A Phase 3 Randomized, Open-label (Sponsor-blind), Active-controlled, Parallel-group, Multi-center, Event Driven Study in Non-dialysis Subjects With Anemia Associated With Chronic Kidney Disease to Evaluate the Safety and Efficacy of Daprodustat Compared to Darbepoetin Alfa
Phase: PHASE3
Conditions: Anaemia
Sponsor: GlaxoSmithKline

2015N230102_09
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The GlaxoSmithKline group of companies
200808
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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 
non-dialysis subjects with anemia associated with chronic kidney 
disease to evaluate the safety and efficacy of daprodustat 
compared to darbepoetin alfa.
Short Title:
Anemia Studies in CKD: Erythropoiesis via a Novel PHI 
Daprodustat-Non-Dialysis (ASCEND-ND)
Compound Number:
GSK1278863
Development Phase:
IIIA
Effective Date:
30-JUL-2020
Protocol Amendment Number:  05
Copyright 2020 the GlaxoSmithKline group of companies.  All rights reserved.  
Unauthorised copying or use of this information is prohibited.

2015N230102_09
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Revision Chronology
GlaxoSmithKline Document 
Number
Date
Version
2015N230102_00
2016-MAY-27
Original
2015N230102_01
2016-JUN-09
Republishing
2015N230102_02
2016-SEP-20
Amendment No. 1
Amendment 1 applies only to Austria, Belgium, Czech Republic, Denmark, Estonia, 
Germany, Hungary, Italy, 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 g/dL.

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.
2015N230102_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 appendix relating to darbepoetin alfa pre-filled syringe incidents, 
malfunctions and user errors deleted. 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, transfusions; new timepoint 
for weight at Day 1; 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 24hr ABPM 
assessments, for recording the times the subject awakens and goes to sleep during 
this 24 hour ABPM period, and for the end of the 24hr urine collection 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 addition of kidney transplant added to prompt 
completion of page in eCRF.

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
Time and Events Table 13 for ‘Subjects Transitioning to Dialysis’ modified. Main 
changes include new timepoint at Week 2 for iron therapy; new timepoint at Week 
52 for Kt/Vurea assessment; and transfusions and kidney transplant added to prompt 
completion of page in eCRF.

For the negatively adjudicated events in 200808, 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 
2015N230102_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.  

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.

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’ modified.  Main changes include addition of Informed Consent activity; 
revised footnotes to allow for more latitude for timing to do Day 1 ECG and 
extended time to do ultrasound and/or additional testing; more clarity around 
randomized treatment dispensing and compliance; removed capture of rescue 
medications from unscheduled visit (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 

2015N230102_09
CONFIDENTIAL
The GlaxoSmithKline group of companies
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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 as to how weight, blood pressure, and laboratory assessments are 
to be done for those transitioning to dialysis.  

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.

Changed timepoint for blinded data cut need for psychometric validation of the 
Chronic Kidney Disease-Anemia Questionnaire.

Revised statistical section to change from two-sided testing at the 5% level to one-
sided testing at the 2.5% level; to clarify progression of CKD endpoint population 
and analysis model and for secondary endpoints, to change significance levels to p-
values; to correct the timepoint for various Patient Reported Outcomes; to add a 
more complete description of the adjustments to statistical model; 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.

Modified Time and Events Table 13 ‘Schedule of Assessments Year 1 to the End 
of Study for Subjects Transitioning to Dialysis’.  Main changes include footnotes to 
remove Kt/V and URR measurement for daily HHD; 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 storage biomarkers to be 
collected except if not permitted by IRB/EC or refused by subject; and addition of 
Argentina only pregnancy requirement.

Changes to ABPM sub-study to add atrial fibrillation/flutter screening, remove 
home BP monitoring, 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.
2015N230102_07
2019-AUG-16
Amendment No.4

2015N230102_09
CONFIDENTIAL
The GlaxoSmithKline group of companies
200808
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Summary of Changes

Within entry criteria, added retest values for Hgb at Day 1, an additional retest 
opportunity for TSAT to determine eligibility at Week -8, and revised the 
definition of current uncontrolled hypertension.

Added a consideration to allow for conduct of study visits on or before the first 
dialysis session of the week for subjects on 3x/week HD.

Added hypothetical risk information, new required assessments (eGFR, 
ultrasound), and randomized treatment stopping criteria for subjects with ADPKD.

Added new AESI of worsening of hypertension.

Added secondary objective/endpoint to assess renal progression via change in 
eGFR.

Removed “mean hours” from several endpoints given the WPAI questionnaire 
being used does not support the mean hours impaired calculation.

Edited Risk Assessment information to align with version 10 of the Investigator’s 
Brochure.

Revised Year 2 sub-bullet reasons to correct a typographical error and 
inconsistency.

For subjects transitioning to dialysis, clarified the last historical Kt/Vurea 
measurement obtained per standard of care can be used and corrected the footnote 
numbering for serum pregnancy testing.

Stated recruitment in the ABPM sub-study is closed in Amendment 4.

Added additional entry criteria to PK sub-study to exclude subjects transitioning or 
already transitioned to dialysis at the time they consider enrollment in the PK sub-
study.

Added wording to PK sub-study to indicate if the sub-study recruitment does not 
make its pre-specified target, depending on the number of subjects with data, a 
limited number of analyses and data summaries may be produced

Other changes include formatting and administrative changes.
2015N230102_09
30-JUL-2020
Amendment No.5

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.

Updated pregnancy reporting timelines to align with revised Sponsor timings.

1
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Dear Ale x,  
 
T o a p pr o ve t he cli nical pr ot oc ol  i n dicate d bel o w, re pl y t o t his e mail a n d state y o ur a p pr o val.  
 
P R O T O C O L N U M B E R: 2 0 0 8 0 8  
D O C U M E N T I D E N TI FI E R:  2 0 1 5 N 2 3 0 1 0 2 _ 9 
A M E N D M E N T N U M B E R: 0 5  
P R O T O C O L TI T L E: A p hase 3 ra n d o mize d, o pe n-la bel (s p o ns or- bli n d), acti ve-c o ntr olle d, parallel- gr o u p, 
m ulti-ce nter, e ve nt dri ve n st u d y i n n o n- dial ysis s u bjects w it h a ne mia ass ociate d wit h c hr o nic ki d ne y disease t o 
e val uate t he safet y a n d efficac y of da pr o d ustat c o m pare d t o dar be p oeti n alfa  
 
Na me of S p o ns or Si g nat or y:  Ale xa n der R. C o bitz, M. D., P h D 
 
Title of S p o ns or Si g nat or y: Cli nical De vel o p me nt Lea d  
P P D
 
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2015N230102_09
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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:  2016-000542-65

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INVESTIGATOR PROTOCOL AGREEMENT PAGE
For protocol 200808
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

2015N230102_09
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TABLE OF CONTENTS
PAGE
1.
PROTOCOL SYNOPSIS FOR STUDY 200808......................................................13
2.
INTRODUCTION....................................................................................................15
2.1.
Background ................................................................................................15
2.2.
Study Rationale ..........................................................................................15
3.
OBJECTIVE(S) AND ENDPOINT(S) ......................................................................16
4.
STUDY DESIGN ....................................................................................................17
4.1.
Overall Design ............................................................................................17
4.2.
Type and Number of Subjects.....................................................................19
4.3.
Design Rationale ........................................................................................19
4.4.
Dose Justification........................................................................................19
4.4.1.
Daprodustat.................................................................................19
4.4.2.
Randomized treatment Dose Adjustment Scheme.......................20
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...................................................21
5.
SELECTION OF STUDY POPULATION AND WITHDRAWAL CRITERIA .............21
5.1.
Inclusion Criteria.........................................................................................21
5.2.
Exclusion Criteria........................................................................................22
5.3.
Screening/Run-in Failures ..........................................................................25
5.4.
Subject Retention .......................................................................................25
5.5.
Permanent Discontinuation of Randomized Treatment ...............................25
5.5.1.
Procedures for Subject Follow-up ................................................26
5.6.
Withdrawal from Study................................................................................26
5.6.1.
Withdrawal of Consent for Contact...............................................26
5.6.2.
Subjects Deemed Lost to Follow-up.............................................27
5.7.
Subject and Study Completion....................................................................27
6.
PLACEBO RUN-IN AND RANDOMIZED TREATMENT .........................................27
6.1.
Placebo Run-in and Randomized Treatment ..............................................27
6.2.
Randomized Treatment Assignment...........................................................28
6.3.
Randomized Treatment Starting Dose, Dose Steps and Dose 
Adjustment..................................................................................................29
6.3.1.
Daprodustat Dosing Information ..................................................29
6.3.2.
Darbepoetin Alfa Dosing Information ...........................................30
6.3.3.
Daprodustat and Darbepoetin Alfa Dose Adjustment 
Algorithm .....................................................................................31
6.3.4.
Randomized Treatment Temporary Interruption...........................31
6.3.5.
Randomized Treatment Discontinuation ......................................32
6.4.
Blinding.......................................................................................................32
6.5.
Packaging and Labeling..............................................................................32
6.6.
Preparation/Handling/Storage/Accountability..............................................32
6.7.
Compliance with Randomized Treatment Administration ............................33
6.8.
Treatment of Randomized Treatment Overdose .........................................33
6.9.
Treatment after the End of the Study ..........................................................33

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6.10.
Concomitant Medications and Non-Drug Therapies....................................33
6.10.1.
Permitted Medications and Non-Drug Therapies..........................34
6.10.2.
Prohibited Medications and Non-Drug Therapies.........................34
6.11.
Standard of Care ........................................................................................34
6.11.1.
Iron Management Criteria ............................................................34
6.12.
Rescue Therapy .........................................................................................35
6.13.
Subjects Transitioning to Dialysis ...............................................................36
7.
STUDY ASSESSMENTS AND PROCEDURES .....................................................36
7.1.
Time and Events Table...............................................................................38
7.2.
Screening and Critical Baseline Assessments ............................................45
7.3.
Efficacy.......................................................................................................45
7.4.
Safety .........................................................................................................45
7.4.1.
Events Referred to the Clinical Events Committee.......................45
7.4.2.
Other CV Events..........................................................................46
7.4.3.
Adverse Events (AE) and Serious Adverse Events (SAEs)..........46
7.4.3.1.
Time period and Frequency for collecting AE 
and SAE information...................................................47
7.4.3.2.
Method of Detecting AEs and SAEs ...........................47
7.4.3.3.
Follow-up of AEs and SAEs........................................47
7.4.3.4.
Regulatory Reporting Requirements for SAEs............48
7.4.4.
Adverse Events of Special Interest ..............................................48
7.4.5.
Possible Suicidality Related Adverse Events ...............................48
7.4.6.
Pregnancy ...................................................................................49
7.4.7.
Height and Weight .......................................................................49
7.4.8.
Blood Pressure and Heart Rate ...................................................49
7.4.9.
Electrocardiogram (ECG).............................................................50
7.4.10.
Ultrasound ...................................................................................50
7.4.11.
Clinical Laboratory Assessments .................................................51
7.4.12.
Liver Chemistry Stopping Criteria ................................................53
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.
Chronic Kidney Disease - Anemia Questionnaire (CKD-
AQ)..............................................................................................55
7.7.2.
Patient Global Impression of Severity (PGI-S) and Patient 
Global Impression of Change (PGI-C) .........................................56
7.7.3.
Health Related Quality of Life (SF-36) .........................................56
7.7.4.
Health Status (EQ-5D-5L & EQ-VAS) ..........................................56
7.7.5.
Work Productivity and Activity Impairment (WPAI-ANS-
CPV)............................................................................................56
8.
DATA MANAGEMENT ...........................................................................................57
9.
STATISTICAL CONSIDERATIONS AND DATA ANALYSES .................................57
9.1.
Hypotheses.................................................................................................57
9.1.1.
CV Safety (MACE) Co-Primary Hypothesis..................................57
9.1.2.
Hgb efficacy Co-Primary Hypothesis............................................58
9.2.
Sample Size Considerations.......................................................................59
9.2.1.
Sample Size Assumptions ...........................................................59
9.2.2.
Sample Size Sensitivity................................................................60

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9.2.3.
Sample Size Re-estimation or Adjustment...................................60
9.3.
Data Analysis Considerations .....................................................................61
9.3.1.
Analysis Populations....................................................................61
9.4.
Key Elements of Analysis Plan ...................................................................61
9.4.1.
Primary Analyses.........................................................................61
9.4.1.1.
Primary CV Safety Analysis (co-primary)....................61
9.4.1.2.
Primary Efficacy Analysis (co-primary) .......................62
9.4.2.
Secondary Analyses ....................................................................62
9.4.2.1.
Principal Secondary Analyses ....................................62
9.4.2.2.
Analysis of Patient Reported Outcomes .....................63
9.4.2.3.
Safety Analyses..........................................................63
9.4.3.
Multiplicity Strategy......................................................................64
9.4.4.
Covariates and Subgroups of Interest..........................................64
9.4.5.
Interim Analysis ...........................................................................65
9.4.6.
Psychometric Analyses of the Chronic Kidney Disease-
Anemia Questionnaire (CKD-AQ) ................................................66
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 ...............................................................................68
10.6.
Records Retention......................................................................................68
10.7.
Provision of Study Results to Investigators, Posting of Information 
on Publically Available Clinical Trials Registers and Publication .................69
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.....................................................70
10.8.4.
Steering Committee.....................................................................70
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.............................79
12.4.
Appendix 4: Risk Assessment.....................................................................80
12.5.
Appendix 5: Female Eligibility Criteria.........................................................93
12.6.
Appendix 6: Randomized Treatment Dose Adjustment Schemes ...............95
12.7.
Appendix 7: Time and Events Table for Subjects Transitioning to 
Dialysis .......................................................................................................96
12.8.
Appendix 8: Definition of and Procedures for Recording, Evaluating, 
Follow-Up and Reporting of Adverse Events...............................................99
12.8.1.
Definition of Serious Adverse Events.........................................100
12.8.2.
Recording of AEs and SAEs ......................................................101
12.8.3.
Evaluating AEs and SAEs..........................................................102
12.8.4.
Reporting of SAEs to PPD.........................................................103

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12.9.
Appendix 9: Liver Safety Required Actions and Follow up 
Assessments ............................................................................................104
12.10. Appendix 10: Liver Safety Drug Restart Guidelines ..................................107
12.11. Appendix 11: Collection of Pregnancy Information....................................109
12.12. Appendix 12: Genetic Research ...............................................................110
12.13. Appendix 13: A Sub-study of the Effect of Daprodustat Compared to 
Darbepoetin Alfa on BP in Non-dialysis Subjects with Anemia 
Associated with CKD who are not Currently Using ESA Therapy..............113
12.13.1. Introduction and Rationale .........................................................113
12.13.2. Objectives and Endpoints ..........................................................113
12.13.3. Study Design .............................................................................115
12.13.3.1. ABPM Quality Control Criteria ..................................115
12.13.3.2. Eligibility Criteria - Screening....................................115
12.13.3.3. Study Assessments..................................................116
12.13.3.4. Permanent Discontinuation of Randomized 
Treatment.................................................................118
12.13.3.5. Antihypertensive Medication Changes......................118
12.13.3.6. Withdrawal from ABPM Sub-Study...........................118
12.13.4. Sample Size and Power Calculations ........................................118
12.13.5. Statistical Analysis.....................................................................118
12.14. Appendix 14: A Sub-study to Collect PK Samples in Non-dialysis 
Subjects with Anemia Associated with CKD..............................................121
12.14.1. Rationale ...................................................................................121
12.14.2. Objectives and Endpoints ..........................................................121
12.14.3. Study Design .............................................................................122
12.14.4. Additional Inclusion Criteria .......................................................122
12.14.5. Study Assessments ...................................................................122
12.14.6. Sample Size ..............................................................................123
12.14.7. PK/Pharmacodynamic Analyses ................................................123
12.15. Appendix 15: Country Specific Requirements...........................................124
12.15.1. French Administrative Considerations and Specifics
Requirements ............................................................................124
12.15.2. Country-Specific Requirements for Czech Republic for 
Acceptable Contraceptive Methods............................................127
12.16. Appendix 16: Protocol Changes................................................................128
12.16.1. Changes Resulting from Protocol Amendment 1........................128
12.16.1.1. Summary of Changes...............................................128
12.16.1.2. List of Specific Changes ...........................................128
12.16.2. Changes Resulting from Protocol Amendment 2........................130
12.16.2.1. Summary of Changes...............................................130
12.16.2.2. List of Specific Changes ...........................................131
12.16.3. Changes Resulting from Protocol Amendment 3........................153
12.16.3.1. Summary of Changes...............................................153
12.16.3.2. List of Specific Changes ...........................................154
12.16.4. Changes Resulting from Protocol Amendment 4........................205
12.16.4.1. Summary of Changes...............................................205
12.16.4.2. List of Specific Changes ...........................................205
12.16.5. Changes Resulting from Protocol Amendment 5........................226
12.16.5.1. Summary of Changes...............................................226
12.16.5.2. List of Specific Changes ...........................................226

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1.
PROTOCOL SYNOPSIS FOR STUDY 200808
This Phase 3 study will evaluate the safety and efficacy of daprodustat (GSK1278863) 
compared to the recombinant human erythropoietin (rhEPO), darbepoetin alfa, in the 
treatment of anemia associated with chronic kidney disease (CKD) in non-dialysis (ND) 
subjects.  
Primary Objective(s)/Endpoint(s)
Objectives
Endpoints
Co-primary (tested in parallel for non-inferiority)

To compare daprodustat to darbepoetin alfa
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 darbepoetin alfa
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 ND subjects with anemia associated with CKD.  

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 
erythropoiesis-stimulating agents (ESA1) therapy, if present, 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 region, by whether they are currently using an ESA, 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 subcutaneous (SC) darbepoetin alfa. 

Both treatment arms (daprodustat and darbepoetin alfa) 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. Dose changes will be made 
programmatically by the Interactive Response Technology (IRT) system for both 
randomized treatment arms.
                                                
1 ESAs refer to any rhEPO or methoxy PEG-epoetin beta.

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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 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.

GSK will provide randomized treatment:  daprodustat or darbepoetin alfa.  
Type and Number of Subjects
This study will randomize approximately 4500 subjects (2250 subjects per treatment arm) 
with anemia associated with CKD not on dialysis and will enroll two groups of subjects:

Group 1 (not using ESAs):  subjects not currently receiving ESAs with a baseline 
HemoCue Hgb 8-10 g/dL. 

Group 2 (ESA users):  subjects currently receiving ESA with a baseline HemoCue 
Hgb 8-11 g/dL. 
The proportion of subjects not using ESAs (Group 1) and ESA users (Group 2) 
randomized into the study is expected to be approximately 60% and 40%, respectively. 
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 darbepoetin 
alfa 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, including factors for treatment and the prognostic randomization 
stratification factors (region and current ESA use), will be used. 
For Hgb efficacy, the primary question is whether daprodustat is non-inferior to 
darbepoetin alfa for change from baseline in Hgb. The analysis will be based on the mean 
change in central laboratory Hgb between baseline and the efficacy EP (defined as mean 
over 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 (region and current ESA use), 
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.
I N T R O D U C TI O N
2. 1.
B a c k gr o u n d
Da pr o d ustat ( G S K 1 2 7 8 8 6 3) is a h y p o xia -i n d uci ble fact or pr ol yl  h ydr o x y lase i n hi bit or 
( HI F-P HI) c urre ntl y  bei n g i n vesti gate d as a treat me nt f or a ne mia ass ociated wit h C K D i n 
b ot h dial y sis a n d N D s u bjects, wit h a de q uate safet y a n d efficac y ha vi n g bee n 
de m o nstrate d i n cli nical trials u p t o 2 4 wee ks’ d urati o n. B ot h pre -cli nical a n d cli nical 
data s h o w t hat da pr o d ustat sti m ulates er y t hr o p oieti n ( E P O) pr o d ucti o n, res ulti n g i n 
i ncrease d er yt hr o p oiesis a n d ele vati o n i n H g b c o nce ntrati o ns. T hese i ncreases i n H g b are 
ac hie ve d wit h pea k plas ma E P O e x p os ures s u bsta ntiall y  l o wer t ha n t h ose o bser ve d wit h 
r h E P Os. Data fr o m c o m plete d cli nical a n d precli nical st u dies are pr o vi de d i n t he c urre nt 
I n vesti gat or Br oc h ure (I B) a n d I B s u p ple me nt(s) (if a p plica ble). 
2. 2.
St u d y R ati o n al e
C CI
Base d o n its mec ha nis m of acti o n t o sti m ulate er yt hr o p oiesis via i n hi biti o n of HI F -pr ol yl  
h y dr o x yl ase e nz y m es, da pr o d ustat is p ost ulate d t o be ass ociate d wit h fe wer M A C E b y 
raisi n g H g b wit h o ut t he s u pra p hys i ol o gic E P O c o nce ntrati o ns ass ociate d wit h r h E P O 
t hera py,
A P hase 2 B cli nical trial i n N D s u bjects wit h a ne mia ass ociate d wit h C K D de m o nstrate d 
t hat da pr o d ustat ca n c orrect a n d mai ntai n H g b u p t o 2 4 wee ks, wit h mi ni mal effects o n 
plas ma E P O c o nce ntrati o n. Da pr o d ustat treat me nt f or u p t o 2 4 wee ks de m o nstrate d a n 
a d verse e ve nt ( A E) pr ofile c o nsiste nt wit h t he patie nt p o p ulati o n. Data fr o m c o m plete d 
cli nical st u dies are pr o vi de d c urre nt I B a n d I B s u p ple me nt(s) (if a p plica ble ).
T his P hase 3 st u d y  will e val uate t he safety a n d t he efficac y of da pr o d ustat c o m pare d t o 
dar be p oeti n alfa f or t he treat me nt of a ne mia ass ociate d wit h C K D i n N D s u bjects. B ot h 
c o-pri mar y  e n d p oi nts m ust meet n o n-i nferi ority of da pr o d ustat t o dar be p oeti n alfa f or t he 
st u d y t o be s uccessf ul a n d f or a nalys es t o pr o gress t o testi n g pri nci pal sec o n dar y 
e n d p oi nts.  Data fr o m t his trial are i nte n de d t o s u p p ort t he use of da pr o d ustat f or t he 
treat me nt of a ne mia ass ociate d wit h C K D i n patie nts n ot o n dial ysis.
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3.
OBJECTIVE(S) AND ENDPOINT(S)
Objectives
Endpoints
Co-primary (tested in parallel for non-inferiority)

To compare daprodustat to darbepoetin alfa
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 darbepoetin alfa
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 darbepoetin alfa 
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 the effect of daprodustat to 
darbepoetin alfa on progression of CKD

Time to progression of CKD1
Safety 

To compare the safety and tolerability of 
daprodustat to darbepoetin alfa

Incidence and severity of AEs and serious 
adverse events (SAEs) including AEs of special 
interest2

Reasons for discontinuation of randomized 
treatment

Absolute values and changes from baseline in 
laboratory parameters, BP and heart rate
1.
Progression of CKD defined as: 40% decline in estimated glomerular filtration rate (eGFR) from baseline 
(confirmed 4-13 weeks later) OR end stage renal disease (ESRD) as defined by either 
a) initiating chronic dialysis for 90 days or, 
b) not initiating chronic dialysis when dialysis is indicated or,
c) kidney transplantation.
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.
Additional secondary and exploratory objectives/endpoints are listed in Appendix 2.

