Sub-studies; ABPM 
sub-study assessments. 44hr ABPM end, record awake and sleep times, and 44 urine collection prompts and timepoints added.
Protocol Activity
(visits ±1 week)
(Note: All visit timings are 
relative to Day 1)
Screening
Day 1 through Week 52
Post-Week 52 
through End of Study
Week -8 Week -4 Day -211 Day -141
Day -12
Day 1
Week 4
Week 8 & 
12
Week 16, 
20 & 24
Week 28
Week 28 
(End of 
week 
visit)
Week 52 Week 100, 
148, 208
End of 
Study
ABPM sub-study(Appendix 12): 
                      Informed Consent
X
       Home BP monitoring(twice
                       daily for PRIOR 4 
                     consecutive days)
X
X
X
X
X
              44 hour ABPM start
X
X
             44 hour ABPM end
X
X
Record awake and sleep times
X
X
Pre- and post-dialysis weight
X4
Section 7.1 Time and Events Table; Table 8 Schedule of Assessments for Patient Reported Outcomes, Genetics and Sub-studies; footnote 
4 removed
4. Additional to the timepoints specified in Table 7. Post-dialysis weight to be measure, before the ABPM device is attached.

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Section 7.1 Time and Events Table; Table 9 Schedule of Assessments for Subjects Permanently Discontinuing Randomized Treatment; IRT 
system call; IRT system call removed at all visits except Early Treatment Discontinuation Visit and End of Study Visit.
Protocol Activity
All assessments pre-dialysis unless otherwise specified
(Note: All visit timings are relative to Day 1)
Early Treatment Discontinuation Visit 
(within 2 weeks of discontinuing 
randomized treatment)
Day 1 through Week 527
Week 4, 16, 28, 40, 52 ± 2 weeks
Unscheduled
IRT system call
X
X
X
Protocol activity (visits ± 2 week)
(Note: All visit timings are relative 
to Day 1)
Year 27
Year 37
Year 47
Unscheduled
End of 
Study8
Week 
64
Week 
76
Week 
88
Week 
100
Week 
112
Week 
124
Week 
136
Week 
148
Week 
160
Week 
172
Week 
184
Week 
196
Week 
208
IRT system call
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Section 7.1 Time and Events Table; Table 9 Schedule of Assessments for Subjects Permanently Discontinuing Randomized Treatment;
iron therapy, transfusions assessment line, new timepoints added at Weeks 4, 16, 28, 40, 52 and unscheduled visits.
Protocol Activity
All assessments pre-dialysis unless otherwise specified
(Note: All visit timings are relative to Day 1)
Early Treatment Discontinuation Visit 
(within 2 weeks of discontinuing 
randomized treatment)
Day 1 through Week 527
Week 4, 16, 28, 40, 52 ± 2 weeks
Unscheduled
Iron therapy,  transfusions1
X
X
X

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Section 7.1 Time and Events Table; Table 9 Schedule of Assessments for Subjects Permanently Discontinuing Randomized Treatment; 
hospitalization line; kidney transplant added.
Protocol Activity
All assessments pre-dialysis unless otherwise specified
(Note: All visit timings are relative to Day 1)
Early Treatment Discontinuation Visit 
(within 2 weeks of discontinuing 
randomized treatment)
Day 1 through Week 527
Week 4, 16, 28, 40, 52 ± 2 weeks
Unscheduled
Hospitalization1 , kidney transplant1
X
X
X
Protocol activity (visits ± 2 week)
(Note: All visit timings are relative to 
Day 1)
Year 27
Year 37
Year 47
Unscheduled
End of 
Study8
Week 
64
Week 
76
Week 
88
Week 
100
Week 
112
Week 
124
Week 
136
Week 
148
Week 
160
Week 
172
Week 
184
Week 
196
Week 
208
Hospitalization1, kidney transplant1
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Section 7.1 Time and Events Table; Table 9 Schedule of Assessments for Subjects Permanently Discontinuing Randomized Treatment; 
VEO assessments; reference to footnote 9 added.
Protocol Activity
All assessments pre-dialysis unless otherwise specified
(Note: All visit timings are relative to Day 1)
Early Treatment Discontinuation Visit 
(within 2 weeks of discontinuing 
randomized treatment)
Day 1 through Week 527
Week 4, 16, 28, 40, 52 ± 2 weeks
Unscheduled
PGI-S, PGI-C4, 9
X
SF-364, 9
X
EQ-5D-5L& EQ-VAS4, 5, 9
X

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Section 7.1 Time and Events Table; Table 9 Schedule of Assessments for Subjects Permanently Discontinuing Randomized Treatment; 
new footnote added; footnote 9.
9  Subjects who are unable to or require assistance to read must not complete the questionnaires.

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Section 7.4 Safety; paragraph 2. ECG text deleted as the paragraph refers to safety 
endpoints. ECGs are not safety endpoints (baseline ECG is for entry criteria and annual 
ECG is for good patient care in a population with high CV risk.).
Safety endpoints will include monitoring of safety endpoint events including deaths 
(Section 7.4.1), other CV events (Section 7.4.2), AEs of special interest (Section 7.4.4), 
AEs, SAEs and AEs leading to discontinuation of randomized treatment, laboratory 
parameters, electrocardiogram (ECG) parameters, BP and HR.  
Section 7.4.1.Events Referred to the Clinical Events Committee; final paragraph; 
sentence 2. Text updated to reflect that the reporting process has changed and the 
investigator-reported term (not the adjudicator-reported term) will be used.
Negatively adjudicated events will be reported as AEs or SAEs using the investigator
adjudicator-reported event term.
Section 7.4.3.Adverse Events (AE) and Serious Adverse Events (SAEs); paragraph 3; 
sentence 3. Text updated to reflect that the reporting process has changed and the 
investigator-reported term (not the adjudicator-reported term) will be used.
Negatively adjudicated events will be reported as AEs or SAEs using the investigator
adjudicator-reported event term.
Section 7.4.7 Darbepoetin Alfa Pre-filled Syringe Incidents, Malfunctions and User
Errors. Section deleted as darbepoetin alfa pre-filled syringes are not subject to device 
reporting requirements.
Darbepoetin alfa pre-filled syringes are being provided for use in this study.  In order to 
fulfil regulatory reporting obligations worldwide, the investigator is responsible for the 
detection and documentation of events meeting the definitions of incident or malfunction 
that occur during the study with darbepoetin alfa pre-filled syringes. 
The definition of an incident or malfunction can be found in Appendix 11. Detailed 
information on pre-filled syringe incidents, malfunctions and user errors will be collected 
on the Medical Device Incident Report Form – Darbepoetin Alfa Pre-filled Syringe.
Incidents fulfilling the definition of an AE/SAE will also follow the processes outlined in 
Section 7.4.3 and Appendix 7 of the Protocol.
Section 7.4.9 Electrocardiograms (ECG); paragraph 4.Additional text added for clarity.
All ECGs 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 
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Section 7.4.10.Ultrasound, paragraph 2, sentence 2. New text to allow for the use of a 
more sensitive imaging study to assess entry criteria as an alternative to ultrasound.
A documented ultrasound of the kidneys within the 6 months prior to screening may be 
used to assess entry criteria (see Section 5.2), 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.
Section 9.2.1 Sample Size Assumption; last paragraph. New text relating to country-
specific amendment for France.
Note: The country-specific requirements for France ONLY for the sample size 
consideration are provided in Appendix 14 (see Section 12.14.1, Item 2 for details).
Section 9.4.2.1 Principal Secondary Analyses; bullet point 1 under paragraph 3. Addition 
of the word symptomatic prior to deep vein thrombosis and pulmonary embolism.

MACE or a thromboembolic event (vascular access thrombosis, a symptomatic
deep vein thrombosis or a symptomatic pulmonary embolism.
Section 10.8.2. Clinical Events Committee; paragraph 1. Addition of the word 
symptomatic prior to deep vein thrombosis and pulmonary embolism.
An external independent Clinical Events Committee blinded to treatment allocation will 
adjudicate all events reported during this study that constitute the co-primary CV safety 
endpoint of MACE [composite of all-cause mortality, non-fatal MI and non-fatal stroke], 
the principal CV secondary composite endpoints of MACE plus additional components 
including events of vascular access thrombosis, symptomatic deep vein thrombosis, 
symptomatic pulmonary embolism, CV mortality and hospitalization for HF. 
Section 12.1 Appendix 1 Abbreviations and Trademarks. New abbreviations added and 
abbreviations not found in the protocol deleted.
ANSM
L'Agence nationale de sécurité du médicament et des 
produits de santé 
CMO
Chief medical officer 
CNIL
Commission Nationale de I'Informatique et des Libertés
CRA
Clinical Research Assistant 
CTR
Clinical Trials Register

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CT
Computed tomography
DGF
Delayed graft function 
MRI
Magnetic resonance imaging
Section 12.2 Appendix 2: Secondary and Exploratory Objectives/ Endpoints; Objective 
‘To compare daprodustat to rhEPO on additional CV safety endpoints’; endpoint 
bullet 3; death changed to mortality.

To compare daprodustat to rhEPO on 
additional CV safety endpoints

CV death mortality or non-fatal MI2
Section 12.2 Appendix 2: Secondary and Exploratory Objectives/ Endpoints; Exploratory 
Objective ‘To further compare daprodustat and rhEPO on Hgb variability’; endpoint 
bullet 4.

To further compare daprodustat and 
rhEPO on Hgb variability

Number (%) of subjects with a Hgb<7.5 g/dL
Section 12.2 Appendix 2: Secondary and Exploratory Objectives/ Endpoints. New 
exploratory objective added.

To compare the effect of daprodustat 
to rhEPO on delayed graft function 
(DGF) after deceased donor kidney 
transplantation

Number (%) of subjects experiencing DGF 
after deceased donor kidney 
transplantation (where DGF is defined as 
the use of dialysis within 7 days of the 
transplant)

Length of time that subjects experience 
DGF after deceased donor kidney 
transplantation
Section 12.5; Appendix 5 Female Eligibility Criteria; last paragraph before bullet 2. New 
text relating to country-specific amendment for Czech Republic
Note:  See Section 12.14.2 for the country-specific requirements for the Czech 
Republic ONLY relating to acceptable contraceptive methods during participation 
in this study. 

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Section 12.6; Appendix 6: Randomized Treatment Dose Adjustment Scheme; line 9 
column 3 of table; word visit added for clarity.
HemoCue Hgb (g/dL) 
at current study visit1
HemoCue Hgb change since last 
study visit1
Randomized Treatment Dose 
Adjustment5
123
Any change  
Repeat Hgb and average values6; if 
confirmed, temporary hold the dose and 
re-check Hgb at next study visit1; 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.
Section 12.6; Appendix 6: Randomized Treatment Dose Adjustment Scheme; footnote 1; 
last bullet point.

For subjects transitioning to dialysis changing dialysis modality from HD to PD:  
Visits every 4 weeks for 12 weeks.
Section 12.6; Appendix 6: Randomized Treatment Dose Adjustment Scheme; footnote 2; 
word visit added for clarity.
2.
This rule applies to any mandated visit or unscheduled visit, provided it has been 
at least 2 weeks from the prior study visit.
Appendix 11 Definition of Darbepoetin Alfa Pre-filled Syringe Incidents. Section deleted 
as darbepoetin alfa pre-filled syringes are not subject to device reporting requirements.
Definition:

Incident – Any malfunction or deterioration in the characteristics and/or performance 
of the pre-filled syringe, as well as any inadequacy in the labeling or the instructions 
for use which, directly or indirectly, might lead to or might have led to the death of a 
patient/user/other persons or to a serious deterioration in their state of health.

Not all incidents lead to death or serious deterioration in health.  The non-occurrence 
of such a result might have been due to other fortunate circumstances or to the 
intervention of health care personnel.
It is sufficient that:
-
an incident associated with a pre-filled syringe happened and
-
the incident was such that, if it occurred again, might lead to death or a serious 
deterioration in health.
A serious deterioration in state of health can include:
-
life-threatening illness
-
permanent impairment of body function or permanent damage to a body structure

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-
a condition necessitating medical or surgical intervention to prevent one of the 
above 
-
fetal distress, fetal death or any congenital abnormality or birth defects
Examples of incidents

a patient, user, care giver or professional is injured as a result of failure or misuse of 
the pre-filled syringe 

a patient’s treatment is interrupted or compromised by failure of the pre-filled syringe

a patient’s health deteriorates due to failure of the pre-filled syringe
Appendix 12; Section 12.12.3.3 Study Assessments; Week 28 Study Visit; sentence 3. 
Wording change for clarity.
The time and date of study medication administration, before and while on wearing the 
ABPM device, will be recorded
Appendix 14 Country Specific Requirements. Text deleted as country specific 
requirements added.
No county specific requirements exist
Appendix 14 Country Specific Requirements; new Section 12.14.1  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 subject 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.
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.
9.
Concerning the “STUDY CONDUCT CONSIDERATIONS” 

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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 
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).

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10. 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 electronic 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.
11. 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 
electronic 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 
electronic 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.

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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. 
12. 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.
13. 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 
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.
Appendix 15 Country Specific Requirements; new Section 12.15.2  Country-Specific 
Requirements for the Czech Republic; addition of text relating to acceptable
contraceptive methods for the Czech Republic.
Purpose and Justification:
The purpose of this Czech Republic country-specific requirement is to specify acceptable
contraceptive methods for use during participation in the study 200807. This is as a result 
of recent Czech Republic legislative requirements of CA directive KLH 22 dated 
22Mar2016 for contraception methods.
Czech Republic Specific Contraception Requirements will apply in addition to the list of 
methods stated in Appendix 5:
Men and women able to have children and sexually active, must use acceptable methods 
of birth control from 30 days prior to the first dose of randomized treatment and until 
completion of the Follow-up visit (4-6 weeks after the end of randomized treatment).

Methods of birth control include, one highly reliable method (such as intrauterine 
device, sterilisation of one of the partners, hormonal birth control methods) plus 
one supplementary barrier method (such as condom, diaphragm) with a 
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
Two barrier methods used in combination with spermicide, are considered 
as reliable contraception methods. 
The study doctor will discuss with the subject the methods of birth control that should be 
used while he/she is in this study and will help the subject to select the methods that are 
appropriate for him/her.

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12.15.3.
Changes Resulting from Protocol Amendment 3
This is an amendment to the protocol amendment dated 2017-OCT-12.
This amendment applies to all countries.
12.15.3.1. Summary of Changes

Added retest values for Hgb and TSAT to determine eligibility at Week -8.

Broadened exclusion to include participation in an interventional study with an 
investigational agent or device.

Removed option to have Early Treatment Discontinuation visit supersede the 
scheduled study visit.  

Provided guidance for those receiving HD two times a week who are randomized to 
the epoetin alfa arm and require three times a week epoetin alfa dosing.

Added a provision that in unexpected circumstances where the supply to the site is 
interrupted, then local standard of care for anemia management during this time 
period may be considered.  

Added new darbepoetin alfa dose strengths (not available in all countries).

Added direction regarding randomized treatment and study continuation for subjects 
who will be away from the research site for an extended period of time.

Clarified timeframe for iron management criteria.

Clarified “frequency of dialysis” inclusion criterion and valid study visit days by 
dialysis type. 

Clarified baseline dose for the purposes of the rescue algorithm for subjects switching 
from HD to PD who are randomized to rhEPO.

Shortened visit window for the Week 2 and 4 visits and clarified visit window for 
Week -4 and Day 1 visits.

Modified Time and Events Table 7 ‘Schedule of Assessments Year 1 to End of 
Study’.  Main changes include addition of Informed Consent activity; revised
footnotes to remove Kt/V and URR measurement for daily HHD and allowance of 
extended timing to do Day 1 ECG and to do ultrasound and/or additional testing; 
more clarity around randomized treatment dispensing and compliance, including 
provisions for deferring dose changes till the next HD treatment; removed capture of 
rescue medications from unscheduled and early termination visits as rescue 
evaluation is triggered at scheduled visits; added footnote to clarify biomarkers will 
be stored for future analyses except if not permitted by IRB/EC or refused by subject; 
addition of Argentina only pregnancy requirement; and removal of footnote at Week -
4 visit for only collecting SAEs related to study participation or a GSK product as it 
did not apply.

