Clinical trial NCT02879305
Conditions: Anaemia Aspergillosis, Allergic Bronchopulmonary
Keywords: erythropoiesis stimulating agents GSK1278863 daprodustat anemia chronic kidney disease hemoglobin recombinant human erythropoietin
Sponsor: GlaxoSmithKline
Start date: 2016-09-28; Completion date: 2020-11-09
Enrollment: 2964 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this multi-center event-driven study in participants with anemia associated with chronic kidney disease (CKD) to evaluate the safety and efficacy of daprodustat.

Detailed description:

Arms: arm 1: Participants will receive oral daprodustat once daily. arm 2: Participants on peritoneal dialysis (PD) will be administered darbepoetin alfa subcutaneously (SC) and participants on hemodialysis (HD) will be administered epoetin alfa intravenously (IV).
Interventions: intervention 1: Daprodustat intervention 2: rhEPO intervention 3: Placebo intervention 4: Iron therapy
Intervention descriptions: intervention 1: Daprodustat dose is based on prior ESA dose, the dose is adjusted thereafter in order to achieve the target range. intervention 2: The initial ESA dose is based on converting the prior ESA dose to the nearest available study rhEPO dose and is administered IV. The dose is adjusted thereafter in order to achieve the target range. intervention 3: Oral placebo tablets will be taken from Week -4 up to randomization (Day 1). intervention 4: Participants will receive supplemental iron therapy if ferritin is \<=100 ng/mL or TSAT is \<=20%. The investigator will choose the route of administration and dose of iron.

Protocol documents:
Prot_000.pdf: 
2015N226659_07
CONFIDENTIAL
The GlaxoSmithKline group of companies
200807
1
TITLE PAGE
Division: Worldwide Development
Information Type: Protocol Amendment
Title:
A phase 3 randomized, open-label (sponsor-blind), active-
controlled, parallel-group, multi-center, event driven study in 
dialysis subjects with anemia associated with chronic kidney 
disease to evaluate the safety and efficacy of daprodustat 
compared to recombinant human erythropoietin, following a 
switch from erythropoietin-stimulating agents.
Short Title:
Anemia Studies in CKD: Erythropoiesis via a Novel PHI 
Daprodustat-Dialysis (ASCEND-D)
Compound Number:
GSK1278863
Development Phase:
IIIA
Effective Date:
30-JUL-2020
Protocol Amendment Number:  04
Copyright 2020 the GlaxoSmithKline group of companies.  All rights reserved.  
Unauthorised copying or use of this information is prohibited.


2015N226659_07
CONFIDENTIAL
The GlaxoSmithKline group of companies
200807
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Revision Chronology
GlaxoSmithKline
Document Number
Date
Version
2015N226659_00
2016-MAY-27
Original
2015N226659_01
2016-JUN-09
Republishing
2015N226659_02
2016-SEP-20
Amendment No. 1
Amendment 1 applies only to Austria, Belgium, Czech Republic, Denmark, Estonia, 
Germany, Hungary, Italy, Norway, Poland, Portugal, Romania, Spain, Sweden and the 
United Kingdom.

Text added to clarify when the end of the study will occur.

Removal of requirement to reduce ESA dose if Week -8 Hgb is >11.5 g/dL (study 
rationale and inclusion criteria).

Additional guidance added to iron management criteria

New exploratory objective to compare the effect of daprodustat to rhEPO on delayed 
graft function (DGF) after deceased donor kidney transplantation added.
2015N226659_03
2016-OCT-12
Amendment No. 2

Changes from country-specific Amendment 1 applied to global amendment

Country-specific requirements for France and Czech Republic added.

Section and 6 relating to darbepoetin alfa pre-filled syringe incidents, malfunctions 
and user errors. Section deleted as darbepoetin alfa pre-filled syringes are not subject 
to device reporting requirements.

Time and events Table 7 ‘Schedule of Assessments Year 1 to End of Study’
modified. Main changes include new timepoints at Run-in (Week -4) and Week 2 for 
collection of information related to iron therapy; new timepoint at Week 52 for 
Kt/Vurea assessment; and transfusions and kidney transplant added to prompt 
completion of page in eCRF.

Time and Events Table 8 ‘Schedule of Assessments for Patient Reported Outcomes, 
Genetics and Sub-studies’ modified. Main changes are changes to the ABPM sub-
study assessments including prompts for the end of the 44hr ABPM assessments and 
prompts for recording the times the subject awakens and goes to sleep during this 44 
hour ABPM period.

Time and events Table 9 ‘Schedule of Assessments for Subjects Permanently 
Discontinuing Randomized Treatment’ modified. Main changes include IRT system 
call removed at all visits except Early Treatment Discontinuation Visit and End of 
Study Visit; new timepoints for collection of information related to iron therapy, 
transfusions; and kidney transplant added to prompt completion of page in eCRF.


2015N226659_07
CONFIDENTIAL
The GlaxoSmithKline group of companies
200807
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
Text added to clarify those randomized to rhEPO who transition from HD to PD will 
change from epoetin alfa to darbepoetin alfa.  

Text relating to the timing of dialysis in relation to the study visit has been amended. 
The original text ‘For subjects receiving PD or home HD >3x/week, study visits 
must occur within 48 hours of their last dialysis session’ was inaccurate as PD is a 
daily treatment.

For the negatively adjudicated events in 200807, the reporting process has been 
updated and the investigator-reported term (not the adjudicator-reported term) will 
be used.

In addition to allowing a historical (last 6 months) kidney ultrasound to be used to 
assess entry criteria, a provision was added for a more sensitive imaging study (e.g., 
MRI, CT) to be used to assess entry criteria.

Other changes include minor wording changes for clarity, updating of section 
numbering and cross referencing, formatting changes and administrative changes. 
2015N226659_05
2017-OCT-05
Amendment No. 3

Added retest values for Hgb and TSAT to determine eligibility at Week -8.

Broadened exclusion to include participation in an interventional study with an 
investigational agent or device.

Removed option to have Early Treatment Discontinuation visit supersede the 
scheduled study visit.  

Provided guidance for those receiving HD two times a week who are randomized to 
the epoetin alfa arm and require three times a week epoetin alfa dosing.

Added a provision that in unexpected circumstances where the supply to the site is 
interrupted, then local standard of care for anemia management during this time 
period may be considered.  

Added new darbepoetin alfa dose strengths (not available in all countries).

Added direction regarding randomized treatment and study continuation for subjects 
who will be away from the research site for an extended period of time.

Clarified timeframe for iron management criteria.

Clarified “frequency of dialysis” inclusion criterion and valid study visit days by 
dialysis type. 

Clarified baseline dose for the purposes of the rescue algorithm for subjects switching 
from HD to PD who are randomized to rhEPO.

Shortened visit window for the Week 2 and 4 visits and clarified visit window for 
Week -4 and Day 1 visits.

Modified Time and Events Table 7 ‘Schedule of Assessments Year 1 to End of 
Study’.  Main changes include addition of Informed Consent activity; revised 
footnotes to remove Kt/V and URR measurement for daily HHD and allowance of 
extended timing to do Day 1 ECG and to do ultrasound and/or additional testing; 
more clarity around randomized treatment dispensing and compliance, including 
provisions for deferring dose changes till the next HD treatment; removed capture of 
rescue medications from unscheduled and early termination visits as rescue 
evaluation is triggered at scheduled visits; added footnote to clarify biomarkers will 
be stored for future analyses except if not permitted by IRB/EC or refused by subject; 


2015N226659_07
CONFIDENTIAL
The GlaxoSmithKline group of companies
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addition of Argentina only pregnancy requirement; and removal of footnote at Week -
4 visit for only collecting SAEs related to study participation or a GSK product as it 
did not apply.

Modified Time and Events Table 8 ‘Schedule for Assessments for Patient Reported
Outcomes, Genetics and Sub-studies’ modified to add healthcare resource utilization 
data collection, to streamline ABPM assessments and to add timing for informed 
consent and additional eligible collection visits for PK sub-study.

Modified Time and Events Table 9 “Schedule of Assessments for Subjects 
Permanently Discontinuing Randomized Treatment” to remove capture of rescue 
medications (rescue evaluation is triggered at on-treatment scheduled visits), to add 
healthcare resource utilization data collection, and to complete ABPM assessments.

Added direction to see CEC Site Manual for full scope of reporting requirements.

Add clarifications for PD subjects as to how weight, blood pressure, and laboratory 
assessments are to be done.  

Clarified timing of assessments relative to dialysis for SBP, DBP, HR and laboratory 
assessments.

Added reminder for the ordering of assessments for blood pressure and that the over-
read of the Day 1 ECG is required to confirm eligibility. 

Updated PRO section to add healthcare resource utilization data being collected for 
completeness and updated endpoint labels for EQ-5D-5L & EQ-VAS.

Revised statistical section to change from two-sided testing at the 5% level to one-
sided testing at the 2.5% level; correct the comparator for the Null and Alternative 
hypotheses; to change significance levels to p-values; to add a more complete 
description of the adjustments to statistical model; to update hyporesponder analyses; 
and to add additional text regarding the interim analysis process.

Added exploratory endpoints around Hgb variability, iron parameters, transfusions, 
and dose adjustment scheme.

Edited Risk Assessment information to align with version 8 of the Investigator’s 
Brochure. 

Updated FSH level to confirm menopause.