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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 ND subjects with anemia associated with CKD. 

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 ESA2
therapy, if present, continues during the screening and run-in periods.  

The treatment period consists of (Figure 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.  

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 Independent 
Data Monitoring Committee (IDMC) recommends bringing the study to an earlier 
close.

All subjects will remain in the study (including subjects that start dialysis or receive a 
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 region (see Appendix 3), by whether they are currently 
using an ESA, and by participation in the ABPM sub-study. Region and ESA use at 
study entry 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. [Note: 
recruitment in the ABPM sub-study is closed in Amendment 4.]

Following stratification, subjects will be randomized 1:1 to receive oral daprodustat 
or SC darbepoetin alfa. A central randomization approach will be used to protect 
                                                
2 ESAs refer to any rhEPO or methoxy PEG-epoetin beta.

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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 darbepoetin alfa) 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 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 (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 (subjects not using ESAs only) (Appendix 13) [Note: 
recruitment in the ABPM sub-study is closed in Amendment 4]

Pharmacokinetic (PK) sub-study (Appendix 14)

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).

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4.2.
Type and Number of Subjects
This study will randomize approximately 4500 subjects (2250 subjects per treatment arm) 
with anemia associated with CKD not on dialysis and will enroll two groups of subjects:

Group 1 (not using ESAs):  subjects not currently receiving ESAs with a baseline 
HemoCue Hgb 8-10 g/dL. 

Group 2 (ESA users):  subjects currently receiving ESA with a baseline HemoCue 
Hgb 8-11 g/dL. 
The proportion of subjects not using ESAs (Group 1) and ESA-users (Group 2) 
randomized into the study is expected to be approximately 60% and 40%, respectively. 
4.3.
Design Rationale
This study includes 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. 
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 of darbepoetin alfa 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 

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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. 
For subjects not using ESAs (Group 1), the goal of the selected starting doses in this 
study is to increase the Hgb concentration from baseline (Day 1) to the target range of 10-
11 g/dL. Starting doses of 2 or 4 mg were selected, and are estimated to increase steady-
state Hgb, on average, by 1 or 2 g/dL, respectively.
For ESA users (Group 2), the goal of the selected starting doses in this study is to 
maintain Hgb achieved on the prior ESA dose, that is, on average, result in no change 
from baseline Hgb. Starting doses of 1, 2 or 4 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 darbepoetin alfa) dose adjustment algorithm 
was designed to minimize unnecessary dose adjustments by allowing for visit-to-visit 
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. After administration of daprodustat, data suggest that 

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t he i ncreases i n H g b are ac hie ve d wit h E P O e x p os ure l o wer t ha n t h ose o bser ve d wit h 
r h E P O.  Treat me nt of a ne mia of C K D wit h r h E P O is ass ociate d wit h i ncrease d C V ris k 
w hic h is p ost ulate d t o be relate d t o t he ass ociate d i ncreases i n E P O e x p os ure w it h r h E P O 
[Szczec h , 2 0 0 8];
4. 5. 3.
O v er all B e n efit: Ri s k C o n cl u si o n
Da pr o d ustat de m o nstrates a p ositi ve be nefit vs. ris k base d o n t he e vi de nce as f oll o ws. I n 
cli nical trials u p t o 2 4 wee ks i n d urati o n, da pr o d ustat treats H g b t o tar get ra n ge, a n d t here 
are n o a d verse e ve nts t hat ha ve bee n i de ntifie d as relate d t o treat me nt wit h da pr o d ustat .
T his pr ot oc ol e m pl o y s preca uti o ns t o miti gate k n o w n a n d p ote ntial ris ks t o ra n d o mized 
s u bjects ( See A p pe n di x 4 ). Gi ve n t hese preca uti o ns, as well as t he p ote ntial be nefit t hat 
da pr o d ustat h ol ds f or t he treat me nt of a ne mia ass ociate d wit h C K D c o m pare d t o t he 
c urre nt sta n dar d, t he o verall be nefit ris k bala nce is c o nsi dere d t o be p ositi ve.
5.
S E L E C TI O N O F S T U D Y P O P U L A TI O N A N D 
WI T H D R A W A L C RI T E RI A
S pe cific i nf or mati o n re gar di n g war ni n gs, preca uti o ns, c o ntrai n dicati o ns, A Es, a n d ot her 
perti ne nt i nf or mati o n o n t he ra n d o mize d treat me nt is pr o vi de d i n t he I B, I B 
s u p ple me nt(s) (if a p plica ble), pr o d uct la bels f or dar be p oeti n alfa a n d ot her perti ne nt 
d oc u me nt s (e. g., St u d y Refere nce Ma n ual ( S R M), i nf or me d c o nse nt).
De viati o ns fr o m i ncl usi o n a n d e xcl usi o n criteria are n ot all o we d beca use t he y ca n 
p ote ntiall y  je o par dize t he scie ntific i nte grit y of t he st u d y, re g ulat or y acce pta bilit y or 
s u bject safety.
5. 1.
I n cl u si o n Crit eri a
A s u bject will be eli gi ble f or i ncl usi o n i n t his st u d y o nl y if all of t he f oll o wi n g criteria 
a p pl y at scree ni n g ( Wee k - 8) a n d r a n d o miz ati o n ( D a y 1) , u nless ot her wise s pecifie d.   
1.
A ge (c o nfir m at scree ni n g o nl y): 1 8 t o 9 9 y ears of a ge (i ncl usi ve).   
2.
C K D st a ge (c o nfir m at scree ni n g o nl y): Ki d ne y Disease O utc o mes Q ualit y  
I nitiati ve ( K D O QI) C K D sta ges 3, 4, or 5 defi ne d b y e G F R usi n g t he C K D 
E pi de mi ol o g y  C olla b orati o n ( C K D-E PI) f or m ula [Le ve y , 2 0 0 9].
3.
E S As:    

Gr o u p 1 ( n ot usi n g E S As): N o E S A use wit hi n t he 6 wee ks pri or t o scree ni n g a n d 
n o E S A use bet wee n scree ni n g a n d ra n d o mizati o n ( Da y 1).

C CI
Gr o u p 2 ( E S A users): Use of a n y a p pr o ve d E S A (see f o ot n ote i n ta ble bel o w) f or 
t he 6 wee ks pri or t o scree ni n g a n d c o nti n ui n g bet wee n scree ni n g a n d 
ra n d o mizati o n.  
C CI

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4. HemoCue Hgb (range inclusive): Hgb defined by ESA use:  
Group 1
(not using ESAs)
Group 2 
(ESA users)
Week -
8
Hgb 8 to 10 g/dL1 (5 to 6.2 mmol/L)
If Hgb is 10.1 to 10.4 g/dL2 (6.3-6.5 mmol/L), 
up to two retests are allowed; the retest value 
must be between 8 to 10 g/dL (5 to 6.2 
mmol/L).
Hgb 8 to12 g/dL (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 10 g/dL (5 to 6.2 mmol/L)
If Hgb is 10.1 to 10.4 g/dL4 (6.3-6.5 mmol/L), 
up to two retests are allowed; the retest value 
must be between 8 to 10 g/dL (5 to 6.2 
mmol/L).
Hgb 8 to 11 g/dL (5 to 6.8 mmol/L) and
receiving at least the minimum ESA dose3
If Hgb is 11.1 to 11.4 g/dL4 (6.9-7.1 mmol/L), 
up to two retests are allowed; the retest value 
must be between 8 to 11 g/dL (5 to 6.8
mmol/L).
1.
Conversion from g/dL to g/L is 1:10, e.g., Hgb of 8 to 10 g/dL is equivalent to 80-100 g/L. 
2.
The first retest will use the original Week -8 blood sample. If this value is >10 g/dL (Group 1) or >12 g/dL 
(Group 2), 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.
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.
The first retest will use the original Day 1 blood sample. If this value is >10 g/dL (Group 1) or >11 g/dL (Group 
2), 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.
5. Compliance with placebo [randomization (Day 1) only]:  ≥80% and ≤120% 
compliance with placebo during run-in period (NOTE: for ESA users, this is in 
addition to ESA treatment).
6. 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 15 (see Section 12.15.1 Item 3 for details).
7. Other study eligibility criteria considerations: The country-specific requirements 
for France ONLY for inclusion in this study are provided in Appendix 15 (see Section 
12.15.1 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) and randomization (Day 1), unless otherwise specified.    
CKD related criteria
1.
Dialysis:  On dialysis or clinical evidence of impending need to initiate dialysis
within 90 days after study start (Day 1).

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2.
Kidney transplant: Planned living-related or living-unrelated kidney transplant 
within 52 weeks after study start (Day 1).
Anemia-related criteria
3.
Ferritin (screening only):  ≤100 ng/mL (≤100 g/L).
4.
Transferrin saturation (TSAT) (screening only):  ≤20%. If the laboratory report 
indicates TSAT is 18-20%, then up to two retests can be obtained using a new blood 
sample.  These retests may occur during screening and run-in up to two weeks prior 
to anticipated randomization (Day 1); the final retest value must be >20% to confirm 
eligibility.  
5.
Aplasias: History of bone marrow aplasia or pure red cell aplasia.
6.
Other causes of anemia: Untreated pernicious anemia, thalassemia major, sickle 
cell disease or myelodysplastic syndrome.
7.
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
8.
MI or acute coronary syndrome:  ≤4 weeks prior to screening through to 
randomization (Day 1).
9.
Stroke or transient ischemic attack:  ≤4 weeks prior to screening through to 
randomization (Day 1).
10. Heart failure (HF): Chronic Class IV HF, as defined by the New York Heart 
Association (NYHA) functional classification system.
11. Current uncontrolled hypertension: Current uncontrolled hypertension as 
determined by the investigator.
12. 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.
Other disease-related criteria
13. 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%.

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
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.
14. 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
15. Severe allergic reactions: History of severe allergic or anaphylactic reactions or 
hypersensitivity to excipients in the investigational product (refer to daprodustat IB) 
or darbepoetin alfa (refer to product labeling).  
16. Drugs and supplements: Use of strong inhibitors of CYP2C8 (e.g., gemfibrozil) or 
strong inducers of CYP2C8 (e.g., rifampin/rifampicin).
17. 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).
18. Prior treatment with daprodustat:  Any prior treatment with daprodustat for a 
treatment duration of >30 days.
General health-related criteria
19. Females ONLY:  Subject is pregnant [as confirmed by a positive urine 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 12.15.2 for the country-specific requirements for the Czech 
Republic ONLY relating to acceptable contraceptive methods during participation in 
this study.
20. Other Conditions:  Any other condition, clinical or laboratory abnormality, or 
examination finding that the investigator considers would put the subject at 
unacceptable risk, which may affect study compliance (e.g., intolerance to 
darbepoetin alfa) or prevent understanding of the aims or investigational procedures 
or possible consequences of the study. 

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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 additional three 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 and those that transition to dialysis.  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).

ADPKD subjects only: following further imaging, condition of the cystic disease 
in the kidney(s) has worsened more than expected given the clinical scenario and 
no other cause for the kidney function decline and/or cyst enlargement can be 
identified (Section 7.4.10).

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Note: Subjects starting dialysis should not be withdrawn from the study and should 
continue randomized treatment as per protocol (Section 6.13). 
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 in-clinic 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 and study procedures, but states an expectation that 
follow up information will always be required. Subjects will agree to this at the time of 
consenting.

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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.

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 or darbepoetin alfa) received by the subject during the 
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.  

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During the treatment period, iron therapy (supplied locally) will be administered as per 
the iron management criteria (Section 6.11.1).  
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
Placebo 
Daprodustat 1 mg, 2 mg, 4 mg, 
7 mm round, compound radius, white film 
coated tablets
9 mm
Daprodustat 6 mg, 8 mg, 10 mg 
9 mm round, compound radius, white film 
coated tablets
GSK will provide randomized treatment for the darbepoetin alfa group as prefilled 
syringes (PFS) for SC or IV injection.  Doses from 20 µg to 400 µg will be administered 
using the strengths below (Table 2). See Section 6.3.2 for the specific darbepoetin alfa 
dose steps and dosing frequency details. Additional details on PFS strengths to deliver the 
total 4-weekly dose are captured in the SRM.
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.
Darbepoetin alfa should be administered SC by the subject/caregiver or in the clinic. IV 
darbepoetin alfa can be considered for those subjects transitioning to hemodialysis.  
6.2.
Randomized Treatment Assignment
Subjects will be stratified as outlined in Section 4.1 and randomized 1:1 to receive oral 
daprodustat or SC darbepoetin alfa. 
Those subjects who are ESA users at study entry will discontinue their ESA therapy prior 
to randomization so that the randomization date (Day 1) should coincide, as closely as 

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possible, with the date of next scheduled ESA administration. Examples of switching are 
provided in the SRM. 
6.3.
Randomized Treatment Starting Dose, Dose Steps and Dose 
Adjustment
6.3.1.
Daprodustat Dosing Information
Daprodustat Starting Dose:
For subjects not using ESAs (Group 1), once daily oral daprodustat starting doses are 
assigned based on the HemoCue Hgb concentration at randomization (Day 1) (Table 3).  
Assigning the lowest starting dose of 2 mg allows for a one dose step decrease, if 
required.  
Table 3
Daprodustat Starting Dose (not using ESAs)
Baseline (Day 1)  
Hgb (g/dL)
Daprodustat Starting Dose (mg, once daily)
8 to <9
4
9 to 10
2
For ESA users (Group 2), starting doses are assigned based on the ESA dose at 
randomization (Day 1) (Table 4).
Table 4
Daprodustat Starting Dose (ESA Users)
Prior ESA Dose at Randomization (Day 1)
Daprodustat 
Starting Dose
epoetins (incl biosimilars)
(convert SC to IV U/week) 1
darbepoetin alfa
(g /4wk 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
1
>2000 to <20000 
>30 to 300 
>40 to 360
2
≥20000  
>300 
>360
4
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.  

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6.3.2.
Darbepoetin Alfa Dosing Information
Darbepoetin Alfa Starting Dose:
Group 1 (not using ESA):  The SC darbepoetin alfa starting dose will be determined 
based on weight and baseline Hgb.  Subjects with baseline (Day 1) Hgb values of 9 
to10 g/dL will be assigned a starting dose of 0.45 g/kg, with the lowest starting dose 
being 30 g to allow for a one dose step decrease, if required, and a top starting dose of 
60 g.  Those with baseline (Day 1) Hgb values of 8 to <9 g/dL will receive one dose 
step higher.
Baseline (Day 1)
Hgb (g/dL)
Darbepoetin Alfa Starting Dose
How Delivered
8 to <9
If <78 kg starting dose 40 µg 
If 78-112 kg starting dose 60 µg 
If >112 starting dose 80 µg
40 µg every 4 weeks
60 µg every 4 weeks 
80 µg every 4 weeks
9 to 10
If <78 kg starting dose 30 µg  
If 78-112 kg starting dose 40 µg   
If >112 starting dose 60 µg 
30 µg every 4 weeks
40 µg every 4 weeks 
60 µg every 4 weeks
Group 2 (ESA users): The starting dose is as follows:

For subjects already on SC darbepoetin alfa, 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 a SC 
darbepoetin alfa equivalent dose, rounded to the nearest study dose.
Darbepoetin Alfa Dose Steps:
Dose-steps of darbepoetin alfa are pre-defined in this study (Table 5). Darbepoetin alfa
dose adjustments (increases and decreases) are 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 PFS will be used to deliver the total 4-weekly dose; this information is 
provided in the SRM.  Those receiving the highest dose of darbepoetin alfa who require a 
dose increase will maintain the same dose, while those receiving the lowest dose of 
darbepoetin alfa that require a dose decrease will have doses withheld.  

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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 Darbepoetin Alfa Dose Adjustment Algorithm
The protocol-specified randomized treatment (daprodustat or darbepoetin alfa) 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 darbepoetin alfa 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.
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. 

Subjects who cannot return to the site for a period >5 weeks during the first 52 weeks 
and >13 weeks thereafter. 
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

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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.
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.  

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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 darbepoetin 
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 darbepoetin alfa 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 darbepoetin alfa who have randomized treatment 
administered in the clinic, the details of each administered darbepoetin alfa 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.
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 hemodialysis (HD) or peritoneal dialysis (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 heart rate and hematologic abnormalities.
Consult the approved product label for information on overdose for darbepoetin 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 

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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)
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; 

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
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).
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 starting or post-rescue2 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 values3
OR
-
More than two units of PRBC were needed for transfusion (and was not related to 
acute bleeding).

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1.
Two consecutive dose increases if starting/post-rescue dose is daprodustat 12 mg or darbepoetin alfa 200 µg 
over 4 weeks; one dose increase if starting/post-rescue dose is daprodustat 16 mg or darbepoetin alfa 300 µg 
over 4 weeks; and no prior dose increase if starting/post-rescue dose is daprodustat 24 mg or darbepoetin alfa 
400 µg over 4 weeks (top dose)
2.
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.
3.
Repeat HemoCue Hgb at the same study visit to confirm Hgb (using the same sample); take average of 2 values.
6.13.
Subjects Transitioning to Dialysis
Subjects starting dialysis should not be withdrawn from the study, and should continue in 
the study as described below: 

All subjects transitioning to dialysis during the study will continue in the study on 
randomized treatment to achieve and/or maintain Hgb within the target range of 
10-11 g/dL. 
o
Subjects transitioning to dialysis must follow the time and events schedule 
detailed in Appendix 7.

Study visit can be on a dialysis or non-dialysis day. 
o
However, for subjects on 3x/week HD, the designated study visit must not
occur on or before the first dialysis session of the week except in special
circumstances after consultation with the PPD Medical Monitor.

For subjects randomized to darbepoetin alfa who transition to hemodialysis, 
o
Study treatment may be given IV if given during hemodialysis.
o
For those transitioning to hemodialysis where the investigator is not affiliated 
with the dialysis center, darbepoetin alfa may continue to be administered SC.

For subjects transitioning to dialysis after Week 52, unscheduled visits every 4 weeks 
(1 week) for 12 weeks may be required until the subject’s Hgb has stabilized 
following transition to dialysis.

For subjects with ADPKD only:  As per Section 7.4.10, as clinically feasible, an 
ultrasound should be performed PRIOR to subjects transitioning to dialysis.  
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. 
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).  