Modified Time and Events Table 8 ‘Schedule for Assessments for Patient Reported 
Outcomes, Genetics and Sub-studies’ modified to add healthcare resource utilization 
data collection, to streamline ABPM assessments and to add timing for informed 
consent and additional eligible collection visits for PK sub-study.

Modified Time and Events Table 9 “Schedule of Assessments for Subjects 
Permanently Discontinuing Randomized Treatment” to remove capture of rescue 

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medications (rescue evaluation is triggered at on-treatment scheduled visits), to add 
healthcare resource utilization data collection, and to complete ABPM assessments.

Added direction to see CEC Site Manual for full scope of reporting requirements.

Add clarifications for PD subjects as to how weight, blood pressure, and laboratory 
assessments are to be done.  

Clarified timing of assessments relative to dialysis for SBP, DBP, HR and laboratory 
assessments.

Added reminder for the ordering of assessments for blood pressure and that the over-
read of the Day 1 ECG is required to confirm eligibility. 

Updated PRO section to add healthcare resource utilization data being collected for 
completeness and updated endpoint labels for EQ-5D-5L & EQ-VAS.

Revised statistical section to change from two-sided testing at the 5% level to one-
sided testing at the 2.5% level; correct the comparator for the Null and Alternative 
hypotheses; to change significance levels to p-values; to add a more complete 
description of the adjustments to statistical model; to update hyporesponder analyses; 
and to add additional text regarding the interim analysis process.

Added exploratory endpoints around Hgb variability, iron parameters, transfusions, 
and dose adjustment scheme.

Edited Risk Assessment information to align with version 8 of the Investigator’s 
Brochure. 

Updated FSH level to confirm menopause.

Provision for possible adjustment to the Dose Adjustment Algorithm triggers for Hgb 
values 7.5 g/dL to <9.5 g//dL based on the review of blinded instream aggregate Hgb 
data.

Changes to ABPM sub-study to add atrial fibrillation/flutter screening, remove home 
BP monitoring, change from 44- to 24-hour APBM, change in time-point for 
assessment (from Week 28 to Week 16), and adjustments to objectives, endpoints and 
analysis. 

Clarified additional inclusion and added additional eligible visits to collect PK 
samples in PK sub-studies.

Other changes include spelling corrections or minor wording changes for clarity, 
formatting changes (for consistency), a missing reference (epoetin alfa IV:SC 
conversion), and administrative changes.
12.15.3.2. List of Specific Changes
Cover page.  Added back protocol “Short Title”.
Short Title:
Anemia Studies in CKD: Erythropoiesis via a Novel PHI 
Daprodustat-Dialysis (ASCEND-D)
Section 1. Protocol Synopsis for Study 200807; Overall Design, 1st bullet and Section 
12.1. Appendix 1: abbreviations.  Corrected ESA abbreviation. Revised analysis 
provided.

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
This is a randomized, open-label (sponsor blind), active-controlled, parallel-group, 
multi-center, event-driven study in dialysis subjects with anemia associated with 
CKD who are currently treated with erythropoietinerythropoiesis-stimulating agents 
(ESAs1).
ESA
ErthropoetinErythropoiesis-stimulating agent
Section 1. Protocol Synopsis for Study 200807; Analysis 1st paragraph. Revised analysis 
provided.
The study’s co-primary endpoints will each be tested for non-inferiority using a one-
sided 2.5% significance level and the relevant confidence bound from a two-sided 95% 
confidence interval (CI) (upper bound for MACE and lower bound for the Hgb co-
primary endpoint) for each test. 
Section 3 Objectives and Endpoints; safety endpoint.  Changed “study treatment” to 
“randomized treatment” to more correctly describe endpoint.  
Safety 

To compare the safety and tolerability of 
daprodustat to rhEPO

Incidence and severity of AEs and serious adverse 
events (SAEs) including AEs of special interest1

Reasons for discontinuation of studyrandomized
treatment

Absolute values and changes from baseline in 
laboratory parameters, BP and heart rate (HR)
Section 4.1. Overall Design; 7th bullet. Clarified how stratification factors are considered 
prognostically important.

Subjects will be stratified by dialysis type [HD* or PD], by region (see Appendix 3), 
and by participation in the ABPM sub-study. Dialysis type and region are considered 
to be stratification factors that areconsidered to be potentially prognostically 
important, i.e., predictive of study endpoints while participation in the ABPM sub-
study is an administrative stratification factor intended solely to ensure a similar 
number of sub-study subjects in each of the two randomized groups.  
Section 4.5.2. Benefit Assessment; 1st paragraph. Clarifited other ESAs.
In clinical trials of up to 24 weeks in duration, in subjects with anemia associated with 
CKD, daprodustat has been shown to treat Hgb to target range. Daprodustat may present 
several important advantages over rhEPO and other ESAs 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 daprodustat, data 
suggest that the 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, 200]; therefore, daprodustat has the potential to raise 
Hgb without the same CV risk associated with rhEPO and its analogs.

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Section 5.1. Inclusion Criteria; inclusion #3. Added retest for Hgb values within the 
variability threshold for testing to determine Week -8 eligibility, with associated footnote 
(inserted new footnote 2).
Hgb Range
Week -8

Hgb 8 to 12 g/dL1 (5 to 7.45 mmol/L). 

If Hgb is 12.1 to 12.4 g/dL2 (7.5-7.7 mmoL/L), up to two retests are allowed; the 
retest value must be between 8 to 11.5 g/dL (5 to 7.4 mmol/L).
Day 1

Hgb 8 to 11 g/dL (5 to 6.8 mmol/L) and receiving at least the minimum ESA dose3.

Hgb >11 g/dL to 11.5 g/dL (6.8 mmol/L to 7.1 mmol/L) and receiving greater than 
the minimum ESA dose3. 
1.
Conversion from g/dL to g/L is 1:10, e.g., Hgb of 8 to 10 g/dL is equivalent to 80-100g/L. 
2.
The first retest will use the original Week -8 blood sample. If this value is >12 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.  For in-center HD, retests will be pre-dialysis, in between dialysis 
sessions for HHD subjects at the study visits, and at the study visits for PD subjects, as per 
standard of care.
3.
Minimum ESA dose:  epoetins (including biosimilars):  1500 units (U)/week intravenous (IV) or 1000 
U/week SC; darbepoetin alfa:  20 g/4 weeks SC/IV; methoxy PEG-epoetin:  30 g/month SC/IV
Section 5.1. Inclusion Criteria; inclusion #5.  Updated frequency of dialysis descriptions.  
5. Frequency of Dialysis.
a. HD (in-center):  ≥2 times/week 
b. PD: Daily PD ≥5 times/week
c. Home HD: short daily or nocturnal (≥3x/week) ≥2 times/week
Section 5.1. Inclusion Criteria; inclusion #7.  Clarified study visit this is confirmed.
7.
Informed consent (screening only): capable of giving signed informed consent 
which includes compliance with the requirements and restrictions listed in the 
consent form and in this protocol.
Section 5.2. Exclusion Criteria; exclusion #1.  Added “or living-unrelated”. 
1. Kidney transplant: Planned living-related or living-unrelated kidney transplant 
within 52 weeks after study start (Day 1).
Section 5.2. Exclusion Criteria; exclusion #3. Added retest for TSAT values within the 
variability threshold for testing to determine Week -8 eligibility.  
3. Transferrin saturation (TSAT) (screening only):  ≤20%.  If TSAT is 18-20%, 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.  

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Section 5.2. Exclusion Criteria; exclusion #5. Added Untreated.
5. Other causes of anemia:  Untreated pernicious anemia, thalassemia major, sickle cell 
disease or myelodysplastic syndrome.
Section 5.2 Exclusion Criteria; exclusion #11.  Clarified situation where exclusion does 
not apply.
11. QTcB (Day 1): QTcB >500 msec, or QTcB >530 msec in subjects with bundle 
branch block.  There is no QTc exclusion for subjects with a predominantly ventricular
paced rhythm.
Section 5.2. Exclusion Criteria; exclusion #16. Broadened exclusion to include 
participation in a study with an investigational agent or device.
16. Prior investigational product exposure:  Use of an investigational agent ≤30 days 
or within five half lives of the investigational agent (whichever is longer) prior to 
screening. Note: at screening, this exclusion applies to use of the investigational agent 
within 30 days or within five half lives (whichever is longer). Other study 
participation:  Use of other investigational agent or device prior to screening 
through to randomization (Day 1):

Note: at screening, this exclusion applies to use of the investigational agent 
within 30 days or within five half lives (whichever is longer).
Section 5.5. Permanent Discontinuation of Randomized Treatment; revised bullet and 
new text. Removed “chronic” from prohibited medication use stopping criterion and 
added text to clarify that subjects may be reapproached about restarting randomized 
treatment.

Need for chronic (more than 14 days use) of prohibited medication (Section
6.10.2)
Subjects may be reapproached about restarting randomized treatment in certain 
circumstances if the sponsor and the investigator agree.
Section 5.5.1. Procedures for Subject Follow-up; bullet 1.  Deleted second sentence in 
first bullet.

Early Treatment Discontinuation visit:  This visit should occur within 2 weeks of 
stopping randomized treatment. This visit supersedes the scheduled study visit if 
the Early Treatment Discontinuation visit falls on the same date as a scheduled 
study visit. 
Section 6.1 Placebo Run-in and Randomized Treatment. Added footnote that in 
unexpected circumstances where the supply to the site is interrupted, then local standard 
of care for anemia management during this time period may be considered.
The term ‘randomized treatment’ is used throughout the protocol to describe either study 
treatment (i.e., daprodustat or darbepoetin alfa) received by the subject during the 

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treatment period as per the protocol design.  Randomized treatment will be provided 
by GSK3.
3 If the supply to the site is interrupted due to unexpected circumstances (e.g., natural disaster), local 
standard of care for anemia management may be considered during that time period, without the 
need to withdraw the subject from the study or to permanently discontinue randomized treatment.  
Section 6.1 Placebo Run-in and Randomized Treatment. Added new EU-sourced 
darbepoetin alfa PFS strengths.
Table 2
Description of Darbepoetin Alfa PFS
PFS Strengths
PFS Volume 
20 µg*
0.5 mL
30 µg* 
0.3 mL
40 µg
0.4 mL
60 µg
0.3 mL
80 µg*
0.4 mL
100 µg
0.5 mL
150 µg
0.3 mL
*Not available in all countries. 
Section 6.3.1. Daprodustat Dosing Information; Table 3, Added reference for epoetin IV 
to SC conversion (reference added to Reference list).
1. Standardized rhEPO IV dose (U/week) = 161/113 * (epoetin SC dose (units)) / (frequency) [Beserab, 2002]
Beserab A, Reyes C, Hornberger J. Meta-Analysis of Subcutaneous Versus 
Intravenous Epoetin in Maintenance Treatment of Anemia in Hemodialysis 
Patients. Am J of Kidney Dis 2002;40: 439-446.
Section 6.3.2. rhEPO Dosing Information.  Added clarity how to dose three times a week 
study rhEPO to a subject on HD two times a week. 
For subjects who are on HD two times a week and are randomized to the epoetin 
alfa arm and require three times a week epoetin alfa dosing, the weekly dose should 
be split as close to equally, using the study-allocated dose vials of epoetin alfa, across 
the two dialysis treatments.
Section 6.3.2. rhEPO Dosing Information; Tables 4 and 5. Clarified “every week” 
frequency to be “once a week”.

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Table 4
Epoetin Alfa Dose Steps
Total  Weekly Dose
Dose and Frequency
1500
1500 U every once a week
2000
2000 U every once a week
3000
3000 U every once a week
4000
4000 U every once a week
5000
5000 U every once a week
6000
6000 U every once a week
8000
8000 U every once a week
10000
10000 U every once a week
12000
4000 U 3 three times a week
15000
5000 U 3 three times a week
18000
6000 U 3 three times a week
21000
7000 U 3 three times a week
24000
8000 U 3 three times a week
27000
9000 U 3 three times a week
30000
10000 U 3 three times a week
36000
12000 U 3 three times a week
42000
14000 U 3 three times a week
48000
16000 U 3 three times a week
60000
20000 U 3 three times a week
Table 5
Darbepoetin Alfa Dose Steps
Total 4-Weekly Dose
PFS Dose and Frequency
20 µg
20 µg every 4 weeks
30 µg
30 µg every 4 weeks
40 µg
40 µg every 4 weeks
60 µg
60 µg every 4 weeks
80 µg
80 µg every 4 weeks
100 µg
100 µg every 4 weeks
150 µg
150 µg every 4 weeks
200 µg
100 µg every 2 weeks
300 µg
150 µg every 2 weeks
400 µg
100 µg every 1 once a week
Section 6.3.3. Daprodustat and rhEPO Dose Adjustment Algorithm; 2nd paragraph and 
new text. Added clarifier around dispensing of randomized treatment from Week 52 
onwards and rationale for the possible adjustment to the Dose Adjustment Algorithm 
based on the review of blinded instream aggregate Hgb data.  

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From Week 52 onwards, additional study visits to check Hgb and dispense randomized 
treatment (where directed by the IRT system) will be required under the circumstances 
outlined in Appendix 6.
In order to mitigate subjects remaining below the Hgb target range for an extended 
period of time, adjustments to the algorithm may be implemented by the sponsor as 
outlined in Appendix 6 based on the review of blinded instream aggregate Hgb data.  
Section 6.3.4. Randomized Treatment Extended Interruption; new section.  Added 
direction regarding randomized treatment and study continuation for subjects who will 
be away from the research site for an extended period of time.
6.3.4. Randomized Treatment Temporary Interruption
Every effort must be made to continue randomized treatment and to complete study 
visits, where able; however, sites should contact PPD Remote Site Monitor-Local if a 
subject cannot return to the research site on a temporary basis for any one of the 
following situations:

Subjects who are hospitalized for any duration. 

HD or PD subjects receiving oral daprodustat or PD subjects receiving SC 
darbepoetin alfa who cannot return to the site for a period >5 weeks.

HD subjects receiving IV rhEPO who cannot return to the site in time for the 
next scheduled dose. 
In exceptional circumstances, local standard of care for anemia management during 
this time period may be considered based on consultation with the PPD Medical 
Monitor.  If non-study ESAs are administered, doses should be recorded on the 
Prior/Concomitant Medications – ESA eCRF page.    
Section 6.10.2. Prohibited Medications and Non-Drug Therapies; new text.  Added 
clarification that no other investigational agents or devices are permitted during the 
study.
No other investigational agents or devices are permitted from study entry through 
completion of the study, with the exception of the randomized treatment 
administered for this study.
Section 6.11.1. Iron Management Criteria; paragraph 1.  Added clarifier for when the 
criteria start and stop.
The investigator will follow the iron management criteria from randomization (Day 
1) through the end of the study treatment period for subjects receiving randomized 
treatment.
Section 6.12. Rescue Criteria; paragraph 2. Minor clarification in wording to match 
wording in IRT system.