Provision for possible adjustment to the Dose Adjustment Algorithm triggers for Hgb 
values 7.5 g/dL to <9.5 g//dL based on the review of blinded instream aggregate Hgb 
data.

Changes to ABPM sub-study to add atrial fibrillation/flutter screening, remove home 
BP monitoring, change from 44- to 24-hour APBM, change in time-point for 
assessment (from Week 28 to Week 16), and adjustments to objectives, endpoints and 
analysis. 

Clarified additional inclusion and added additional eligible visits to collect PK 
samples in PK sub-studies.

Other changes include spelling corrections or minor wording changes for clarity, 
formatting changes, a missing reference (epoetin alfa IV:SC conversion), and 
administrative changes.


2015N226659_07
CONFIDENTIAL
The GlaxoSmithKline group of companies
200807
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2015N226659_07
30-JUL-2020
Amendment No. 4

Revised MACE NI margin in order to align the NI margin with similar studies that 
have already compared the effects of HIF-PHIs on MACE versus rhEPO.

Revised target MACE as a result of the change to the non-inferiority margin.

Updated the analysis of the hemoglobin co-primary endpoint based on FDA feedback.

Updated terminology (i.e., use of ‘supportive’) to be consistent with ICH-E9 
addendum.

Multiplicity adjustment strategy updated from Hommel to Holm-Bonferroni based on 
FDA feedback.

Added AESI of worsening of hypertension to footnote (included in IB, version 10).

Edited Risk Assessment information to include worsening of hypertension.

Updated pregnancy reporting timelines to align with revised Sponsor timings.


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


2015N226659_07
CONFIDENTIAL
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7
MEDICAL MONITOR/SPONSOR INFORMATION PAGE
Medical Monitor/SAE Contact Information: 
As this is a multinational study medical monitor/SAE contact information will be 
provided as a separate document.
Sponsor Legal Registered Address: 
GlaxoSmithKline Research & Development Limited
980 Great West Road
Brentford
Middlesex, TW8 9GS
UK
PPD is the contract research organization for this study.
In some countries, the clinical trial sponsor may be the local GlaxoSmithKline Affiliate 
Company (or designee). If applicable, the details of the alternative sponsor and contact 
person in the territory will be provided to the relevant regulatory authority as part of the 
clinical trial application.   
IND Number:  101,291 
EudraCT: 2016-000541-31


2015N226659_07
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INVESTIGATOR PROTOCOL AGREEMENT PAGE
For protocol 200807 
I confirm agreement to conduct the study in compliance with the protocol, as amended by 
this protocol amendment.
I acknowledge that I am responsible for overall study conduct. I agree to personally 
conduct or supervise the described study.
I agree to ensure that all associates, colleagues and employees assisting in the conduct of 
the study are informed about their obligations. Mechanisms are in place to ensure that site 
staff receives the appropriate information throughout the study. 
Investigator Name:
Investigator Address:
Investigator Phone Number:
Investigator Signature
Date


2015N226659_07
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TABLE OF CONTENTS
PAGE
1.
PROTOCOL SYNOPSIS FOR STUDY 200807......................................................13
2.
INTRODUCTION....................................................................................................15
2.1.
Brief Background ........................................................................................15
2.2.
Study Rationale ..........................................................................................15
3.
OBJECTIVE(S) AND ENDPOINT(S) ......................................................................16
4.
STUDY DESIGN ....................................................................................................16
4.1.
Overall Design ............................................................................................16
4.2.
Type and Number of Subjects.....................................................................18
4.3.
Design Rationale ........................................................................................18
4.4.
Dose Justification........................................................................................19
4.4.1.
Daprodustat.................................................................................19
4.4.2.
Randomized Treatment Dose Adjustment Scheme......................19
4.5.
Benefit:Risk Assessment ............................................................................20
4.5.1.
Risk Assessment .........................................................................20
4.5.2.
Benefit Assessment.....................................................................20
4.5.3.
Overall Benefit:Risk Conclusion...................................................20
5.
SELECTION OF STUDY POPULATION AND WITHDRAWAL CRITERIA .............20
5.1.
Inclusion Criteria.........................................................................................21
5.2.
Exclusion Criteria........................................................................................22
5.3.
Screening/ Run-in Failures .........................................................................24
5.4.
Subject Retention .......................................................................................24
5.5.
Permanent Discontinuation of Randomized Treatment ...............................24
5.5.1.
Procedures for Subject Follow-up ................................................25
5.6.
Withdrawal from Study................................................................................25
5.6.1.
Withdrawal of Consent for Contact...............................................25
5.6.2.
Subjects Deemed Lost to Follow-up.............................................26
5.7.
Subject and Study Completion....................................................................26
6.
PLACEBO RUN-IN AND RANDOMIZED TREATMENT .........................................26
6.1.
Placebo Run-in and Randomized Treatment ..............................................26
6.2.
Randomized Treatment Assignment...........................................................27
6.3.
Randomized Treatment Starting Dose and Dose Adjustment .....................28
6.3.1.
Daprodustat Dosing Information ..................................................28
6.3.2.
rhEPO Dosing Information ...........................................................28
6.3.3.
Daprodustat and rhEPO Dose Adjustment Algorithm...................30
6.3.4.
Randomized Treatment Temporary Interruption...........................31
6.3.5.
Randomized Treatment Discontinuation ......................................31
6.4.
Blinding.......................................................................................................31
6.5.
Packaging and Labeling..............................................................................32
6.6.
Preparation/Handling/Storage/Accountability..............................................32
6.7.
Compliance with Randomized Treatment Administration ............................32
6.8.
Treatment of Randomized Treatment Overdose .........................................33
6.9.
Treatment after the End of the Study ..........................................................33
6.10.
Concomitant Medications and Non-Drug Therapies....................................33


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


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


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


2015N226659_07
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1.
PROTOCOL SYNOPSIS FOR STUDY 200807
This Phase 3 study will evaluate the safety and efficacy of daprodustat (GSK1278863) 
compared to recombinant human erythropoietin (rhEPO) in the treatment of anemia 
associated with chronic kidney disease (CKD) in subjects on dialysis. 
Primary Objective(s)/Endpoint(s)
Objectives
Endpoints
Co-primary (tested in parallel for non-inferiority)

To compare daprodustat to rhEPO for 
cardiovascular (CV) safety (non-inferiority)

Time to first occurrence of adjudicated major 
adverse cardiovascular event (MACE) 
[composite of all-cause mortality, non-fatal 
myocardial infarction (MI) and non-fatal stroke]

To compare daprodustat to rhEPO for 
hemoglobin (Hgb) efficacy (non-inferiority)

Mean change in Hgb between baseline and 
evaluation period (EP, mean over Weeks 28 to 
52)
Overall Design

This is a randomized, open-label (sponsor blind), active-controlled, parallel-group, 
multi-center, event-driven study in dialysis subjects with anemia associated with 
CKD who are currently treated with erythropoiesis-stimulating agents (ESAs1).

This study will comprise four study periods:  a 4-week screening period, a 4-week 
placebo run-in period, a treatment period and a follow-up period. Prior ESA therapy 
continues during the screening and run-in periods.

The total duration of the study is dependent upon the accumulation of 664 adjudicated 
first MACE (i.e., it is event-driven) unless review of interim data by the Independent 
Data Monitoring Committee (IDMC) recommends bringing the study to an earlier 
close.

Subjects will be stratified by dialysis type, by region, and by participation in the 
ambulatory blood pressure monitoring (ABPM) sub-study. 

Following stratification, subjects will be randomized 1:1 to receive oral daprodustat 
or rhEPO [intravenous (IV) epoetin alfa or subcutaneous (SC) darbepoetin alfa]. 

Both treatment arms (daprodustat and rhEPO) will follow a protocol-specified 
randomized treatment dose adjustment algorithm to achieve and/or maintain Hgb 
within the target range of 10-11g/dL. Dose changes will be made programmatically 
by the Interactive Response Technology (IRT) system for both randomized treatment 
arms.

To ensure subjects remain iron replete and to minimize the potential for iron 
overload during the study, the investigator will follow the iron management criteria 
from randomization through the end of the study treatment period.
                                                