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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 
onward is ±1 week (7-9 weeks).  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.
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 the End of the Study
Protocol activity (visits ±1 week, except Weeks 2 and 4 which are 
±3 days)
(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)
X20
IRT system transaction 
X
X
X
X
X
X
X
X
Subject reminder, inform site staff of changes in health1
X
X
Check/confirm entry criteria, weight
X
X
History: medical, hospitalization, transfusion
demography, height
X
SBP/DBP, HR (single readings unless otherwise indicated)
X
X
X (triplicate)
X
X
X
X (triplicate)
X
ECG
X17
X
Ultrasound of kidneys and adrenal glands 
X16
Placebo run-in or randomized treatment dispensing (start 
administration on day of dispensing)
X(placebo)
X
X9
X
X
X
X 9
Placebo run-in or randomized treatment compliance
X (placebo)
X11
X
X
X
X11
Iron therapy, transfusions2
X
X
X
X
X
X
X
X
Rescue medication(s) for Initial Intervention 2,3 
X
X
X
Females only: estradiol and FSH (if required) 
X
FRP only: urine pregnancy test 4,18
X
X
X
X
HemoCue Hgb
X
X
X
X
X
X
X
X
Hematology5  
X
X
X
X
Hgb only 
X
X
Clinical chemistry5
X
X
X
X
X
Ferritin, total iron, UIBC 5
X
X
X
X
Hepcidin  
X
X
X
HbA1c6, lipids (non-fasting)
X
X
hsCRP, iPTH
X
Wk 28
X
Urine albumin/ creatinine ratio 
X
Wk 4, Wk 28
X
Storage biomarkers (blood, urine)19
X
Wk 28
X
Hospitalization 2, transition to dialysis2,7, kidney transplant2
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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Table 7
Schedule of Assessments Year 1 to the End of the Study (Continued)
Protocol activity (visits ±1 week)
(Note: All visit timings are relative 
to Day 1)
Year 2
Year 3
Year 4
Unscheduled10,12 End of 
Study15
Follow-up
(4-6 weeks after
stopping 
randomized 
treatment)
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 transaction 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
SBP/DBP, HR (single readings 
unless otherwise indicated)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X 
(triplicate)
X
ECG
X
X
X
Randomized treatment dispensing
(start administration on day of 
dispensing)
X
X
X
X
X
X
X
X
X
X
X
X
X
X9
Randomized treatment compliance
X
X
X
X
X
X
X
X
X
X
X
X
X
X11
X
Iron therapy, transfusions2
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Rescue medication(s) for Initial 
Intervention2,3 
X
X
X
X
X
X
X
X
X
X
X
X
X
FRP only: urine pregnancy test4,18
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
Hematology5  
X
Hgb 
only
X
Hgb 
only
X
Hgb 
only
X
Hgb 
only
X
Hgb 
only
X
Hgb 
only
X
X
X
X
Clinical chemistry5
X
X
X
X
X
X
X
X
X
X
Ferritin, total iron, UIBC5  
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Hepcidin, HbA1c6, lipids (non-
fasting), hsCRP
X
iPTH
X
X
Urine albumin/ creatinine ratio 
X
X
X
Hospitalization2, transition to 
dialysis 2,7, kidney transplant2
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
ADPKD subjects only:  eGFR
X
X
X
X
X
X

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Protocol activity (visits ±1 week)
(Note: All visit timings are relative 
to Day 1)
Year 2
Year 3
Year 4
Unscheduled10,12 End of 
Study15
Follow-up
(4-6 weeks after
stopping 
randomized 
treatment)
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
ADPKD subjects only:  Ultrasound
X21
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; HR, heart rate; ECG, electrocardiogram; ADPKD, autosomal dominant polycystic kidney disease
1.
Health changes include new symptoms or medical problems (e.g., pregnancy, hospitalizations) and changes in medication.
2.
Record in eCRF, if applicable.
3.
See details on rescue in Section 6.12.
4.
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 6) during the study pregnancy tests are no longer required.
5.
See details on hematology and clinical chemistry in Section 7.4.11.
6.
HbA1c assessment only in subjects with diabetes on Day 1 or diagnosed during the study.
7.
Subjects transitioning to dialysis must follow the time and events schedule detailed in Appendix 7. See also Section 6.13 for additional details.
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 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 5.  
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, 
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. Day 1 ECG may be performed as early as the Week – 4 visit through the Day 1 visit; If performed on Day 1, it must be over-read prior to randomization.
18. For Argentina ONLY: pregnancy testing will be performed every 4 weeks for FRP as required by local law.
19. Biomarker samples will be stored for future analyses for all subjects, except if not permitted by IRB/EC or refused by subject.
20. Informed consent will be obtained prior to any study procedures.
21. Ultrasound of the kidneys will be performed within one month of discontinuing randomized treatment after the EOS visit or as soon as clinically feasible. See Section 7.4.10 for 
additional details.  

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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
Week -4 
(Next day 
visit)
Day 
1
Week
4
Week
8 & 12
Week
16, 20 & 24
Week 16 
(Next day 
visit)
Week
28
Week
32, 36, 40, 
44, 48
Week
52
Week 100, 
148, 208
Symptoms of aCKD questionnaire1
X
X
X
X
X
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
Work Productivity and Activity 
Impairment Questionnaire (WPAI-
ANS-CPV)2
X
X
X
X
X
X
Healthcare resource utilization
(subject-reported)
X
X
X
X
X
X
X
X (& Follow 
up)
Genetics sample3
X
ABPM sub-study (Appendix 13):
                          Informed Consent 
X4
X4
Atrial fibrillation/flutter screening 
X5
                    24 hour ABPM start 
X6
X (Week 
16)
                     24 hour ABPM end
X6
X
Record awake and sleep times
X7
X7
      24 hour urine collection start 
(sodium, aldosterone & creatinine)
X6
X (Week 
16)10
           24 hour urine collection end
X6
X10
PK sub-study (Appendix 14):  
                          Informed Consent  
X8
X8
X8
X8
X8
X8
X8

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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
Week -4 
(Next day 
visit)
Day 
1
Week
4
Week
8 & 12
Week
16, 20 & 24
Week 16 
(Next day 
visit)
Week
28
Week
32, 36, 40, 
44, 48
Week
52
Week 100, 
148, 208
                           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 12.13.3.3)
6. Baseline ABPM and 24 hour urine will be performed at Week -4 or at an unscheduled visit up until 1 week prior to randomization (Day 1). 
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 (i.e., PK is collected at one visit only, based on convenience for the subject/site).
10. For subjects transitioning to dialysis, 24 hour urine collection to be done as able.

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Table 9
Schedule of Assessments for Subjects Permanently Discontinuing Randomized Treatment
Protocol Activity
(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
IRT system transaction
X
SBP/DBP, HR  
X (triplicate)
X
X
ECG
X
Iron therapy, transfusions1
X
X
X
Urine (serum if transitioned to dialysis) pregnancy test 
(FRP only)
X8
HemoCue Hgb
X
X
X
Hematology3
X
X
Clinical chemistry3
X
X
Ferritin, total iron, UIBC, hepcidin, lipids, iPTH
X
Hospitalization1 , transition to dialysis1, 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
CKD-AQ, 5, 10
X
PGI-S, PGI-C5, 10
X
SF-365, 10
X
EQ-5D-5L& EQ-VAS5, 6, 10
X
WPAI-ANS-CPV4, 5, 10
X
ADPKD subjects only:  Ultrasound
X12
ABPM sub-study (Appendix 13):           24 hour ABPM
X (Week 16)
Record awake and sleep times
X (Week 16)2
24 hour urine collection (sodium, aldosterone & creatinine
X (Week 16)11

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Table 9
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 
Study 9
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 
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, transition to 
dialysis1, 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
Transition to dialysis1
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
ADPKD subjects only: 
eGFR13
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. If local dialect or language is available. 
5. Only completed at Early Treatment Discontinuation visit if the randomized treatment discontinuation occurs on or before Week 52
6. Only in selected countries. See Appendix 3.
7. Phone visits are acceptable in exceptional circumstances. 
8. Additional pregnancy test required at subsequent visit. Must be at least 4 weeks after the end of randomized treatment.
9. Investigator will inform subject when to attend this End of Study visit.
10. Subjects who are unable to or require assistance to read must not complete the questionnaires.
11.For subjects transitioning to dialysis, 24 hour urine collection to be done as able.
12. Ultrasound of the kidneys will be performed within one month of discontinuing randomized treatment or as soon as clinically feasible. See Section 7.4.10  for additional details. 
13. Collect samples as able, as outlined below; if subject refuses, document in subject source notes.

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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 5.1). 
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 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 study 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 9.
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)

Progression of CKD (two components to be adjudicated):
-
initiating chronic dialysis for <90 days or 
-
not initiating chronic dialysis when dialysis is indicated 
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 CEC 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 8.
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 

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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 8. 
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 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 7.4.3.3), 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 8.

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 8.
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 

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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 8 .
7.4.3.4.
Regulatory Reporting Requirements for SAEs
Prompt notification by the investigator to PPD of SAEs related to placebo run-in 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 

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(PSRAE) eCRF form should be completed (in addition to the AE and SAE pages, as 
appropriate).
This event may include, but is not limited to, one that involves suicidal ideation, a 
preparatory act toward imminent suicidal behavior, a suicide attempt, or a completed 
suicide. The investigator will exercise his or her medical and scientific judgment in 
deciding whether an event is possibly related to suicidality.
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 11.
7.4.7.
Height and Weight
Height and weight will be measured as specified in the Time and Events Table 
(Section 7.1). Weight should be measured with the subject wearing indoor daytime 
clothing with no shoes. 
For subjects that transition to dialysis, weight will be measured,

For in-center HD subjects: pre and post-dialysis, when possible, or at study visits 
between dialysis sessions 

For HHD subjects: at study visits between dialysis sessions

For PD subjects:  at study visits, as per standard of care
7.4.8.
Blood Pressure and Heart Rate
Measurement of systolic blood pressure (SBP), diastolic blood pressure (DBP) and heart 
rate (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 subjects in a seated position after at least a 5-
minute rest period, and will be before collection of blood samples for laboratory 
testing, where applicable.

For subjects transitioning to dialysis, SBP, DBP and HR will be measured,
o
For in-center HD subjects: pre and post-dialysis, when possible, or at 
study visits between dialysis sessions 
o
For HHD subjects: at study visits between dialysis sessions
o
For PD subjects:  at study visits, as per standard of care

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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).
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 collection of 
blood samples for laboratory testing.
For subjects transitioning to dialysis, ECGs will be performed before measurement of 
SBP, DBP, 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.
For randomized subjects with ADPKD:

An ultrasound of the kidneys will be performed when subjects permanently 
discontinue randomized treatment, preferably within one month of discontinuation of 
randomized treatment or as soon as clinically feasible. This may occur during the 
study OR after the completion of the end of study visit. See Table 7 and Table 9 for 
details.  

As clinically feasible, an ultrasound should be performed PRIOR to the following:
o
Transition to dialysis
o
Bilateral nephrectomy
o
Kidney transplant.

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
An additional ultrasound may be performed at any time during the study based on 
investigator’s clinical judgment (e.g., deterioration of kidney function as measured by 
eGFR in the absence of other identifiable causes). Other imaging techniques (e.g., 
MRI) can be performed at the investigator’s discretion.  

If an additional imaging study is performed, and the condition of the cystic disease in 
the kidney(s) has worsened more than expected given the clinical scenario, then 
randomized treatment should be temporarily stopped.  Subsequently, if no other 
cause for the kidney function decline and/or cyst enlargement can be identified, 
randomized treatment should be permanently discontinued after consultation with the 
PPD Medical Monitor.
7.4.11. Clinical Laboratory Assessments
Table 10, must be conducted in accordance with the Laboratory Manual, and Protocol 
Time and Events Schedule (Section 7.1). For subjects transitioning to dialysis (Table 
12), 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.
All study-required laboratory assessments will be performed by a central laboratory with 
the exception of HemoCue Hgb and urine pregnancy tests which will be performed at the 
clinical site. The results of each HemoCue Hgb must be entered into the subject’s eCRF.

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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
Sodium (serum)
AST
Carbon Dioxide (total)
Potassium (serum)
ALT
Albumin
Calcium (total and 
albumin-adjusted)
Inorganic phosphate 
Urea (serum)
Creatinine (serum)
Bilirubin (total and 
direct/indirect) 
Chloride (serum)
eGFR
Iron 
parameters
Iron (serum)
Ferritin
UIBC
Hepcidin
TIBC 
TSAT
Lipid 
parameters
Total cholesterol
LDL-C (direct)
HDL-C
Other 
laboratory 
tests
Urine/serum hCG 
pregnancy test2,3
FSH4
hsCRP
Urine albumin/
creatinine ratio 
Estradiol4
iPTH
HemoCue Hgb
HbA1c5
Stored sample (blood, 
urine)
24 hour urine collection 
(sodium, aldosterone 
and creatinine)6
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 9.
2.
For females of reproductive potential only.
3.
Serum pregnancy tests. Only for subjects that transition to dialysis during the study.
4.
Screening only. As needed in postmenopausal women where their menopausal status is in doubt (see 
Inclusion Criteria Section 5.1)
5.
Only in subjects with diabetes.
6.
ABPM sub-study only. See Appendix 14.
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.

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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
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*

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Liver Safety Required Actions and Follow up Assessments Section can be found in 
Appendix 9.
Phase 3-4 Liver Chemistry Increased Monitoring Algorithm with Continued 
Therapy for ALT 3xULN but <8xULN
Liver Safety Required Actions and Follow up Assessments Section can be found in 
Appendix 9.
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 randomized treatment restart is signed by the subject
Refer to Appendix 10 for full guidance. 
7.5.
Genetics
Information regarding genetic research is included in Appendix 12. Samples for genetic 
analysis will be taken at the time points specified in the Time and Events Table (Section 
7.1).
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*

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7.6.
Storage Biomarkers
Blood (serum and plasma) and urine samples will be collected as outlined in the Time 
and Events Table (Section 7.1) for potential future analysis of biomarkers of CV risk, 
iron metabolism and biomarkers for progression of CKD.
7.7.
Patient Reported Outcomes
The patient-reported effect of daprodustat and darbepoetin alfa on symptoms, health-
related quality of life (HR-QoL), health status (e.g., utility) and work productivity and 
activity impairment will be assessed.  Symptoms will be assessed using a symptoms 
questionnaire which is specific to anemia of CKD (CKD-AQ).  Overall 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 EuroQol 5 Dimension 5 Level 
Health Utility Index (EQ-5D-5L) and the EuroQol Visual Analogue Scale (EQ-VAS). 
Work productivity and regular daily activity impairment will be measured via the Work 
Productivity and Activity Impairment Questionnaire for the specific health problem of 
Anemia, Clinical Practice Version 2.0 (WPAI-ANS- CPV; V2.0).  In addition, healthcare 
resource utilization will be assessed including out-patient visits and healthcare time.
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.
The CKD-AQ, PGI-S, PGI-C, HR-QoL and Health Status questionnaires should be 
completed by subjects at a clinic visit, in the order specified: PGI-S, PGI-C, CKD-AQ, 
SF-36, EQ-5D-5L and EQ-VAS, then the WPAI-ANS- CPV. Subjects who are unable to 
or require assistance to read must not complete the questionnaires.
7.7.1.
Chronic Kidney Disease - Anemia Questionnaire (CKD-AQ)
A novel symptom questionnaire – CKD-AQ has been developed to collect concepts of 
interest for the anemia of CKD population.  Unlike the Functional Assessment of Cancer 
Therapy – Anemia (FACT-AN) and Functional Assessment of Chronic Illness Therapy –
Fatigue (FACIT-Fatigue) which have not demonstrated content validity specific for the 
anemia of CKD population, the novel CKD-AQ instrument was developed to verify and 
ensure that concepts specific for anemia of CKD were captured and measured.  It will 
measure both the frequency and/or severity in anemia of CKD concepts such as 
Weakness, Energy, Tiredness, Shortness of Breath, Exertion, Chest Pain, Memory, 
Concentration, Standing, Sleep and Distress over the past seven days.  

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7.7.2.
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. 
7.7.3.
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.  The questionnaire contains 36 questions within these domains 
that ask the subject to recall how they felt during the past seven days.
7.7.4.
Health Status (EQ-5D-5L & EQ-VAS)
EQ-5D-5L consists of 2 concepts – the EQ-5D-5L descriptive system and the 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.
7.7.5.
Work Productivity and Activity Impairment (WPAI-ANS-CPV)
The WPAI-ANS-CPV is an anemia specific questionnaire designed as a self-reported 
quantitative assessment of social functioning related to work and regular daily activities.  
It contains two main concepts- work productivity impairment measured via absenteeism 
(time missed from work), presenteeism (impairment at work) and regular daily activity 
impairment. The questionnaire contains 6 questions and asks the patient to recall work 
and activity impairment over the past 7 days.  

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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 darbepoetin alfa
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 darbepoetin alfa
for Hgb efficacy(non-inferiority)

Mean change in Hgb between baseline and EP 
(mean over Weeks 28 to 52)
The co-primary endpoints will each be tested for non-inferiority 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 darbepoetin alfa, 
expressed by the following statistical hypotheses: 

Null: daprodustat is inferior to darbepoetin alfa, with at least a 25% increased 
relative risk of first MACE (i.e. the hazard ratio is ≥1.25)

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
Alternative: daprodustat is non-inferior to darbepoetin alfa (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 (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 1.25.
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 darbepoetin alfa 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 not on 
dialysis 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 darbepoetin alfa 
for the mean change in Hgb between baseline and the EP (Weeks 28 to 52). The 
following statistical hypotheses will be tested: 

Null: The difference in mean change in Hgb between baseline and EP, between 
treatment arms (daprodustat - darbepoetin alfa), is less than or equal to -0.75 g/dL.

Alternative: The difference in mean change in Hgb between baseline and EP, 
between treatment arms (daprodustat - darbepoetin alfa), 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 (region and 
current ESA use) and factors for baseline Hgb and treatment will be used to obtain a 
point estimate and two-sided 95% CI for the treatment difference (daprodustat -
darbepoetin alfa) and generate the corresponding p-value for the non-inferiority test. 
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 
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progression of CKD. 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 darbepoetin (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). Other 
assumptions behind the sample size calculation include:

Projected annual adjudicated first MACE rate of 9.3%. 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 50%, 30% and 20% 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. 
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 expected enrolment and an annual MACE rate of 9.3%, it is anticipated that the 
the 664 adjudicated first MACE target will be reached approximately 4.2 years from 
when the first subject is randomized. It is anticipated that more than 80% of randomized
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 4000 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 15 (see Section 12.15.1, Item 2 for details).

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9.2.2.
Sample Size Sensitivity
The estimated 9.3% annual MACE rate is based on a blinded summary of ASCEND-ND 
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 10-11 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 the analysis will have more than 99% power for non-inferiority and 
a high level of precision to estimate the treatment effect (two-sided 95% CI half width is 
expected to be approximately 0.105 g/dL, assuming a 30% non-evaluable rate for 
efficacy). The largest (most negative) difference between arms that would meet the 
statistical criterion for non-inferiority would be -0.645 g/dL. If the two-sided 95% CI is 
completely negative (i.e. lies fully within the range -0.75 to <0 g/dL) non-inferiority 
would still be concluded.
9.2.3.
Sample Size Re-estimation or Adjustment
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 for a minimum of one year follow-up may be adjusted.    
The current COVID-19 pandemic has significantly impacted subject enrolment such that 
it is considered likely that enrolment will be closed prior to reaching the target of 4,500 
subjects.

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9.3.
Data Analysis Considerations
9.3.1.
Analysis Populations
The primary population for all 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 (region and current ESA use), 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 
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.

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In addition, analyses of MACE as described above 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 described in Section 9.4.4
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 darbepoetin alfa 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 not on dialysis with anemia secondary to CKD and assuming subjects do not die 
before the end of the EP. The analysis will use an analysis of covariance (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 (region and current ESA use), 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 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.
9.4.2.
Secondary Analyses
9.4.2.1.
Principal Secondary Analyses
Conditional on the co-primary endpoints achieving 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 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)

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
Alternative: daprodustat is superior to darbepoetin alfa (i.e. the hazard ratio is 
less than 1.0 for time-to-event endpoints, or the mean difference is less than 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.
The principal secondary endpoints are listed below. The statistical modeling approach 
described for MACE in Section 9.4.1.1 will be repeated for these adjudicated composite 
events:

MACE or a thromboembolic event (vascular access thrombosis, symptomatic 
deep vein thrombosis or symptomatic pulmonary embolism)

MACE or hospitalization for HF
The progression of CKD endpoint is as follows:

Progression of CKD [40% decline in eGFR from baseline (confirmed 4-13 weeks 
later) OR ESRD]
ESRD definition: a) initiating chronic dialysis for ≥90 days* or b) not initiating chronic dialysis 
when dialysis is indicated (adjudicated) or c) receipt of a kidney transplant. *adjudicate only if 
the duration of dialysis is <90 days.
This endpoint will be restricted to the subset of subjects with eGFR≥15 ml/min/1.73m2 at 
baseline. Since all-cause mortality is not included as a component of the composite 
endpoint, Fine and Gray’s subdistribution hazards analysis model will be used to account 
for this competing risk and the cumulative incidence function accounting for this 
competing risk of death will be provided. Further details will be provided in the RAP. 
For sensitivity, all-cause mortality will be included in the composite endpoint and 
traditional Kaplan-Meier methodology applied for analysis.
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 of Patient Reported Outcomes
Analysis to compare the subject reported effects of daprodustat and darbepoetin alfa on 
symptoms, health related quality of life, health status and productivity, as discussed in 
Section 7.7, will be described in the RAP.  A blinded cut of the data will be taken when 
approximately 250 subjects complete the Week 28 visit for the purpose of psychometric 
validation of the CKD-AQ symptoms questionnaire.  Details of the planned analysis for 
this will be described in a separate psychometric analysis plan (See Section 9.4.6).
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 

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stopping treatment or study will be presented graphically and assessed. Full details of all 
safety data reporting are described in the RAP.
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.
Figure 2
Multiplicity controlled statistical testing plan
9.4.4.
Covariates and Subgroups of Interest
The 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.
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. 

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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-values 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 
See Appendix 3
Country 
See Appendix 3
Prior rhEPO dose 
<3,000 U/week, ≥3,000 U/week
rhEPO user
No, yes
Baseline Hgb 
rhEPO Naïve: <9, ≥9 g/dL
rhEPO Users:  <9, 9 to <10, 10 to 11 g/dL
BMI 
<30, ≥30 kg/m2
Weight 
< 75kg, ≥75kg 
CKD stage (based on eGFR)
Stage 3: 30-<60 mL/min/1.73m2; Stage 4: 15 - <30 
mL/min/1.73m2; Stage 5: <15 mL/min/1.73m2
Baseline hsCRP
≤3 mg/L, >3 mg/L
United states
US, Non-US
Additional exploratory subgroups may be defined in the RAP.
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 

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in the IDMC charter regarding whether the study should continue unchanged, be 
modified or be terminated.  
There are no prospectively defined interim analyses 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.
9.4.6.
Psychometric Analyses of the Chronic Kidney Disease- Anemia 
Questionnaire (CKD-AQ)
In order to establish and evaluate the measurement properties of the CKD-QA, an interim 
cut of blinded observations of at least 250 subjects who completed the Week 28 visit will 
be taken. The data cut will require the following variables through Week 28: PGI-C, PGI-
S, Hgb, SF-36, WPAI-ANS-CPV, demographic and baseline clinical characteristics.   
The interim data cut will be used to conduct confirmatory factor analysis in order to 
establish a scoring algorithm for potential instrument domains and to evaluate the
reliability, validity and responsiveness of the instrument without regard to treatment 
group. A full description of the data cut, variables of interest and analyses to establish the 
scoring and to evaluate the measurement properties of the CKD-QA will be specified a 
priori within a separate psychometric analysis plan.
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

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
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.  