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This rescue algorithm does not apply to subjects with a decrease in 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 vascular access).   
Section 6.12. Rescue Criteria; Table 6. Minor clarification for visits where rescue 
evaluation can be triggered and in title of Table 6.
Table 14
Rescue Algorithm for Anemia TherapyManagement
Evaluate Subject for Rescue if:  
HemoCue Hgb remains <9 g/dL (at a scheduled study visit, Week 4 onwards) despite three1 consecutive 
dose increases above the starting2 or post-rescue3 dose (where HemoCue Hgb is <9 g/dL prior to each 
dose increase) OR HemoCue Hgb is <7.5 g/dL despite a dose increase at the prior study visit.
Section 6.12. Rescue Criteria; footnotes.  Inserted new footnote #2 to clarify baseline 
dose for the purposes of the rescue algorithm for subjects switching from HD to PD who 
are randomized to rhEPO  and made a minor change in #3 (previously #2).
2.For subjects who have switched from HD to PD who are randomized to rhEPO, the baseline dose for the purposes of 
the rescue algorithm is the new darbepoetin alfa dose..
3.For subjects who previously arewere evaluated for rescue and who are able to continue in the trial, “post-rescue” 
dose is the dose of randomized treatment that a subject is receiving at the study visit after initial intervention.
Section 6.13. Subjects Changing Dialysis Modality; 1st sentence. Clarification added on 
randomized treatment to receive if switching dialysis modality. 
Subjects changing dialysis modality should not be withdrawn from the study, and 
shouldwill continue in on the same randomized treatment arm (daprodustat or rhEPO)
they were originally assigned.
Section 7. Study Assessments and Procedures; 1st and 2nd bullets. Clarified valid study 
visit days.

For subjects on 3-5x/week HD, the designated study visit must not occur on the 
first dialysis session of the week, i.e., immediately following the longest 
interval between HD sessions.  For example, if on a Monday-Wednesday-Friday 
schedule, the study visit should be on Wednesday or Friday.

For subjects on PD or home HD, study visits can occur on any day of the week. 
Section 7. Study Assessments and Procedures; new paragraph.  Inserted new text to 
clarify the visit schedule for study visits through Day 1.  
The Week -4 and Day 1 visits should be completed 4 weeks ±1 week after the last 
visit; however, the total duration of the Screening and Run-In periods (from Week -
8 to Day 1) should be 8 weeks ±1 week (i.e., 7-9 weeks).  
Section 7. Study Assessments and Procedures; paragraphs after bullets.  Inserted new 
text to state the revised visit window for the Week 2 and 4 visits and made minor changes 

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to visit structure a separate paragraph as it applies to all study visits and corrected 
spelling of center.
The visit window for those on randomized treatment for the Week 2 and Week 4 
visits is ±3 days.  The visit window specified for those on randomized treatment from 
Week 8 onwards is ±1 week.
In exceptional circumstances, minor changes to visit structure may be permitted after 
consultation with the PPD Medical Monitor.
Study assessments should preferably be done at dialysis centers; however, in some 
circumstances (i.e., where the dialysis centrecenter and research site are not co-located) 
assessments can be performed at the research site.

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Section 7.1. Table 7 Schedule of Assessments Year 1 to the End of the Study.  Updated visit window text.
Protocol activity (visits ±1 week, except Weeks 2 and 4 
which are ±3 days)
All assessments pre-dialysis unless otherwise specified
(Note: All visit timings are relative to Day 1)
Day 1 through Week 52
Screen
Week -8
Run-in
Week -4
Day 113
Week 2
Full study visit
Week 4, 16, 28, 
40
Abbreviated study visit
Week 8, 12, 20, 24, 32, 36, 
44, 48  
Week 52 Unscheduled10
Section 7.1. Time and Events Table; Table 7 Schedule of Assessments Year 1 to Week 52.  Added Informed Consent activity and 
associated footnote (#22).
Protocol activity (visits ±1 week)
All assessments pre-dialysis unless otherwise specified
(Note: All visit timings are relative to Day 1)
Day 1 through Week 52
Screen
Week -8
Run-in
Week -4
Day 113
Week 2
Full study visit
Week 4, 16, 28, 
40
Abbreviated study visit
Week 8, 12, 20, 24, 32, 36, 
44, 48  
Week 52 Unscheduled10
Informed Consent (main study)
X22
22.Informed consent will be obtained prior to any study procedures.
Section 7.1. Table 7 Schedule of Assessments Year 1 to the End of the Study and Table 9 Schedule of Assessments for Subjects 
Permanently Discontinuing Randomized Treatment.  Clarified name of IRT system transaction.
Protocol activity (visits ±1 week)
All assessments pre-dialysis unless otherwise specified
(Note: All visit timings are relative to Day 1)
Day 1 through Week 52
Screen
Week -8
Run-in
Week -4
Day 113
Week 2
Full study visit
Week 4, 16, 28, 
40
Abbreviated study visit
Week 8, 12, 20, 24, 32, 36, 
44, 48  
Week 52 Unscheduled10
IRT system calltransaction17
X
X
X
X
X
X
X
X
Year 2
Year 3
Year 4
Unscheduled10, 
12
End of 
Study15
Follow-up
(4-6 weeks after 
stopping 
randomized 
treatment)
Protocol activity (visits ±1 week)
All assessments pre-dialysis unless 
otherwise specified
(Note: All visit timings are relative to Day 
1)
Week 
64
Week 
76
Week 
88
Week 
100
Week 
112
Week 
124
Week 
136
Week 
148
Week 
160
Week 
172
Week 
184
Week 
196
Week 
20814

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IRT system calltransaction17
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Protocol Activity
All assessments pre-dialysis unless otherwise specified
(Note: All visit timings are relative to Day 1)
Early Treatment Discontinuation 
Visit (within 2 weeks of 
discontinuing randomized 
treatment)
Day 1 through Week 527
Week 4, 16, 28, 40, 52 ± 2 weeks
Unscheduled
IRT system calltransaction
X
Section 7.1. Table 7 Schedule of Assessments Year 1 to the End of the Study and Table 9 Schedule of Assessments for Subjects 
Permanently Discontinuing Randomized Treatment; Weight and SBP/DBP, HR. Updated text for PD subjects.
Protocol activity (visits ±1 week)
All assessments pre-dialysis unless otherwise specified
(Note: All visit timings are relative to Day 1)
Day 1 through Week 52
Screen
Week -8
Run-in
Week -4
Day 113
Week 2
Full study visit
Week 4, 16, 28, 
40
Abbreviated study visit
Week 8, 12, 20, 24, 32, 36, 
44, 48  
Week 52 Unscheduled10
Weight (pre- and post-dialysis for in-center HD subjects; 
between treatments for HHD; at study visits per standard 
of care for and PD subjects) and EDW
X
X
X
X
X
X
X
X
SBP/DBP, HR (pre- and post-dialysis for in-center HD 
subjects; between treatments for HHD; at study visits per 
standard of care for and PD subjects) (single readings 
unless otherwise indicated)
X
X
X (triplicate)
X
X
X
X (triplicate)
X
Year 2
Year 3
Year 4
Unscheduled10 End of 
Study15
Follow-up
(4-6 weeks after 
stopping 
randomized 
treatment)
Protocol activity (visits ±1 week)
All assessments pre-dialysis unless 
otherwise specified
(Note: All visit timings are relative to Day 
1)
Week 
64
Week 
76
Week
88
Week 
100
Week 
112
Week 
124
Week 
136
Week 
148
Week 
160
Week 
172
Week 
184
Week 
196
Week 
20814

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Weight (pre- and post-dialysis for in-center 
HD subjects; between treatments for HHD; 
at study visits per standard of care for 
and PD subjects) and EDW
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
SBP/DBP, HR (pre- and post-dialysis for 
in-center HD subjects; between treatments 
for HHD; at study visits per standard of 
care for and PD subjects) (single readings 
unless otherwise indicated)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
(triplicate)
X
Protocol Activity
All assessments pre-dialysis unless otherwise specified
(Note: All visit timings are relative to Day 1)
Early Treatment Discontinuation 
Visit (within 2 weeks of 
discontinuing randomized 
treatment)
Day 1 through Week 527
Week 4, 16, 28, 40, 52 ± 2 weeks
Unscheduled
SBP/DBP, HR (pre- and post-dialysis for in-center HD subjects;
between treatments for HHD; at study visits per standard of 
care for and PD subjects) (single readings unless otherwise 
indicated)
X (triplicate)
X
X
Section 7.1. Time and Events Table; Table 7 Schedule of Assessments Year 1 to Week 52.  Added footnote #2 to Day 1 timepoint and 
updated wording of this footnote to provide flexibility around ECG timing.
Protocol activity (visits ±1 week)
All assessments pre-dialysis unless otherwise specified
(Note: All visit timings are relative to Day 1)
Day 1 through Week 52
Screen
Week -8
Run-in
Week -4
Day 113
Week 2
Full study visit
Week 4, 16, 28, 
40
Abbreviated study visit
Week 8, 12, 20, 24, 32, 36, 
44, 48  
Week 52 Unscheduled10
ECG 2
X2
X
2. Day 1 ECG may be performed as early as the Week -4 visit through the Day 1 visit on a dialysis day on a dialysis day (if 3 times/week dialysis, cannot be done on the 
first dialysis session of the week).  If performed on Day 1, it must be pre-dialysis and over-read prior to randomization. All other ECGs assessments may be recorded pre or 
post dialysis and require over-reading.

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Section 7.1. Time and Events Table; Table 7 Schedule of Assessments Year 1 to Week 52.  Updated footnote #16 to include a broadened 
window to conduct ultrasound and time to complete additional testing if required.
16. Ultrasound of the kidneys and adrenal glands will be performed between the Week -4 and Day 1 visits as early as 6 weeks prior to the Day 1 visit. If results of kidney and 
adrenal ultrasound require follow-up testing, then the run-in period can be extended by 1 additional week.
Section 7.1. Table 7 Schedule of Assessments Year 1 to the End of the Study.  Clarified footnotes associated with Unscheduled visits and 
text and footnotes regarding randomized treatment dispensing and compliance; added flexibility for administering randomized treatment 
after the study visit day (new footnote #19).
Protocol activity (visits ±1 week)
All assessments pre-dialysis unless otherwise specified
(Note: All visit timings are relative to Day 1)
Day 1 through Week 52
Screen
Week -8
Run-in
Week -4
Day 113
Week 2
Full study visit
Week 4, 16, 28, 
40
Abbreviated study visit
Week 8, 12, 20, 24, 32, 36, 
44, 48  
Week 52 Unscheduled10
Placebo run-in or randomized treatment dispensing (start 
administration on day of dispensing)19
X
(placebo)
X
X911
X
X
X
X911
Placebo run-in or randomized treatment compliance19
X (placebo)
X11
X
X
X
X11
Year 2
Year 3
Year 4
Unscheduled10,12 End of 
Study15
Follow-up
(4-6 weeks after 
stopping 
randomized 
treatment)
Protocol activity (visits ±1 week)
All assessments pre-dialysis unless 
otherwise specified
(Note: All visit timings are relative to Day 
1)
Week 
64
Week 
76
Week 
88
Week 
100
Week 
112
Week 
124
Week 
136
Week 
148
Week 
160
Week 
172
Week 
184
Week 
196
Week 
20814
Randomized treatment dispensing (start 
administration on day of 
dispensing)17,19
X
X
X
X
X
X
X
X
X
X
X
X
X
X9, 11, 12
Randomized treatment compliance17,19
X
X
X
X
X
X
X
X
X
X
X
X
X
X11, 12
X
10. If a subject lost their placebo run-in or randomized treatment, it is not necessary to perform the unscheduled visit assessments other then than dispensing placebo run-in or 
randomized treatment. 
11. Required only if dose is changed or randomized treatment is dispensed (year 2 onwards). Compliance checking will be required when a dose of randomized treatment is 
changed.
12. Additional visits to check Hgb and dispense randomized treatment (where directed by the IRT system) are required under the circumstances described in Appendix 6.  
Hematology and chemistry samples are not required.  For any unscheduled visit, compliance checking will be required when a dose of randomized treatment is changed.

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17. Treatment will be dispensed every 4±1 weeks; an IRT call transaction will be required; perform randomized treatment compliance. 
19. In circumstances where the new dose of randomized treatment cannot be dispensed on the day of the study visit, the new dose of randomized treatment can be 
dispensed at next HD treatment. For visits after Day 1, prior randomized treatment should be continued unless on dose hold, Hgb ≥12 g/dL. Compliance is deferred 
until randomized treatment is returned.
Section 7.1. Table 7 Schedule of Assessments Year 1 to the End of the Study and Table 9 Schedule of Assessments for Subjects 
Permanently Discontinuing Randomized Treatment. Clarified Rescue Medication activity and removed X for unscheduled and Early 
Termination visits given rescue evaluation is only triggered at scheduled visits; for the latter, also removed footnote #2.
Protocol activity (visits ±1 week)
All assessments pre-dialysis unless otherwise specified
(Note: All visit timings are relative to Day 1)
Day 1 through Week 52
Screen
Week -8
Run-in
Week -4
Day 113
Week 2
Full study visit
Week 4, 16, 28, 
40
Abbreviated study visit
Week 8, 12, 20, 24, 32, 36, 
44, 48  
Week 52 Unscheduled10
Rescue medication(s) for Initial Intervention3 ,4 
X
X
X
X
Year 2
Year 3
Year 4
Unscheduled10,12 End of 
Study15
Follow-up
(4-6 weeks after 
stopping 
randomized 
treatment)
Protocol activity (visits ±1 week)
All assessments pre-dialysis unless 
otherwise specified
(Note: All visit timings are relative to Day 
1)
Week 
64
Week 
76
Week 
88
Week 
100
Week 
112
Week 
124
Week 
136
Week 
148
Week 
160
Week 
172
Week 
184
Week 
196
Week 
20814
Rescue medication(s) for Initial 
Intervention3,4 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Protocol Activity
All assessments pre-dialysis unless otherwise specified
(Note: All visit timings are relative to Day 1)
Early Treatment Discontinuation 
Visit (within 2 weeks of 
discontinuing randomized 
treatment)
Day 1 through Week 527
Week 4, 16, 28, 40, 52 ± 2 weeks
Unscheduled
Rescue medication1,2
X
2. See details on rescue in Section 6.12.
Section 7.1. Table 7 Schedule of Assessments Year 1 to the End of the Study.  Added pregnancy requirement (new footnote #20) for 
Argentina only as required by local law.