1 ESAs refer to any rhEPO or methoxy PEG-epoetin beta.


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


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


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


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


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assessments to be confirmed, while the run-in period will be used to establish compliance 
with placebo and study procedures in an attempt to minimize withdrawn consent post-
randomization. 
The stabilization period from Day 1 to Week 28 allows subjects to have their randomized 
treatment dose titrated to achieve the Hgb target range. This period of time provides the 
best opportunity for subjects to be titrated to their optimal dose of randomized treatment 
prior to the efficacy EP (Weeks 28 to 52). A percentage of subjects may still need dose 
titration during the EP. After Week 52, minimal dose changes may be required to 
maintain Hgb within the target range.
The selection of the rhEPO control (epoetin alfa for HD subjects; darbepoetin alfa for PD 
subjects) is based on clinical practice in the majority of participating countries. 
This study will be open-label (sponsor blind) because it would be complex to double-
blind due to the differing number of dose steps between randomized treatments, leading 
to potential dosing errors. Additionally, it is potentially unethical to blind the different 
route of administration of randomized treatment.
4.4.
Dose Justification
Starting doses, dose steps, and elements of the dose adjustment scheme are provided in 
Section 6.3 and Appendix 6.
4.4.1.
Daprodustat
Daprodustat starting doses were selected to reach the target Hgb concentration after 
approximately one red blood cell (RBC) lifespan of treatment (almost 3 months, 
pharmacodynamic steady-state), without the need for any individual dose adjustments.  
However, due to the between-subject variability in Hgb response to a given dose of 
daprodustat and the relatively narrow Hgb target range, individual dose adjustments of 
daprodustat are expected during the first few months of treatment. 
The daprodustat starting doses and dose steps (including the highest dose level, 24 mg) 
selected for this study are consistent with those utilized in the completed 6-month Phase 
2B studies, and were based on exposure-response longitudinal modeling of Hgb data 
collected across the Phase 2 program. Covariate analyses elucidated that baseline Hgb, 
body-weight, and prior ESA dose (if applicable) were the most relevant covariates of Hgb 
response to daprodustat.  Simulations showed the effect of body-weight was not clinically 
important for dosing, but the relationship between prior ESA dose and response was used 
to determine starting doses of daprodustat relative to a subject’s prior ESA dose. 
Starting doses of 4, 6, 8 and 12 mg were selected and are estimated to maintain Hgb 
levels observed with their prior ESA therapy.
4.4.2.
Randomized Treatment Dose Adjustment Scheme
A randomized treatment (daprodustat and rhEPO) dose adjustment algorithm was 
designed to minimize unnecessary dose adjustments by allowing for visit-to-visit 


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variability, and it is informed by the change in Hgb from the previous visit when 
evaluating the need for a dose adjustment (Appendix 6).   
4.5.
Benefit:Risk Assessment
Summaries of findings from both clinical and non-clinical studies conducted with 
daprodustat can be found in the daprodustat IB and IB supplement(s) (if applicable). 
4.5.1.
Risk Assessment
The potential risks of clinical significance including AEs of special interest 
(Section 7.4.4), and the mitigation strategies for this protocol taking into account the 
results of completed clinical and nonclinical studies with daprodustat, are outlined in 
Appendix 4.  In addition to the mitigation strategies outlined, an IDMC will monitor 
accruing safety data for this trial (Section 10.8.1).
4.5.2.
Benefit Assessment
In clinical trials of up to 24 weeks in duration, in subjects with anemia associated with 
CKD, daprodustat has been shown to treat Hgb to target range. Daprodustat may present 
several important advantages over rhEPO and its analogs.  It is an oral medication and 
does not require cold-chain storage as does rhEPO, thus increasing ease of use for 
patients and health care providers.  
 
.  Treatment of anemia of CKD with rhEPO is associated with increased CV risk 
which is postulated to be related to the associated increases in EPO exposure with rhEPO 
[Szczech, 2008];
4.5.3.
Overall Benefit:Risk Conclusion
Daprodustat demonstrates a positive benefit vs. risk based on the evidence as follows. In 
clinical trials up to 24 weeks in duration, daprodustat treats Hgb to target range, and there 
are no adverse events that have been identified as related to treatment with daprodustat.
This protocol employs precautions to mitigate known and potential risks to randomized 
subjects (See Appendix 4). Given these precautions, as well as the potential benefit that 
daprodustat holds for the treatment of anemia associated with CKD compared to the 
current standard, the overall benefit risk balance is considered to be positive.
5.
SELECTION OF STUDY POPULATION AND 
WITHDRAWAL CRITERIA
Specific information regarding warnings, precautions, contraindications, AEs, and other 
pertinent information on the randomized treatment is provided in the IB, IB 
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supplement(s) (if applicable), product labels for epoetin alfa and darbepoetin alfa, and 
other pertinent documents (e.g., Study Reference Manual (SRM), informed consent).
Deviations from inclusion and exclusion criteria are not allowed because they can 
potentially jeopardize the scientific integrity of the study, regulatory acceptability or 
subject safety.
5.1.
Inclusion Criteria
A subject will be eligible for inclusion in this study only if all of the following criteria 
apply at screening (Week -8) and randomization (Day 1) unless otherwise specified.   
1.
Age (confirm at screening only): 18 to 99 years of age (inclusive).
2. ESAs:   Use of any approved ESA for at least the 6 weeks prior to screening and 
between screening and randomization.
3.
Hgb concentration measured by HemoCue (range is inclusive):
Hgb Range
Week -8

Hgb 8 to 12 g/dL1 (5 to 7.4 mmol/L).

If Hgb is 12.1 to 12.4 g/dL2 (7.5-7.7 mmol/L), up to two retests are allowed; the 
retest value must be between 8 to 12 g/dL (5 to 7.4 mmol/L).
Day 1

Hgb 8 to 11 g/dL (5 to 6.8 mmol/L) and receiving at least the minimum ESA dose3.

Hgb >11 g/dL to 11.5 g/dL (6.8 mmol/L to 7.1 mmol/L) and receiving greater than 
the minimum ESA dose3. 
1.
Conversion from g/dL to g/L is 1:10, e.g., Hgb of 8 to 10 g/dL is equivalent to 80-100g/L. 
2.
The first retest will use the original Week -8 blood sample. If this value is >12 g/dL, one additional retest 
can be performed using a new blood sample on the study visit day.  The final retest value is entered into 
the IRT system. For in-center HD, retests will be pre-dialysis, in between dialysis sessions for HHD 
subjects at the study visits, and at the study visits for PD subjects, as per standard of care.
3.
Minimum ESA dose:  epoetins (including biosimilars):  1500 units (U)/week intravenous (IV) or 1000 
U/week SC; darbepoetin alfa:  20 g/4 weeks SC/IV; methoxy PEG-epoetin:  30 g/month SC/IV
4.
Dialysis: On dialysis >90 days prior to screening and continuing on the same mode 
of dialysis from screening (Week -8) through to randomization (Day 1).
5.
Frequency of Dialysis:
a. HD (in-center):  ≥2 times/week 
b. PD: ≥5 times/week
c. Home HD: ≥2 times/week
6.
Compliance with placebo [randomization (Day 1) only]: ≥80% and ≤120% 
compliance with placebo during run-in period (NOTE: this is in addition to ESA 
treatment).


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7.
Informed consent (screening only): capable of giving signed informed consent 
which includes compliance with the requirements and restrictions listed in the consent 
form and in this protocol.
Note: The country-specific requirements for France ONLY for the informed consent 
process are provided in Appendix 14 (see Section 12.14.1, Item 3 for details).
8.
Other study eligibility criteria considerations: The country-specific requirements 
for France ONLY for inclusion in this study are provided in Appendix 14 (see Section 
12.14.1 Item 1 for details).
5.2.
Exclusion Criteria
A subject will not be eligible for inclusion in this study if any of the following criteria 
apply at screening (Week -8) or randomization (Day 1), unless otherwise specified. 
CKD related criteria
1.
Kidney transplant: Planned living-related or living-unrelated kidney transplant 
within 52 weeks after study start (Day 1).
Anemia related criteria
2.
Ferritin (screening only):  ≤100 ng/mL (≤100 g/L). 
3.
Transferrin saturation (TSAT) (screening only): ≤20%.  If TSAT is 18-20%, then 
a retest using a new blood sample can be obtained within 7 days of the final 
laboratory report; the final retest value must be >20% to confirm eligibility.
4.
Aplasias: History of bone marrow aplasia or pure red cell aplasia.
5.
Other causes of anemia: Untreated pernicious anemia, thalassemia major, sickle 
cell disease or myelodysplastic syndrome.
6.
Gastrointestinal (GI) bleeding: Evidence of actively bleeding gastric, duodenal, or 
esophageal ulcer disease OR clinically significant GI bleeding ≤4 weeks prior to 
screening through to randomization (Day 1).
CV disease-related criteria
7.
MI or acute coronary syndrome:  ≤4 weeks prior to screening through to 
randomization (Day 1).
8.
Stroke or transient ischemic attack:  ≤4 weeks prior to screening through to 
randomization (Day 1).
9.
Heart failure (HF): Chronic Class IV HF, as defined by the New York Heart 
Association (NYHA) functional classification system.
10. Current uncontrolled hypertension: Current uncontrolled hypertension as 
determined by the investigator that would contraindicate the use of rhEPO.
11. QTcB (Day 1): QTcB >500 msec, or QTcB >530 msec in subjects with bundle 
branch block.  There is no QTc exclusion for subjects with a predominantly 
ventricular paced rhythm.


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Other disease-related criteria
12. Liver disease: (any one of the following):

Alanine transaminase (ALT) >2x upper limit of normal (ULN) (screening only)

Bilirubin >1.5xULN (screening only)
NOTE: Isolated bilirubin >1.5xULN is acceptable if bilirubin is fractionated and 
direct bilirubin <35%.

Current unstable liver or biliary disease per investigator assessment, generally 
defined by the presence of ascites, encephalopathy, coagulopathy, 
hypoalbuminaemia, esophageal or gastric varices, persistent jaundice, or cirrhosis.
NOTE: Stable chronic liver disease (including asymptomatic gallstones, chronic 
hepatitis B or C, or Gilbert’s syndrome) are acceptable if subject otherwise meets 
entry criteria.
13. Malignancy: History of malignancy within the 2 years prior to screening through to 
randomization (Day 1) or currently receiving treatment for cancer, or complex 
kidney cyst (e.g. Bosniak Category II F, III or IV) >3cm. Note:  The only exception 
is localized squamous cell or basal cell carcinoma of the skin that has been 
definitively treated 4 weeks prior to screening.
Concomitant medication and other randomized treatment-related criteria
14. Severe allergic reactions: History of severe allergic or anaphylactic reactions or 
hypersensitivity to excipients in the investigational product (refer to daprodustat IB), 
or epoetin alfa or darbepoetin alfa (refer to product labeling).  
15. Drugs and supplements: Use of strong inhibitors of CYP2C8 (e.g., gemfibrozil) or 
strong inducers of CYP2C8 (e.g., rifampin/rifampicin).
16. Other study participation:  Use of other investigational agent or device prior to 
screening through to randomization (Day 1).   