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. 

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
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.  

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.

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
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 
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, hospitalization for HF, and 
components of the progression of CKD endpoint (Section 7.4.1).

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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.  
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.
Levey AS, Stevens LA, Schmid CH, Zhang YL, Castro AF 3rd, Feldman HI et al; CKD-
EPI (Chronic Kidney Disease Epidemiology Collaboration). A New Equation to Estimate 
Glomerular Filtration Rate. Ann Intern Med 2009;150(9):604-12
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;74:791-8

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12.
APPENDICES
12.1.
Appendix 1: Abbreviations and Trademarks
Abbreviations
ABPM
Ambulatory blood pressure monitoring
ADPKD
Autosomal dominant polycystic kidney disease
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
CKD-AQ
Chronic Kidney Disease - Anemia Questionnaire
CKD-EPI
Chronic kidney disease Epidemiology Collaboration 
CNIL
Commission Nationale de I'Informatique et des Libertés
CPK
Creatine phosphokinase 
CRA
Clinical Research Assistant 
CTR
Clinical Trials Register
CT
Computed tomography
CV
Cardiovascular
DBP
Diastolic blood pressure
DGF
Delayed graft function 
ECG
Electrocardiogram
eCRF
Electronic case report form
eGFR
Estimated glomerular filtration rate
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
ESRD
End stage renal disease
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 
HDL-c
High density lipoprotein-C

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HDPE
High density polyethylene
HF
Heart failure
Hgb
Hemoglobin
HHD
Home hemodialysis
HIF
Hypoxia-inducible factor
HR
Heart rate
HR-QoL
Health Related Quality of Life
HRT
Hormone replacement therapy
hsCRP
High sensitivity C-reactive protein
KDIGO
Kidney Disease Improving Global Outcomes
KDOQI
Kidney Disease Outcomes Quality Initiative
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
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
MRI
Magnetic resonance imaging
MSDS
Material Safety Data Sheet
ND
Non-dialysis
NO
Nitric oxide
NYHA
New York Heart Association
PASP
Pulmonary Artery Systolic Pressure
PCS
Physical Component Score
PD
Peritoneal dialysis 
PEG
Polyethylene glycol
PGI-C
Patient Global Impression of Change
PGI-S
Patient Global Impression of Severity
PFS
Pre-filled syringe
PHI
Prolyl hydroxylase inhibitor
PK
Pharmacokinetic
PP
Per protocol
PPD
Pharmaceutical Product Development, LLC
PRBC
Packed red blood cells

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PRS
Project Requirement Specification 
PSRAE
Possible Suicidality Related Adverse Events 
QC
ABPM 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
SF-36
Short Form -36
SRM
Study Reference Manual
TIBC
Total iron binding capacity
TSAT
Transferrin saturation
UIBC
Unsaturated iron binding capacity
U
Units
ULN
Upper limit of normal
US
United States
WBC
White blood cells
WPAI-ANS-CPV
Work Productivity and Activity Impairment 
Questionnaire:
Anemic Symptoms Clinical Practice Version 
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 (tested for superiority1, no multiplicity 
adjustment)

To compare daprodustat and 
darbepoetin alfa 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

Individual components of CKD progression2

To compare daprodustat to 
darbepoetin alfa 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 
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 
darbepoetin alfa 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
darbepoetin alfa on the time to rescue 
(defined as permanently stopping 
randomized treatment and due to 
meeting rescue criteria)

Time to stopping randomized treatment due to meeting 
rescue criteria

To compare daprodustat to 
darbepoetin alfa 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 Weeks 
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 
darbepoetin alfa on the symptom 
severity and change

Change from Baseline at Weeks 8, 12, 28, 52 by 
domain and overall symptom score on the CKD-AQ

Change from Baseline at Weeks 8,12, 28, 52 in PGI-S

To compare daprodustat to 
darbepoetin alfa on renal function

eGFR change from baseline at Week 52

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Objectives
Endpoints
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

N (%) of subject who met iron management criteria

To further compare daprodustat to 
darbepoetin alfa 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 
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

To compare daprodustat to 
darbepoetin alfa on lipid parameters 

Observed and % change from baseline in lipid 
parameters by visit [total cholesterol, direct low density 
lipoprotein cholesterol (LDL-C), high density lipoprotein 
cholesterol (HDL-C)]

To compare daprodustat to 
darbepoetin alfa on renal function

eGFR observed and change from baseline across all 
visits to end of treatment

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Objectives
Endpoints

Serum creatinine observed and change from baseline 
across all visits to end of treatment

Urine albumin/creatinine  ratio observed and change 
from baseline across all visits to end of treatment

N (%) transitioning to dialysis

To compare the effect of daprodustat 
to darbepoetin alfa 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 
darbepoetin alfa on HRQoL and Utility 
score

Change from baseline in Health Utility (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 
darbepoetin alfa on the symptom 
severity and change

Shift tables (Baseline to Weeks 8, 12, 28, & 52) in PGI-
S

N(%) of patients within each PGI-C symptom change 
level at Weeks 8, 12, 28, 52.

Change from baseline at Weeks 8, 12, 28, 52 by item 
on the CKD-AQ

To further compare daprodustat to 
darbepoetin alfa on work productivity 
and regular daily activity impairment

N (%) of patients currently employed at Baseline, 
Weeks 8, 12, 28, 52, yearly, EOS on the WPAI-ANS-
CPV

Percent work time missed at Baseline, Weeks 8,12, 28, 
52, yearly, EOS on the WPAI-ANS-CPV

Change from baseline in percent work time missed at 
Weeks 8, 12, 28, 52, yearly and EOS on the WPAI-
ANS-CPV

Percent impaired (equivalent) at Baseline, Weeks 8,12, 
28, 52, yearly, EOS on the WPAI-ANS-CPV

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Objectives
Endpoints

Change from baseline in percent impaired (equivalent) 
at Weeks 8, 12, 28, 52, yearly and EOS on the WPAI-
ANS-CPV

Overall percent work impairment (equivalent) at 
baseline, Weeks 8,12, 28, 52, yearly, EOS on the 
WPAI-ANS-CPV

Change from baseline in overall percent work 
impairment (equivalent) at Weeks 8, 12, 28, 52, yearly, 
EOS on the WPAI-ANS-CPV

Percent activity impairment at Baseline, Weeks 8,12, 
28, 52, yearly, EOS on the WPAI-ANS-CPV

Change from baseline in percent activity impairment at 
Weeks 8, 12, 28, 52, yearly, EOS on the WPAI-ANS-
CPV
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; for CKD progression only, two components to be adjudicated.

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12.3.
Appendix 3: Stratification by Region- Region Groupings
Region
Countries2
1

Vietnam

India 

Malaysia1

Philippines

Republic of 
Korea1

Singapore1 
Taiwan1

Thailand

Hong Kong
2

Bulgaria

Turkey

Czech Republic 
Estonia

Hungary

Poland

Romania

Russian 
Federation

Ukraine

Slovakia

South Africa
3

Australia1

Austria

Belgium

Canada1

Denmark1

France

Germany

Greece

Italy

Israel

Netherlands1

New Zealand1

Portugal

Spain1

Sweden1

United Kingdom1
4

Argentina

Brazil1

Colombia

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 leading to thrombosis 
and/or tissue ischemia
In animal studies, excessive erythropoiesis (Hgb/Hct > upper limit 
normal) attributed to daprodustat was associated with vascular 
congestion/inflammation, microthrombi, and tissue ischemia in a 
number of organs.
In the phase 2 proof of concept study, a high incidence of 
discontinuation due to hemoglobin stopping criteria (Hgb > 13.5 g/dL 
or Hgb increased > 1 g/dL over any 2-week period) was observed.  In 
non-dialysis subjects administered 10 mg, 25 mg, 50 mg or 100 mg 
of daprodustat daily, a total of 21 of 61 subjects (34%) met these 
criteria.  In hemodialysis-dependent subjects administered either 10 
mg or 25 mg of daprodustat daily, a total of 8 of 31 subjects (26%) 
met these criteria.
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.
Integrated AE data [including 2 global phase 2b studies (24-week 
treatment duration) and 2 Japanese phase 3 studies (52-week 
treatment duration)]: Few subjects experienced a possible thrombosis 
related adverse event in the setting of excessive erythropoiesis 
[3/688 (0.5%) subjects on daprodustat vs. 0/404 on rhEPO].
Following review of clinical data received to date, this has not been 
identified as a safety concern for daprodustat when dose is managed 
appropriately according to target Hgb. However, experience with 
daprodustat is currently insufficient to fully characterize this risk.

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 

Specific eligibility criteria related to current 
uncontrolled hypertension are outlined in 
Section 5.2.

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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 (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.

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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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. Clinical studies with marketed 
rhEPO/analogs have suggested “higher” target hemoglobin, rate of 
hemoglobin rise of greater than 1 g/dL in any 2-week period, and/or 
higher doses may contribute to these risks.
In non-clinical studies conducted to date, not observed at tolerated 
doses when hemoglobin/hematocrit within normal range for species.
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)]: No 
meaningful difference was seen between treatment groups in the 
overall incidence of this AESI: [39/688 (5.5%) daprodustat vs. 25/404 
(6%) rhEPO; 0.92 relative risk (95% confidence interval: 0.55, 1.53)].  
Within this composite AESI, the most frequent event types were heart 
failure (at least 12 events daprodustat vs. at least 13 events rhEPO) 
and thrombosis (at least 14 events daprodustat vs. at least 8 event 
rhEPO); and a numerical imbalance was noted in events of 
myocardial ischemia (at least 7 events daprodustat vs. at least 1 
event rhEPO). The small number of events makes it difficult to draw 
any firm conclusions.
The clinical data received to date from completed clinical trials with 
daprodustat are insufficient to substantiate or refute this risk.

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.
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 rodents, stomach erosions were observed with intravenous and 
oral administration of 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.

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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.
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)]: No 
meaningful difference was seen between treatment groups in reports 
of this AESI [17 (2.7%) daprodustat vs. 10 (2.3%) rhEPO; 1.16 
relative risk (95% confidence interval: 0.52, 2.58)].
Following review of clinical data received to date, GI erosions have 
not been identified as a safety concern for daprodustat.
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 
VEGF plasma concentrations was observed at doses ranging 
from 10 to 150 mg. 

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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
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.
Integrated AE data [including 2 global phase 2b studies (24-week 
treatment duration) and 2 Japanese phase 3 studies (52-week 
treatment duration)]: No meaningful difference was seen between 
treatment groups in the occurrence of this AESI: [8/688 (1.1%) 
daprodustat vs. 4/404 (0.9%) rhEPO; 1.14 relative risk (95% 
confidence interval: 0.31, 4.28)].
Clinical experience to date is not yet sufficient to substantiate or 
refute this 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 

Unblinded monitoring of safety data by an 
IDMC in-stream throughout the study.

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were slightly higher than the vehicle control group. However, these 
hypoxia-induced PRVP changes were within the range of PRVP 
changes noted among untreated rats.
Results from a clinical study of acute hypoxic challenge in healthy 
volunteers demonstrated that short-term (5 days) therapy with 
daprodustat 5mg or 100mg has no clinically significant effect on 
transthoracic echocardiographic (ECHO) estimates of pulmonary 
artery systolic pressure (PASP) under either normoxic or hypoxic 
conditions.

ECHO assessments performed in Phase 2b studies (24 weeks 
treatment duration) did not identify any clinically meaningful 
changes in PASP in 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. A post-hoc analysis was performed using a 
definition of PAH often cited in the literature [Navaneethan, 
2016]. Subjects with sPAP >35 mmHg and/or tricuspid 
regurgitation maximum jet velocity (TRV) >2.5 m/s were 
considered as having PAH.  Regardless of baseline status of 
PAH, there was no clinically meaningful difference in the 
proportion of subjects with on-treatment PAH between the two 
treatment groups:  

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o
Subjects with PAH at baseline: 35/113 (31%) vs. 21/54 
(39%) (ND) and 37/115 (32%) vs. 7/21 (33%) (HD), 
daprodustat vs. control, respectively.
o
Subjects without PAH at baseline: 25/113 (22%) vs. 
12/54 (22%) (ND) and 22/115 (19%) vs. 6/21 (29%) 
(HD), daprodustat vs. control, respectively.
Integrated AE data [including 2 global phase 2b studies (24-week 
treatment duration) and 2 Japanese phase 3 studies (52-week 
treatment duration)]: Four (0.5%) non-serious AEs in the daprodustat 
group vs 0 in rhEPO. 

Review of subject level information did not suggest adverse 
treatment effect: 2 subjects from phase2b that met protocol 
specified stopping criteria on scheduled ECHO had non-serious 
AEs of ‘pulmonary arterial pressure increased’ and 2 subjects 
from Japan Phase 3 had non-serious AE ‘pulmonary 
hypertension’ in setting of concurrent serious AEs of acute 
pulmonary embolus and mitral regurgitation (respectively) 
identified during hospitalization for coronary angiography.
Following review of clinical data received to date, this has not been 
identified as a safety concern for daprodustat.   
Cardiomyopathy
Published data suggest that cardiac effects of HIF stabilization are 
likely a function of the mechanism, extent, and duration of the effects, 
and can range from protective to detrimental depending upon the 
specific model and experimental conditions utilized.
With lifetime exposure to daprodustat in a 2-year rat oral 
carcinogenicity study, an exacerbation of rat spontaneous, 
progressive cardiomyopathy (PCM)(focal myofiber 
degeneration/necrosis with inflammatory infiltrates) was observed at 
doses of 0.8 mg/kg/day and above, although total incidence and 
severity distribution within any daprodustat-group were within 
historical control ranges.  This is consistent with an equivocal 
threshold for exacerbation of spontaneous, progressive 

Unblinded monitoring of safety data by an 
IDMC in-stream throughout the study.

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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.
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)]: No 
meaningful difference was seen between treatment groups in reports 
of this AESI [1 (0.1%) daprodustat vs. 1 (0.2%) rhEPO; 0.64 relative 
risk (95% confidence interval: 0.02, 18.07)].
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.
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 25mg, changes in VEGF plasma concentrations were 
variable but similar relative to control.

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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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.
Integrated AE data [including 2 global phase 2b studies (24-week 
treatment duration) and 2 Japanese phase 3 studies (52-week 
treatment duration)]: No meaningful difference was seen between 
treatment groups in reports of this AESI [9 (2.9%) daprodustat vs. 6 
(2.5%) rhEPO; 1.19 relative risk; (95% confidence interval: 0.42, 
3.43)].
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.
Integrated AE data [including 2 global phase 2b studies (24-week 
treatment duration) and 2 Japanese phase 3 studies (52-week 
treatment duration)]: No meaningful difference was seen between 
treatment groups in reports of this AESI [2 (0.3%) daprodustat vs. 1 
(0.2%) rhEPO; 1.20 relative risk; (95% confidence interval: 0.07, 
20.87) and the incidence of musculoskeletal AEs was generally lower 
in the daprodustat treatment group].
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.
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 

Co-administration of daprodustat with strong 
CYP2C8 inhibitors (e.g., gemfibrozil) and 

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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.
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 
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.
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 
6.10 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.
Cyst progression in patients with autosomal 
dominant polycystic kidney disease (ADPKD)
Published data provide in vivo evidence for a potential role of HIF-1a 
in the growth of polycystic kidneys; Hif-1a deletion was sufficient to 
significantly mitigate a progressive polycystic phenotype in an 
ADPKD mouse model, while conversely pharmacologic HIF-1a 
stabilization was sufficient to convert a mild polycystic disease into a 
severely aggravated phenotype with marked loss of renal function. 
However, the dose of FG-2216 (a PHI) used resulted in a significant 

Kidney function will be monitored throughout 
the dosing period as outlined in Time and 
Events Table Section 7.1.

Ultrasounds will be performed as outlined in 
Section 7.4.10

Monitoring of emerging safety data by an 
internal GSK Safety Review Team.

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erythropoietic response as reflected by ≥10% relative increases in 
hematocrit over the course of the study (Kraus, 2018; Hofherr, 2018).
A review of the non-clinical data from toxicity studies conducted with 
daprodustat does not indicate an exacerbation in incidence or 
severity of kidney cysts in daprodustat-treated animals in comparison 
to controls.  However, the wild type animals used in these toxicity 
studies have a very low background incidence of renal cysts and are 
not comparable to the mice used in the Kraus article (Kraus, 2018) 
which are an inducible kidney epithelium-specific Pkd1-deletion 
model.
There is limited experience with daprodustat in subjects with ADPKD 
in completed clinical trials. In the Japan phase 3 study in non-dialysis 
subjects, there were 5 subjects with ADPKD (all CKD stage 5) in 
each treatment group.  Mean baseline eGFR was 10 mL/min/1.73m2 
in the daprodustat subjects vs. 16 mL/min/1.73m2 in the rhEPO 
subjects.  The mean (SD) percent change from baseline at Week 52 
in eGFR was: -18% (8) vs. -21% (14) in daprodustat vs. rhEPO, 
respectively.
Following review of clinical data received to date, this has not been 
identified as a safety concern for daprodustat.
Other
rhEPO risks (Control)
See risks outlined in table for daprodustat for excessive 
erythropoiesis leading to thrombosis and/or tissue ischemia, death, 
MI, stroke, heart failure, thromboembolic events, thromboembolism, 
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 
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.

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
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(1):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
Hofherr A, Busch T, Kottgen M. HIF-1drives cyst growth in advanced stages of 
autosomal dominant polycystic kidney disease.  Kidney International 2018;94: 849–851 
Kraus A, Peters DJM, Klanke B et al., HIF-1α promotes cyst progression in a mouse 
model of autosomal dominant polycystic kidney disease. Kidney International 2018
94(5):887-899
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
Navaneethan SD, for CRIC investigators: Prevalence, Predictors, and Outcomes of 
Pulmonary Hypertension in CKD. J Am Soc Nephrol 2016; 27:877–886
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 urine 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.
2. Intrauterine device or intrauterine system.
3. Combined estrogen and progestogen oral contraceptive [Trussell, 2011].
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 12.15.2 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 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: 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 transitioning to dialysis:  Visits every 4 weeks for 12 weeks.

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: Time and Events Table for Subjects Transitioning to Dialysis
Table 12
Schedule of Assessments Year 1 to the End of the Study for Subjects Transitioning to Dialysis
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
Week 2
Full study visit
Week 4, 16, 28, 40
Abbreviated study visit
Week 8, 12, 20, 24, 32, 36, 44, 48  
Week 52
Unscheduled8
IRT system transaction
X
X
X
X
X
Subject reminder, inform site staff of changes in health1
X
Weight (pre- and post-dialysis for in-center HD subjects (when 
possible); between treatments for HHD; at study visits as per 
standard of care for PD) and EDW
X
X
X
X
X
SBP/DBP, HR (pre- and post-dialysis for in-center HD subjects 
(when possible); between treatments for HHD; as per standard 
of care for PD) (single readings unless otherwise indicated)
X
X
X
X (triplicate)
X
Kt/Vurea 14
X
X
ECG 2
X
Randomized treatment dispensing (start administration on day 
of dispensing)16
X15
X
X
X
X9,15
Randomized treatment compliance16
X9
X
X
X
X9
Iron therapy, transfusions3
X
X
X
X
X
Rescue medication3 ,4 
X
X
X
FRP only:  Serum pregnancy test 5,17
X
X
HemoCue Hgb
X
X
X
X
X
Hematology6  
X
Hgb only 
X
X
Clinical chemistry6
X
X
X
Ferritin, total iron, UIBC 6
X
X
Hepcidin  
X
X
HbA1c7, lipids (non-fasting) 
X
hsCRP, iPTH
Wk 28
X
Storage biomarkers13
Wk 28
X
Hospitalization 3, kidney transplant3
X
X
X
X
X
Non-serious AEs, SAEs, AEs of special interest, clinical events 
X
X
X
X
X
Review concomitant medications
X
X
X
X
X

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Table 12
Schedule of Assessments Year 1 to the End of the Study for Subjects Transitioning to Dialysis (continued…)
Year 2
Year 3
Year 4
Unscheduled8,10 End of 
Study14
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 
20811
IRT system transaction
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 (when possible); 
between treatments for HHD; at study 
visits as 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 (when possible); 
between treatments for HHD; at study 
visits as 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 14
X
X
X
X
X
X
X
ECG 2
X
X
X
Randomized treatment dispensing (start 
administration on day of dispensing)16
X
X
X
X
X
X
X
X
X
X
X
X
X
X15
Randomized treatment compliance16
X
X
X
X
X
X
X
X
X
X
X
X
X
X9
X
Iron therapy, transfusions3
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Rescue medication3,4 
X
X
X
X
X
X
X
X
X
X
X
X
X
FRP only: serum pregnancy test5,17
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
Unscheduled8,10 End of 
Study14
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 
20811
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
1.
Health changes include new symptoms or medical problems (e.g., pregnancy, hospitalizations) and changes in medication
2.
ECG assessments may be recorded pre or post dialysis. 
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 6) 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.
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. 
9.
Required only if dose is changed or randomized treatment is dispensed.
10. Additional visits to check Hgb and dispense randomized treatment 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.
11. Further visits every 12 weeks as required.
12. Investigator will inform subject when to attend this End of Study visit (Section 6.3.4).
13. Biomarker samples will be stored for future analyses for all subjects, except if not permitted by IRB/EC or refused by subject.
14. A historical Kt/Vurea measurement can be used.  If a Kt/Vurea measurement is not available, then a urea reduction ratio measurement is acceptable. Kt/Vurea and urea reduction 
ratio measurements are not required for daily HHD.
15. If dose does not change, then randomized treatment is returned to subject.
16. 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. Prior randomized treatment should be continued unless on dose hold, Hgb ≥12 g/dL.  Compliance is deferred until randomized treatment is returned.
17. For Argentina ONLY:  Pregnancy testing will be performed every 4 weeks for FRP as required by local law.
For schedule of assessments for patient reported outcomes, genetics and sub-studies refer to Table 8 in the main body of the protocol. For 
schedule of assessments for subjects permanently discontinuing randomized treatment refer to Table 9 in the main body of the protocol.