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Protocol activity (visits ±1 week)
All assessments pre-dialysis unless otherwise specified
(Note: All visit timings are relative to Day 1)
Day 1 through Week 52
Screen
Week -8
Run-in
Week -4
Day 113
Week 2
Full study visit
Week 4, 16, 28, 
40
Abbreviated study visit
Week 8, 12, 20, 24, 32, 36, 
44, 48  
Week 52 Unscheduled10
FRP only:  Serum pregnancy test 5,20
X
X
X
X
Year 2
Year 3
Year 4
Unscheduled10 End of 
Study15
Follow-up
(4-6 weeks after 
stopping 
randomized 
treatment)
Protocol activity (visits ±1 week)
All assessments pre-dialysis unless 
otherwise specified
(Note: All visit timings are relative to Day 
1)
Week 
64
Week 
76
Week 
88
Week 
100
Week 
112
Week 
124
Week 
136
Week 
148
Week 
160
Week 
172
Week 
184
Week 
196
Week 
20814
FRP only: serum pregnancy test5,20
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
20. For Argentina ONLY:  Pregnancy testing will be performed every 4 weeks for FRP as required by local law.
Section 7.1. Time and Events Table; Table 7 Schedule of Assessments Year 1 to Week 52.  Added footnote #21 to permit omission of 
storage biomarker collection under certain circumstances.
Protocol activity (visits ±1 week)
All assessments pre-dialysis unless otherwise specified
(Note: All visit timings are relative to Day 1)
Day 1 through Week 52
Screen
Week -8
Run-in
Week -4
Day 113
Week 2
Full study visit
Week 4, 16, 28, 
40
Abbreviated study visit
Week 8, 12, 20, 24, 32, 36, 
44, 48  
Week 52 Unscheduled10
Storage biomarkers21
X
Wk 28
X
21. Biomarker samples will be stored for future analyses for all subjects, except if not permitted by IRB/EC or refused by subject.
Section 7.1 Table 7 Schedule of Assessments Year 1 to the End of the Study and Table 9 Schedule of Assessments for Subjects Permanently 
Discontinuing Randomized Treatment Year 1 through End of Study. Removed footnote #8 from the Run-in Week -4 visit, as it did not 
apply, and changed MACE to clinical events to more accurately represent safety data collected (both tables).
Protocol activity (visits ±1 week)
All assessments pre-dialysis unless otherwise specified
(Note: All visit timings are relative to Day 1)
Day 1 through Week 52
Screen
Week -8
Run-in
Week -4
Day 113
Week 2
Full study visit
Week 4, 16, 28, 
40
Abbreviated study visit
Week 8, 12, 20, 24, 32, 36, 
44, 48  
Week 52 Unscheduled10

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Non-serious AEs, SAEs, AEs of special interest, MACE
clinical events
X8
X8
X
X
X
X
X
X
Year 2
Year 3
Year 4
Unscheduled10 End of 
Study15
Follow-up
(4-6 weeks after 
stopping 
randomized 
treatment)
Protocol activity (visits ±1 week)
All assessments pre-dialysis unless 
otherwise specified
(Note: All visit timings are relative to Day 
1)
Week 
64
Week 
76
Week 
88
Week 
100
Week 
112
Week 
124
Week 
136
Week 
148
Week 
160
Week 
172
Week 
184
Week 
196
Week 
20814
Non-serious AEs, SAEs, AEs of special 
interest, MACEclinical events 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Protocol Activity
All assessments pre-dialysis unless otherwise specified
(Note: All visit timings are relative to Day 1)
Early Treatment Discontinuation 
Visit (within 2 weeks of 
discontinuing randomized 
treatment)
Day 1 through Week 527
Week 4, 16, 28, 40, 52 ± 2 weeks
Unscheduled
Non-serious AEs, AEs of special interest, SAEs, MACEclinical 
events
X
X
X
Protocol activity (visits ± 2 week)
(Note: All visit timings are relative 
to Day 1)
Year 27
Year 37
Year 47
Unscheduled
End of 
Study8
Week 
64
Week 
76
Week 
88
Week 
100
Week 
112
Week 
124
Week 
136
Week 
148
Week 
160
Week 
172
Week 
184
Week 
196
Week 
208
Non-serious AEs, SAEs, AEs of 
special interest, MACEclinical 
events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Section 7.1. Time and Events Table; Table 8 Schedule of Assessments for Patient Reported Outcomes, Genetics and Sub-studies. Added 
healthcare resource utilization for completeness. For ABPM sub-study, updated footnote #4 re: timing of informed consent, removed 
Home BP monitoring, added atrial fibrillation/flutter screening, and revised visit assessment timings and corresponding new footnote 
(#6).  For PK sub-study, added Informed Consent timing and additional timepoints for PK sample collection.  Reordered all footnotes. 

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Protocol Activity
(visits ±1 week)
(Note: All visit timings are relative to
Day 1)
Screening
Day 1 through Week 52208
Post-Week 
52 through 
End of 
Study
End of 
Study
Week -8 Week -4 Day -211 Day -141 Day - 12
Day 
1
Week
4
Week
8 & 12
Week
16, 20 & 
24
Week 28
Week 32, 
36, 40, 
44, 48 
(End of 
week 
visit)
Week
52
Week 100, 
148, 208
Healthcare resource utilization
(subject reported)
X
X
X
X
X
X
X (& 
Follow 
up)
ABPM sub-study (Appendix 12):
                            Informed Consent 
X4
X4
Home BP monitoring(twice daily for 
PRIOR 4 consecutive days)
X
X
X
X
X
Atrial fibrillation/flutter screening 
X5
                    4424 hour ABPM start
X6
X
X (Week 
16)
X
                     44 hour ABPM end
X
X
Record awake and sleep times
X7
X7 (Week 
16)
X
PK sub-study (Appendix 13)
                            Informed Consent 
X8
X8
X8
X8
X8
X8
X8
                           PK assessment
X9
X9
X9
X9
X9
X9
1. Subjects who are unable to or require assistance to read must not complete the questionnaires.
2. Only in selected countries. See Appendix 3.
3. Informed consent for optional Genetic research should be obtained before collecting a sample. To minimize potential study bias, the genetic sample should be collected on Day 1.
4. Informed consent for ABPM sub-study can be obtained at Week -8 or at the Week -4 visit prior to conducting any ABPM sub-study assessments
5. Heart rate will be assessed prior to ABPM, subjects with irregular heart beat will undergo an ECG to assess if atrial fibrillation/flutter is present (see Section 12.12.3.3.)

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6. Baseline ABPM will be performed at any mid-week dialysis visit starting at Week -4 until 1 week prior to randomization (Day 1); the device will be returned at the next 
visit, which ideally is no later than 1 week prior to randomization to allow for QC of the ABPM.  
7. Subject will record sleep and awake times during the ABPM session.
8. Informed consent for PK sub-study can be obtained anytime from Day 1 (once the subjects is confirmed to have been randomized to daprodustat) till Week 52, i.e., last 
study visit where PK sampling can be obtained.
9. Blood samples will be collected at any single study visit from the Week 4 through Week 52 visit the Week 4 OR Week 8 OR Week 12 (i.e., PK is collected at one visit only, 
based on convenience for the subject/site). 
5. Subjects who are unable to or require assistance to read must not complete the questionnaires.
Section 7.1. Time and Events Table; Table 9 Schedule of Assessments for Subjects Permanently Discontinuing Randomized Treatment; 
new rows. Added requirements for ABPM sub-study, including a footnote to clarify ABPM sub-study requirement to record sleep and 
wake time during the ABPM session.
Protocol Activity
All assessments pre-dialysis unless otherwise specified
(Note: All visit timings are relative to Day 1)
Early Treatment Discontinuation 
Visit (within 2 weeks of 
discontinuing randomized
treatment)
Day 1 through Week 527
Week 4, 16, 28, 40, 52 ± 2 weeks
Unscheduled
ABPM sub-study (Appendix 12Appendix 12):                     
24 hour ABPM
X (Week 16)
Record awake and sleep times
X (Week 16)2
2.
Subject will record sleep and wake time during the ABPM session.
Section 7.1. Time and Events Table; Table 9 Schedule of Assessments for Subjects Permanently Discontinuing Randomized Treatment; 
new row. Added healthcare resource utilization for completeness.
Protocol Activity
All assessments pre-dialysis unless otherwise specified
(Note: All visit timings are relative to Day 1)
Early Treatment Discontinuation Visit 
(within 2 weeks of discontinuing 
randomized treatment)
Day 1 through Week 52
Week 4, 16, 28, 40, 52 ± 2 weeks7
Unscheduled
Healthcare resource utilization (subject reported)
X

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Section 7.4.1. Events Referred to the Clinical Events Committee; 1st paragraph.  Added 
reference to CEC Site Manual for scope of reporting requirements.
Investigators should refer any event suspected to be one of the following events below to 
the Clinical Events Committee for adjudication:.  See CEC Site Manual for full scope 
of reporting requirements.  
Section 7.4.1. Events Referred to the Clinical Events Committee; 2nd paragraph after 
bullets.  Added clarity where to find description of source documentation required to 
support adjudication of events.  
Source documentation required to support the adjudication of the events is described in 
the SRM CEC Site Manual.
Section 7.4.4. Adverse Events of Special Interest; revised last sentence for clarity.
The results of any investigation should be recorded inon the AE page and the relevant 
AE of special interest page of the subject’s eCRF.
Section 7.4.7. Height and Weight; 3rd sentence; corrected spelling of center.
For in-centercentre HD subjects, weight will be measured pre and post-dialysis. For 
HHD subjects, weight will be done at study visits between dialysis sessions.  For PD 
subjects, this assessment will be done at study visits, as per standard of care. For
HHD and PD subjects these assessments will be done between treatments.
Section 7.4.8. Blood Pressure and Heart Rate; new text.  Added clarity for PD subjects as 
to the timing of the assessments and for the ordering of the various assessments. 
For in-centercentre HD subjects, SBP, DBP and HR will be measured pre and post-
dialysis. For HHD and PD subjects, these assessments will be done at study visits
between dialysis sessions.  For PD subjects, this assessment will be done at study 
visits, as per standard of care.
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).
Section 7.4.9. Electrocardiogram (ECG); new text 2nd and 4th paragraphs.  Additional 
clarity provided about Day 1 ECG requirements. 
For At the Day 1 visit when an ECG is performed, two additional ECGs are required if 
the initial ECG indicates prolonged QTc (see Section 5.2) using the automated or 
manually calculated QTcB value.  
ECG data will be read locally by a physician with experience in reading and 
interpreting ECGs.  The over-read of the Day 1 ECG is required to confirm 
eligibility. Additional details are provided in the SRM.

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Section 7.4.11. Clinical Laboratory Assessments; 1st and 2nd paragraph. Added new text 
to clarify the relative timing of laboratory assessments to dialysis and corrected spelling 
of center.
All protocol required laboratory assessments, as defined in Table 10, must be conducted 
in accordance with the Laboratory Manual, and Protocol Time and Events Schedule 
(Section 7.1). Laboratory assessments will be done pre-dialysis for in-center HD 
subjects, in between dialysis sessions for HHD subjects at the study visits, and at the 
study visits for PD subjects, as per standard of care.
Laboratory requisition forms must be completed and samples must be clearly labeled 
with the subject number, protocol number, site/centrecenter number, and visit date.
Section 7.7. Patient Reported Outcomes; new text in 1st paragraph. Clarified healthcare 
resource utilization data to be collected.
In addition, healthcare resource utilization will be assessed including out-patient 
visits.
Section 7.7. Patient Reported Outcomes; new text in 2nd paragraph. Added provision for 
sponsor discussion if PRO assessments cannot be conducted.
All questionnaires used in this study have been translated and culturally adapted for use 
in local country languages and will be administered electronically only.  Specific 
instructions on how the subject is to complete the scales and the process for data entry is 
provided in the SRM.  If there are exceptional circumstances whereby the electronic 
PRO assessments cannot be conducted, the completion of these assessments will be 
discussed with the sponsor on a case-by-case basis.
Section 7.7.3. Health Status (EQ-5D-5L & EQ-VAS); paragraph 2. Updated endpoint 
labels.
The EQ VAS records the respondent’s self-rated health on a vertical, visual analogue 
scale where the endpoints are labeled ‘the best health you can imaginebest imaginable 
health state’ and ‘the worst health you can imagineworst imaginable health state’. This 
information is used as a quantitative measure of health outcome as judged by individual 
subjects.
Section 9. Statistical Considerations and Data Analyses; paragraph after table. Change 
from two-sided testing at the 5% level to one-sided testing at the 2.5% level.
The co-primary endpoints will each be tested using a one-sided 2.5% significance level 
and the relevant confidence bound of the a two-sided 95% CI (upper bound for 
MACE and lower bound for the Hgb co-primary endpoint). The type I error rate will 
be strictly controlled at the one-sided 2.5% level across the co-primary analyses as both 
non-inferiority tests need to be met for the trial to be considered successful and for 
statistical analysis to proceed to evaluate MACE superiority and superiority for the 
principal secondary objectives/endpoints. 

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Section 9.1.1. CV Safety (MACE) Co-Primary Hypothesis; last paragraph. Added two-
sided to 95% CIs.
Statistical significance of non-inferiority will be assessed at the twoone-sided 2.5% level.  
A Cox-Proportional-Hazards-Regression model, adjusting for treatment and prognostic 
randomization stratification factors (region and current ESA use), will be used to estimate 
the hazard-ratio, its two-sided 95% CI and to generate the p-value for the non-inferiority 
test. Non-inferiority will be achieved if the upper limit of the two-sided 95% CI is below 
the margin of 1.20.
Section 9.1.2. Hgb efficacy Co-Primary Hypothesis; 3rd paragraph. Changed to one-
sided 2.5% level and added two-sided to 95% CI.
Statistical significance of non-inferiority will be assessed at the twoone-sided 2.5% level. 
An ANCOVA model including prognostic randomization stratification factors (dialysis 
type and region), baseline Hgb and treatment will be used to obtain a point estimate and 
the two-sided 95% CI for the treatment difference (daprodustat -rhEPO) and generate the 
p-value for the non-inferiority test
Section 9.2.1. Sample Size Assumptions; paragraph after bullets. Changed to one-sided 
2.5% level and added two-sided to 95% CI.
The target of 945 adjudicated first MACE will permit a two-sided 95% CI of (0.880, 
1.136) to describe the results for an observed hazard ratio of 1. The largest hazard ratio 
point estimate (two-sided 95% CI) that would meet the statistical criterion for non-
inferiority is 1.056 (0.930, 1.200) and for superiority, the minimum observable effect 
would be a 12% relative risk reduction in favor of daprodustat, corresponding to a hazard 
ratio of 0.880. 
Conditional on both co-primary endpoints achieving non-inferiority at the one-sided 
2.5% level, statistical testing will progress to evaluate MACE and the principal secondary 
endpoints for superiority.
Section 9.2.2. Sample Size Sensitivity; 1st paragraph. Corrected referencing.
The estimated (base case) 15% annual rhEPO MACE rate is based on a review of 
randomized clinical trials in dialysis (peginesatide EMERALD studies [Macdougall, 
2013] and NHS study [Besarab, 1998]), observational data in dialysis patients (GSK 
report from the Dialysis Outcomes and Practice Patterns Study (DOPPS)[DOPPS, 2014]
and the USRDS 2013 annual report [USRDS, 2013]) and considering the planned 
regional distribution for recruitment. 
Section 9.2.2. Sample Size Sensitivity; last paragraph. Added two-sided to 95% CI.
The planned study size far exceeds this requirement and provides more than 99% power 
for non-inferiority and a high level of precision to estimate the treatment effect (two-
sided 95% CI half width of 0.128 g/dL, assuming 30% of subjects will be non-evaluable 
for efficacy). The largest (most negative) difference between arms that would meet the 
statistical criterion for non-inferiority would be -0.622 g/dL. If the two-sided 95% CI is 

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completely negative (i.e. lies fully within the range -0.75 to <0g/dL) non-inferiority 
would still be concluded.
Section 9.2.3. Sample Size Re-estimation or Adjustment; last sentence. Minor revisions.
GSK and the Executive Steering Committee will review blinded data periodically during 
the course of the study and should emerging data suggest that the overall event rate 
and/or the enrollment rate (main study or sub-studies) diverges significantly from 
protocol assumptions either the sample size required to achieve the event target and/or 
the requirement forwith a minimum of one year follow-up may be adjusted.    
Section 9.4.1.1. Primary CV Safety Analysis (co-primary); 1st paragraph. Clarified two-
sided 95% CI and one-sided p-value.
The statistical model is a Cox Proportional Hazards regression model, adjusting for 
treatment and the prognostic randomization stratification factors (dialysis type and 
region), to estimate the hazard ratio, two-sided 95% CI and one-sided p-value for the 
statistical non-inferiority test. Non-inferiority will be established if the upper limit of the 
two-sided 95% CI is less than the margin of 1.20. Cumulative time from randomization to 
first event or end of trial will be evaluated using Kaplan-Meier methodology and 
displayed graphically. Treatment comparisons from the Cox regression model will be 
presented as hazard ratios and two-sided 95% CIs and displayed on forest plots.
Section 9.4.1.2. Primary Efficacy Analysis (co-primary); 1st paragraph. Added two-sided 
95% CI and one-sided p-value.
The ANCOVA model will include prognostic randomization stratification factors 
(dialysis type and region), 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.
Section 9.4.2.1. Principal Secondary Analyses; paragraphs 1 through 2.  Revised to one-
sided 2.5% level, statistical section, revised hypotheses to be tested, and changed 
darbepoetin alfa to rhEPO.
Conditional on the co-primary endpoints achieving at least non-inferiority at the twoone-
sided 2.5% level, statistical testing will progress to superiority for MACE and the 
principal secondary endpoints.  The hypotheses to be tested for these endpoints are as 
follows: 

Null: daprodustat is equal not superior to rhEPO darbepoetin alfa (i.e. the 
hazard ratio is greater than or equal to 1.0 for time-to-event endpoints, or the 
mean difference is greater than or equal to 0 for continuous endpoints)

Alternative: daprodustat is not equal superior to rhEPO darbepoetin alfa (i.e. the 
hazard ratio is not equal less than to 1.0 for time-to-event endpoints, or the mean 
difference is not equal less than l to 0 for continuous endpoints)
These tests will be multiplicity adjusted based on a family-wise Type I error rate set at 
the twoone-sided 2.5% level, see Section 9.4.3 for further details.