Note: at screening, this exclusion applies to use of the investigational agent within 
30 days or within five half lives (whichever is longer).  
17. Prior treatment with daprodustat:  Any prior treatment with daprodustat for 
treatment duration of >30 days.
General health-related criteria
18. Females ONLY: Subject is pregnant [as confirmed by a positive serum human 
chorionic gonadotrophin (hCG) test for females of reproductive potential (FRP) 
only], subject is breastfeeding, or subject is of reproductive potential and does not 
agree to follow one of the contraceptive options listed in the List of Highly Effective 
Methods for Avoiding Pregnancy in Appendix 5.
Note:  See Section 12.14.2 for the country-specific requirements for the Czech 
Republic ONLY relating to acceptable contraceptive methods during participation in 
this study. 
19. Other Conditions:  Any other condition, clinical or laboratory abnormality, or 
examination finding that the investigator considers would put the subject at 


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


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


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
In-clinic and phone visits

Follow-up via medical records review and/or other treating physician

Follow-up via family member or other third party contact
If all of these options are refused, then no further study visits or study-related telephone 
contacts will be conducted and the subject will be considered to have withdrawn consent. 
The principal investigator will be required to document that all alternative options have 
been reviewed with the subject.
For these subjects, information regarding vital status will continue to be collected from 
available sources including those in the public domain based on accepted local laws and 
regulations. Where permitted, a third party may be used to obtain information.
5.6.2.
Subjects Deemed Lost to Follow-up

Investigators should make every effort to contact subjects who are deemed lost to 
follow-up and who have not withdrawn consent to follow-up contact.

As permitted by local regulations, a third party may be used to locate alternative 
subject contact information that will be provided to the investigator. All attempts to 
contact subjects will be documented in the subject’s source notes and a final status 
contact will be recorded in the eCRF. 
5.7.
Subject and Study Completion
A completed subject is one who has completed all periods of the study through the End of 
Study visit with the following exception: subjects who die while on study are also 
considered as having completed the study.
6.
PLACEBO RUN-IN AND RANDOMIZED TREATMENT
6.1.
Placebo Run-in and Randomized Treatment
Prior to randomization, oral placebo tablets will be dispensed at Week -4 with 
instructions to take one tablet daily through the run-in period.
The term ‘randomized treatment’ is used throughout the protocol to describe either study 
treatment (i.e., daprodustat, darbepoetin alfa or epoetin alfa) received by the subject 
during the treatment period as per the protocol design.  Randomized treatment will be 
provided by GSK3. 
During the treatment period, iron therapy (supplied locally) will be administered as per 
the iron management criteria (Section 6.11.1).  
                                                
3 If the supply to the site is interrupted due to unexpected circumstances (e.g., natural disaster), local 
standard of care for anemia management may be considered during that time period, without the need to 
withdraw the subject from the study or to permanently discontinue randomized treatment. 


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


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Subjects will discontinue their ESA therapy prior to randomization so that the 
randomization date (Day 1) should coincide, as closely as possible, with the date of next 
scheduled ESA administration. Examples of switching are provided in the SRM. 
6.3.
Randomized Treatment Starting Dose and Dose Adjustment
6.3.1.
Daprodustat Dosing Information
Daprodustat Starting Dose:
The starting dose of daprodustat will be assigned based on prior ESA dose at 
randomization (Day 1) (Table 3).
Table 3
Daprodustat Starting Dose
ESA Dose at Randomization(Day 1)
Daprodustat
Starting Dose
epoetins (incl biosimilars)
(U/week IV) 1
darbepoetin 
(g/4week SC/IV) 2
methoxy PEG-epoetin 
beta (g/month SC/IV) 3, 4
(mg, once 
daily)
   1500 to 2000 
   20 to 30
   30 to 40 
4
>2000 to <10000 
>30-150 
>40 to 180
6
10000 to <20000 
>150-300 
>180 to 360 
8
20000  
>300   
>360   
12
PEG=polyethylene glycol
1.
Standardized rhEPO IV dose (U/week) = 161/113 * (epoetin SC dose (units)) / (frequency) [Beserab, 2002]
2.
Conversion of 250 U:1 g (epoetin IV:darbepoetin alfa) utilized and rounded to the nearest available dose 
strength [Sterner, 2008] 
3.
Conversion of 1:1.2 g (darbepoetin alfa:methoxy PEG-epoetin beta) ) utilized and rounded to the nearest 
available dose strength [Choi, 2013] 
4.
Conversion of 208 U:1 g (epoetin IV: methoxy PEG-epoetin beta)
Daprodustat Dose Steps:
The available dose steps of daprodustat are outlined below.  Dose adjustments will result 
in the daprodustat dose being increased or decreased by one dose step at a time.  Those 
receiving the highest dose of daprodustat who require a dose increase will maintain the 
same dose, while those receiving the lowest dose of daprodustat that require a dose 
decrease will have doses withheld.  
6.3.2.
rhEPO Dosing Information
rhEPO Starting Dose:
The starting dose for subjects receiving rhEPO is as follows:

For subjects with a baseline (Day 1) Hgb ≤11 g/dL 


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


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


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


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


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6.8.
Treatment of Randomized Treatment Overdose
There is no specific antidote for overdose with daprodustat. The expected manifestations 
of daprodustat overdosage include signs and symptoms associated with an excessive 
and/or rapid increase in Hgb concentration. Daprodustat is highly protein bound; thus, 
clearance of daprodustat by HD or PD is very low and these are not effective methods to 
enhance the elimination of daprodustat. Daprodustat metabolites are, in part, cleared via 
hemodialysis. In the event of a suspected overdose, it is recommended that the 
appropriate supportive clinical care be instituted, as dictated by the subject’s clinical 
status. Additionally, subjects should be monitored closely for CV events, increased HR 
and hematologic abnormalities.
Consult the approved product label for information on overdose for darbepoetin alfa and 
epoetin alfa.
6.9.
Treatment after the End of the Study
Subjects will not receive any additional treatment from GSK after completion of the 
study. The investigator is responsible for ensuring that consideration has been given to 
post-study care of the subject’s medical condition.
6.10.
Concomitant Medications and Non-Drug Therapies
Concomitant medications, including over-the-counter medications and supplements, 
taken during the study will be recorded in the eCRF.  Start/stop dates and route of 
administration will be recorded for general concomitant medications. Additional details 
(e.g., changes in dose, reason for change, reason for addition or termination) will be 
recorded for certain medications at each visit (e.g., iron and anti-hypertensive 
medications).
6.10.1.
Permitted Medications and Non-Drug Therapies
Unless specified as a prohibited medication in Section 6.10.2, all concomitant 
medications should be considered permitted provided they are not contraindicated for the 
individual subject concerned.
Co-administration of daprodustat with moderate CYP2C8 inhibitors (e.g., clopidogrel, 
teriflunomide, deferasirox) should be performed with caution. If one of these 
medications is started, stopped or the dose is changed, Hgb should subsequently be 
monitored every 4 weeks for the following 12 weeks.
6.10.2.
Prohibited Medications and Non-Drug Therapies
Use of any of the following prescription drugs from screening (Week -8) until 7 days 
after the last dose of randomized treatment is prohibited and will constitute a protocol 
violation. 

Strong inhibitors of CYP2C8 (e.g., gemfibrozil)

Strong inducers of CYP2C8 (e.g., rifampin/rifampicin)


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No other investigational agents or devices are permitted from study entry through 
completion of the study, with the exception of the randomized treatment administered for 
this study.
6.11.
Standard of Care
During the study (from screening), investigators are expected to monitor the subject’s 
overall clinical status to ensure standards of care are met to enable consistency of practice 
with Kidney Disease Improving Global Outcomes (KDIGO) guidelines or local 
equivalent (e.g., phosphate and albumin).
For this study, specific iron management criteria and a dose adjustment algorithm for 
randomized treatment will apply. These were developed to reflect global clinical practice.
6.11.1.
Iron Management Criteria
Subjects must remain iron replete throughout the study.  The investigator will follow the 
iron management criteria from randomization (Day 1) through the end of the study 
treatment period for subjects receiving randomized treatment.  
Iron therapy will be administered if ferritin is ≤100 ng/mL and/or TSAT is ≤20%.  The 
investigator should choose the route of administration and dose of iron based on the 
subject’s iron status and local clinical practice.  
All iron (excluding multivitamins) must be stopped and cannot be administered if; 

Ferritin >800 ng/mL and TSAT  >20%, or 

TSAT  >40% 
Investigators should be guided by local/regional guidelines and may stop administration 
of iron at a lower ferritin or TSAT level as long as subjects are maintained at a ferritin 
>100 ng/mL and TSAT >20%.
The Steering Committee (Section 10.8.4) will monitor blinded subject iron data in an 
ongoing fashion to ensure compliance.
6.12.
Rescue Therapy
A rescue algorithm is provided to minimize subjects having an inadequate response to the 
treatment for their anemia for an extended period of time and to enable consistency in the 
application of rescue therapy across the study.  Details are provided in Table 6.
This rescue algorithm does not apply to subjects with a low Hgb as a result of an acute or 
subacute event with an identifiable cause (e.g., GI bleed, blood loss due to surgery or 
vascular access).  In these cases, treatment should be directed to the specific cause and 
randomized treatment will be continued.  If a subject is transfused as part of the 
treatment, then the randomized treatment will be maintained at the current dose (unless 
Hgb is ≥12 g/dL which requires a dose hold).