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12.8.
Appendix 8: Definition of and Procedures for Recording, 
Evaluating, Follow-Up and Reporting 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.
12.8.1. 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, 

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influenza, 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.
12.8.2. 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.

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
The investigator will attempt to establish a diagnosis of the event based on signs, 
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.
12.8.3. 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 

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important that the investigator always make an assessment of causality for 
every event 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.
12.8.4. 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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12.9.
Appendix 9: 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
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 

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

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GSK Medical Governance approval is 
granted (refer to Appendix 10)

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
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

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 
formincluding acetaminophen, herbal 
remedies, other over the counter 
medications.

Record alcohol use on the liver event 
alcohol intake case report form
For bilirubin or INR criteria:

Anti-nuclear antibody, anti-smooth 
muscle antibody, Type 1 anti-liver kidney 
microsomal antibodies, and quantitative 
total immunoglobulin G (IgG or gamma 
globulins).

Serum acetaminophen adduct 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 

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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.  
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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12.10.
Appendix 10: 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 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 

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stable liver 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 8.

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12.11.
Appendix 11: 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 8. 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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12.12.
Appendix 12: 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 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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12.13.
Appendix 13: A Sub-study of the Effect of Daprodustat 
Compared to Darbepoetin Alfa on BP in Non-dialysis 
Subjects with Anemia Associated with CKD who are not 
Currently Using ESA Therapy
12.13.1.
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, especially during the period of hemoglobin correction.  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 subjects with CKD 
to establish an association with mortality [Agarwal, 2010]. 
This sub-study is intended to compare daprodustat to darbepoetin alfa on BP as assessed 
by ABPM in ND subjects with anemia associated with CKD.
While multiple mechanisms likely underlie ESA-induced hypertension, reduced urinary 
sodium excretion is hypothesized to be a major mechanism by which ESAs potentiate 
hypertension and non-responsive BP dipping in patients with CKD [Krapf, 2009].  
Patients with CKD may also excrete less urinary sodium since they have lower levels of 
renal nitric oxide (NO).  Patients with CKD produce more reactive oxygen species that 
reduces NO, and NO normally stimulates urinary sodium excretion [Ge, 2006]. As 
daprodustat activates HIF signaling, and one of the downstream targets of HIF is nitric 
oxide synthase, daprodustat may augment urinary sodium excretion, reduce SBP and 
restore a responsive nocturnal BP dipping pattern.  Therefore, in addition to comparing 
the effects of daprodustat to darbepoetin alfa on SBP in this sub-study, an exploratory 
objective is to compare urinary sodium and aldosterone excretion with daprodustat versus 
darbepoetin alfa, which may include excretion over 24 hrs or normalized to urinary 
creatinine.
12.13.2.
Objectives and Endpoints
Objectives
Endpoints
Primary

To compare daprodustat to 
darbepoetin alfa for effect on SBP 
(superiority) by ABPM in ND subjects 
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 darbepoetin alfa independently 

Change in 24 hour average SBP from baseline to end of 
sub-study1 within each treatment group

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Objectives
Endpoints
on SBP, DBP and mean arterial 
blood pressure (MAP) by ABPM in 
the ABPM ITT population 

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 darbepoetin alfa 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 darbepoetin alfa 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

To compare daprodustat to 
darbepoetin alfa 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:

dippers (normal) when the reduction in the average SBP 
during the sleeping period was >10% to 20% of mean 
SBP during waking hours,

extreme dippers when this reduction was >20%,

non-dippers when the reduction was <10%, and

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 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

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Objectives
Endpoints

To compare the effect of treatment 
with daprodustat to darbepoetin alfa 
on heart rate by ABPM in the ABPM 
ITT population

Change from baseline to end of sub-study1in 24 hour 
average heart rate between treatment groups as 
measured by ABPM relative to time since administration 
of medication
Exploratory

To compare urinary sodium 
excretion with daprodustat to 
darbepoetin alfa in the ABPM ITT 
population

Difference between treatment groups in urinary sodium 
excretion from baseline to end of sub-study1

To compare the effect of treatment 
with daprodustat versus darbepoetin 
alfa on urinary aldosterone in the 
ABPM ITT population

Difference between treatment groups in urinary 
aldosterone excretion from baseline to end of sub-
study1
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.
12.13.3.
Study Design
This is a multicenter sub-study of the main ASCEND-ND 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: 
recruitment in the ABPM sub-study is closed in Amendment 4.]
12.13.3.1. ABPM Quality Control Criteria
Subjects will need to wear the ABPM device for two 24-hour sessions during the study: 
at Week -4 or at any time up until 1 week prior to randomization (baseline ABPM) and 
then at Week 16.  The ABPM device will be placed after the 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 12.13.3.3).
12.13.3.2. 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.

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2. Use of the same antihypertensive class treatment, including equivalent dose and 
category, (including diuretics) 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 clinic values obtained at Week -8 and 
Week -4 using the methodology described in the SRM.
4. Not using ESA’s as defined in Section 5.1.
5. Willing and able to wear ABPM device for 24 hours on two separate sessions and to 
collect their urine during these same two separate 24 hour sessions.
6. Valid ABPM at baseline [randomization (Day 1) only].
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. Evidence of atrial fibrillation or atrial flutter at the time of baseline ABPM 
assessment (see Section 12.13.3.3).
2. Subjects who are at high risk for loss to follow-up (e.g., subjects who may require 
frequent hospitalizations).
3. Oscillometer/sphygmomanometer cuff cannot accommodate their upper arm 
circumference.
4. BP cannot be measured in the arm opposite of current vascular access.
12.13.3.3. 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 and the collection of a 24 hour urine sample will be initiated at 
the Week-4 visit but may be performed at a subsequent clinic visit provided it occurs at 
least 1 week prior to randomization.  
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.

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The ABPM device is attached by site personnel and will be removed by site personnel 
after 24 hours of wear (see SRM for guidance on attachment of ABPM device) when the 
subject returns the next day.
The subject will also collect their urine over 24 hours in a urine collection jug that will be 
issued at the visit, the subject will return their 24 hour urine sample the next day.  This 
urine sample will be assessed for sodium, aldosterone and creatinine.  It is recommended 
that the subject maintains their prescribed dietary intake of sodium during urine 
collection (see SRM for guidance on collection of urine).
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. 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.
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, after all main study assessments have been completed, the ABPM device 
will be placed on the subject’s arm by site personnel and the subject will wear the device 
for 24 hours until it is removed by site personnel the next day.  The time of 
administration of study medication, before and while wearing the ABPM device, will be 
recorded.  The subject will also be issued a urine collection jug during this clinic visit in 
which they will collect their urine over 24 hours and return it the next day when the 
ABPM device is removed (for subjects transitioning to dialysis, 24 hour urine collection 
to be done as able).  It is recommended that the subject maintains their prescribed dietary 
intake of sodium during urine collection.
If the ABPM fails the QC criteria (same as baseline), up to two additional attempts may 
be made.  No further attempts are allowed.  The subject will continue study visits in the 
main study as scheduled.

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12.13.3.4. 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 and 
24 hour urine collection assessments unless consent to participate in the ABPM sub-study 
is withdrawn (see also Section 5.5).
12.13.3.5. Antihypertensive Medication Changes
It is preferred that no changes are made to antihypertensive medications while the subject 
is part of the sub-study. 
If changes in 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 
change.
12.13.3.6. 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.
12.13.4.
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 darbepoetin alfa), 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).  Given the planned 
sample size, 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 interim analysis is planned.
12.13.5.
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 

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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 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.

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Changes from baseline in 24 hour urine sodium excretion and 24-hour urine aldosterone 
excretion at end of sub-study will be analyzed in a similar manner to the primary ABPM 
endpoint, except that the statistical model for analysis will be an ANCOVA with terms 
for treatment and baseline 24 hour urine parameter. 
Additional statistical considerations will be addressed in the RAP.
References
Agarwal RJ. 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 Ame Coll Cardiol. 2014; 64:1071-1078.
Ge Y, Bagnall A, Stricklett PK, et al. Collecting duct-specific knockout of the endothelin 
B receptor causes hypertension and sodium retention. Am J Physiol Renal Physiol. 2006; 
291: F1274–F1280.
Krapf R, Hulter HN. Arterial Hypertension Induced by Erythropoietin and 
Erythropoiesis-Stimulating Agents (ESA). Clin J Am Soc Nephrolo 2009: 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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12.14.
Appendix 14: A Sub-study to Collect PK Samples in Non-
dialysis Subjects with Anemia Associated with CKD
12.14.1.
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.
12.14.2.
Objectives and Endpoints
Objectives
Endpoints
Primary

To summarize the PK parameters of 
daprodustat and three major 
metabolites in ND 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.

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12.14.3.
Study Design
This is a multicenter sub-study of daprodustat study 200808 (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.  
12.14.4.
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.

Subjects must not be transitioning or already transitioned to dialysis.
12.14.5.
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, 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.
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.  

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12.14.6.
Sample Size
It is estimated that 150 sub-study subjects are required to have approximately 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 
enrolled.  See Section 9.2.3 for more information about sample size adjustments.  
Approximately 30% (n50) of subjects in this sub-study would be expected to meet the 
combined safety endpoint (and n100 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), 50 subjects would be sufficient to have 
approximately 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.
12.14.7.
PK/Pharmacodynamic 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 12.14.2), 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.  In the event that sub-study 
recruitment does not make its pre-specified target, a limited number of analyses and data 
summaries may be produced depending on the number of subjects with data.  Further 
details will be provided in the RAP of the main study.

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12.15.
Appendix 15: Country Specific Requirements
12.15.1.
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 (CRA) 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 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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12.15.2.
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 200808. 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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12.16.
Appendix 16: Protocol Changes
12.16.1.
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, Poland, Portugal, Romania, Spain, Sweden and the United 
Kingdom
12.16.1.1. 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 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.
12.16.1.2. 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 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 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 fall within the Hgb target range (10 to 
11 g/dL).

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Section 5.1 Inclusion Criteria; criteria number 4
4. HemoCue Hgb (range inclusive): Hgb defined by ESA use:  
Group 1
(not using ESAs)
Group 2 
(ESA users)
Week -8
Hgb 8 to 10 g/dL1
(5 to 6.2 mmol/L)
Hgb 8 to12 g/dL (5 to 7.5 mmol/L) under conditions below:
Hgb 8 to 11 g/dL (5 to 6.8 mmol/L):  continue on ESA  
Hgb >11 to 12 g/dL (>6.8 to 7.5 mmol/L): required to decrease 
(not hold) ESA dose, aiming to achieve  Hgb 11 g/dL by Day 1
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 darbepoetin alfa 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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12.16.2.
Changes Resulting from Protocol Amendment 2
This is an amendment to the original protocol dated 2016-JUN-09.
This amendment applies to all countries
12.16.2.1. 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 deleted. 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, transfusions; new timepoint for 
weight at Day 1; 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 24hr ABPM assessments, for 
recording the times the subject awakens and goes to sleep during this 24 hour ABPM 
period, and for the end of the 24hr urine collection 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 addition of  kidney transplant added to prompt completion of page 
in eCRF.

Time and Events Table 13 for ‘Subjects Transitioning to Dialysis’ modified. Main 
changes include new timepoint at Week 2 for iron therapy; new timepoint at Week 
52 for Kt/Vurea assessment; and transfusions and kidney transplant added to prompt 
completion of page in eCRF.

For the negatively adjudicated events in 200808, 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.

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12.16.2.2. 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 4.3 Design Rationale; paragraph 1; sentence number 3. Text deleted as 
requirement to reduce ESA dose if Week -8 Hgb is >11 g/dL removed.
This study includes 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 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 fall within the Hgb target range (10 to 
11 g/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 
supplement(s) (if applicable), product labels for darbepoetin alfa and other pertinent 
documents (e.g., Study Reference Manual (SRM), informed consent).

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Section 5.1 Inclusion Criteria; criteria number 4. Text deleted as requirement to reduce 
ESA dose if Week -8 Hgb is >11 g/dL removed.
4. HemoCue Hgb (range inclusive): Hgb defined by ESA use:  
Group 1
(not using ESAs)
Group 2 
(ESA users)
Week -8
Hgb 8 to 10 g/dL1
(5 to 6.2 mmol/L)
Hgb 8 to12 g/dL (5 to 7.5 mmol/L) under conditions below:
Hgb 8 to 11 g/dL (5 to 6.8 mmol/L):  continue on ESA  
Hgb >11 to 12 g/dL (>6.8 to 7.5 mmol/L): required to decrease 
(not hold) ESA dose, aiming to achieve  Hgb 11 g/dL by Day 1
Section 5.1 Inclusion Criteria; criteria number 6; 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 15 (see Section 12.5.1, Item 3 for details).
Section 5.1 Inclusion Criteria; criteria number 7. New exclusion criteria relating to 
country-specific amendment for France.
      7  Other study eligibility criteria considerations: The country-specific
      requirements for France ONLY for inclusion in this study are
      provided in Appendix 15 (see Section 12.15.1, Item 1 for details).
Section 5.2 Exclusion Criteria; criteria number 19. New text added relating to the Czech 
Republic
19   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 12.15.2 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 6.3.2 Darbepoetin Alfa Dosing Information, Darbepoetin Alfa Starting Dose 
table. Typos corrected.
Baseline (Day 1)
Hgb (g/dL)
Darbepoetin Alfa Starting Dose
How Delivered
8 to <9
If <78 kg starting dose 40 µg 
If 78-112 kg starting dose 60 µg 
If >112 starting dose 80 µg
40 µg every 4 weeks
60 µg every 4 weeks 
80 µg every 4 weeks
9 to 10
If <78 kg starting dose 30 µg   
If 78-112 kg starting dose 40 µg   
If >112 starting dose 60 µg 
30 µg every 4 weeks
40 µg every 4 weeks 
60 µg every 4 weeks
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).

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Section 6.13 Subjects Transitioning to Dialysis; new bullet point; bullet point 3.

Study visit can be on a dialysis or non-dialysis day. 
o
However, for subjects on 3x/week HD, the designated study visit must not
occur on or before the first dialysis session of the week.
Section 6.13 Subjects Transitioning to Dialysis; bullet point 4. Sub-bullet 2. Text updated
o
For those transitioning to hemodialysis where the investigator is not affiliated 
with the dialysis center, darbepoetin alfa may continue to be administered SC., 
and laboratory assessments and other procedures may be performed on a non-
dialysis day.

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Section 7.1 Time and Events Table; Table 7 Schedule of Assessments Year 1 to End of Study; new timepoint for weight; Day 1 in addition 
to Week -8. Weight moved from the ‘History: medical, hospitalization, transfusion demography, height’ assessment line to ‘Check/confirm 
entry criteria’ assessment line to accommodate the additional timepoint.
Protocol activity (visits ±1 week)
(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
Check/confirm entry criteria, weight
X
X
History: medical, hospitalization, transfusion
demography, height, weight
X
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)
(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; 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

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Hospitalization 2, transition to dialysis2,7, kidney 
transplant2
X
X
X
X
X
Protocol activity (visits ±1 week)
(Note: All visit timings are relative 
to Day 1)
Year 2
Year 3
Year 4
Unscheduled10 End of 
Study15
Follow-up
(4-6 weeks after
stopping 
randomized 
treatment)
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
Hospitalization2, transition to 
dialysis 2,7, kidney transplant2
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.

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Section 7.1 Time and Events Table; Table 8 Schedule of Assessments for Patient Reported Outcomes, Genetics and Sub-studies; 
superscript removed from Work Productivity and Activity Impairment Questionnaire (WPAI-ANS-CPV) line
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 - 13
Day 
1
Week
4
Week
8 & 12
Week
16, 20 & 
24
Week
28
Week 28 
(Next day 
visit)
Week
52
Week 100, 
148, 208
End of 
Study
Work Productivity and Activity 
Impairment Questionnaire  (WPAI-
ANS-CPV)4
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; reference to footnote 5 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 - 13
Day 
1
Week
4
Week
8 & 12
Week
16, 20 & 
24
Week
28
Week 28 
(Next 
day visit)
Week
52
Week 100, 
148, 208
End of 
Study
Symptoms of aCKD questionnaire5
X
X
X
X
X
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
Work Productivity and Activity 
Impairment Questionnaire  (WPAI-
ANS-CPV)5
X
X
X
X
X
X

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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.
Section 7.1 Time and Events Table; Table 8 Schedule of Assessments for Patient Reported Outcomes, Genetics and Sub-studies; ABPM 
sub-study assessments; X removed from Week 28 informed consent line; 24hr ABPM end, record awake and sleep times, and 24 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 - 13
Day 
1
Week
4
Week
8 & 12
Week
16, 20 & 
24
Week
28
Week 28 
(Next day 
visit)
Week
52
Week 100, 
148, 208
End of 
Study
ABPM sub-study (Appendix 13):
                                     Informed 
Consent 
X
X
 Home BP monitoring(twice daily for
                PRIOR 4 consecutive days)
X
X
X
X
X
24 hour ABPM start 
X
X
24 hour ABPM end
X
X
Record awake and sleep times
X
X
     24 hour urine collection 
start(sodium,
                    aldosterone and 
creatinine)
X
X
                 24 hour urine collection 
end
X
X

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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 2, 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 , transition to dialysis1, 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 , transition to 
dialysis1, 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 10 added.
Protocol Activity
(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
CKD-AQ, 5, 10
X
PGI-S, PGI-C5, 10
X
SF-365, 10
X
EQ-5D-5L& EQ-VAS5, 6, 10
X
WPAI-ANS-CPV4, 5, 10
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 10.
10  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 (Section7.4.2), 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 7.4.8 Blood Pressure and Heart Rate; bullet point 3; new bullet point.

For subjects transitioning to dialysis, SBP, DBP and HR will be measured pre 
and post-dialysis, whenever possible (e.g., in-center HD). Otherwise these 
assessments will be done between dialysis sessions.

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Section 7.4.9 Electrocardiograms (ECG); new final paragraph.
For subjects transitioning to dialysis, ECGs will be performed before measurement 
of SBP, DBP, HR and before collection of blood samples for laboratory testing, 
where applicable (e.g., would not apply if ECG is performed post-HD).
Section 7.4.10.Ultrasound, paragraph 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 7.4.11 Clinical Laboratory Assessments; Table 10; other laboratory assessments. 
Foot numbering corrected.
Laboratory 
Assessments
Parameters
Other 
laboratory 
tests
Urine/serum hCG 
pregnancy test2,4,3
FSH 5 FSH 4
hsCRP
Urine albumin/
creatinine ratio 
Estradiol 5 Estradiol 4
iPTH
HemoCue Hgb
HbA1c 6 HbA1c 5
Stored sample (blood, 
urine)
24 hour urine collection 
(sodium, aldosterone 
and creatinine)6
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 15 (see Section 12.5.1, 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 

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including events of vascular access thrombosis, symptomatic deep vein thrombosis, 
symptomatic pulmonary embolism, CV mortality, hospitalization for HF, and 
components of the progression of CKD endpoint (Section 7.4.1).
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 
CNIL
Commission Nationale de I'Informatique et des 
Libertés
CRA
Clinical Research Assistant 
CTR
Clinical Trials Register
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 darbepoetin alfa on additional CV safety endpoints’; endpoint 
bullet 3; death changed to mortality.

To compare daprodustat to darbepoetin 
alfa 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 darbepoetin alfa on Hgb variability’; 
endpoint bullet 4.

To further compare daprodustat and 
darbepoetin alfa on Hgb variability

Number (%) of subjects with a Hgb<7.5 g/dL

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Section 12.2 Appendix 2: Secondary and Exploratory Objectives/ Endpoints; new 
exploratory objective added.

To compare the effect of daprodustat 
to darbepoetin alfa 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 12.15.2 for the country-specific requirements for the Czech 
Republic ONLY relating to acceptable contraceptive methods during participation 
in this study. 
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 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.