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Section 9.4.2.1. Principal Secondary Analyses; last paragraph.  Changed significance 
levels to p-values and added two-sided to 95% CIs.
All analyses of secondary endpoints are of exploratory nature, summary statistics and 
nominal twoone-sided 5% significance levels p-values will be used for any treatment 
comparisons. 
Section 9.4.3. 2nd paragraph; revised to one-sided 2.5% level.
The procedure will be conducted based on a family-wise Type I error rate set at the 
twoone-sided 2.5% level. Details of the Hommel procedure will be fully described in the 
RAP.
Section 9.4.3. Figure 2; updated figure to align with two-sided 95% CI and one-sided 
Type 1 error rate set at 2.5%.  
Figure 2
Multiplicity controlled statistical testing plan
Section 9.4.4. Covariates and Subgroups of Interest; paragraph 2. Revised sentence to 
more complete describe adjustments to statistical model.
Statistical models will be adjusted for the covariates used in the original analysis,
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.
Section 9.4.4. Covariates and Subgroups of Interest; paragraphs 3-5. Updated 
hyporesponder analyses.
rhEPO hyporesponder subgroup definition:  rhEPO hyporesponders will be identified 
either by the ESA Resistance Index (ERI) [HERO study, Johnson, 2015] or by treatment 

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at baseline with a very high dose of IV epoetin alpha.  For each subject, baseline ERI will 
be calculated as the dry weight adjusted weekly mean ESA dose during the 8 week 
screening period divided by baseline Hgb concentration. Subjects with baseline ERI 
≥2 U/kg/wk/g/L for epoetin-treated subjects; ≥0.008 g/kg/wk/g/L for darbepoetin-
treated subjects and ≥0.01 g/kg/wk/g/L for methoxy-PEG-epoetin-treated subjects will 
be included in the pre-specified subgroup. In addition, subjects will be included if being 
treated at baseline with greater than or equal to the equivalent of 450 U/kg/week of IV 
epoetin alpha. This latter criterion covers subjects at higher body weight for which the 
ERI calculation is less accurate and is based on the NICE anemia guidelines of June 2015 
[NICE, 2015].  Sensitivity analyses will explore alternative subgroup definitions: an 
ERI cut-point of ≥1.5 (or equivalent depending on ESA treatment) or using baseline 
prior rhEPO dose above the top 20th percentile for the study population.
rhEPO hyporesponder subgroup analysis plan:  It is anticipated that approximately 
10-15% of subjects may be classified as rhEPO hyporesponders according to this 
definition, thus resulting in a subgroup size of potentially 300-450 subjects. The subgroup 
efficacy analysis will follow the same structure as that defined for the full study, 
assessing the comparative treatment effect in mean Hgb change between baseline and EP 
in subjects regardless of adherence to study treatment as well as in subjects who 
adhere to randomized treatment and using the same non-inferiority margin of -0.75 g/dL. 
For at least 90% power to demonstrate non-inferiority, 86 evaluable rhEPO 
hyporesponders are required per arm.  The statistical model (ANCOVA) will include 
terms for prognostic randomization stratification factors, baseline Hgb, treatment, 
hyporesponder subgroup and treatment by subgroup interaction. Point estimates and two-
sided 95% CIs will be generated to describe the treatment effect separately for rhEPO 
hyporesponders and the complement set of rhEPO non-hyporesponders; non-inferiority 
would be established if the lower limit of the two-sided 95% CI is greater than -0.75 
g/dL. In addition, a nominal one-sided non-inferiority p-value and a nominal one-
sided superiority p-value for the difference between the two groups will be 
generated.  If non-inferiority is met for rhEPO hyporesponders, the analysis would 
proceed to determine whether daprodustat is more effective at achieving Hgb target levels 
compared to rhEPO with superiority established if the lower limit of the 95% CI exceeds 
0 g/dL. Sensitivity analyses will explore alternative subgroup definitions either by raising 
the ERI cut-points to ≥2.5 and ≥3.0 (or equivalent depending on ESA treatment) or using 
baseline prior rhEPO dose above the top 20th percentile for the study population.
A formal comparative assessment of CV risk in this subgroup is not prospectively 
planned because, given the sample size, While it is unlikely, given the sample size, that 
a sufficient number of adjudicated first MACE will occur to support a robust model-
based analysis, subgroup analyses are planned for the co-primary MACE and 
principal secondary CV endpoints. The statistical analysis model (Cox Proportional 
Hazards) will include terms for prognostic randomization stratification factors, 
treatment, hyporesponder subgroup and treatment by subgroup interaction. Point 
estimates and two-sided 95% CIs for the hazard ratio will be generated to describe 
the treatment effect separately for rhEPO hyporesponders and the complement set 
of rhEPO non-hyporesponders; non-inferiority would be established if the upper 
limit of the two-sided 95% CI is less than 1.20.  At a minimum, the incidence of 

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MACE, its components and the principal secondary CV endpoints will be descriptively 
summarized by treatment group.
Summary statistics for baseline characteristics and dosing experience will be generated 
and exploratory analyses conducted for secondary endpoints associated with Hgb, iron 
utilization, rescue (including transfusion), BP, symptoms and HR-QoL.
Section 9.4.5. Interim Analysis; 2nd paragraph. Added additional point for IDMC 
considerations regarding futility.
In addition to MACE, any decisions regarding futility will take into account data related 
to: 1) components of MACE, 2) endpoints describing BP, 3) efficacy in rhEPO 
hyporesponders, 4) other safety and efficacy data across the daprodustat clinical program,
and 5) emerging data in the public domain pertaining to safety or efficacy of HIF-prolyl 
hydroxylase inhibitors, and 6) any other data considered to be relevant by the IDMC.  
The IDMC will make a recommendation to GSK and the ESC chair as outlined in the 
IDMC charter regarding whether the study should continue unchanged, be modified or 
be terminated.  
Section 11. References. updated references; added two missing references (GSK DOPPS 
report and USRDS) and corrected year of publication of Hommel reference.
GSK Document Number WEUKBRE7146. Cardiovascular event rates, red blood cell
transfusion rates, and anaemia management practices in CKD patients across 12 countries
from the Dialysis Outcomes and Practice Patterns Study (DOPPS). 30-JUN-2014
(preliminary report).
Hommel G. A stagewise rejective multiple test procedure based on a modified Bonferroni 
test. Biometrika 19988; 75:383-386
U.S. Renal Data System. USRDS 2013 Annual Data Report: Atlas of Chronic Kidney
Disease and End-Stage Renal Disease in the United States, National Institutes of Health,
National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD 2013;
Volume 2 (Chapter 5):263-270.
Section 12.1. Appendix 1: Abbreviations and Trademarks. Updated abbreviation list.
MCS
Mental Component Score
PASP
Pulmonary Artery Systolic Pressure
PCS
Physical Component Score
sPAP
Systolic pulmonary artery pressure
Section 12.2. Appendix 2:  Secondary and Exploratory Objectives/ Endpoints; secondary 
and exploratory endpoints.  Minor updates to secondary MACE and health outcome 
endpoints; exploratory objective and endpoint for blood transfusion; exploratory 
endpoints for Hgb variability, iron parameter, blood transfusion, and dose adjustment; 
and to footnote #2. 
Secondary Objectives
Secondary Endpoints (tested for superiority1, no multiplicity 

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adjustment)

To compare daprodustat to rhEPO on 
additional CV safety endpoints 

Individual MACE components2 (All-cause mortality, CV 
mortality, fatal or non-fatal MI, fatal or non-fatal stroke2)

MACE or hospitalization for HF2 (recurrent events 
analysis)

CV mortality or non-fatal MI2

All-cause hospitalization

All cause hospital re-admission within 30 days

MACE or hospitalization for HF or thromboembolic 
events2

Hospitalization for HF2

Thromboembolic events2

To compare daprodustat to rhEPO on 
HRQoL and Utility score

Mean change in SF-36 HRQOL scores (Physical 
Component Score (PCS), Mental Component 
Score (MCS) and 8 health domains) between baseline 
and Weeks 8, 12, 28, 52, of particular interest are the 
changes from baseline in the vitality and physical 
functioning domains at Wk 28 and 52

Change from baseline in Health Utility (EQ-5D-5L) score 
at Week 52 

Change from baseline in EQ VAS at Week 52
Exploratory Objectives
Exploratory Endpoints (statistical testing not planned)

To further compare daprodustat and 
darbepoetin alfa on Hgb variability

Hgb observed and change from baseline across all 
visits to end of treatment

% of time Hgb is above, within and below the range of 
10-11.5 g/dL during EP and MP

Number (%) of subjects with mean Hgb above, within 
and below the Hgb analysis range during EP and at the 
end of treatment 

Number (%) of subjects with a Hgb <7.5 g/dL during 
the EP and MP

Number of times Hgb <7.5 g/dL during the EP and 
MP

Number (%) of subjects with a >1g/dL increase in Hgb 
over 2 weeks (assessed at Week 2 and Week 4) or a >2 
g/dL increase in Hgb within any 4 week period from 
Week 4 to Week 52

Number (%) of subjects with a >1g/dL decrease in 
Hgb over 2 weeks (assessed at Week 2 and Week 4) 
or a >2 g/dL decrease in Hgb within any 4 week 
period from Week 4 to Week 52

N (%) of subjects with a Hgb value ≥ 12 g/dL during the 
EP and MP

Number of times Hgb ≥ 12 g/dL during the EP and MP

% of time Hgb ≥ 12 g/dL during the EP and MP

To compare daprodustat to 
darbepoetin alfa on measures of iron 
parameters

Observed and change from baseline in hepcidin, ferritin, 
TSAT, total iron, TIBC across all visits to end of 
treatment

Average quarterly ferritin

Average quarterly TSAT 

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
Average quarterly IV iron dose/subject

N (%) of subject who met iron management criteria

N (%) of subjects who reduced IV iron supplementation 
relative to baseline (defined as total iron (mg) over 4 
weeks prior to randomization) toduring EP (defined as 
average monthly IV iron dose (mg) over Weeks 28 to 52)

To compare daprodustat to 
darbepoetin alfa on the need for RBC 
and whole blood transfusions

Number (%) of subjects who receive at least one RBC or 
whole blood transfusions by Week 52 and by end of 
treatment

Number of RBC and whole blood transfusions per 100 
patient years 

Number of RBC and whole blood units per 100 patient 
years

Evaluate the dose adjustment schemes 
Assigned dose by visit and at Day 1, Week 28, Week 
52, and yearly

Most recent dose prior to Week 28, Week 52, yearly 
and End of Treatment

Number (%) of patients with 0, 1, 2, or >2 dose 
adjustments during the following periods:
o
Day 1 - < Week 28
o
Week 28 - < Week 52
o
Day 1 - < End of Treatment

Number of dose adjustments during the following 
periods:
o
Day 1 - < Week 28
o
Week 28 - < Week 52
o
Day 1 - < End of Treatment

Number of dose adjustments per year during Day 1 -
< End of Treatment

Final (mean and median) dose at Week 28, Week 52 and 
at end of treatment

Number (%) of patients with 0, 1, 2 or >2 dose 
adjustments during the following periods: Day 1 - <Week 
28, Week 28 – Week 52, Day 1 – Week 52, Day 1 – the 
end of treatment

Number of dose adjustments during the following 
periods: Day 1 - <Week 28, Week 28 – Week 52, Day 1 –
Week 52, Day 1 – the end of treatment

Time dose held for Hgb≥12 g/dL
2. Events adjudicated all or in part. 

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Section 12.4. Appendix 4: Risk Assessment. Updates included throughout to align with version 8 of the Investigator’s Brochure.
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.
Following review of clinical data received to date, this has not been 
identified as a safety concern for daprodustat.
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.

Specific eligibility criteria related to 
requirements for entry Hgb are detailed in 
Section 5.1.

Hgb will be closely monitored throughout the 
dosing period as outlined in the Time and 
Events Table Section 7.1.

Specific guidance for dose adjustment, dose 
interruption, or discontinuation of daprodustat 
based on achieved Hgb (including rate of 
change) is provided in Section 6.3 and 
Section 6.12.

Unblinded monitoring of safety data by an 
IDMC in-stream throughout the study.
Death, MI, stroke, congestive HFheart failure,
thromboembolic events venous thromboembolism, 
thrombosis of vascular access at Hgb levels which are 
within the normal range (i.e. not polycythemic 
conditions)
Marketed rhEPO and its analogs/ESAs 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 conducted to date, 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. Following review of clinical data received to date, this 
has not been identified as a safety concern for daprodustat.

Specific eligibility criteria related to CV risk are 
outlined in Section 5.2.

Hgb will be closely monitored throughout the 
dosing period as outlined in the Time and 
Events Table Section 7.1.

Unblinded monitoring of safety data by an 
IDMC in-stream throughout the study.

Planned formal interim analyses with stopping 
guidelines for evidence of increased CV risk 
as outlined in Section 9.4.5.

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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 rodentsrats, stomach erosions were observed with intravenous and 
oral administration of daprodustat.
Stomach erosions/ulcers also reported in rats with some 
marketed rhEPO/ and its analogs.Gender-averaged systemic 
exposure (AUC) at the no observed adverse effect levels (NOAEL) are 
3.3 -fold (monkeys) and 737 -fold (rats) above human exposure (25 
mg daprodustat).
In clinical trials to date with daprodustat, mild-moderate GI signs and 
symptoms represent the most frequently reported adverse event, 
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 in-stream throughout the study.
Cancer-related mortality and tumor progression and 
recurrence
Marketed rhEPOs 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 a 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 

Specific eligibility criteria related to personal 
history of malignancy or subjects with 
complex kidney cyst are outlined in Section 
5.2.

Stopping criteria for subjects with treatment 
emergent malignancy are outlined in Section 
5.5.

Unblinded monitoring of safety data by an 
IDMC in-stream throughout the study.

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daprodustat has been associated with:
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 
mice and dogs, up to 26 weeks2 years in rats and mice, and up to 39 
weeks in monkeys.

Unblinded monitoring of safety data by an 
IDMC in-stream throughout the study.

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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, Tthese
hypoxia-induced PRVP changes fallwere within the range of PRVP 
differences changes noted among non-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 echocardiographically (ECHO) estimatesd of systolic
pulmonary artery systolic pressure (sPASP) 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 
PASPsPAP in subjects not on dialysis for daprodustat. In hemodialysis 
subjects, mean absolute change from baseline in sPAPPASP was 
similar for both treatment groups; however, there was a numeric 
imbalance (Daprodustat: 8 [7%]; Control 0) in subjects reaching the 
sPAPPASP 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 subjects 
with resolution of sPAPPASP 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 subjects meeting the sPAPPASP PCI criterion. Overall, there is 
insufficient evidence to conclude a relationship to treatment with 
daprodustat.
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 

Unblinded monitoring of safety data by an 
IDMC in-stream throughout the study.

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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. Small increases in cardiac troponin in 6 month rat study with 
daprodustat were consistent with the background finding of 
spontaneous rodent cardiomyopathy.  There were no elevations 
observed in cardiac troponin in 9 month monkey study with 
daprodustat
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.
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 degeneration [Campochiaro, 2006].
Administration of 60 mg/kg daprodustat to mice caused minimal 
increases in circulating VEGF while significant EPO increases were 
observed.

Suspected proliferative retinopathy, macular 
edema, choroidal neovascularization or
symptoms consistent with these events should 
be investigated by ophthalmologic consultation 
as clinically warranted.

Unblinded monitoring of safety data by an 
IDMC in-stream throughout the study.