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


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7.
STUDY ASSESSMENTS AND PROCEDURES
Protocol waivers or exemptions are not allowed with the exception of immediate safety 
concerns. Adherence to the study design requirements, including those specified in the 
Time and Events Table, are essential and required for study conduct.
This section lists the procedures and parameters of each planned study assessment.  The 
exact timing of each assessment is listed in the Time and Events Table Section 7.1. 
Because Hgb levels become more variable with increased time between dialysis sessions, 
the designated study visit should occur during the dialysis session with the shortest 
interval from the previous session. Study visit days should be scheduled as follows: 

For subjects on 3-5x/week HD, the designated study visit must not occur on the 
first dialysis session of the week, i.e., immediately following the longest interval 
between HD sessions.  For example, if on a Monday-Wednesday-Friday schedule, 
the study visit should be on Wednesday or Friday.

For subjects on PD, study visits can occur on any day of the week. 

For subjects on 2x/week HD, the study visit must occur on the day of the dialysis 
session that is closest to the previous session. For example, if a subject receives 
dialysis on a Monday and Thursday, the study visit should be on the Thursday (2 
days from the previous dialysis session) rather than the Monday (3 days from the 
previous dialysis session). 
The Week -4 and Day 1 visits should be completed 4 weeks ±1 week after the last visit; 
however, the total duration of the Screening and Run-In periods (from Week -8 to Day 1) 
should be 8 weeks ±1 week (i.e., 7-9 weeks).  
Post-randomization visits should be referenced back to the Randomization visit (Day 1).  
The visit window for those on randomized treatment for the Week 2 and Week 4 visits is 
±3 days.  The visit window specified for those on randomized treatment from Week 8 
onwards is ±1 week.  However, during the first 52 weeks, to ensure continuity of 
randomized treatment, study visits must be no more than 5 weeks apart. In exceptional 
circumstances, minor changes to visit structure may be permitted after consultation with 
the PPD Medical Monitor.
Study assessments should preferably be done at dialysis centers; however, in some 
circumstances (i.e., where the dialysis center and research site are not co-located) 
assessments can be performed at the research site.
Supplementary study conduct information is provided in the SRM. The SRM provides 
administrative and detailed technical information that does not impact subject safety.


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


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


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


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


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provided the size and cyst category has been reported. If a more sensitive imaging study [e.g., magnetic resonance imaging (MRI), computed tomography (CT)] has been 
performed within this timeframe and a report is available, this may be used in place of the ultrasound. See Section 7.4.10.
17. Treatment will be dispensed every 4±1 weeks; an IRT transaction will be required; perform randomized treatment compliance. 
18. A historical Kt/Vurea measurement within the last 12 weeks can be used.  If a Kt/Vurea measurement is not available, then a urea reduction ratio (URR) measurement is 
acceptable. Kt/Vurea and URR measurements are not required for daily HHD.
19. In circumstances where the new dose of randomized treatment cannot be dispensed on the day of the study visit, the new dose of randomized treatment can be dispensed at next 
HD treatment. For visits after Day 1, prior randomized treatment should be continued unless on dose hold, Hgb ≥12 g/dL. Compliance is deferred until randomized treatment is 
returned.
20. For Argentina ONLY: Pregnancy testing will be performed every 4 weeks for FRP as required by local law.
21. Biomarker samples will be stored for future analyses for all subjects, except if not permitted by IRB/EC or refused by subject.
22. Informed consent will be obtained prior to any study procedures. 


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


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


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


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


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


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


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


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7.4.3.4.
Regulatory Reporting Requirements for SAEs
Prompt notification by the investigator to PPD of SAEs related to placebo or randomized 
treatment is essential so that legal obligations and ethical responsibilities towards the 
safety of subjects and the safety of a product under clinical investigation are met. 
GSK has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a product under clinical investigation. GSK will 
comply with country specific regulatory requirements relating to safety reporting to the 
regulatory authority, Institutional Review Board (IRB)/Independent Ethics Committee 
(IEC) and investigators.
Investigator safety reports are prepared for suspected unexpected serious adverse 
reactions according to local regulatory requirements and GSK policy and are forwarded 
to investigators as necessary.
An investigator who receives an investigator safety report describing a SAE(s) or other 
specific safety information (e.g., summary or listing of SAEs) from GSK will file it with 
the IB and will notify the IRB/IEC, if appropriate according to local requirements.
7.4.4.
Adverse Events of Special Interest
The investigator or site staff will be responsible for detecting, documenting and reporting 
any events that may represent the AEs of special interest listed below (using preferred 
terms):

Thrombosis and/or tissue ischemia secondary to excessive erythropoiesis

Worsening of hypertension

Cardiomyopathy  

Pulmonary artery hypertension (see also Section 7.4.2)

Cancer-related mortality and tumor progression and recurrence 

Esophageal and gastric erosions

Proliferative retinopathy, macular edema, choroidal neovascularization 

Exacerbation of rheumatoid arthritis
The results of any investigation should be recorded on the AE page and the relevant AE 
of special interest page of the subject’s eCRF.
7.4.5.
Possible Suicidality Related Adverse Events
If during the study there is an occurrence of an AE or SAE which in the investigator’s 
opinion, is possibly related to suicidality, the Possible Suicidality Related Adverse Events 
(PSRAE) eCRF form should be completed (in addition to the AE and SAE pages, as 
appropriate).


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This event may include, but is not limited to, one that involves suicidal ideation, a 
preparatory act toward imminent suicidal behavior, a suicide attempt, or a completed 
suicide. The investigator will exercise his or her medical and scientific judgment in 
deciding whether an event is possibly related to suicidality.
7.4.6.
Pregnancy
Details of all pregnancies in female subjects will be collected from the start of dosing and 
until seven days after the last dose.
If a pregnancy is reported then the investigator should inform PPD within 24 hours of 
learning of the pregnancy and should follow the procedures outlined in Appendix 10.
7.4.7.
Height and Weight
Height and weight will be measured as specified in the Time and Events Table (Section 
7.1). Weight will be measured with the subject wearing indoor daytime clothing with no 
shoes. For in-center HD subjects, weight will be measured pre and post-dialysis. For 
HHD subjects, weight will be done at study visits between dialysis sessions.  For PD 
subjects, this assessment will be done at study visits, as per standard of care.
EDW will be reported at each study visit as specified in the Time and Events Table 
(Section 7.1).
7.4.8.
Blood Pressure and Heart Rate
Measurement of systolic blood pressure (SBP), diastolic blood pressure (DBP) and HR 
will be taken at the time points specified in the Time and Events Table Section 7.1.

One measurement each of SBP, DBP and HR will be taken, except at Day 1, 
Week 52, End of Study visit, and at the Early Treatment Discontinuation visit (if 
applicable), when SBP, DBP and HR will be measured in triplicate. 

Measurements will be taken with the subject in a semi-supine or seated position in 
the dialysis chair after at least a 5-minute rest period (pre- and post-dialysis).
For in-center HD subjects, SBP, DBP and HR will be measured pre and post-dialysis. For 
HHD subjects, these assessments will be done at study visits between dialysis sessions.  
For PD subjects, this assessment will be done at study visits, as per standard of care.
SBP, DBP, and HR will be performed before collection of blood samples for laboratory 
testing, where applicable (e.g., would not apply for post-HD measurement).
7.4.9.
Electrocardiogram (ECG)
ECG measurements will be taken at the time points specified in the Time and Events 
Table (Section 7.1). Full 12-lead ECGs will be recorded with the subject in a supine 
position. HR, PR interval, QRS duration, and QT (uncorrected) interval will be measured. 
QTcB will be calculated (machine-read or manually).