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Appendix 7 Time and Events Table for Subjects Transitioning to Dialysis; Table 13 Schedule of Assessments Year 1 to the End of the 
Study for Subjects Transitioning to Dialysis. (a) Day 1 column removed; (b) iron therapy, transfusions assessment line new timepoint at 
Week 2; (c) Kt/Vurea assessment line, new timepoint at Week 52 and footnote for Kt/Vurea  (footnote 14) added;(d) hospitalization line; 
kidney transplant added; (e) removal of ultrasound assessment line.
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
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
Unscheduled9
IRT system call17
X
X
X
X
X
X
Subject reminder, inform site staff of changes in health1
X
X
Weight (pre- and post-dialysis for in-center HD subjects, 
between treatments  for HHD and PD subjects) and EDW
X
X
X
X
X
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 (triplicate)
X
X
X
X (triplicate)
X
Kt/Vurea 14
X
X
X
ECG 2
X
X
Ultrasound of kidneys and adrenal glands 
Randomized treatment dispensing
X
X8, 10
X
X
X
X8,10
Randomized treatment  compliance
X (placebo)
X10
X
X
X
X10
Iron therapy,transfusions3
X
X
X
X
X
X
Rescue medication3 ,4 
X
X
X
X
FRP only:  Serum pregnancy test 5
X
X
X
HemoCue Hgb
X
X
X
X
X
X
Hematology6  
X
X
Hgb only 
X
X
Clinical chemistry6
X
X
X
X
Ferritin, total iron, UIBC 6
X
X
X
Hepcidin  
X
X
X
HbA1c7, lipids (non-fasting) 
X
X
hsCRP, iPTH
X
Wk 28
X
Storage biomarkers 
X
Wk 28
X
Hospitalization 3, kidney transplantation3
X
X
X
X
X

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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
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
Unscheduled9
Non-serious AEs, SAEs, AEs of special interest, MACE 
X
X
X
X
X
X
Review concomitant medications
X
X
X
X
X
X
Appendix 7 Time and Events Table for Subjects Transitioning to Dialysis; Table 13 Schedule of Assessments Year 1 to the End of the 
Study for Subjects Transitioning to Dialysis;
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
Appendix 7 Time and Events Table for Subjects Transitioning to Dialysis; Table 13 Schedule of Assessments Year 1 to the End of the 
Study for Subjects Transitioning to Dialysis; footnote13.
13  Treatment will be dispensed every 4 1 weeks. IRT call will be required every 4 weeks
Appendix 7 Time and Events Table for Subjects Transitioning to Dialysis; Table 13 Schedule of Assessments Year 1 to the End of the 
Study for Subjects Transitioning to Dialysis; footnote for Kt/Vurea   assessment (footnote 14) added
14  A historical Kt/Vurea value measurement within the last 24 12 weeks can be used.  If a Kt/Vurea measurement is not 
available, then a urea reduction ratio (URR) measurement is acceptable.

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Section 12.12, Appendix 12 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
-
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 13; Section 12.13.2 objectives and endpoints; secondary objectives; typo 4 
hour average SBP should read 24 hour average SBP.

To compare daprodustat to 
darbepoetin alfa on BP
parameters in the ABPM per-
protocol population

Change in:

24 hour average SBP

24 hour average DBP

24 hour average mean arterial pressure
from Baseline to Week 28 within each 
treatment group

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Appendix 13; Section 12.13.3.3 Study Assessments; Week 28 Study Visit; sentence 2. 
Wording change for clarity.
The time of administration of study medication, before and while on wearing the ABPM 
device, will be recorded
Appendix 13; Section 12.13.3.3 Study Assessments; Week 28 Study Visit; sentence 3.
The subject will also be issued a urine collection jug during this clinic visit in which they 
will collect their urine over 24 hours and return it the next day when the ABPM device is 
removed (for subjects transitioning to dialysis, 24 hour urine collection to be done as
able).  
Section 12.15, Appendix 15 Country Specific Requirements. Text deleted as country 
specific requirements added.
No county specific requirements exist
Appendix 15 Country Specific Requirements; new Section 12.15.1  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: 

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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 IB), 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 (CRA) 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 

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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.
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.
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. 

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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.
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 200808.. 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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12.16.3.
Changes Resulting from Protocol Amendment 3
This is an amendment to the protocol amendment dated 2016-OCT-12.
This amendment applies to all countries.
12.16.3.1. 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.  

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.

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’ modified.  Main changes include addition of Informed Consent activity; 
revised footnotes to allow for more latitude for timing to do Day 1 ECG and extended 
time to do ultrasound and/or additional testing; more clarity around randomized 
treatment dispensing and compliance; removed capture of rescue medications from 
unscheduled visit (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 
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 as to how weight, blood pressure, and laboratory assessments are to 
be done for those transitioning to dialysis.  

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.

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
Changed timepoint for blinded data cut need for psychometric validation of the 
Chronic Kidney Disease-Anemia Questionnaire.

Revised statistical section to change from two-sided testing at the 5% level to one-
sided testing at the 2.5% level; to clarify progression of CKD endpoint population and 
analysis model and for secondary endpoints, to change significance levels to p-values;
to correct the timepoint for various Patient Reported Outcomes; to add a more 
complete description of the adjustments to statistical model; 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.

Modified Time and Events Table 13 ‘Schedule of Assessments Year 1 to the End of 
Study for Subjects Transitioning to Dialysis’.  Main changes include footnotes to 
remove Kt/V and URR measurement for daily HHD; 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 storage biomarkers to be collected except if not permitted by 
IRB/EC or refused by subject; and addition of Argentina only pregnancy 
requirement..

Changes to ABPM sub-study to add atrial fibrillation/flutter screening, remove home 
BP monitoring, 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.
12.16.3.2. List of Specific Changes
Cover page.  Added back protocol “Short Title”.
Short Title:
Anemia Studies in CKD: Erythropoiesis via a Novel PHI 
Daprodustat-Non-Dialysis (ASCEND-ND)
Revision Chronology; table.  Corrected date for republished amendment and document 
number for Amendment No. 2.
2015N230102_01
2016-JUN-109
Republishing

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2015N230102_032015N226659_03
2016-OCT-12
Amendment No. 2
Section 1. Protocol Synopsis for Study 200808; Overall Design, 1st bullet AND Section 
12.1. Appendix 1: abbreviations.  Corrected ESA abbreviation. Revised analysis 
provided.

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 
erythropoietinerythropoiesis-stimulating agents (ESA1) therapy, if present, continues 
during the screening and run-in periods.
ESA
ErthropoetinErythropoiesis-stimulating agent
Section 1. Protocol Synopsis for Study 200808; 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 4.1. Overall Design; 7th bullet. Clarified how stratification factors are considered 
prognostically important.

Subjects will be stratified by region (see Appendix 3), by whether they are currently 
using an ESA, and by participation in the ABPM sub-study. Region and ESA use at 
study entry 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 #4. Added retest for Hgb values within the 
variability threshold for testing to determine Week -8 eligibility.  
Group 1
(not using ESAs)
Group 2 
(ESA users)
Week -
8
Hgb 8 to 10 g/dL1 (5 to 6.2 mmol/L)
If Hgb is 10.1 to 10.4 g/dL2 (6.3-6.5
mmol/L), up to two retests are allowed;
the retest value must be between 8 to 10 
g/dL (5 to 6.2 mmol/L).
Hgb 8 to12 g/dL (5 to 7.45 mmol/L).
If Hgb is 12.1 to 12.4 g/dLe (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 10 g/dL 
(5 to 6.2 mmol/L)
Hgb 8 to 11 g/dL (5 to 6.8 mmol/L) and
receiving at least the minimum ESA dose23
1.
Conversion from g/dL to g/L is 1:10, e.g., Hgb of 8 to 10 g/dL is equivalent to 80-100 g/L. 
2.
The first retest will use the original Week -8 blood sample. If this value is >10 g/dL (Group 1) or >12 
g/dL (Group 2), 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.
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 #6.  Clarified study visit this is confirmed.
6. 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 #2.  Added “or living-unrelated.”
2. Kidney transplant: Planned living-related or living-unrelated kidney transplant 
within 52 weeks after study start (Day 1).
Section 5.2. Exclusion Criteria; exclusion #4. Added retest for TSAT values within the 
variability threshold for testing to determine Week -8 eligibility.  
4. 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.
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 #12.  Clarified situation where exclusion does 
not apply.
12. 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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Section 5.2. Exclusion Criteria; exclusion #17. Broadened exclusion to include 
participation in a study with an investigational agent or device.
17. 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; 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 
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

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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; Table 5. Clarified “every week” frequency to 
be “once 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.  
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.

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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. 

Subjects who cannot return to the site for a period >5 weeks during the first 52 
weeks and >13 weeks thereafter.  
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 will 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.
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; paragraph 2 and Table 6. Minor clarification for visits 
where rescue evaluation can be triggered.

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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; footnote #2.  Made a minor change in footnote #2.
2.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.
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; 3rdparagraph.  Inserted new text to state 
the revised visit window for the Week 2 and 4 visits and made minor changes to visit 
structure a separate paragraph as it applies to all study visits.
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 (i.e., 7-9 weeks).
In exceptional circumstances, minor changes to visit structure may be permitted after 
consultation with the PPD Medical Monitor.

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Section 7.1. Time and Events Table; 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)
(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 (#20).
Protocol activity (visits ±1 week)
(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)
X20
20. Informed consent will be obtained prior to any study procedures.
Section 7.1. Time and Events Table; Table 7 Schedule of Assessments Year 1 to Week 52.  Clarified name of IRT system transaction.
Protocol activity (visits ±1 week)
(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 calltransaction
X
X
X
X
X
X
X
X
Protocol activity (visits ±1 week)
(Note: All visit timings are relative 
to Day 1)
Year 2
Year 3
Year 4
Unscheduled10,12 End of 
Study15
Follow-up
(4-6 weeks after
stopping 
randomized 
treatment)
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 calltransaction
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X

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Protocol Activity
(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 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. Time and Events Table; Table 7 Schedule of Assessments Year 1 to Week 52.  Added new footnote #17 to Day 1 timepoint to 
provide flexibility around ECG timing.
Protocol activity (visits ±1 week)
(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
X17
X
17. Day 1 ECG may be performed as early as the Week -4 visit through the Day 1 visit; if performed on Day 1, it must be over-read prior to randomization.
Section 7.1. Time and Events Table; 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.
Protocol activity (visits ±1 week)
(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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Placebo run-in or randomized treatment dispensing (start 
administration on day of dispensing)
X(placebo)
X
X9, 11
X
X
X
X 9, 11
Protocol activity (visits ±1 week)
(Note: All visit timings are relative 
to Day 1)
Year 2
Year 3
Year 4
Unscheduled10,12 End of 
Study15
Follow-up
(4-6 weeks after
stopping 
randomized 
treatment)
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)
X
X
X
X
X
X
X
X
X
X
X
X
X
X9,11,12
Randomized treatment compliance
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 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.
Section 7.1. Time and Events Table; 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, except Weeks 2 and 4 
which are ±3 days)
(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 Intervention 3 ,4 
X
X
X
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)
(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 
Intervention 3,4 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Protocol Activity
(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. Time and Events Table; Table 7 Schedule of Assessments Year 1 to the End of the Study.  Added pregnancy requirement (new 
footnote #18) for Argentina only as required by local law.
Protocol activity (visits ±1 week)
(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: urine pregnancy test 4,18
X
X
X
X
Protocol activity (visits ±1 week)
(Note: All visit timings are relative 
to Day 1)
Year 2
Year 3
Year 4
Unscheduled10 End of 
Study15
Follow-up
(4-6 weeks after
stopping 
randomized 
treatment)
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: urine pregnancy test4,18
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
18. 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 #19 to permit omission of 
storage biomarker collection under certain circumstances.

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Protocol activity (visits ±1 week)
(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 biomarkers (blood, urine)19
X
Wk 28
X
19.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. Time and Events Table; 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)
(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
Non-serious AEs, SAEs, AEs of special interest, MACE
clinical events 
X8
X8
X
X
X
X
X
X
Protocol activity (visits ±1 week)
(Note: All visit timings are relative 
to Day 1)
Year 2
Year 3
Year 4
Unscheduled10 End of 
Study15
Follow-up
(4-6 weeks after
stopping 
randomized 
treatment)
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

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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 
Study 9
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 208
Post-
Week 52 
through 
End of 
Study
End of 
Study
Week -8 Week -4
Day -
211
Day -141
Week -4 
(Next day 
visit) Day -
13
Day 
1
Week
4
Week
8 & 12
Week
16, 20 
& 24
Week 16 
(Next day 
visit) Week
28
Week 
28
Week
32, 36, 
40, 44, 
48Week 
28 (Next 
day visit) 
Week
52
Week 
100, 148, 
208
Healthcare resource utilization
(subject reported)
X
X
X
X
X
X
X
X (& 
Follow 
up)
ABPM sub-study (Appendix 13):
                            Informed Consent 
X4
X4
Home BP monitoring(twice daily for 
PRIOR 4 consecutive days)
X
X
X
X
Atrial fibrillation/flutter screening 
X5
                    24 hour ABPM start 
X6
X
X (Week 
16)
                    24 hour ABPM end
X6
X
X
X
Record awake and sleep times
X7
X7
X
      24 hour urine collection start 
(sodium, aldosterone & creatinine)
X6
X
X (Week 
16)10
X
            24 hour urine collection end
X6
X10
X
PK sub-study (Appendix 14):  
                            Informed Consent 
X8
X8
X8
X8
X8
X8
X8
                           PK assessment
X9
X9
X
X9
X9
X9
1. Subjects who are unable to or require assistance to read must not complete the questionnaires.

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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 12.13.3.3)
6. Baseline ABPM and 24 hour urine will be performed at Week -4 or at an unscheduled visit up until 1 week prior to randomization (Day 1). 
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). 
10. For subjects transitioning to dialysis, 24 hour urine collection to be done as able.
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 (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 12):                       24 hour 
ABPM
X (Week 16)
Record awake and sleep times
X (Week 16)2
24 hour urine collection (sodium, aldosterone & creatinine
X (Week 16)11
2.Subject will record sleep and wake time during the ABPM session.
11. For subjects transitioning to dialysis, 24 hour urine collection to be done as able.
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.

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Protocol Activity
(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; new text. Added clarity for subjects that transition to 
dialysis. 
For subjects that transition to dialysis, weight will be measured,

For in-center HD subjects: pre and post-dialysis, when possible, or at study 
visits between dialysis sessions 

For HHD subjects: at study visits between dialysis sessions 

For PD subjects:  at study visits, as per standard of care 
Section 7.4.8. Blood Pressure and Heart Rate; 2nd and 3rd bullets. Added clarity around 
the ordering of the various assessments and for subjects transitioning to dialysis.

Measurements will be taken with subjects in a seated position after at least a 5-
minute rest period, and will be before collection of blood samples for 
laboratory testing, where applicable.

For subjects transitioning to dialysis, SBP, DBP and HR will be measured pre and 
post-dialysis, whenever possible (e.g., in-center HD). Otherwise these assessments 
will be done between dialysis sessions.,
o
For in-center HD subjects: pre and post-dialysis, when possible, or at 
study visits between dialysis sessions 
o
For HHD subjects: at study visits between dialysis sessions 
o
For PD subjects:  at study visits, as per standard of care 
Section 7.4.9. Electrocardiogram (ECG); new text 2nd and 4th paragraphs.  Additional 
clarity provided about Day 1 ECG requirements.

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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.
Section 7.4.11. Clinical Laboratory Assessments; first 3 paragraphs. Deleted repeated 
text (1st paragraph); added text for subjects transitioning to dialysis (2nd paragraph), and 
corrected spelling of center (3rd paragraph).
All study-required laboratory assessments will be performed by a central laboratory with 
the exception of HemoCue Hgb and urine pregnancy tests which will be performed at the 
clinical site. The results of each HemoCue Hgb must be entered into the subject’s eCRF.
Table 10, must be conducted in accordance with the Laboratory Manual, and Protocol 
Time and Events Schedule (Section 7.1). For subjects transitioning to dialysis (Table 
13), 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 and healthcare time.
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 7.7.1. Chronic Kidney Disease – - Anemia Questionnaire (CKD-AQ); last 
sentence. For consistency used “seven” in set of “7”.
It will measure both the frequency and/or severity in anemia of CKD concepts such as 
Weakness, Energy, Tiredness, Shortness of Breath, Exertion, Chest Pain, Memory, 
Concentration, Standing, Sleep and Distress over the past 7seven days.  

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Section 7.7.4. 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.
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 
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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.
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 
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 

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principal secondary endpoints.  The hypotheses to be tested for these endpoints are as 
follows: 

Null: daprodustat is equal not superior to 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 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 less than 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.
Section 9.4.2.1. Principal Secondary Analyses; last two paragraphs.  Clarified 
progression of CKD endpoint population and analysis model.
The progression of CKD endpoint is as follows:

Progression of CKD [40% decline in eGFR from baseline (confirmed 4-13 weeks 
later) OR ESRD]
ESRD definition: a) initiating chronic dialysis for ≥90 days* or b) not initiating chronic dialysis 
when dialysis is indicated (adjudicated) or c) receipt of a kidney transplant. *adjudicate only if 
the duration of dialysis is <90 days.
The analysis of progression of CKDThis endpoint will be restricted to the subset of 
subjects with eGFR≥15 ml/min/1.73m2 at baseline. Since all-cause mortality is not 
included as a component of the composite endpoint, Fine and Gray’s subdistribution 
hazards analysis model will be used to account for this competing risk and statistical 
approach will calculate the cumulative incidence function accounting for this competing 
risk of death will be provided.
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 9.4.2.2. Analysis of Patient Reported Outcomes; 1st paragraph.  Corrected timing 
of data cut from week 52 to Week 28.
A blinded cut of the data will be taken when approximately 250 subjects complete the 
week 52Week 28 visit for the purpose of psychometric validation of the CKD-AQ 
symptoms questionnaire.  
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.

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Section 9.4.3. Figure 2; updated figure to align with two-sided 95% CIs 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-values calculated.
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.  

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Section 9.4.6. Psychometric Analyses of the Chronic Kidney Disease- Anemia 
Questionnaire (CKD-AQ).  Corrected timing of data cut from Week 52 to Week 28.
In order to establish and evaluate the measurement properties of the CKD-QA, an interim 
cut of blinded observations of at least 250 subjects who completed the week 52 Week 28
visit will be taken.  The data cut will require the following variables through week 52
Week 28: PGI-C, PGI-S, Hgb, SF-36, WPAI-ANS-CPV, demographic and baseline 
clinical characteristics.   
Section 11. References. 4th reference; corrected year of publication of Hommel reference.
Hommel G. A stagewise rejective multiple test procedure based on a modified Bonferroni 
test. Biometrika 19988; 75:383-386
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 (tested for superiority1, no multiplicity 
adjustment)
To compare daprodustat and darbepoetin 
alfa 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

Individual components of CKD progression2
To compare daprodustat to darbepoetin 
alfa 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 Weeks 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

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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

N (%) of subject who met iron management criteria

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

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
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; for CKD progression only, two components to be 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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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 rodents 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. 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.

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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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 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 

Unblinded monitoring of safety data by an 
IDMC in-stream throughout the study.

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mice and dogs, up to 26 weeks2 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 fall were within the range of PRVP 
differenceschanges 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 sPAP PASP 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 sPAP 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 sPAP 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.  

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Cardiomyopathy
Published data suggest that cardiac effects of HIF stabilization are 
likely a function of the mechanism, extent, and duration of the effects, 
and can range from protective to detrimental depending upon the 
specific model and experimental conditions utilized.
With lifetime exposure to daprodustat in a 2-year rat oral 
carcinogenicity study, an exacerbation of rat spontaneous, 
progressive cardiomyopathy (PCM)(focal myofiber 
degeneration/necrosis with inflammatory infiltrates) was 
observed at doses of 0.8 mg/kg/day and above, although total 
incidence and severity distribution within any daprodustat-
group were within historical control ranges.  This is consistent 
with an equivocal threshold for exacerbation of spontaneous, 
progressive cardiomyopathy at 0.8 mg/kg/day which is also the 
threshold dose for observing increased Hct values in individual 
rats. 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.

Unblinded monitoring of safety data by an 
IDMC in-stream throughout the study.
Proliferative retinopathy, macular edema, choroidal 
neovascularization
Increases in local (ocular) VEGF production with retinal 
neovascularization and macular edema observed in diabetic 
retinopathy and to choroidal leakage, edema and neovascularization 
seen in age-related macular degeneration [Campochiaro, 2006].

Suspected proliferative retinopathy, macular 
edema, choroidal neovascularization or
symptoms consistent with these events 
should be investigated by ophthalmologic 
consultation as clinically warranted.

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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 25mg, 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.

Unblinded monitoring of safety data by an 
IDMC in-stream throughout the study.
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 (pioglitazone) 
showed that there is no PK interaction at these doses of 
daprodustat.

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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Population PK analysis from completed Phase 2 studies suggests 
that co-administration of daprodustat with clopidogrel (a moderate 
CYP2C8 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 
thromboembolismthromboembolic 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 sentence. Corrected method of 
pregnancy testing. 
A female subject is eligible to participate if she is not pregnant (as confirmed by a 
negative serumurine hCG test for females of reproductive potential only), not 
breastfeeding, or at least one of the following conditions applies:
Section 12.5. Appendix 5:  Female Eligibility Criteria; 1st bullet; bolded 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 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.

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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.  
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 transitioning to dialysis:  Visits every 4 weeks for 12 weeks.

For subjects changing dialysis modality from HD to PD:  Visits every 4 weeks for 12 weeks.