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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 studies.
No ocular abnormalities with daprodustat were seen in non-clinical 
studies of up to 13 weeks duration in mice and dogs, 26 weeks in rats, 
and 39 weeks in monkeys.  
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].
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.

Unblinded monitoring of safety data by an 
IDMC in-stream throughout the study.

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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.
Even though 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 after approximately 10-14 days of dosing with rifampin 
(Brodie, 2013 and 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: in vitro, with an IC50 value of 21 
µM.  A clinical drug interaction study between 25mg and 100mg 
daprodustat with a CYP2C8 substrate (i.e., pioglitazone) showed 
that there is no PK interaction at these doses of daprodustat.  
Population PK analysis from completed Phase 2 studies suggests that 
co-administration of daprodustat with clopidogrel (a moderate CYP2C8

Co-administration of daprodustat with strong 
CYP2C8 inhibitors (e.g., gemfibrozil) and 
inducers (e.g., rifampin/rifampicin) is not 
permitted as outlined in Section 6.10.2.

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 6.3
and Appendix 6.

Specific guidance on the management of 
potential drug-drug interactions and 
concomitant medications is provided in 
Section 6.10.

Hgb will be closely monitored throughout the 
dosing period as outlined in the Time and 
Events Table Section 7.1.

Specific guidance for dose adjustment, dose 
interruption, or discontinuation of daprodustat 
based on achieved Hgb is provided in Section 
6.3 and Appendix 6.

Unblinded monitoring of safety data by an 
IDMC in-stream throughout the study.

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inhibitor) leads to a ~ 2-fold increase in AUC, with no clinically-
significant increase in the measured Hgb response. Co-administration 
of daprodustat with moderate CYP2C8 inhibitors (i.e., clopidogrel, 
teriflunomide, deferasirox) should be performed with caution.
Co-administration of daprodustat with potent BCRP inhibitors has the 
potential to increase exposure of daprodustat. Use of BCRP inhibitors 
(mostly weak) was found to result in a small change in metabolite 
exposure (20% increase in AUC).
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: in vitro, with IC50 values 
of 6 µM and 11 µM, respectively. A clinical drug interaction study 
between 25mg and 100mg daprodustat with either a CYP2C8 
substrate or an OATP1B1/1B3 substrate (rosuvastatin) showed that 
there is no PK interaction at these doses of daprodustat.

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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, venous thromboembolismthromboembolic 
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, venous thromboembolism
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 5.2.

Specific eligibility criteria related to personal 
history of pure red cell aplasia are outlined in 
Section 5.2.

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Section 12.4. Appendix 4: References. Added new references.
Brodie MJ, Mintzer S, Pack AM, Gidal Gary E, Vecht CJ, Schmidt D. Enzyme induction 
with antiepileptic drugs: Cause for concern? Epilepsia 2013 54(1):11–27.
Ohnhaus EE, Breckenridge AM, Park BK. Urinary excretion of 6-Hydroxycortisol and 
the Time Course Measurement of Enzyme Induction in Man. Eur J Clin Pharmacol
1989; 36: 39-46.
Section 12.5. Appendix 5:  Female Eligibility Criteria; 1st bullet; clarification on timing 
for using highly effective contraceptive methods to avoid pregnancy.
Reproductive potential and agrees to follow one of the options listed in the Modified List 
of Highly Effective Methods for Avoiding Pregnancy in FRP from 30 days prior to the 
first dose of randomized treatment and until seven days after the last dose of 
randomized treatment and completion of the Follow-up visit (4-6 weeks after the end 
of randomized treatment);
Section 12.5. Appendix 5:  Female Eligibility Criteria; # 2 under Non-reproductive 
potential definitions. Removed upper boundary of FSH to confirm menopause, corrected 
conventional units for FSH and added SI units for FSH.
2.Postmenopausal defined as 12 months of spontaneous amenorrhea. In questionable 
cases, a blood sample with simultaneous FSH and estradiol consistent with menopause 
is confirmatory (FSH ≥23.0-116.3 MIU/mL (≥23.0 IU/L) and estradiol ≤10 pg/mL (or 
≤37 pmol/L) is confirmatory).
Section 12.6. Appendix 6:  Randomized Treatment Dose Adjustment Schemes; dose steps 
2 and 3. Added provision for possible adjustment to the Dose Adjustment Algorithm, 
steps 2 and 3, based on the review of blinded instream aggregate Hgb data.  
HemoCue Hgb (g/dL) at 
current study visit1
HemoCue Hgb change since last 
study visit1
Randomized Treatment Dose 
Adjustment5
<7.52
Any change
Repeat Hgb and average values6; if 
confirmed, increase to the next higher dose 
step
7.5 to <9.5
Decreasing or No change7
Increase to the next higher dose step   
7.5 to <9.5
Increasing8
Maintain dose 
7.No change may be redefined as an increase of <0.5 g/dL based on the review of blinded instream aggregate Hgb 
data.
8.Increasing may be redefined as an increase of ≥0.5 g/dL based on the review of blinded instream aggregate Hgb 
data.
Section 12.6. Appendix 6:  Randomized Treatment Dose Adjustment Schemes; footnote 
#1. Added clarifications regarding dispensing of randomized treatment and streamlined 
reasons for requiring additional study visits to check Hgb.  

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1.
Study visit” refers to mandated study visits (every 4 weeks through Week 52; then every 12 weeks).  From Week 
52 onwards, additional study visits to check Hgb and dispense randomized treatment (where directed by the IRT 
system) are required under the following circumstances (additional visits have a visit window of ±1 week):

When Hgb at last study visit is outside of the target range, i.e., <10 or >11 g/dL:  Visit 4 weeks later to 
assess for dose adjustment.

When the randomized treatment dose is interrupted: Visits every 4 weeks until study treatment is restarted.

When the dose of randomized treatment is changed or restarted in the previous 12 weeks ±1 week: Visits 
every 4 weeks for 12 weeks. 

When Hgb at last study visit is ≥9.5 to <10 g/dL:  Visit 4 weeks later to assess for dose adjustment.

When Hgb at last study visit is >11-≤11.5 g/dL:  Visit 4 weeks later to assess for dose adjustment.

When a medication that is a moderate CYP2C8 inhibitor (i.e., clopidogrel, teriflunomide, deferasirox) is 
started, stopped, or the dose is changed: Visits every 4 weeks for 12 weeks.

When Hgb at the last study visit is <9 g/dL (includes those being evaluated for rescue):  Visit 4 weeks later to 
assess for dose adjustment. .

When the investigator determines it clinically necessary to evaluate a subject sooner than 12 weeks later: 
Visit 4 weeks later to assess for dose adjustment. 

For subjects changing dialysis modality from HD to PD:  Visits every 4 weeks for 12 weeks. 
Section 12.12. Appendix 12: A Sub-study of the Effect of Daprodustat Compared to 
rhEPO on BP in Hemodialysis Dependent Subjects with Anemia Associated with Chronic 
Kidney Disease who Switch from ESAs; revisions throughout. Changes to ABPM sub-
study to add atrial fibrillation/flutter screening, remove home BP monitoring, change 
from 44- to 24-hour APBM, change in time-point for assessment (from Week 28 to Week 
16), and adjustments to objectives, endpoints and analysis to account for design changes.
Introduction and Rationale: (paragraph 3)
This sub-study is intended to compare daprodustat to rhEPO on BP as assessed by ABPM 
in dialysis-dependent subjects with anemia associated with CKD who switch from ESAs. 
Home BP monitoring will be used to establish baseline BP eligibility criteria and to 
compare the change in average BP between treatment groups as a secondary objective.  
Objectives and Endpoints
Objectives
Endpoints
Primary
8.
To compare daprodustat to rhEPO for 
effect on SBP (superiority) by ABPM in 
subjects receiving maintenance 
hemodialysis in the ABPM ITT population
9.
Change in 4424 hour average SBP from 
baseline to Week 28 end of sub-study1
between treatment groups
Secondary

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Objectives
Endpoints

To assess the effect of daprodustat and 
rhEPO independently within treatment 
group on SBP, DBP and mean arterial 
blood pressure (MAP) by ABPM in the 
ABPM ITT population 

Change in 4424 hour average SBP from 
baseline to Week 28 end of sub-study1 within 
each treatment group

Change in 4424 hour average DBP from 
baseline to Week 28 end of sub-study1 within 
each treatment group

Change in 4424 hour average MAP from 
baseline to Week 28 end of sub-study1 within 
each treatment group

To compare the effect of daprodustat to 
rhEPO on DBP and MAP by ABPM in the 
ABPM ITT population

Change in 4424 hour average DBP from 
baseline to Week 28 end of sub-study1
between treatment groups

Change in 4424 hour average MAP from 
baseline to Week 28 end of sub-study1
between treatment groups

To compare the effect of daprodustat to 
rhEPO on BP parameters in the ABPM 
per-protocol population

Change in:

4424 hour average SBP

4424 hour average DBP

4424 hour average mean arterial pressure
from baseline to Week 28 end of sub-study1
between treatment groups

To assess the effect of daprodustat and 
rhEPO on BP parameters in the ABPM 
per-protocol population
Change in:

4424 hour average SBP

4424 hour average DBP

4424 hour average mean arterial pressure
from baseline to Week 28 end of sub-study1
within each treatment group

To compare the percentage of subjects in 
each treatment group requiring a change 
in antihypertensive medications in the 
ABPM ITT population

Difference between treatment groups in 
percentage of subjects requiring no change 
in number or dosage of antihypertensive 
medications

Difference between treatment groups in 
percentage of subjects requiring an increase in 
number or dosage of antihypertensive 
medications

Difference between treatment groups in 
percentage of subjects requiring a decrease in 
number or dosage of antihypertensive 
medications

To compare the percentage of subjects 
in each treatment group requiring a 
change in antihypertensive medications 
in the ABPM per-protocol population

Difference between treatment groups in 
percentage of subjects requiring an increase in 
dosage of antihypertensive medications

Difference between treatment groups in 
percentage of subjects requiring a decrease in 
dosage of antihypertensive medications

To characterize the dipping pattern of 
sleeping BP in each treatment group in 
the ABPM ITT and ABPM per-protocol 
populations

4424 hour BP profile as measured by ABPM, 
with subjects categorized according to their 
sleeping BP behaviors as:
o dippers (normal) when the reduction in the 

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Objectives
Endpoints
average SBP during the sleeping period 
was >10% to 20% of mean SBP during 
waking hours,
o extreme dippers when this reduction was 
>20%,
o non-dippers when the reduction was <10%, 
and
o reverse dippers when the mean sleep SBP 
was higher than the awake SBP [Bakris, 
2014]

To compare the percentage of subjects 
that convert from non-dipper status to 
dipper status between treatment groups 
in the ABPM ITT and ABPM per-protocol 
populations

Difference between treatment groups in 
percentage of subjects that convert from non-
dipper status at baseline to dipper status at 
Week 28 end of sub-study1

To compare the percentage of subjects 
that convert from dipper status to non-
dipper status between treatment groups 
in the ABPM ITT and ABPM per-protocol 
populations

Difference between treatment groups in 
percentage of subjects that convert from dipper 
status at baseline to non-dipper status at Week 
28 end of sub-study1

To compare the effect of treatment with 
daprodustat to rhEPO on change in 
average home BP between treatment 
groups in the ABPM ITT and ABPM per-
protocol populations

Change in SBP and DBP from baseline to Week 
28 between treatment groups

To compare the effect of treatment with 
daprodustat to rhEPO on pulse heart 
rate by ABPM in the ABPM ITT 
population

Change from baseline to Week 28 end of sub-
study1 in 4424 hour average pulseheart rate
between treatment groups as measured by 
ABPM relative to time since administration of 
medication
1. The end of the sub-study is defined as Week 16, or Week 28 for subjects completing the sub-study 
prior to Amendment 2.
Study Design
This is a multicenter sub-study of the main ASCEND-D study.  Subjects who qualify for 
the main study will be assessed for enrolment.  Approximately 300136 subjects from 60-
90 centers in selected countries that are participating in the main study will be 
randomized.  
Note: if the target number of randomized subjects in the ABPM sub-study is not 
achieved when the main study is fully enrolled, recruitment may be extended to 
allow randomization in the ABPM sub-study to complete. Home BP monitoring will 
be done to establish baseline eligibility for subject participation and will continue through 
to Week 28 study visits.
ABPM Quality Control Criteria

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Subjects will need to wear the ABPM device for two 24-hour sessions during the study: 
at a mid-week dialysis visit starting at Week -4 until 1 week at Day -14prior to 
randomization (baseline ABPM) and then at Week 2816.  The ABPM device will be 
placed after assessments for the main study have been completed. ABPM Quality Control 
(QC) criteria as defined in the Project Requirement Specification (PRS) for ABPM must 
be met.
Subjects will be expected to wear the ABPM device twicefor 4424 hours at each session.  
The ABPM device will measure BP and pulseheart rate every 30 minutes during both 
awake and asleep hours.  The times the subject awakens and goes to sleep during this 
4424 hour period will be recorded.
For each session the ABPM Quality Control (QC) criteria as defined in the Project 
Requirement Specification (PRS) for ABPM must be met.  If these criteria are not 
met the ABPM may be repeated (see Section 12.12.3.3).
Eligibility Criteria – Screening
Additional Inclusion Criteria
In addition to meeting entry criteria for the main study, a subject will be eligible for 
inclusion in this sub-study only if all of the following criteria apply.
1. Signed written informed consent prior to beginning sub-study-related procedures.  
Note:  Consent to participate in this sub-study is separate from consent to participate 
in the main study, and needs towill be signed either at Week -8 or at Week -4 prior 
to ABPM assessments.
2. Use of the same antihypertensive treatment for the 6 weeks prior to the Screening 
visit, through the entire Screening period and at randomization.
3. Average home SBP of 150170 mmHg based on the average of pre-dialysis clinic 
values obtained at as assessed starting Day 21Week -8 and Week -4 (prior to 
ABPM) using the methodology described in the SRM.
4. Willing and able to wear ABPM device for 4424 hours on two separate sessions.
5. Valid ABPM measurementsat baseline [randomization (Day 1) only].
6. Dialysis schedule of three times per week.
7. Average awake-time SBP of ≤150 mmHg as assessed by a valid baseline ABPM
[randomization (Day 1) only].
Additional Exclusion Criteria
A subject will not be eligible for inclusion in this sub-study if any of the following 
criteria apply:
1. Receiving peritoneal dialysis or home HD.

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2. Subjects who are at high risk for loss to follow-up (e.g., subjects who are known to 
not regularly attend dialysis, subjects who may require frequent hospitalizations or 
vascular access interventions).
3. Current or historyEvidence of atrial fibrillation or atrial flutter at time of baseline 
ABPM assessment (see Section 12.12.3.3). 
4. Oscillometer/sphygmomanometer cuff cannot accommodate their upper arm 
circumference.
5. BP cannot be measured in the arm opposite of current vascular access.
6. Subjects who experience, on average, >5% increase in weight above EDW between 
mid-week dialysis treatments between Week -48 and Day -14 baseline ABPM 
reading. (e.g., Monday to Wednesday or Wednesday to Friday if dialysis days are 
Monday, Wednesday, Friday).
Study Assessments
Week -48 Study Visit:
Subject’s consent for ABPM is obtained (Note: if missed this may be obtained at 
Week -4 prior to ABPM assessments).  
Week -4 Study Visit:
After the Week-4 main study assessments are completed and consent for participation in 
this ABPM sub-study is obtained, the subject will be given the home BP monitor and 
instructed on its use.  Between Week -4 and Week -3, the subject must become familiar 
with obtaining twice daily home BP readings.  Specific directions for measuring home 
BP will be provided in the SRM. 
Screening Home Blood Pressure Monitoring
Starting at Day -21, the subject will obtain twice daily home BP readings for 4 
consecutive days; initiation of home BP measurements will be on a mid-week dialysis 
day.  For example, subjects on a Monday, Wednesday, Friday dialysis schedule, the first 
home BP recording must be obtained on a Wednesday morning.  For subjects on a 
Tuesday, Thursday and Saturday dialysis schedule, the first home BP reading must be 
obtained on Thursday morning.  Home BP results will be transmitted to the study center 
in real-time.  Home BP readings should be obtained in the morning and evening (ideally 
spaced at least 8 hours apart), at least 1 hour after eating and not within 1 hour of 
awakening.  These readings will establish BP eligibility for ABPM participation
Day -14 Study Visit: This clinic visit will be used to initiate aA baseline ABPM reading
(prior to randomization and first dose of study medication) and must occur at the be 
initiated at a mid-week dialysis visit and may be performed following completion of 
the Week -4 study assessments or at a subsequent mid-week dialysis visit provided it 
occurs at least 1 week prior to randomization. 