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For the Day 1 ECG, two additional ECGs are required if the initial ECG indicates 
prolonged QTc (see Section 5.2) using the automated or manually calculated QTcB 
value.  The average QTcB value of all three ECGs will be used to determine eligibility 
(see Section 5.2). Additional details are provided in the SRM.
ECG data will be read locally by a physician with experience in reading and interpreting 
ECGs.  The over-read of the Day 1 ECG is required to confirm eligibility. Additional 
details are provided in the SRM.
All ECGs will be performed before measurement of SBP, DBP, and HR and before 
collection of blood samples for laboratory testing, where applicable (e.g., would not 
apply if ECG is performed post-HD).
7.4.10.
Ultrasound
An ultrasound of the kidneys and adrenal glands will be performed prior to 
randomization (Day 1). It is understood that the adrenal glands will not always be able to 
be visualized. Non-visualization of the adrenals is not a reason to exclude from 
randomization. Further details are provided in the SRM.
A documented ultrasound of the kidneys within the 6 months prior to screening may be 
used to assess entry criteria (see Section 5.2), provided the size and cyst category has 
been reported. If a more sensitive imaging study (e.g., MRI, CT) has been performed 
within this timeframe and a report is available, this may be used in place of the 
ultrasound.
7.4.11.
Clinical Laboratory Assessments
All protocol required laboratory assessments, as defined in Table 10, must be conducted 
in accordance with the Laboratory Manual, and Protocol Time and Events Schedule 
(Section 7.1). Laboratory assessments will be done pre-dialysis for in-center HD 
subjects, in between dialysis sessions for HHD subjects at the study visits, and at the 
study visits for PD subjects, as per standard of care.
Laboratory requisition forms must be completed and samples must be clearly labeled 
with the subject number, protocol number, site/center number, and visit date. Details for 
the preparation and shipment of samples will be provided by the laboratory and are 
detailed in the SRM. Reference ranges for all safety parameters will be provided to the 
site by the laboratory responsible for the assessments.
If additional non-protocol specified laboratory assessments are performed at the 
institution’s local laboratory and result in a change in subject management or are 
considered clinically significant by the investigator (e.g., SAE or AE or dose 
modification) the results must be recorded in the source notes.
Refer to the SRM for appropriate processing and handling of samples.


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


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


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


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7.6.
Storage Biomarkers
Blood (serum and plasma) samples will be collected as outlined in the Time and Events 
Table (Section 7.1) for potential future analysis of biomarkers of CV risk and iron 
metabolism.
7.7.
Patient Reported Outcomes
The patient-reported effect of daprodustat and rhEPO on symptom, health-related quality 
of life (HR-QoL), and health status (e.g. utility) will be assessed.  Symptom severity will 
be assessed using the Patient Global Impression of Severity (PGI-S) and overall symptom 
change using the patient global impression of change (PGI-C). Quality of life will be 
measured via SF-36 and health status via the EQ-5D-5L and EQ-5D-VAS.  In addition, 
healthcare resource utilization will be assessed including outpatient visits.
All questionnaires used in this study have been translated, and culturally adapted for use 
in local country languages and will be administered electronically. Specific instructions 
on how the subject is to complete the scales and the process for data entry is provided in 
the SRM.  If there are exceptional circumstances whereby the electronic PRO 
assessments cannot be conducted, the completion of these assessments will be discussed 
with the sponsor on a case-by-case basis.
The severity, HR-QoL and Health Status questionnaires should be completed by subjects 
at a clinic visit, in the order specified: PGI-S, PGI-C, SF-36 then EQ-5D-5L and EQ-
VAS. Subjects who are unable to or require assistance to read must not complete the 
questionnaires.
7.7.1.
Patient Global Impression of Severity (PGI-S) and Patient Global 
Impression of Change (PGI-C)
The PGI-S is a 1-item questionnaire designed to assess subject’s impression of disease 
severity of their anemia of CKD.  It is measured on a 5-point disease severity scale 
(absent, mild, moderate, severe, or very severe) during the past 24 hours.
The PGI-C is a 1-item questionnaire designed to assess a subject’s impression of 
symptoms change of their anemia of CKD.  It is measured on a 7-point Likert-type 
response scale (very much improved, moderately improved, minimally improved, no 
change, minimally worse, moderately worse, or very much worse) since they first started 
the study. 
7.7.2.
Health Related Quality of Life (SF-36)
The SF-36 acute version is a general health status questionnaire designed to elucidate the 
subject’s self perception of their health on several domains, including physical 
functioning, role physical, bodily pain, vitality, social functioning, role emotional, mental 
health, and general health over the past seven days.  The questionnaire contains 36 
questions that ask the subject to recall how they felt during the past seven days.


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


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


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
Alternative: The difference in mean change in Hgb between baseline and EP, 
between treatment arms (daprodustat -rhEPO), is greater than -0.75 g/dL 
The non-inferiority margin is pre-defined as -0.75 g/dL; determined based upon a 
combination of clinical judgment, statistical reasoning and regulatory guidance for 
designing non-inferiority trials. 
Statistical significance of non-inferiority will be assessed at the one-sided 2.5% level. An 
ANCOVA model including prognostic randomization stratification factors (dialysis type 
and region), baseline Hgb and treatment will be used to obtain a point estimate and the
two-sided 95% CI for the treatment difference (daprodustat -rhEPO) and generate the p-
value for the non-inferiority test. The non-inferiority p-value will show strength of 
evidence against the null hypothesis. Non-inferiority will be established if the lower limit 
of the two-sided 95% CI for the treatment difference is greater than -0.75 g/dL.
The co-primary endpoints will be tested first. Non-inferiority needs to be established for 
both co-primary’s to proceed to evaluate MACE for superiority as well as the principal 
secondary endpoints for superiority. Principal secondary endpoints include prioritized 
composites for MACE (including thromboembolic events and hospitalizations for HF) 
and IV iron utilization (defined as the average monthly IV iron dose used to Week 52). 
Statistical testing of MACE for superiority as well as the principal secondary endpoints 
will be adjusted for multiplicity (Section 9.4.3).
9.2.
Sample Size Considerations
9.2.1.
Sample Size Assumptions
The size of this event driven trial is based on the co-primary CV safety objective and is 
determined by a fixed event target of 664 adjudicated first MACE. This provides 
approximately 90% power to establish non-inferiority assuming a true underlying 3% 
lower relative risk of MACE in favor of daprodustat compared to rhEPO (i.e., hazard 
ratio=0.97) and 82% power for non-inferiority under the assumption that the true 
underlying risk of MACE is the same in both arms (i.e., hazard ratio=1.00). Other 
assumptions behind the sample size calculation include:

Projected annual adjudicated first MACE rate of 11%. All-cause death is expected 
to be the most prevalent component, followed by non-fatal MI and then non-fatal 
stroke (projected break down of 60%, 30% and 10% respectively). 

Variance under the alternative hypothesis (i.e. hazard ratio=0.97) 

1% annual lost to follow-up without vital status

A two-sided 95% CI is used for analysis
The target of 664 adjudicated first MACE will permit a two-sided 95% CI of (0.859, 
1.164) to describe the results for an observed hazard ratio of 1. The largest hazard ratio 
point estimate (two-sided 95% CI) that would meet the statistical criterion for non-
inferiority is 1.074 (0.922, 1.250) and for superiority, the minimum observable effect 
would be a 14.1% relative risk reduction in favor of daprodustat, corresponding to a 
hazard ratio of 0.859. 


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


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


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MACE analysis. A sensitivity “tipping point” analysis utilizing multiple imputation for 
randomized subjects who have withdrawn from the study will be performed, as well as a
supportive “on-drug” analysis to evaluate the comparative treatment effect during the 
time that subjects remain on randomized treatment (plus a window of 28 days). Full 
details will be provided in the RAP.
In addition, analyses will be performed for each component of MACE (all-cause
mortality, MI and stroke) to understand individual contributions to the overall MACE 
result and to assess component directional consistency. These analyses will not be 
multiplicity adjusted. Further subgroup and covariate adjusted analyses of specific 
clinical interest are detailed in Section 9.4.4 and the RAP.
9.4.1.2.
Primary Efficacy Analysis (co-primary)
Mean change in Hgb between baseline and the EP (Weeks 28 to 52): The primary 
efficacy estimand is the effect of daprodustat relative to rhEPO on the change in Hgb 
from baseline to the average of all values in the EP, regardless of adherence to treatment 
including interruptions and discontinuation, the use of non-randomized ESA medication 
for any reason including rescue therapy, or the use of blood transfusions, in subjects on 
dialysis currently treated with an ESA with anemia secondary to CKD and assuming 
subjects do not die before the end of the EP. The analysis will use an ANCOVA model. 
For each subject, baseline Hgb will be the value obtained on Day 1, prior to taking 
randomized treatment, and Hgb during EP will be determined by calculating the mean of 
all available and imputed Hgb values between Weeks 28 to 52 inclusive regardless of 
adherence to randomized treatment. The ANCOVA model will include prognostic 
randomization stratification factors (dialysis type and region), baseline hemoglobin and 
treatment. It will provide a point estimate and two-sided 95% CI for the treatment effect 
together with the one-sided non-inferiority test p-value. Non-inferiority will be 
established if the lower limit of the two-sided 95% CI is greater than the margin of -0.75 
g/dL. Imputation will be used for missing Hgb data; further details will be provided in the 
RAP.
Sensitivity and Supportive Analyses: Sensitivity analyses for the primary estimand will 
include a multiple imputation-based “tipping point” analysis where assumptions are 
adjusted until non-inferiority is lost by imputing data for subjects who did not fully 
complete the EP. A supportive analysis will evaluate efficacy in those subjects who 
adhere to randomized treatment, defined as ITT subjects with at least one on-treatment 
Hgb during the EP (this approach corresponds to evaluating an efficacy estimand). A 
supportive “tipping point” analysis as that described above for the primary analysis will 
be performed for this “on-drug” analysis. In addition, a per-protocol supportive analysis 
will estimate the treatment effect in subjects who strongly adhere to the protocol, and 
supportive analyses to explore a shorter EP (Weeks 28 to 36) will be performed for the 
co-primary effectiveness estimand and “on-drug” efficacy estimand. Full details of all 
sensitivity and supportive analyses will be provided in the RAP.