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Section 12.7. Appendix 7: Time and Events Table for Subjects Transitioning to Dialysis; Table 13 Schedule of Assessments Year 1 to 
Follow-up visit.  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
Week 2
Full study visit
Week 4, 16, 28, 
40
Abbreviated study visit
Week 8, 12, 20, 24, 32, 36, 44, 48 
Week 52
Unscheduled9
Section 12.7. Appendix 7: Time and Events Table for Subjects Transitioning to Dialysis; Table 13 Schedule of Assessments Year 1 to 
Follow-up visit.  Updated weight and SBP/DBP, HR 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
Week 2
Full study visit
Week 4, 16, 28, 40
Abbreviated study visit
Week 8, 12, 20, 24, 32, 36, 44, 48 
Week 52
Unscheduled98
Weight (pre- and post-dialysis for in-center HD subjects 
(when possible); between treatments for HHD; at study 
visits as per standard of care for and PD subjects) and 
EDW
X
X
X
X
X
SBP/DBP, HR (pre- and post-dialysis for in-center HD 
subjects (whenever possible); between treatments for 
HHD; as per standard of care for andPD subjects) 
(single readings unless otherwise indicated)
X
X
X
X (triplicate)
X

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Year 2
Year 3
Year 4
Unscheduled98,10 End of 
Study14
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 
2081311
Weight (pre- and post-dialysis for in-
center HD subjects (when possible);
between treatments for HHD; at study 
visits as per standard of care for
andPD 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 (when possible);
between treatments for HHD; at study 
visits as per standard of care for
andPD subjects) (single readings unless 
otherwise indicated)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X 
(triplicate)
X
Section 12.7. Appendix 7: Time and Events Table for Subjects Transitioning to Dialysis; Table 13 Schedule of Assessments Year 1 to 
Follow-up visit.  Updated footnotes associated with Unscheduled visits (including new footnote #15), corrected footnotes for IRT system 
call and clarified name of IRT system transaction, randomized treatment dispensing and compliance, made minor edits to footnotes #8,
and #9; added flexibility for administering randomized treatment after the study visit day (new footnote #16).
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
Week 2
Full study visit
Week 4, 16, 28, 40
Abbreviated study visit
Week 8, 12, 20, 24, 32, 36, 44, 48 
Week 52
Unscheduled98
IRT system calltransaction17
X
X
X
X
X
Randomized treatment dispensing (start administration 
on day of dispensing)16
X15,10
X
X
X
X1015
Randomized treatment compliance16
X910
X
X
X
X109

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Year 2
Year 3
Year 4
Unscheduled98,10 End of 
Study14
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 
2081311
IRT system calltransaction17
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Randomized treatment dispensing (start 
administration on day of 
dispensing)16
X
X
X
X
X
X
X
X
X
X
X
X
X
X15 8,10,11
Randomized treatment compliance1617
X
X
X
X
X
X
X
X
X
X
X
X
X
X9 10,11
X
8.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. 
9.Required only if dose is changed or randomized treatment is dispensed (year 2 onwards).
15.If dose does not change, then randomized treatment is returned to subject.
16.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 12.7. Appendix 7: Time and Events Table for Subjects Transitioning to Dialysis; Table 13 Schedule of Assessments Year 1 to 
Follow-up visit.  Updated footnote #14 to remove requirement to measure Kt/Vurea for those receiving daily HHD.
14.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 measurement is acceptable.
Kt/Vurea and urea reduction ratio measurements are not required for daily HHD.
Section 12.7. Appendix 7: Time and Events Table for Subjects Transitioning to Dialysis; Table 13 Schedule of Assessments Year 1 to 
Follow-up visit.  Removed X for unscheduled and Early Termination visits given rescue evaluation is only triggered at scheduled visits.

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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
Week 2
Full study visit
Week 4, 16, 28, 
40
Abbreviated study visit
Week 8, 12, 20, 24, 32, 36, 44, 48 
Week 52
Unscheduled9
Rescue medication3 ,4 
X
X
X
X
Year 2
Year 3
Year 4
Unscheduled9 End of 
Study14
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 
20813
Rescue medication3,4 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Section 12.7. Appendix 7: Time and Events Table for Subjects Transitioning to Dialysis; Table 13 Schedule of Assessments Year 1 to 
Follow-up visit.  Added pregnancy requirement (new footnote #17) for Argentina only as required by local law.
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
Week 2
Full study visit
Week 4, 16, 28, 
40
Abbreviated study visit
Week 8, 12, 20, 24, 32, 36, 44, 48 
Week 52
Unscheduled9
FRP only: serum pregnancy test5,17
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Year 2
Year 3
Year 4
Unscheduled9 End of 
Study14
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 
20813
FRP only: serum pregnancy test5,17
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
17. For Argentina ONLY:  Pregnancy testing will be performed every 4 weeks for FRP as required by local law.

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Section 12.7. Appendix 7: Time and Events Table for Subjects Transitioning to Dialysis; Table 13 Schedule of Assessments Year 1 to 
Follow-up visit.  Minor revision to fix spelling of “transplant”.
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
Week 2
Full study visit
Week 4, 16, 28, 
40
Abbreviated study visit
Week 8, 12, 20, 24, 32, 36, 44, 48 
Week 52
Unscheduled9
Hospitalization 3, kidney transplantation3
X
X
X
X
X
Year 2
Year 3
Year 4
Unscheduled9 End of 
Study14
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 
20813
Hospitalization3, kidney transplantat3
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Section 12.7. Appendix 7: Time and Events Table for Subjects Transitioning to Dialysis; Table 13 Schedule of Assessments Year 1 to 
Week 52.  Added footnote #13 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
Week 2
Full study visit
Week 4, 16, 28, 
40
Abbreviated study visit
Week 8, 12, 20, 24, 32, 36, 44, 48 
Week 52
Unscheduled9
Storage biomarkers13
Wk 28
X
13. Biomarker samples will be stored for future analyses for all subjects, except if not permitted by IRB/EC or refused by subject.

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Section 12.7 Appendix 7: Time and Events Table for Subjects Transitioning to Dialysis; Table 13 Schedule of Assessments Year 1 to 
Follow-up visit.  Changed MACE to clinical events to more accurately represent safety data collected.
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
Week 2
Full study visit
Week 4, 16, 28, 
40
Abbreviated study visit
Week 8, 12, 20, 24, 32, 36, 44, 48 
Week 52
Unscheduled9
Non-serious AEs, SAEs, AEs of special interest, MACE
clinical events
X
X
X
X
X
Year 2
Year 3
Year 4
Unscheduled9
End of 
Study14
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 
20813
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

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Section 12.13. Appendix 13: A Sub-study of the Effect of Daprodustat Compared to 
Darbepoetin Alfa on BP in Non-dialysis Subjects with Anemia Associated with CKD who 
are not Currently Using ESA Therapy; revisions throughout. Changes to ABPM sub-
study to add atrial fibrillation/flutter screening, remove home BP monitoring, 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 darbepoetin alfa on BP as assessed 
by ABPM in ND subjects with anemia associated with CKD.   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.
While multiple mechanisms likely underlie ESA-induced hypertension, reduced urinary 
sodium excretion is hypothesized to be a major mechanism by which ESAs potentiate 
hypertension and non-responsive BP dipping in patients with CKD [Krapf, 2009].  
Patients with CKD may also excrete less urinary sodium since they have lower levels of 
renal nitric oxide (NO).  Patients with CKD produce more reactive oxygen species that 
reduces NO, and NO normally stimulates urinary sodium excretion [Ge, 2006]. As 
daprodustat activates HIF signaling, and one of the downstream targets of HIF is nitric 
oxide synthase, daprodustat may augment urinary sodium excretion, reduce SBP and 
restore a responsive nocturnal BP dipping pattern.  Therefore, in addition to comparing 
the effects of daprodustat to darbepoetin alfa on SBP in this sub-study, an exploratory 
objective is to compare urinary sodium and aldosterone excretion with daprodustat versus 
darbepoetin alfa, which may include excretion over 24 hrs or normalized to urinary 
creatinine.
Objectives and Endpoints
Objectives
Endpoints
Primary

To compare daprodustat to 
darbepoetin alfa for effect on SBP 
(superiority) by ABPM in ND subjects 
in the ABPM ITT population

Change in 24 hour average SBP from baseline to Week 
28 end of sub-study1 between treatment groups
Secondary

To assess the effect of daprodustat 
and darbepoetin alfa independently 
on SBP, DBP and mean arterial 
blood pressure (MAP) by ABPM in 
the ABPM ITT population 

Change in 24 hour average SBP from baseline Week 28
end of sub-study1 within each treatment group

Change in 24 hour average DBP from baseline to Week 
28 end of sub-study1 within each treatment group

Change in 24 hour average MAP from baseline to Week 
28 end of sub-study1 within each treatment group

To compare the effect of daprodustat 
to darbepoetin alfa on DBP and MAP 
by ABPM in the ABPM ITT 
population

Change in 24 hour average DBP from baseline to Week 
28 end of sub-study1 between treatment groups

Change in 24 hour average MAP from baseline to Week 
28 end of sub-study1 between treatment groups

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Objectives
Endpoints

To compare the effect of daprodustat 
to darbepoetin alfa 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 Week 28 end of sub-study1
between treatment groups

To compare daprodustat to 
darbepoetin alfa 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 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

24-hour BP profile as measured by ABPM, with subjects 
categorized according to their sleeping BP behaviors as:

dippers (normal) when the reduction in the average SBP 
during the sleeping period was >10% to 20% of mean 
SBP during waking hours,

extreme dippers when this reduction was >20%,

non-dippers when the reduction was <10%, and

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 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 darbepoetin alfa 

Change in SBP and DBP from baseline to Week 28 
between treatment groups

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Objectives
Endpoints
on change in average home BP 
between treatment groups in the 
ABPM ITT and ABPM per-protocol 
populations

To compare the effect of treatment 
with daprodustat to darbepoetin alfa 
on pulseheart rate by ABPM in the 
ABPM ITT population

Change from baseline to Week 28 end of sub-study1
in 24 hour average pulseheart rate between treatment 
groups as measured by ABPM relative to time since 
administration of medication
Exploratory

To compare urinary sodium 
excretion with daprodustat to 
darbepoetin alfa in the ABPM ITT 
population

Difference between treatment groups in urinary sodium 
excretion from baseline to Week 28 end of sub-study1

To compare the effect of treatment 
with daprodustat versus darbepoetin 
alfa on urinary aldosterone in the 
ABPM ITT population

Difference between treatment groups in urinary 
aldosterone excretion from baseline to Week 28 end of 
sub-study1
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-ND 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.  Home BP monitoring will be done to establish baseline eligibility for 
subject participation and will continue through to Week 28 study visit.
ABPM Quality Control Criteria
Subjects will need to wear the ABPM device for two 24-hour sessions during the study: 
at Week -4 or at any time up until 1 week at Day -14 prior to randomization (baseline 
ABPM) and then at Week 2816.  The ABPM device will be placed after the assessments 
for the main study have been completed.  Subjects will be expected to wear the ABPM 
device twice for 24 hours at each session.  The ABPM device will measure BP and pulse
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 12.13.3.3).
Eligibility Criteria - Screening
Additional Inclusion Criteria

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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 class treatment, including equivalent dose and 
category, (including diuretics) for the 6 weeks prior to the Screening visit, through the 
entire Screening period and at randomization.
3. Average home SBP of ≤170140 mmHg based on the average of clinic values 
obtained at Week -8 and Week -4 as assessed starting Day -21 (prior to ABPM)
using the methodology described in the SRM.
4. Not using ESA’s as defined in Section 5.1.
5. Willing and able to wear ABPM device for 24 hours on two separate sessions and to 
collect their urine during these same two separate 24 hour sessions.
6. Valid ABPM measurements at baseline [randomization (Day 1) only].
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. Current or historyEvidence of atrial fibrillation or atrial flutter at the time of 
baseline ABPM assessment (see Section 12.13.3.3).
2. Subjects who are at high risk for loss to follow-up (e.g., subjects who may require 
frequent hospitalizations).
3. Oscillometer/sphygmomanometer cuff cannot accommodate their upper arm 
circumference.
4. BP cannot be measured in the arm opposite of current vascular access.
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:
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 

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with obtaining twice daily home BP readings which will be automatically transmitted to 
the study center.  Specific directions for measuring home BP are 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.  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 
and the to collection of a 24 hour urine sample (prior to randomization and first dose of 
study medication). will be initiated at the Week-4 visit but may be performed at a 
subsequent clinic visit provided it occurs at least 1 week prior to randomization.  
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 is attached by site personnel and will be removed by site personnel 
after 24 hours of wear (see SRM for guidance on attachment of ABPM device) when the 
subject returns the next day (i.e., Day 13).
The subject will also collect their urine over 24 hours in a urine collection jug that will be 
issued at this clinic visit the visit, and the subject will return with their 24 hour urine 
sample the next day, (i.e., Day 13).  This urine sample will be assessed for sodium, 
aldosterone and creatinine.  It is recommended that the subject maintains their prescribed 
dietary intake of sodium during urine collection (Ssee SRM for guidance on collection of 
urine).
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. 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.
Day 1 (Randomization):
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:

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
The baseline ABPM procedure can be repeated once.

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 ( 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.
Week 2816 Study Visit:
At the end of the main study Hgb stabilization period (i.e., at Week 2816), after all main 
study assessments have been completed, the ABPM device will be placed on the subject’s 
arm by site personnel and the subject will wear the device for 24 hours until it is removed 
by site personnel the next day.  The time of administration of study medication, before 
and while wearing the ABPM device, will be recorded.  The subject will also be issued a 
urine collection jug during this clinic visit in which they will collect their urine over 24 
hours and return it the next day when the ABPM device is removed (for subjects 
transitioning to dialysis, 24 hour urine collection to be done as able).  It is recommended 
that the subject maintains their prescribed dietary intake of sodium during urine 
collection.
If the ABPM fails the QC criteria (same as baseline), up to two additional attempts may 
be made.  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 and 24 hour urine collection assessments unless consent to participate in the 
ABPM sub-study is withdrawn (see also Section 5.5).
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 darbepoetin alfa), 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 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).  

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Given the planned sample size, 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 interim analysis is planned.
Statistical Analysis
The primary sub-study estimand is to compare the treatment effect on change from 
baseline in 24 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 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 
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 the sub-study28 weeks.  
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-studyWeek 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 baseline to end of sub-studyWeek 28. 
The change from baseline 24 hour average DBP, mean arterial pressure and pulseheart 
rate at end of sub-studyWeek 28 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-studyWeek 28 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 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.
Changes from baseline in 24 hour urine sodium excretion and 24-hour urine aldosterone 
excretion at end of sub-studyWeek 28 will be analyzed in a similar manner to the 
primary ABPM endpoint, except that the statistical model for analysis will be an 
ANCOVA with terms for treatment and baseline 24 hour urine parameter. 
Additional statistical considerations will be addressed in the RAP.
Section 12.14.3. 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 60 to 70 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 12.14.4. Appendix 14: A Sub-study to Collect PK Samples in Dialysis Subjects 
with Anemia Associated with CKD; additional inclusion criteria 2nd bullet. Clarified 2nd
inclusion criteria.

Subject must be receiving randomized to receive daprodustat treatment in the 
main study.
Section 12.14.5. Appendix 14: A Sub-study to Collect PK Samples in Non-dialysis 
Subjects with Anemia Associated with CKD; study assessments – 1st paragraph. Added 
additional eligible collection visits to collect PK samples in PK sub-studies.

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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).
Section 12.14.5. Appendix 14: A Sub-study to Collect PK Samples in Non-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 12.14.5. Appendix 14: 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.

2 0 1 5 N 2 3 0 1 0 2 _ 0 9
C O N FI D E N TI A L
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C h a n g e s R e s ulti n g fr o m Pr ot o c ol A m e n d m e nt 4
T his is a n a me n d me nt t o t he pr ot oc ol a me n d me nt date d 2 0 1 9- A U G -1 6.
T his a me n d me nt a p plies t o all c o u ntries .
1 2. 1 6. 4. 1.
S u m m ar y  of C h a n g e s

Wit hi n e ntr y  criteria, ad de d retest val ues f or H g b at Da y 1, a n a d diti o nal retest 
o p p ort u nit y  f or T S A T t o deter mi ne eli gi bilit y  at Wee k - 8, a n d re vise d t he defi niti o n 
of c urre nt u nc o ntr olle d h y perte nsi o n .

A d de d a c o nsi derati o n t o all o w f or c o n d u ct of st u d y  visits o n or bef ore t he first 
dial y sis sessi o n of t he wee k f or s u bjects o n 3 x/ wee k H D.

A d de d h y p ot hetical ris k i nf or mati o n, ne w re q uire d assess me nts (e G F R, ultras o u n d), 
a n d ra n d o mize d treat me nt st o p pi n g criteria f or s u bjects wit h A D P K D.

A d de d ne w A E SI  of w orse ni n g of h y perte nsi o n.

A d de d sec o n dar y  o bjecti ve/e n d p oi nt t o assess re nal pr o gressi o n via c ha n ge i n e G F R.

Re m o ve d “ mea n h o urs” fr o m se veral e n d p oi nts gi ve n t he W P AI  q uesti o n naire bei n g 
use d d oes n ot s u p p ort t he mea n h o urs i m paire d cal c ulati o n.

E dite d Ris k Assess me nt i nf or mati o n t o ali g n wit h versi o n 1 0 of t he I n vesti gat or’s 
Br oc h ure. 

Re vise d Year 2 s u b -b ullet reas o ns t o c orrect a t y p o gra p hical err or a n d i nc o nsiste nc y .

F or s u bjects tra nsiti o ni n g t o dial y sis, clarifie d t he last hist orical Kt/ V urea 
meas ure me nt o btai ne d per sta n dar d of care ca n be use d a n d c orrecte d t he f o ot n ote 
n u m beri n g f or ser u m pre g na nc y testi n g.

State d recr uit me nt i n t he A B P M s u b- st u d y is cl ose d i n A me n d me nt 4.

A d de d a d diti o nal e ntr y  criteria t o P K s u b-st u d y t o e xcl u de su bjects tra nsiti o ni n g or 
alrea d y tra nsiti o ne d t o dial y sis at t he ti me t he y c o nsi der e nr oll me nt i n t he P K s u b-
st u d y.

A d de d w or di n g t o P K s u b -st u d y t o i n dicate if t he s u b-st u d y recr uit me nt d oes n ot 
ma ke its pre -s pecifie d tar get, de pe n di n g o n t he n u m ber of s u bjects wit h data, a 
li mite d n u m ber of a nalys es a n d data s u m maries ma y be pr o d uce d

Ot her c ha n ges i ncl u de f or matti n g a n d a d mi nistrati ve c ha n ges.
1 2. 1 6. 4. 2.
Li st of S p e cifi c C h a n g e s
C over p a ge. Re m ove d a ut h or list per te m pl ate u p d ate .
A ut h or (s):
 
S p o ns or Si g n at ory. U p d ate d de p art me nt w here s p o ns or si g n at ory w orks t o m atc h c urre nt 
or g a niz ati o n.
Meta b olic Pat h wa y s & Car di o vasc ular Me dici ne Deli ver y U nit
Secti o n 3. O bjectives(s) a n d E n d p oi nt(s). Revise d F o ot n ote # 2 t o a d d ne w A E SI.
2. Defi ne d as t hr o m b osis a n d/ or tiss ue isc he mia sec o n dar y  t o e xcessi ve er yt hr o p oiesis; 
w orse ni n g of h y perte nsi o n ;
P P D
car di o m y o pat h y;  p ul m o nar y arter y h yperte nsi o n; ca ncer-

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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. Added text to the stratification bullet and reference to sub-
studies under Figure 1 to state that the ABPM sub-study has closed recruitment.

Subjects will be stratified by region (see Appendix 3), by whether they are currently 
using an ESA, and by participation in the ABPM sub-study. Region and ESA use at 
study entry 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. [Note: 
recruitment in the ABPM sub-study is closed in Amendment 4.]

This study will include the following sub-studies:

ABPM sub-study (subjects not using ESAs only) (Appendix 13) [Note: 
recruitment in the ABPM sub-study is closed in Amendment 4]
Section 5.1. Inclusion Criteria; inclusion #4. Added retest for Hgb values ro reflect the 
variability threshold for testing to determine Day 1 eligibility (as done for Week -8).    
4.HemoCue Hgb (range inclusive): Hgb defined by ESA use:  
Group 1
(not using ESAs)
Group 2 
(ESA users)
Week -
8
Hgb 8 to 10 g/dL1 (5 to 6.2 mmol/L)
If Hgb is 10.1 to 10.4 g/dL2 (6.3-6.5 mmol/L), 
up to two retests are allowed; the retest value 
must be between 8 to 10 g/dL (5 to 6.2 
mmol/L).
Hgb 8 to12 g/dL (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 10 g/dL (5 to 6.2 mmol/L)
If Hgb is 10.1 to 10.4 g/dL4 (6.3-6.5 
mmol/L), up to two retests are allowed; 
the retest value must be between 8 to 10 
g/dL (5 to 6.2 mmol/L).
Hgb 8 to 11 g/dL (5 to 6.8 mmol/L) and
receiving at least the minimum ESA dose3
If Hgb is 11.1 to 11.4 g/dL4 (6.9-7.1 
mmol/L), up to two retests are allowed; the 
retest value must be between 8 to 11 g/dL 
(5 to 6.8 mmol/L).
1.
Conversion from g/dL to g/L is 1:10, e.g., Hgb of 8 to 10 g/dL is equivalent to 80-100 g/L. 
2.
The first retest will use the original Week -8 blood sample. If this value is >10 g/dL (Group 1) or >12 g/dL 
(Group 2), 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.
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.
The first retest will use the original Day 1 blood sample. If this value is >10 g/dL (Group 1) or >11 g/dL 
(Group 2), 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.

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Section 5.2. Exclusion Criteria; exclusion #2. Added second retest for TSAT values to 
reflect the variability threshold for testing to determine Day 1 eligibility.  
4.Transferrin saturation (TSAT) (screening only):  ≤20%. If the laboratory report 
indicates TSAT is 18-20%, then up to two retests can be obtained using a new blood 
sample. These retests may occur during screening and run-in up to can be objetained 
within 7 days two weeks prior to anticipated randomization (Day 1) of the final 
laboratory report; the final retest value must be >20% to confirm eligibility.   
Section 5.2. Exclusion Criteria; exclusion #2. Revised exclusion given worsening of 
hypertension has been added to the list of AESIs for daprodustat.
11. Current uncontrolled hypertension: Current uncontrolled hypertension as 
determined by the investigator that would contraindicate the use of rhEPO. 
Section 5.5. Permanent Discontinuation of Randomized Treatment.  Added stopping 
criterion for subjects with ADPKD only who have worsening kidney function and no 
other cause has been identified.