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Post-dialysis and prior to ABPM, subjects will be assessed for the presence of atrial 
fibrillation/flutter as follows: subjects with an irregular heart beat detected during 
heart rate measurement will undergo an ECG and those with documented atrial 
fibrillation or atrial flutter will not be eligible for ABPM. 
tThe ABPM device will be placed on the arm opposite current vascular access, and will 
be removed by study personnel at the next dialysis session (i.e., Day 12)by the subject at 
home after a minimum of, after 44 24 hours of wear; the device will be returned to 
the research staff at the next visit, which ideally is no later than 1 week prior to 
randomization to allow for QC of the ABPM. See SRM for guidance on placement of 
ABPM device.
If the subject fails to meet the baseline ABPM QC criteria and agrees to repeat the 
ABPM procedure, then:

The baseline ABPM procedure can be repeated at the next mid-week dialysis 
visit. Note: the atrial fibrillation/flutter assessment should be repeated prior to 
device placement.

Day 1 (randomization) may be delayed.

If the baseline ABPM fails the QC criteria after three attempts, then the 
subject will not be enrolled in this ABPM sub-study.
Subjects will have their body weight measured and recorded in the eCRF both pre- and 
post-dialysis (see SRM for guidance on body weight measurement).
Day 1 (rRandomization/next mid-week dialysis visit):
If the ABPM measurements meet the QC criteria, the subject can be randomized.
If the subject fails to meet the baseline ABPM-QC criteria and agrees to repeat the 
ABPM procedure, then:

The baseline ABPM procedure can be repeated once at the next mid-week dialysis 
visit.

Day 1 (randomization) may be delayed.

If the baseline ABPM fails the QC criteria a second time, then the subject will not 
be enrolled in this ABPM sub-study.
Subjects who either do not qualify for entry into the ABPM sub-study after failing QC 
criteria a secondthird time or who do not desire to continue in the ABPM sub-study 
although they pass the QC criteria, should continue with randomization into the main 
study following the schedule of assessments as outlined in Table 7 of the main protocol if 
appropriate.
Week 4 through Week 28 Study Visits (Home BP Monitoring Continues)
Subjects should obtain home BP readings for the four days prior to each study visit
between Week 4 and Week 28 as outlined in the SRM.

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Week 2816 Study Visit:
At the end of the main study Hgb stabilization period (i.e., atWeek 2816, at the mid-week 
dialysis visit and after all main study assessments have been completed, the subject’s pre-
and post-dialysis weight will be measured and the EDW will be recorded.  
The ABPM device will be placed on the subject’s arm by site personnel and the subject 
will wear the device for 44 hours until the next dialysis session.  After a minimum of 24 
hours of wear, the device will be removed by the subject at home and returned to 
the research staff at the next visit.  The time and date of study medication 
administration, before and while wearing the ABPM device, will be recorded.
If the ABPM fails the QC criteria (same as baseline), up to two additional attempts may 
be made in at subsequent, mid-week dialysis visits.  No further attempts are allowed.  
The subject will continue study visits in the main study as scheduled.
Permanent Discontinuation of Randomized Treatment
A subject who permanently discontinues randomized treatment prior to completing 
the ABPM sub-study should remain in the sub-study and complete the Week 16 
ABPM assessment unless consent to participate in the ABPM sub-study is 
withdrawn (see also Section 5.5).
Estimated Dry Weight and Antihypertensive Medication Changes
It is preferred that no changes are made to EDW and antihypertensive medications while 
the subject is part of the sub-study.  
If changes in EDW and/or antihypertensive medications are necessary, these must be 
documented in the eCRF along with the reasons.  Subjects will remain in the sub-study 
regardless of any changes.
Withdrawal from ABPM Sub-Study
If a subject participating in this sub-study withdraws from the sub-study, the reason for 
the withdrawal must be recorded in the eCRF. The subject will remain in the main study 
unless the subject withdraws consent from the main study.
Sample Size and Power Calculations
The sample size of this sub-study has been designed based on the primary sub-study 
objective to demonstrate superiority in average SBP change from baseline to end of 
sub-study between arms (daprodustat versus rhEPO), measured by ABPM over a 4424
hour assessment period.  Assuming a one-sided 2.5% significance level, a true standard 
deviation for SBP change from baseline measured by ABPM of 11 mmHg [Peixoto, 
2000], and up to a 3020% withdrawal rate from the sub-study, a sample size of 14868
subjects per group (296136 subjects in total) will provide greater than 9080% power to 
detect a -56 mmHg difference in treatment groups (i.e., achieve superiority).  Under these 

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assumptions, superiority will be established if there is more than a 34.2 mmHg mean 
difference observed in favor of daprodustat.
Assuming a 2040% screen failure rate for the additional ABPM entry criteria, 
approximately 370228 subjects that are eligible for the main study will need to be 
screened for the sub-study in order to randomize approximately 296136 subjects. See 
Section 9.2.3 for more information about sample size adjustments.
Unblinded ABPM data will be reviewed by the IDMC during the conduct of the trial as 
part of their data monitoring responsibilities. No formal interim analysis is planned.
Statistical Analysis
The primary sub-study estimand is to compare the treatment effect on change from 
baseline in 4424 hour average SBP at Week 28end of sub-study, in all randomized sub-
study subjects.  The statistical model for analysis will be an ANCOVA with terms for 
treatment and baseline 4424 hour average SBP.  This model will provide a point estimate 
and two-sided 95% CI for the treatment effect and a one-sided p-value for the superiority 
assessment.  Superiority will be established if the p-value is <0.025.  The primary 
analysis population will be the ABPM sub-study-ITT population defined as randomized 
subjects who were also entered into the ABPM sub-study.
Given the nature of ABPM measurement, a high degree of dropout unrelated to 
randomized treatment is anticipated.  The potential high level of missing data poses a 
challenge in the interpretation of the primary ABPM sub-study analysis.  The reason for 
missing ABPM data will be examined to explore the impact of missing data on the sub-
study primary efficacy conclusions.  If the majority (defined as >70%) of the missing 
data is due to either subject unwillingness to repeat the ABPM procedure or due to an un-
evaluable reading, then data will be treated as missing at random and the primary analysis 
will be considered sufficient.  Otherwise, a sensitivity analysis may be performed that 
will use multiple imputation from the active control arm to replace data from both 
treatment groups that was missing due to reasons other than subject unwillingness or un-
evaluable readings.  Further sensitivitysupplementary analyses may include an ABPM 
per-protocol population (PP) analysis, utilizing all ABPM-ITT subjects who are not 
major protocol violators or who did not change BP medications during the sub-study.  
Further details of sensitivity and supplementary analyses will be described in the RAP.
In order to contextualise the primary between-group comparison, a key secondary 
objective is to assess within-group changes from baseline over 28 weeks the sub-study.  
Assessment of within-group changes will support interpretation of the primary analysis 
by identifying whether there was an absence of an increase in BP in one or both treatment 
groups.  To that end, two-sided 95% confidence intervals will be calculated for change 
from baseline in each ABPM parameter separately for each treatment group.  For either 
treatment group, a lack of adverse effect on the primary endpoint of average SBP at and 
of sub-study Week 28 will be concluded if the upper 95% confidence limit is no more 
than 4 mmHg.  This margin was chosen as it is less than the clinically meaningful change 
of 5 mmHg [Whelton, 2002] and it is half the historical increase in SBP observed with 
rhEPO [Krapf, 2009].

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The mean and two-sided 95% CI will be estimated from the primary statistical model for 
within treatment arm SBP change from Bbaseline to Week 28 end of sub-study.
The change from baseline 4424 hour average DBP, mean arterial pressure and pulseheart 
rate at Week 28 end of sub-study will be assessed in a similar way as the primary, using 
analogous ANCOVA models with treatment and baseline as covariates.
The differences in proportion of subjects that increase/decrease their BP medication 
(number or dose) will be assessed using Fisher’s Exact Test.  The differences between 
treatment groups in the proportion of subjects that convert from dippers/non-dippers at 
baseline to non-dippers/dippers at Week 28 end of sub-study will also be assessed using 
Fisher’s Exact Test.
Changes from baseline in home BP measurements (SBP and DBP) at Week 28, utilizing 
all data collected at visits up to Week 28, will be analyzed using mixed model repeated 
measures (MMRM) with a model adjusting for treatment, baseline, time, treatment by 
baseline interaction, and treatment by time interaction.
Plots of the mean 4424 hour average values (two-sided 95% CIs) and mean changes from 
baseline in 4424 hour average values (two-sided 95% CIs) for BP will be provided by 
treatment group.
Additional statistical considerations will be addressed in the RAP.
Section 12.13.3. Appendix 14: A Sub-study to Collect PK Samples in Dialysis Subjects 
with Anemia Associated with CKD; study design – 1st paragraph; minor revisions. 
This is a multicenter sub-study of daprodustat study 200807 (the main study).  
Approximately 40 to 50 centers 200 subjects from centers in selected countries that are 
participating in the main study will be invited to participate in the PK sub-study.
Section 12.13.4. Appendix 13: A Sub-study to Collect PK Samples in Dialysis Subjects
with Anemia Associated with CKD; additional inclusion criteria – 2nd and 3rd bullets. 
Clarified 2nd inclusion criteria and corrected spelling of center in 3rd inclusion criteria.

Subject must be receiving randomized to receive daprodustat treatment in the
main study.

Only subject’s receiving in centrecenter hemodialysis are eligible.
Section 12.13.5. Appendix 13 A Sub-study to Collect PK Samples in Dialysis Subjects 
with Anemia Associated with CKD; study assessments – 1st paragraph. Added additional 
eligible collection visits to collect PK samples in PK sub-studies.
Blood samples will be collected at any single study visit from the Week 4 through 
Week 52, Week 8, or Week 12 visit (i.e., PK is collected at one visit only, based on 
convenience for the subject/site).

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Section 12.13.5. Appendix 13 A Sub-study to Collect PK Samples in Dialysis Subjects 
with Anemia Associated with CKD; study assessments – 2nd and 3rd bullets. Added 
clarifications around the PK visit, i.e., not being on dose hold and recording three prior 
doses.

The dose taken in the clinic should be from the same bottle(s) the subject has 
been using prior to the PK visit, and not from any newly dispensed bottle(s) at 
the PK visit (Note: a subject placed on a dose hold at the previous visit should 
not have PK samples taken; PK collection should be delayed until the visit 
after the subject has restarted study treatment).

Record the date and actual time of the dose taken in the clinic and the three 
doses prior to the visit, and the date and actual time of all PK samples collected. 
Samples may be collected within 20 min of the planned collected time.
Section 12.13.6. Appendix 13: A Sub-study to Collect PK Samples in Dialysis Subjects 
with Anemia Associated with CKD; sample size – 1st paragraph. Clarified sample size is 
an approximate.
The planned enrollment for this PK sub-study is 200 subjects. It is estimated that 150 
sub-study subjects are required to have at least 80% power that the MACE rate in the 
sub-study is within 20% of the MACE rate in main study.  To account for missing or non-
evaluable PK samples, approximately 200 subjects will be enrolledrandomized. See 
Section 9.2.3 for more information about sample size adjustments.  

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12.15.4.
Changes Resulting from Protocol Amendment 4
This is an amendment to the protocol amendment dated 2020-JUL-30.
This amendment applies to all countries.
12.15.4.1. Summary of Changes

Revised MACE NI margin in order to align the NI margin with similar studies that 
have already compared the effects of HIF-PHIs on MACE versus rhEPO.

Revised target MACE as a result of the change to the non-inferiority margin.

Updated the analysis of the hemoglobin co-primary endpoint based on FDA feedback.

Updated terminology (i.e., use of ‘supportive’) to be consistent with ICH-E9 
addendum.

Multiplicity adjustment strategy updated from Hommel to Holm-Bonferroni based on 
FDA feedback.

Added AESI of worsening of hypertension to footnote (included in IB, version 10).

Edited Risk Assessment information to include worsening of hypertension.

Updated pregnancy reporting timelines to align with revised Sponsor timings.
12.15.4.2. List of Specific Changes
Section 1. Overall Design, Revised MACE NI margin in order to align the NI margin with 
similar studies that have already compared the effects of HIF-PHIs on MACE versus 
rhEPO.

The total duration of the study is dependent upon the accumulation of 945664
adjudicated first MACE (i.e., it is event-driven) unless review of interim data by the 
Independent Data Monitoring Committee (IDMC) recommends bringing the study to 
an earlier close.
Section 1. Analysis, Revised MACE NI margin in order to align the NI margin with 
similar studies that have already compared the effects of HIF-PHIs on MACE versus 
rhEPO.
For CV safety, the primary question is whether daprodustat is non-inferior to rhEPO for 
adjudicated MACE. An Intent-to-Treat (ITT) analysis of time to the first occurrence of 
adjudicated MACE using a margin of 1.2025 and a Cox Proportional Hazards regression 
model adjusting for treatment and prognostic randomization stratification factors (dialysis 
type and region), will be used. 
For Hgb efficacy, the primary question is whether daprodustat is non-inferior to rhEPO 
for change from baseline in central laboratory Hgb. The analysis will be based on the 
mean change in Hgb between baseline and the efficacy EP (defined as Weeks 28 to 52) 
using a non-inferiority margin of -0.75 g/dL. An analysis of the ITT Population, 
comprising all subjects with a least one Hgb measurement (on or off treatment) during 
the EP and an analysis of covariance (ANCOVA) model will be used. The model will 
include prognostic randomization stratification factors (dialysis type and region), and 
factors for baseline Hgb and treatment.

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Section 3. Objective(s) and Endpoint(s), Added AESI of worsening of hypertension to 
footnote (included in IB, version 10).
2.
Defined as thrombosis and/or tissue ischemia secondary to excessive erythropoiesis; worsening of 
hypertension; cardiomyopathy; pulmonary artery hypertension; cancer-related mortality and tumor progression 
and recurrence; esophageal and gastric erosions; proliferative retinopathy, macular edema, choroidal 
neovascularization; and exacerbation of rheumatoid arthritis
Section 4.1. Overall Design, Revised target MACE as a result of the change to the non-
inferiority margin.

The total duration of the study is dependent upon the accumulation of 945664
adjudicated first MACE (i.e., it is event-driven) unless review of interim data by the 
Independent Data Monitoring Committee (IDMC) recommends bringing the study to 
an earlier close.

The end of the study will occur after the accumulation of 954664 adjudicated first 
MACE and the last subject has completed their last required study visit (Section 7.1). 
Section 4.1. Overall Design, Streamlined schematic and revised target MACE as a result 
of the change to the non-inferiority margin.
Section 6.3.5. Randomized Treatment Discontinuation, Revised target MACE as a result 
of the change to the non-inferiority margin.
The sponsor will inform investigators when they should have subjects come in for an End 
of Study visit based on the projected occurrence of 945664 first MACE.
Section 7.4.4. Adverse Events of Special Interest, Added AESI of worsening of 
hypertension to footnote (included in IB, version 10).

Worsening of hypertension
Section 7.4.6. Pregnancy, Updated pregnancy reporting timelines to align with revised 
Sponsor timings.