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


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


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Although subgroup analyses aim to assess for consistency with the overall results, they 
may have low power, especially if the subgroup is small or has a low number of events. 
Statistical models will be adjusted for the covariates used in the original analysis, 
subgroup, treatment and treatment by subgroup interaction. Point estimates and two-sided 
95% CIs will be estimated (presented on Forest Plots) and the subgroup by treatment 
interaction p-value calculated. Subgroup analyses will not be adjusted for multiplicity. 
Further subgroups/covariates may be defined in the RAP.
Category
Subgroups
Age 
<65 years , ≥65 years - <75, ≥75 years 
Gender 
Female, Male 
Race group 
American Indian or Alaskan Native, Asian, Black, Native 
Hawaiian or Other Pacific Islander, White, Mixed Race 
Ethnicity 
Hispanic, non-Hispanic 
Region 
Appendix 3
Country 
Appendix 3
Dialysis type 
HD, PD (repeat using HD, HDF/HF, PD)
Dialysis vintage
0 to <2 years, 2 to <5 years, ≥5 years
Prior rhEPO dose 
<7,000 U/week, ≥7,000 U/week
rhEPO Hypo-responsiveness 
No, yes (see below for definition)
Baseline Hgb
<9, 9 to <10, 10 to 11, >11 g/dL
BMI 
<30, ≥30 kg/m2
Weight 
< 75kg, ≥75kg 
Baseline hsCRP
≤3 mg/L, >3 mg/L
United states
US, Non-US
rhEPO hyporesponder subgroup definition:  rhEPO hyporesponders will be identified 
either by the ESA Resistance Index (ERI) [HERO study, Johnson, 2015] or by treatment 
at baseline with a very high dose of IV epoetin alpha.  For each subject, baseline ERI will 
be calculated as the dry weight adjusted weekly mean ESA dose during the 8 week 
screening period divided by baseline Hgb concentration. Subjects with baseline ERI 
≥2 U/kg/wk/g/L for epoetin-treated subjects; ≥0.008 g/kg/wk/g/L for darbepoetin-
treated subjects and ≥0.01 g/kg/wk/g/L for methoxy-PEG-epoetin-treated subjects will 
be included in the pre-specified subgroup. In addition, subjects will be included if being 
treated at baseline with greater than or equal to the equivalent of 450 U/kg/week of IV 
epoetin alpha. This latter criterion covers subjects at higher body weight for which the 
ERI calculation is less accurate and is based on the NICE anemia guidelines of June 2015 
[NICE, 2015]. Sensitivity analyses will explore alternative subgroup definitions: an ERI 
cut-point of ≥1.5 (or equivalent depending on ESA treatment) or using baseline prior 
rhEPO dose above the top 20th percentile for the study population.
rhEPO hyporesponder subgroup analysis plan:  It is anticipated that approximately 
10-15% of subjects may be classified as rhEPO hyporesponders according to this 


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


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


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


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


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provided reasonable access to statistical tables, figures, and relevant reports and will 
have the opportunity to review the complete study results at a GSK site or other 
mutually-agreeable location.

All study investigators will be provided with the full summary of the study results.  
The investigator is encouraged to share the summary results with the study subjects, 
as appropriate.

The procedures and timing for public disclosure of the results summary and for 
development of a manuscript for publication will be in accordance with GSK Policy.
10.8.
Review Committees
In addition to GSK, medical governance will also be provided by the following 
independent committees. Additional information about each committee is included in the 
respective committee charter which is available upon request.
10.8.1.
Independent Data Monitoring Committee
An IDMC will be utilized in this study to ensure external objective review of safety and 
efficacy data in order to protect the ethical and safety interests of subjects and to protect 
the scientific validity of the study.  The schedule of any planned interim analysis and the 
analysis plan for IDMC review is described in the charter.
10.8.2.
Clinical Events Committee
An external independent Clinical Events Committee blinded to treatment allocation will 
adjudicate all events reported during this study that constitute the co-primary CV safety 
endpoint of MACE [composite of all-cause mortality, non-fatal MI and non-fatal stroke], 
the principal CV secondary composite endpoints of MACE plus additional components 
including events of vascular access thrombosis, symptomatic deep vein thrombosis, 
symptomatic pulmonary embolism, CV mortality and hospitalization for HF. 
10.8.3.
Executive Steering Committee
The Executive Steering Committee is the primary external advisory group for GSK. The 
committee provides academic leadership, ensures proper study conduct and conformance 
to the protocol, advises and recommends changes to the protocol based on emerging 
scientific and/or clinical advances, advises on the selection of study sites, communicates 
with the media and external audiences when appropriate, and works with the sponsor to 
assist in patient identification strategies. 
10.8.4.
Steering Committee
The Steering Committee in collaboration with the Executive Steering Committee is 
responsible for the scientific oversight of all aspects of study conduct and will provide 
advice to the National Leader Committee.  


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


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


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12.
APPENDICES
12.1.
Appendix 1: Abbreviations and Trademarks
Abbreviations
ABPM
Ambulatory blood pressure monitoring
AE
Adverse event
ALT
Alanine transaminase
ANCOVA
Analysis of Covariance
ANSM
L'Agence nationale de sécurité du médicament et des 
produits de santé 
AST
Aspartate transaminase
BP
Blood pressure
CEC
Clinical Events Classification
CI
Confidence interval
CKD
Chronic kidney disease
CNIL
Commission Nationale de I'Informatique et des Libertés
CPK
Creatine phosphokinase 
CRA
Clinical Research Assistant 
CT
Computed tomography
CTR
Clinical Trials Register
CV
Cardiovascular
DBP
Diastolic blood pressure
DGF
Delayed graft function
ECG
Electrocardiogram
eCRF
Electronic case report form
EDW
Estimated dry weight
EP
Evaluation period
EPO
Erythropoietin
EQ-5D-5L
EuroQol 5 Dimension 5 Level Health Utility Index
EQ-VAS
EuroQol Visual Analogue Scale 
ESA
Erythropoiesis-stimulating agent
FDA
Food and Drug Administration
FRP
Females of reproductive potential
FSH
Follicle stimulating hormone
GCP
Good Clinical Practice
GI
Gastrointestinal
GSK
GlaxoSmithKline
HbA1c
Glycated hemoglobin
hCG
Human chorionic gonadotrophin
HD
Hemodialysis
HDF
Hemodiafiltration
HDL-c
High density lipoprotein-C
HDPE
High density polyethylene
HF
Heart failure


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Hgb
Hemoglobin
HHD
Home hemodialysis
HIF
Hypoxia-inducible factor
HIF-PHI
Hypoxia inducible factor prolyl hydroxylase inhibitor 
HR
Heart rate
HR-QoL
Health Related Quality of Life
HRT
Hormone replacement therapy
hsCRP
High sensitivity C-reactive protein
IB
Investigator’s Brochure
ICH
International Conference on Harmonization
IDMC
Independent Data Monitoring Committee
IEC
Independent Ethics Committee
iPTH,
Intact parathyroid hormone
IRB
Institutional Review Board
IRT
Interactive Response Technology
ITT
Intent-to-treat
IV
Intravenous
KDIGO
Kidney Disease Improving Global Outcomes
KDOQI
Kidney Disease Outcomes Quality Initiative
LDH
Lactate dehydrogenase 
LDL-C
Low density lipoprotein-C
MACE
Major adverse cardiovascular event
MAP
Mean arterial pressure
MCH
Mean corpuscular hemoglobin;, 
MCHC
Mean corpuscular hemoglobin concentration
MCS
Mental Component Score
MCV
Mean corpuscular volume
MedDRA
Medical Dictionary for Regulatory Activities
MI
Myocardial infarction
mITT
Modified intent-to-treat
MRI
Magnetic resonance imaging
MSDS
Material Safety Data Sheet
NYHA
New York Heart Association
PASP
Pulmonary Artery Systolic Pressure
PCS
Physical Component Score
PD
Peritoneal dialysis
PEG
Polyethylene glycol
PFS
Pre-filled syringe
PGI-C
Patient Global Impression of Change
PGI-S
Patient Global Impression of Severity
PK
Pharmacokinetic
PP
Per protocol
PPD
Pharmaceutical Product Development, LLC
PRBC
Packed red blood cells
PRS
Project specific requirement
PSRAE
Possible Suicidality Related Adverse Events 


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QC
Quality control
RAP
Reporting and Analysis Plan
RBC
Red blood cell
RDW
Red blood cell distribution width
rhEPO
Recombinant human erythropoietin 
SAE
Serious adverse event
SBP
Systolic blood pressure
SC
Subcutaneous
SD
Standard deviation
SDAC
Statistical Data Analysis Center
SRM
Study Reference Manual
TIBC
Total iron binding capacity
TSAT
Transferrin saturation
U
Units
UIBC
Unsaturated iron binding capacity
ULN
Upper limit of normal
US
United States
VEGF
Vascular endothelial growth factor
WBC
White blood cells;
Trademark Information
Trademarks of the GlaxoSmithKline 
group of companies
Trademarks not owned by the 
GlaxoSmithKline group of companies
NONE
HemoCue


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


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Objectives
Endpoints
Exploratory Objectives
Exploratory Endpoints (statistical testing not 
planned)

To further compare daprodustat and rhEPO 
on Hgb variability

Hgb observed and change from baseline across all 
visits to end of treatment

% of time Hgb is above, within and below the 
range of 10-11.5 g/dL during EP and MP

Number (%) of subjects with mean Hgb above, 
within and below the Hgb analysis range during EP 
and at the end of treatment 