ADPKD subjects only: following further imaging, condition of the cystic disease 
in the kidney(s) has worsened more than expected given the clinical scenario and 
no other cause for the kidney function decline and/or cyst enlargement can be 
identified (Section 7.4.10).
Section 6.13. Subjects Transitioning to Dialysis.  Added a consideration to allow for 
conduction of study visits on or before the first dialysis session of the week for subjects on 
3x/week HD to help with flexibility of conducting study visits.

Study visit can be on a dialysis or non-dialysis day. 
o
However, for subjects on 3x/week HD, the designated study visit must not
occur on or before the first dialysis session of the week except in special 
circumstances after consultation with the PPD Medical Monitor.
Section 6.13. Subjects Transitioning to Dialysis. Added guidance for ADPKD subjects 
only.

For subjects with ADPKD only:  As per Section 7.4.10, as clinically feasible, an 
ultrasound should be performed PRIOR to subjects transitioning to dialysis.  
Section 7.1. Table 7 Schedule of Assessments Year 1 to the End of the Study (Year 2 
onwards).  Added assessments for ADPKD subjects only, with associated footnote, and 
defined ADPKD abbreviation as mandated by the Dear Invsetigator Letter.

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Protocol 
activity 
(visits ±1 
week)
(Note: All 
visit 
timings are 
relative to 
Day 1)
Year 2
Year 3
Year 4
Unscheduled10,
12
End of 
Study1
5
Follow-up
(4-6 weeks
after
stopping 
randomize
d 
treatment)
Wee
k 64
Wee
k 76
Wee
k 88
Wee
k 
100
Wee
k 
112
Wee
k 
124
Wee
k 
136
Wee
k 
148
Wee
k 
160
Wee
k
172
Wee
k 
184
Wee
k 
196
Wee
k 
20814
ADPKD 
subjects 
only:  
eGFR
X
X
X
X
X
X
ADPKD 
subjects 
only:  
Ultrasoun
d
X21
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; HR, heart rate; ECG, electrocardiogram; ADPKD, autosomal dominant polycystic kidney disease
21. Ultrasound of the kidneys will be performed within one month of discontinuing randomized treatment after 
the EOS visit or as soon as clinically feasible. See Section 7.4.10 for additional details.
Section 7.1. Table 9 Schedule of Assessments for Subjects Permanently Discontinuing 
Randomized Treatment. Added ultrasound for ADPKD subjects only as mandated by the 
Dear Invsetigator Letter (dated 14 Dec 2018).
Protocol Activity
(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
ADPKD subjects only:  
Ultrasound
X12
12.Ultrasound of the kidneys will be performed within one month of discontinuing randomized treatment or as 
soon as clinically feasible. See Section 7.4.10 for additional details. 
Section 7.1. Table 9 Schedule of Assessments for Subjects Permanently Discontinuing 
Randomized Treatment (Year 2 onwards). Added eGFR assessment for ADPKD subjects 
only for Year 2 onwards as mandated by the Dear Investigator Letter (dated 14 Dec 
2018).
Protocol activity 
(visits ± 2 week)
(Note: All visit 
timings are 
relative to Day 1)
Year 27
Year 37
Year 47
Unscheduled
End 
of 
Study 
9
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
ADPKD subjects 
only:  eGFR13
X
X
X
X
X
X
13.Collect samples as able, as outlined below; if subject refuses, document in subject source notes.

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Section 7.4.4. Adverse Events of Special Interest. Added AESI of worsening of 
hypertension to align with IB, version 10.

Worsening of hypertension
Section 7.4.10.Ultrasound. Added text related to requirements for ADPKD subjects as 
mandated by the Dear Investigator Letter (dated 14 Dec 2018).
For randomized subjects with ADPKD: 

An ultrasound of the kidneys will be performed when subjects permanently 
discontinue randomized treatment, preferably within one month of 
discontinuation of randomized treatment or as soon as clinically feasible. This 
may occur during the study OR after the completion of the end of study visit. See 
Tables 7 and 9 for details.  

As clinically feasible, an ultrasound should be performed PRIOR to the 
following:
o
Transition to dialysis
o
Bilateral nephrectomy
o
Kidney transplant. 

An additional ultrasound may be performed at any time during the study based 
on investigator’s clinical judgment (e.g., deterioration of kidney function as 
measured by eGFR in the absence of other identifiable causes). Other imaging 
techniques (e.g., MRI) can be performed at the investigator’s discretion.  

If an additional imaging study is performed, and the condition of the cystic 
disease in the kidney(s) has worsened more than expected given the clinical 
scenario, then randomized treatment should be temporarily stopped.  
Subsequently, if no other cause for the kidney function decline and/or cyst 
enlargement can be identified, randomized treatment should be permanently 
discontinued after consultation with the PPD Medical Monitor.
Section 12.1. Appendix 1:  Abbreviations and Trademarks. Added abbreviation for 
autosomal dominant polycystic kidney disease for completeness.
ADPKD
Autosomal dominant polycystic kidney disease
Section 12.2. Appendix 2:  Secondary and Exploratory Objectives/Endpoints.  Added 
additional endpoint to evaluate renal progression via change in eGFR.

To compare daprodustat to 
darbepoetin alfa on renal function

eGFR change from baseline at Week 52
Section 12.2. Appendix 2:  Secondary and Exploratory Objectives/Endpoints.  Removed 
“mean hours” from several endpoints given the WPAI questionnaire being used does not 
support the mean hours impaired calculation.

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
To further compare daprodustat to 
darbepoetin alfa on work productivity 
and regular daily activity impairment

Percent and mean hours work time missed at Baseline, 
Weeks 8,12, 28, 52, yearly, EOS on the WPAI-ANS-
CPV

Change from baseline in percent and mean hours work 
time missed at Weeks 8, 12, 28, 52, yearly and EOS 
on the WPAI-ANS-CPV

Percent and mean hours impaired (equivalent) at 
Baseline, Weeks 8,12, 28, 52, yearly, EOS on the 
WPAI-ANS-CPV

Change from baseline in percent and mean hours
impaired (equivalent) at Weeks 8, 12, 28, 52, yearly 
and EOS on the WPAI-ANS-CPV

Overall percent and mean hours work impairment 
(equivalent) at baseline, Weeks 8,12, 28, 52, yearly, 
EOS on the WPAI-ANS-CPV

Change from baseline in overall percent and mean 
hours work impairment (equivalent) at Weeks 8, 12, 
28, 52, yearly, EOS on the WPAI-ANS-CPV

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Section 12.4. Appendix 4:  Risk Assessment. Updated risk table to align with IB, version 10.  This includes the new AESI of worsening of 
hypertension and the addition of a reference for the pulmonary hypertension risk.
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 (Hgb/Hct > upper limit 
normal) attributed to daprodustat was associated with vascular 
congestion/inflammation, microthrombi, and tissue ischemia in a 
number of organs.
In the phase 2 proof of concept study, a high incidence of 
discontinuation due to hemoglobin stopping criteria (Hgb > 13.5 
g/dL or Hgb increased > 1 g/dL over any 2-week period) was 
observed.  In non-dialysis subjects administered 10 mg, 25 mg, 
50 mg or 100 mg of daprodustat daily, a total of 21 of 61 subjects 
(34%) met these criteria.  In hemodialysis-dependent subjects 
administered either 10 mg or 25 mg of daprodustat daily, a total 
of 8 of 31 subjects (26%) met these criteria. 
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.
Integrated AE data [including 2 global phase 2b studies (24-week 
treatment duration) and 2 Japanese phase 3 studies (52-week 
treatment duration)]: Few subjects experienced a possible 
thrombosis related adverse event in the setting of excessive 
erythropoiesis [3/688 (0.5%) subjects on daprodustat vs. 0/404 
on rhEPO].
Following review of clinical data received to date, this has not 
been identified as a safety concern for daprodustat when dose is 
managed appropriately according to target Hgb. However, 

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.

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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
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experience with daprodustat is currently insufficient to fully 
characterize this risk.
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 (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. 

Specific eligibility criteria related to 
current uncontrolled hypertension are 
outlined in Section 5.2.

Blood pressure will be closely monitored 
throughout the dosing period as outlined 
in the Time and Events Table Section 7.

Unblinded monitoring of safety data by an 
IDMC in-stream throughout the study.

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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
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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. Clinical studies with 
marketed rhEPO/analogs have suggested “higher” target 
hemoglobin, rate of hemoglobin rise of greater than 1 g/dL in 
any 2-week period, and/or higher doses may contribute to these 
risks.
In non-clinical studies conducted to date, not observed at tolerated 
doses when hemoglobin/hematocrit within normal range for species.
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)]: No meaningful difference was seen between 
treatment groups in the overall incidence of this AESI: [39/688 
(5.5%) daprodustat vs. 25/404 (6%) rhEPO; 0.92 relative risk (95% 
confidence interval: 0.55, 1.53)].  Within this composite AESI, the 
most frequent event types were heart failure (at least 12 events 
daprodustat vs. at least 13 events rhEPO) and thrombosis (at 
least 14 events daprodustat vs. at least 8 event rhEPO); and a 
numerical imbalance was noted in events of myocardial 
ischemia (at least 7 events daprodustat vs. at least 1 event 

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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Summary of Data/Rationale for Risk
Mitigation Strategy
rhEPO). The small number of events makes it difficult to draw 
any firm conclusions.
The clinical data received to date from completed clinical trials 
with daprodustat are insufficient to conclude substantiate or refute 
this risk.
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 rodents, stomach erosions were observed with intravenous 
and oral administration of daprodustat.
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). 
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.
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)]: No meaningful difference was seen between 
treatment groups in reports of this AESI [17 (2.7%) daprodustat 
vs. 10 (2.3%) rhEPO; 1.16 relative risk (95% confidence interval: 
0.52, 2.58)].
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.

Specific eligibility criteria related to personal 
history of malignancy or subjects with 

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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
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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 
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.
Integrated AE data [including 2 global phase 2b studies (24-week 
treatment duration) and 2 Japanese phase 3 studies (52-week 
treatment duration)]: No meaningful difference was seen 
between treatment groups in the occurrence of this AESI: [8/688 
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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(1.1%) daprodustat vs. 4/404 (0.9%) rhEPO; 1.14 relative risk 
(95% confidence interval: 0.31, 4.28)].
Clinical experience to date is not yet sufficient to substantiate or 
refute this as a safety concern for daprodustat. 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 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 

Unblinded monitoring of safety data by an 
IDMC in-stream throughout the study.

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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. A post-hoc analysis was performed using a 
definition of PAH often cited in the literature [Navaneethan, 
2016]. Subjects with sPAP >35 mmHg and/or tricuspid 
regurgitation maximum jet velocity (TRV) >2.5 m/s were 
considered as having PAH.  Regardless of baseline status 
of PAH, there was no clinically meaningful difference in the 
proportion of subjects with on-treatment PAH between the 
two treatment groups:  
o
Subjects with PAH at baseline: 35/113 (31%) vs. 
21/54 (39%) (ND) and 37/115 (32%) vs. 7/21 (33%) 
(HD), daprodustat vs. control, respectively.
o
Subjects without PAH at baseline: 25/113 (22%) vs. 
12/54 (22%) (ND) and 22/115 (19%) vs. 6/21 (29%) 
(HD), daprodustat vs. control, respectively.
Integrated AE data [including 2 global phase 2b studies (24-week 
treatment duration) and 2 Japanese phase 3 studies (52-week 
treatment duration)]: Four (0.5%) non-serious AEs in the 
daprodustat group vs 0 in rhEPO. 

Review of subject level information did not suggest adverse 
treatment effect: 2 subjects from phase2b that met protocol 
specified stopping criteria on scheduled ECHO had non-
serious AEs of ‘pulmonary arterial pressure increased’ and 
2 subjects from Japan Phase 3 had non-serious AE 

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‘pulmonary hypertension’ in setting of concurrent serious 
AEs of acute pulmonary embolus and mitral regurgitation 
(respectively) identified during hospitalization for coronary 
angiography.
Following review of clinical data received to date, this has not been 
identified as a safety concern for daprodustat.   
Cardiomyopathy
Published data suggest that cardiac effects of HIF stabilization are 
likely a function of the mechanism, extent, and duration of the effects, 
and can range from protective to detrimental depending upon the 
specific model and experimental conditions utilized.
With lifetime exposure to daprodustat in a 2-year rat oral 
carcinogenicity study, an exacerbation of rat spontaneous, 
progressive cardiomyopathy (PCM)(focal myofiber 
degeneration/necrosis with inflammatory infiltrates) was observed at 
doses of 0.8 mg/kg/day and above, although total incidence and 
severity distribution within any daprodustat-group were within 
historical control ranges.  This is consistent with an equivocal 
threshold for exacerbation of spontaneous, progressive 
cardiomyopathy at 0.8 mg/kg/day which is also the threshold dose for 
observing increased Hct values in individual rats. 
Cardiomyopathy has not been associated with naturally occurring 
mutation in man which results in increased HIF stabilization.
ECHO assessments performed in phase 2b studies (24 weeks 
treatment duration) did not identify any clinically meaningful changes 
in LVEF for daprodustat.
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)]: No meaningful difference was seen between 
treatment groups in reports of this AESI [1 (0.1%) daprodustat 
vs. 1 (0.2%) rhEPO; 0.64 relative risk (95% confidence interval: 
0.02, 18.07)].

Unblinded monitoring of safety data by an 
IDMC in-stream throughout the study.

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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.
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.
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 25mg, 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.
Integrated AE data [including 2 global phase 2b studies (24-week 
treatment duration) and 2 Japanese phase 3 studies (52-week 
treatment duration)]: No meaningful difference was seen 
between treatment groups in reports of this AESI [9 (2.9%) 
daprodustat vs. 6 (2.5%) rhEPO; 1.19 relative risk; (95% 
confidence interval: 0.42, 3.43)].

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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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.
Integrated AE data [including 2 global phase 2b studies (24-week 
treatment duration) and 2 Japanese phase 3 studies (52-week 
treatment duration)]: No meaningful difference was seen 
between treatment groups in reports of this AESI [2 (0.3%) 
daprodustat vs. 1 (0.2%) rhEPO; 1.20 relative risk; (95% 
confidence interval: 0.07, 20.87) and the incidence of 
musculoskeletal AEs was generally lower in the daprodustat 
treatment group]. 
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 Navaneethan SD, for CRIC investigators: Prevalence, 
Predictors, and Outcomes of Pulmonary Hypertension in 
CKD. J Am Soc Nephrol 2016, 27:877–886
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.  

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 
6.10 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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Daprodustat is a substrate of BCRP: Population PK analysis from 
Phase 2 studies suggested that while BCRP inhibitors were a 
covariate for daprodustat CL/F (8.6% lower clearance) the predicted 
change in exposure was not considered to be of clinical relevance.  
Daprodustat is an inhibitor of OATP1B1/1B3:. A clinical drug 
interaction study between 25mg and 100mg daprodustat with an 
OATP1B1/1B3 substrate (rosuvastatin) showed that there is no PK 
interaction at these doses of daprodustat.
Cyst progression in patients with autosomal 
dominant polycystic kidney disease (ADPKD)
Published data provide in vivo evidence for a potential role of 
HIF-1a in the growth of polycystic kidneys; Hif-1a deletion was 
sufficient to significantly mitigate a progressive polycystic 
phenotype in an ADPKD mouse model, while conversely 
pharmacologic HIF-1a stabilization was sufficient to convert a 
mild polycystic disease into a severely aggravated phenotype 
with marked loss of renal function. However, the dose of FG-
2216 (a PHI) used resulted in a significant erythropoietic 
response as reflected by ≥10% relative increases in hematocrit 
over the course of the study (Kraus, 2018; Hofherr, 2018).
A review of the non-clinical data from toxicity studies conducted 
with daprodustat does not indicate an exacerbation in incidence 
or severity of kidney cysts in daprodustat-treated animals in 
comparison to controls.  However, the wild type animals used in 
these toxicity studies have a very low background incidence of 
renal cysts and are not comparable to the mice used in the 

Kidney function will be monitored 
throughout the dosing period as outlined 
in Time and Events Table Section 7.1.

Ultrasounds will be performed as outlined 
in Section 7.4.10.

Monitoring of emerging safety data by an 
internal GSK Safety Review Team.

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Kraus article (Kraus, 2018) which are an inducible kidney 
epithelium-specific Pkd1-deletion model.
There is limited experience with daprodustat in subjects with 
ADPKD in completed clinical trials. In the Japan phase 3 study in 
non-dialysis subjects, there were 5 subjects with ADPKD (all 
CKD stage 5) in each treatment group.  Mean baseline eGFR was 
10 mL/min/1.73m2 in the daprodustat subjects vs. 16 
mL/min/1.73m2 in the rhEPO subjects.  The mean (SD) percent 
change from baseline at Week 52 in eGFR was: -18% (8) vs. -21% 
(14) in daprodustat vs. rhEPO, respectively.
Following review of clinical data received to date, this has not 
been identified as a safety concern for 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, 
thromboembolism, 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.
Hofherr A, Busch T, Kottgen M. HIF-1drives cyst growth in advanced stages of autosomal dominant polycystic kidney disease.  
Kidney International 2018;94:849–851 

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Kraus A, Peters DJM, Klanke B et al., HIF-1α promotes cyst progression in a mouse model of autosomal dominant polycystic 
kidney disease. Kidney International 2018;94(5):887-899
Navaneethan SD, for CRIC investigators: Prevalence, Predictors, and Outcomes of Pulmonary Hypertension in CKD. J Am Soc 
Nephrol 2016, 27:877–886 

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Section 12.6. Appendix 6:  Randomized Treatment Dose Adjustment Schemes.  Revised 
Year 2 sub-bullet reasons to correct a typographical error (sub-bullet #1) and 
inconsistency (sub-bullet #2).
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. 
Section 12.7. Appendix 7: Time and Events Table for Subjects Transitioning to Dialysis, 
Table 13 Schedule of Assessments Year 1 to the End of the Study for Subjects 
Transitioning to Dialysis (Year 2 onwards).  Corrected the footnote numbering for serum 
pregnancy test and revised Kt/V footnote (to align with standard of care).
FRP only:  Serum pregnancy test 5,178
14.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 measurement is acceptable. Kt/Vurea and urea reduction ratio measurements are 
not required for daily HHD.
Section 12.13.3. Study Design.  Added text to clarify ABPM sub-study has closed 
recruitment.
This is a multicenter sub-study of the main ASCEND-ND 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: 
recruitment in the ABPM sub-study is closed in Amendment 4.]
Section 12.14.4. Additional Inclusion Criteria. Added additional entry criterion to 
exclude subjects transitioning or already transitioned to dialysis at the time they consider 
enrollment in the PK sub-study.

Subjects must not be transitioning or already transitioned to dialysis.
Section 12.14.7. PK/Pharmacodynamic Analyses. Revised 4th paragraph to outline 
circumstances where limited outputs may be produced.
Based on exploratory graphs (Section 12.14.2), 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.  In the event that sub-study 
recruitment does not make its pre-specified target, depending on the number of 
subjects with data a limited number of analyses and data summaries may be 
produced depending on the number of subjects with data.  Further details will be 
provided in the RAP of the main study.

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12.16.5.
Changes Resulting from Protocol Amendment 5
This is an amendment to the protocol amendment dated 2020-JUL-30.
This amendment applies to all countries.
12.16.5.1. 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.

Updated pregnancy reporting timelines to align with revised Sponsor timings.
12.16.5.2. 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 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 7.4.6. Pregnancy, Updated pregnancy reporting timelines to align with revised 
Sponsor timings.
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 11.
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)

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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 darbepoetin alfa 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 not 
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 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 
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 9.310%. 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 50%, 30% and 20% 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

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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 9.3%, it is anticipated that approximately 3000 
dialysis subjects will be required to achieve the 664 adjudicated first MACE event target 
will be reached approximately after4.2 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. It is 
anticipated that more than 80% of randomized 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 40005000
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 (base case) 9.310% annual rhEPO MACE rate is based on a blinded 
summary of ASCEND-ND data as of April 20, 2020 review of randomized clinical 
trials in ND (peginesatide PEARL studies [Macdougall, 2013], TREAT [Pfeffer, 2009] 
and CHOIR [Singh, 2006]), observational data in ND subjects [USRDS, 2013] and 
considering the planned regional distribution for recruitment Table 11 illustrates the 
impact on power timing of events if the true underlying annual MACE rate differs from 
10% and Table 12 if the true underlying treatment effect is not a hazard ratio of 0.97. 
Table 11
Sensitivity based on a different true underlying annual MACE rate
True annual first MACE rate
Time to accrue 945 first MACE
6%
5.5y
8%
4.5y
10% (base case)
3.9y
12%
3.4y

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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 darbepoetin alfa 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 not on dialysis currently 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” 
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 

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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 [Hommel, 1988] 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 Hommel Holm-Bonferroni procedure will be 
fully described in the RAP.
References. Added Holm-Bonferroni reference as outlined in 9.4.3.
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;75:383-386
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
Pfeffer MA, Burdmann EA, Chen C, Cooper ME, de Zeeuw D, Eckardt KU, et al. for the 
TREAT Investigators. A Trial of Darbepoetin Alfa in Type 2 Diabetes and Chronic 
Kidney Disease. N Engl J Med 2009;361: 2019-2032 
Singh AK, Szczech L; Tang KL, Barnhart H, Sapp S, Wolfson M,  et al. Correction of 
anemia with epoetin alfa in chronic kidney disease N Eng J Med 2006; 355:2085-2098

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USRDS 2013 Annual Data Report: atlas of chronic kidney disease in the United States. 
Volume 1. Available at: http://www.usrds.org/2013/pdf/v1_00_intro_13.pdf
Section 12.11. Appendix 11: 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.