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If a pregnancy is reported then the investigator should inform PPD within 24 hours2 
weeks of learning of the pregnancy and should follow the procedures outlined in 
Appendix 10.
Section 9.1.1. CV Safety (MACE) Co-Primary Hypothesis, Updates to non-inferiority 
margin and relative risk in order to align the non-inferiority margin with similar studies 
that have already compared the effects of HIF-PHIs on MACE versus rhEPO.

Null: daprodustat is inferior to rhEPO, with at least a 250% increased relative risk 
of first MACE (i.e. the hazard ratio is 1.250)

Alternative: daprodustat is non-inferior to rhEPO (i.e. the hazard ratio is <1.250)
The non-inferiority margin is pre-defined as the hazard ratio of 1.250; supported by a 
review of evidence reported in historical randomized trials of rhEPO in dialysis and ND 
CKD subjects and after consideration of the largest point estimate that, by design, would 
meet the statistical criterion for non-inferiority. 
Statistical significance of non-inferiority will be assessed at the one-sided 2.5% level. A 
Cox-Proportional Hazards-Regression model, adjusting for treatment and prognostic 
randomization stratification factors (dialysis type and region), will be used to estimate the 
hazard-ratio, its two-sided 95% CI and to generate the p-value for the non-inferiority test. 
Non-inferiority will be achieved if the upper limit of the two-sided 95% CI is below the 
margin of 1.250.  
Section 9.1.2. Hgb efficacy Co-Primary Hypothesis, Analysis of the hemoglobin co-
primary endpoint was updated based on FDA feedback.
The co-primary Hgb efficacy objective will assess the estimand defined as the effect 
comparative treatment effect in mean Hgb change between baseline and EP (i.e., Weeks 
28 to 52 inclusive) in all randomized subjects; defined as those 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.of daprodustat 
treatment relative to rhEPO on the change in Hgb from baseline to the average of 
all values in the EP, regardless of adherence to treatment including interruptions 
and discontinuations, the use of non-randomized ESA medication for any reason 
including rescue therapy, or the use of blood transfusions, in subjects on dialysis 
currently treated with an ESA with anemia secondary to CKD and assuming 
subjects do not die before the end of the EP. The analysis will test whether daprodustat 
is non-inferior to rhEPO according to the following statistical hypotheses: 
Section 9.2.1 Sample Size Assumptions, Revised target MACE, projected annual 
adjudicated first MACE rate and non-inferiority margin in order to align the non-
inferiority margin with similar studies that have already compared the effects of HIF-
PHIs on MACE versus rhEPO.
The size of this event driven trial is based on the co-primary CV safety objective and is 
determined by a fixed event target of 664945 adjudicated first MACE. This provides 
approximately 90% power to establish non-inferiority assuming a true underlying 3% 
lower relative risk of MACE in favor of daprodustat compared to rhEPO (i.e., hazard 
ratio=0.97) and 8280% power for non-inferiority under the assumption that the true 

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underlying risk of MACE is the same in both arms (i.e., hazard ratio=1.00). Other 
assumptions behind the sample size calculation include:

Projected annual adjudicated first MACE rate of 115%. All-cause death is expected 
to be the most prevalent component, followed by non-fatal MI and then non-fatal 
stroke (projected break down of 60%, 30% and 10% respectively). 

Variance under the alternative hypothesis (i.e. hazard ratio=0.97) 

1% annual lost to follow-up without vital status

A two-sided 95% CI is used for analysis
The target of 664945 adjudicated first MACE will permit a two-sided 95% CI of 
(0.859880, 1.164436) to describe the results for an observed hazard ratio of 1. The largest 
hazard ratio point estimate (two-sided 95% CI) that would meet the statistical criterion 
for non-inferiority is 1.07456 (0.922930, 1.250200) and for superiority, the minimum 
observable effect would be a 14.112% relative risk reduction in favor of daprodustat, 
corresponding to a hazard ratio of 0.859880. 
Conditional on both co-primary endpoints achieving non-inferiority at the one-sided 
2.5% level, statistical testing will progress to evaluate MACE and the principal secondary 
endpoints for superiority. These tests will be multiplicity adjusted, details are provided in 
Section 9.4.3. 
Based on an annual MACE rate of 11%, it is anticipated that approximately 3000 
dialysis subjects will be required to achieve 664 adjudicated first MACE target will be 
reached approximately after3.3 years from when the first subject is randomized. 
Assuming the trial continues to its planned final analysis, and based on recruitment and 
event rate assumptions, enrolment is expected to complete within 1.4 years. All subjects 
will have the opportunity for a minimum of 1 year exposure to treatment and thus the 
opportunity to complete the EP (Weeks 28 to 52). Exposure to daprodustat is expected to 
be in the region of 3,5004,000 patient years with median patient follow-up expected to 
exceed 2 years.
Section 9.2.2. Sample Size Sensitivity, Updated based on blinded MACE accrual.
The estimated 11% annual MACE rate is based on a blinded summary of ASCEND-
D data as of April 20, 2020. Table 11 illustrates the impact on power if the true 
underlying The estimated (base case) 15% annual rhEPO MACE rate is based on a 
review of randomized clinical trials in dialysis (peginesatide EMERALD studies 
[Macdougall, 2013] and NHS study [Besarab, 1998]), observational data in dialysis 
patients (GSK report from the Dialysis Outcomes and Practice Patterns Study  [DOPPS, 
2014]and the USRDS 2013 annual report [USRDS, 2013]) and considering the planned 
regional distribution for recruitment. Table 11 illustrates the impact on timing of events if 
the true underlying annual MACE rate differs from 15% and Table 12 if the true 
underlying treatment effect is not a hazard ratio of 0.97.

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Table 11
Sensitivity based on a different true underlying annual MACE rate
True annual first 
MACE rate
Time to accrue 945 
first MACE
12%
3.9y
14%
3.4y
15% (base case)
3.3y
16%
3.1y
18%
2.8y
Table 112
Sensitivity Based on a Different True Underlying Treatment Effect
Underlying hazard 
ratio for MACE rate
Power for non-
inferiority
0.90
>99%
0.95
945%
0.97 (base case)
90%
1.00
820%
1.03
7065%
1.05
6154%
Section 9.2.3. Sample Size Re-estimation or Adjustment, Updated to reflect no sample 
size re-estimation was performed.
At the time of this protocol amendment, the study was fully enrolled, and as such no 
sample size re-estimation was performed.  It is currently unknown whether the rhEPO 
MACE event rate based on the previous trials has changed due to modifications in rhEPO 
use following emergence of data demonstrating safety concerns with the use of rhEPO. 
GSK and the Executive Steering Committee will review blinded data periodically during 
the course of the study and should emerging data suggest that the overall event rate 
and/or enrolment rate (main study or sub-studies) diverges significantly from protocol 
assumptions either the sample size required to achieve the event target and/or the 
requirements for a minimum one year follow-up may be adjusted.
Section 9.3.1 Analysis Population, Updated terminology to be consistent with ICH-E9 
addendum.
The primary population for the Hgb efficacy analyses will also be the ITT Population. In 
order to assess the sensitivity of the primary efficacy analysis, anA supportive analysis 
of the primary efficacy endpoint will be performed in a Per-Protocol (PP) Population 
defined as all ITT subjects who are not major protocol violators. Details will be defined 
in the RAP and subjects analyzed according to the treatment received.
Section 9.4.1.1. Primary CV Safety Analysis (co-primary), •Revised MACE NI margin in 
order to align the NI margin with similar studies that have already compared the effects 
of HIF-PHIs on MACE versus rhEPO and terminology updated to be consistent with 
ICH-E9 addendum.

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Non-inferiority will be established if the upper limit of the two-sided 95% CI is less than 
the margin of 1.250.
Sensitivity and Supportive Analyses: Sensitivity analysesA sensitivity analysis will be 
performed to address potential effects of drop outs and to evaluate the robustness of the 
co-primary MACE analysis. These will include aA sensitivity “tipping point” analysis 
utilizing multiple imputation for randomized subjects who have withdrawn consent or are 
lost to follow upfrom the study will be performed, as well; and as a supportive “on-
drug” analysis to evaluate the comparative treatment effect during the time that subjects 
remain on randomized treatment (plus a window of 28 days). Full details will be provided 
in the RAP.
Section 9.4.1.2. Primary Efficacy Analysis (co-primary), Analysis of the hemoglobin co-
primary endpoint was updated based on FDA feedback.
Mean change in Hgb between baseline and the EP (Weeks 28 to 52): The primary 
efficacy estimand is the effect of daprodustat relative to rhEPO on the change in Hgb 
from baseline to the average of all values in the EP, regardless of adherence to 
treatment including interruptions and discontinuation, the use of non-randomized 
ESA medication for any reason including rescue therapy, or the use of blood 
transfusions, in subjects on dialysis currently treated with an ESA with anemia 
secondary to CKD and assuming subjects do not die before the end of the EP. 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 subjects with at 
least one Hgb during the EP. The analysis will use an ANCOVA model. For each 
subject, 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 
and imputed Hgb values between Weeks 28 to 52 inclusive regardless of adherence to 
randomized treatment. The ANCOVA model will include prognostic randomization 
stratification factors (dialysis type and region), 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 
Imputation will be used for missing Hgb data; further details will be provided in the 
RAP.
Sensitivity and Supportive 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 subjects who did not fully 
complete the EP. A furthersupportive analysis will evaluate efficacy in those subjects 
who adhere to randomized treatment, defined as ITT subjects with at least one on-
treatment Hgb during the EP (this approach corresponds to evaluating an efficacy 
estimand). A similarsupportive “tipping point” analysis as that described above for the 
primary analysis will be performed for this “on-drug” analysis. In addition, a per-protocol 
sensitivitysupportive analysis will estimate the treatment effect in subjects who strongly 
adhere to the protocol, and sensitivitysupportive analyses to explore a shorter EP (Weeks 
28 to 36) will be performed for the co-primary effectiveness estimand and “on-drug” 

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efficacy estimand. Full details of all sensitivity and supportive analyses will be provided 
in the RAP.
Section 9.4.3. Multiplicity Strategy (text and figure), Multiplicity adjustment strategy 
updated based on FDA feedback. NOTE: update in figure is replacement of Hommel 
procedure with Holm-Bonferroni procedure).
Figure 2 illustrates the structure of the statistical testing plan. First, the co-primary 
endpoints will be evaluated for non-inferiority by comparing each two-sided 95% CI to 
the appropriate non-inferiority margin. Conditional on both co-primary endpoints 
achieving non-inferiority (i.e., passing the gatekeeper), the family of MACE and the 
principal secondary endpoints will be formally tested for superiority using the widely 
known Hommel procedure [GSK Document Number WEUKBRE7146. Cardiovascular 
event rates, red blood cell transfusion rates, and anaemia management practices in CKD 
patients across 12 countries from the Dialysis Outcomes and Practice Patterns Study 
(DOPPS). 30-JUN-2014 (preliminary report). Hommel, 1988] Holm-Bonferroni 
procedure [Holm-Bonferroni, 1979]. The procedure will be conducted based on a 
family-wise Type I error rate set at the one-sided 2.5% level. Details of the Hommel
Holm-Bonferroni procedure will be fully described in the RAP.
Section 9.4.4. Covariates and Subgroups of Interest, Revised MACE NI margin in order 
to align the NI margin with similar studies that have already compared the effects of 
HIF-PHIs on MACE versus rhEPO.
Point estimates and two-sided 95% CIs for the hazard ratio will be generated to describe 
the treatment effect separately for rhEPO hyporesponders and the complement set of 
rhEPO non-hyporesponders; non-inferiority would be established if the upper limit of the 
two-sided 95% CI is less than 1.250.

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References. Added Holm-Bonferroni reference as outlined in 9.4.3.
Besarab A, Bolton WK, Browne JK et al. The effects of normal as compared with low 
hematocrit values in patients with cardiac disease who are receiving hemodialysis and 
epoetin N Eng J Med 1998; 339:584-590.
GSK Document Number WEUKBRE7146. Cardiovascular event rates, red blood cell
transfusion rates, and anaemia management practices in CKD patients across 12 countries
from the Dialysis Outcomes and Practice Patterns Study (DOPPS). 30-JUN-2014
(preliminary report).
Holm S. A simple sequential rejective multiple test procedure. Scandinavian Journal 
of Statistics. 1979; 6: 65-70.
Hommel G. A stagewise rejective multiple test procedure based on a modified Bonferroni 
test. Biometrika 1988; 75:383-386Johnson DW, Pascoe EM, Badve SV et al. on behalf of 
the HERO Study Collaboration Group. A randomized, placebo-controlled trial of 
pentoxifylline on erythropoiesis-stimulating agent hyporesponsiveness in anemic patients 
with CKD: the Handling Erythropoietin Resistance With Oxpentifylline (HERO) trial. 
Am J Kidney Dis. 2015 65(1):49-57
Macdougall IC, Provenzano R, Sharma A, Spinowitz BS, Schmidt RJ, Pergola PE, et al.
Peginesatide for anemia in patients with chronic kidney disease not receiving dialysis. N 
Eng J Med 2013 368:320-332
U.S. Renal Data System. USRDS 2013 Annual Data Report: Atlas of Chronic Kidney
Disease and End-Stage Renal Disease in the United States, National Institutes of Health,
National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD 2013;
Volume 2 (Chapter 5):263-270.
Section 12.4. Appendix 4:  Risk Assessment. Updated risk table to include the AESI of 
worsening of hypertension.
Worsening 
of 
hypertension
In a dog cardiovascular study, single oral doses of daprodustat (up to 90 
mg/kg) did not produce effects on blood pressure.
Marketed rhEPO and its analogues have been associated with risks related 
to uncontrolled hypertension, including the need for initiation of or 
increases in antihypertensive therapy when used in patients with anemia 
of CKD (i.e. 25% Epogen, 27% Mircera, and 40% Aranesp treated patients 
with renal anemia required initiation or increase in their anti-hypertensive 
medications; hypertensive encephalopathy and seizures have been 
reported. The contribution of rhEPO-associated hypertension to the 
unfavourable effects on cardiovascular outcomes remains uncertain).
Integrated AE data from clinical trials with daprodustat [including 2 global 
phase 2b studies (24-week treatment duration) and 2 Japanese phase 3 
studies (52-week treatment duration)]: 
o
The majority (>90%) of subjects had a baseline history of 
hypertension.
o
No meaningful difference was seen between treatment groups in AEs 
(preferred term) of “hypertension” [29/688 (4%) daprodustat vs. 19/404 

Blood 
pressure 
will be 
closely 
monitored 
throughout 
the dosing 
period as 
outlined in 
the Time 
and Events 
Table 
Section 7.1.

Unblinded 
monitoring 
of safety 
data by an 
IDMC in-

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(4%) rhEPO; 0.91 relative risk (RR) (95% confidence interval: 0.5, 1.67)] 
or “blood pressure increased” [16 (2%) daprodustat vs. 7 (2%) rhEPO; 
RR 1.22 (0.48,3.11)]. Results were not substantively different between 
non-dialysis and haemodialysis subjects.
o
Although no clinically meaningful changes in blood pressure were 
observed, subjects in both treatment groups required increases in 
anti-HTN medications:
o
In the 24-week global phase 2b studies, 25/170 (15%) of ND 
subjects receiving daprodustat vs. 18/80 (14%) control and 
22/177 (12%) of HD subjects receiving daprodustat vs. 2/39 
(5%) control.
o
In the 52-week Japan phase 3 studies, 57/149 (38%) of ND 
subjects receiving daprodustat vs. 68/150 (45%) rhEPO and 
51/136 (38%) of HD subjects receiving daprodustat vs. 66/135 
(49%) for rhEPO.
o
The data received to date from completed clinical trials with 
daprodustat are insufficient to refute this risk.
stream 
throughout 
the study.
Section 12.10. Appendix 10: Collection of Pregnancy Information, updated pregnancy 
reporting timelines to align with revised Sponsor timings.

Information will be recorded on the appropriate form and submitted to PPD within 
24 hours2 weeks of learning of a subject's pregnancy.