Number (%) of subjects with a Hgb <7.5 g/dL
during the EP and MP

Number of times Hgb < 7.5 g/dL during the EP and 
MP

Number (%) of subjects with a >1g/dL increase in 
Hgb over 2 weeks (assessed at Week 2 and Week 
4) or a >2 g/dL increase in Hgb within any 4 week 
period from Week 4 to Week 52

Number (%) of subjects with a >1g/dL decrease in 
Hgb over 2 weeks (assessed at Week 2 and Week 
4) or a >2 g/dL decrease in Hgb within any 4 week 
period from Week 4 to Week 52

N (%) of subjects with a Hgb value ≥ 12 g/dL 
during the EP and MP

Number of times Hgb ≥ 12 g/dL during the EP and 
MP

% of time Hgb ≥ 12 g/dL during the EP and MP

To compare daprodustat to rhEPO on 
measures of iron parameters

Observed and change from baseline in hepcidin, 
ferritin, TSAT, total iron, TIBC across all visits to 
end of treatment

Average quarterly ferritin

Average quarterly TSAT

Average quarterly IV iron dose/subject

N (%) of subject who met iron management criteria

N (%) of subjects who reduced IV iron 
supplementation relative to baseline (defined as 
total iron (mg) over 4 weeks prior to randomization) 
during EP (defined as average monthly IV iron 
dose (mg) over Weeks 28 to 52)

To further  compare daprodustat to rhEPO 
on BP and BP medication changes  

Observed and change from baseline in SBP, DBP 
and MAP by visit

Number of BP medications per subject by visit

Change from baseline in the number of BP 
medications per subject by visit

N (%) of subjects who had no change, an increase 
or a decrease in the dosage or number of BP 
medications from baseline by visit

To compare daprodustat to rhEPO on the 
need for RBC and whole blood transfusions

Number (%) of subjects who receive at least one 
RBC or whole blood transfusions by Week 52 and 
by end of treatment


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Objectives
Endpoints

Number of RBC and whole blood transfusions per 
100 patient years 

Number of RBC and whole blood units per 100 
patient years

To compare daprodustat to rhEPO on lipid 
parameters. 

Observed and % change from baseline in lipid 
parameters by visit [total cholesterol, direct low 
density lipoprotein cholesterol (LDL-C), high 
density lipoprotein cholesterol (HDL-C)]

To compare the effect of daprodustat to 
rhEPO on delayed graft function (DGF) after 
deceased donor kidney transplantation

Number (%) of subjects experiencing DGF after 
deceased donor kidney transplantation (where 
DGF is defined as the use of dialysis within 7 days 
of the transplant)

Length of time that subjects experience DGF after 
deceased donor kidney transplantation

Evaluate the dose adjustment schemes

Assigned dose by visit and at Day 1, Week 28, 
Week 52, and yearly

Most recent dose prior to Week 28, Week 52, 
yearly and End of Treatment

Number (%) of patients with 0, 1, 2, or >2 dose 
adjustments during the following periods:
o
Day 1 - < Week 28
o
Week 28 - < Week 52
o
Day 1 - < End of Treatment

Number of dose adjustments during the following 
periods:
o
Day 1 - < Week 28
o
Week 28 - < Week 52
o
Day 1 - < End of Treatment

Number of dose adjustments per year during Day 
1 - < End of Treatment

Time dose held for Hgb≥12 g/dL

To further compare daprodustat to rhEPO on 
HRQoL and Utility score

Change from baseline in Health Utility I (EQ-5D-
5L) score at Weeks 8,12, 28, 52, yearly, EOS

Change from baseline in EQ VAS at Weeks 8, 12, 
28, 52, yearly, EOS

To further compare daprodustat to rhEPO on 
the symptom severity and change

Shift tables (Baseline to Weeks 8, 12, 28, and 52) 
in PGI-S

N(%) of patients within each PGI-C symptom 
change level at Weeks 8, 12, 28, 52.
Conversion from g/dL to g/L is 1:10 and from g/dL to mmol/L is 0.6206.  For example, Hgb of 10 to 11.g/dL is 
equivalent to 100-110g/L or 6.2 to 6.8 mmol/L.
1.
Hgb change from baseline to Wk 52 is tested for non-inferiority, using the -0.75 g/dL margin used in the co-
primary analysis.  % time in range is tested first for non-inferiority, then for superiority.
2.
Events adjudicated.


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


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12.4.
Appendix 4: Risk Assessment
Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Daprodustat 
Excessive erythropoiesis (polycythemia) leading to 
thrombosis and/or tissue ischemia
In animal studies, excessive erythropoiesis attributed to daprodustat 
was associated with vascular congestion/inflammation, microthrombi, 
and tissue ischemia in a number of organs.
Following review of clinical data received to date, this has not been 
identified as a safety concern for daprodustat.
Phase 2 dose-ranging studies, and associated statistical and exposure 
response modelling has informed Phase 3 dose rationale, starting 
doses, dose steps, and dose adjustment scheme to optimize Hgb 
management.

Specific eligibility criteria related to 
requirements for entry Hgb are detailed in 
Section 5.1.

Hgb will be closely monitored throughout the 
dosing period as outlined in the Time and 
Events Table Section 7.1.

Specific guidance for dose adjustment, dose 
interruption, or discontinuation of daprodustat 
based on achieved Hgb (including rate of 
change) is provided in Section 6.3 and 
Section 6.12.

Unblinded monitoring of safety data by an 
IDMC in-stream throughout the study.
Worsening of hypertension
In a dog cardiovascular study, single oral doses of daprodustat (up to 
90 mg/kg) did not produce effects on blood pressure.
Marketed rhEPO and its analogues have been associated with risks 
related to uncontrolled hypertension, including the need for initiation of 
or increases in antihypertensive therapy when used in patients with 
anemia of CKD (i.e. 25% Epogen, 27% Mircera, and 40% Aranesp 
treated patients with renal anemia required initiation or increase in 
their anti-hypertensive medications; hypertensive encephalopathy and 
seizures have been reported. The contribution of rhEPO-associated 
hypertension to the unfavourable effects on cardiovascular outcomes 
remains uncertain).
Integrated AE data from clinical trials with daprodustat [including 2 
global phase 2b studies (24-week treatment duration) and 2 Japanese 

Blood pressure will be closely monitored 
throughout the dosing period as outlined in the 
Time and Events Table Section 7.1.

Unblinded monitoring of safety data by an 
IDMC in-stream throughout the study.


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


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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
this risk.
IDMC in-stream throughout the study.

Planned formal interim analyses with stopping 
guidelines for evidence of increased CV risk 
as outlined in Section 9.4.5.


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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Esophageal and gastric erosions
In animal studies, undesirable GI effects including emesis, abnormal 
feces and/or decreased food consumption/body weight loss and 
stomach erosions/ ulcers with hemorrhage were observed with 
daprodustat.  
In rats, stomach erosions were observed with intravenous and oral 
administration of daprodustat.
Stomach erosions/ulcers also reported in rats with some marketed 
rhEPO and its analogs.
In clinical trials to date with daprodustat, mild-moderate GI signs and 
symptoms represent the most frequently reported adverse event, 
however causal association has not been established.
Following review of clinical data received to date, GI erosions have not 
been identified as a safety concern for daprodustat.

Suspected GI bleeding or significant 
symptoms consistent with erosions or ulcers 
should be investigated diagnostically (i.e. 
endoscopic examination) as clinically 
warranted.

Unblinded monitoring of safety data by an 
IDMC in-stream throughout the study.
Cancer-related mortality and tumor progression and 
recurrence
Marketed rhEPO and its analogs have been associated with increased 
risk of cancer related morbidity and mortality when used in patients 
with cancer.
Administration of 60mg/kg daprodustat to mice caused minimal 
increases in circulating VEGF while significant EPO increases were 
observed.
There were no test article-related neoplastic findings in a 2-year rat 
(oral daprodustat) or mouse (daprodustat + subcutaneous injection of 
the 3 major human metabolites; M2, M3 and M13) carcinogenicity 
studies.
In clinical studies conducted to date, administration of daprodustat has 
been associated with:
Once daily administration:

In studies up to 4 weeks duration, a dose-ordered increase in 

Specific eligibility criteria related to personal 
history of malignancy or subjects with 
complex kidney cyst are outlined in Section 
5.2.

Stopping criteria for subjects with treatment 
emergent malignancy are outlined in Section 
5.5.

Unblinded monitoring of safety data by an 
IDMC in-stream throughout the study.


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VEGF plasma concentrations was observed at doses ranging 
from 10 to 150 mg. 

In studies up to 24 weeks duration at doses up to 25mg, changes 
in VEGF plasma concentration were variable but similar relative 
to control.

Systemic EPO concentrations within the physiologic range.
Three times weekly administration:

In studies up to 4 weeks duration at doses of 10 to 30 mg:
o
Dose dependent increases in plasma VEGF and EPO 
concentrations were observed.
o
Pre-dose concentrations of EPO and VEGF were near 
or below baseline indicating no accumulation of EPO or 
VEGF after three times weekly dosing.
Following review of clinical data received to date, this has not been 
identified as a safety concern for daprodustat. 
Pulmonary artery hypertension (PAH)
A role for HIF-regulated pathways in the pathophysiology of PAH has 
been suggested based on well established effects of acute and chronic 
hypoxia in man on the pulmonary vasculature (vasoconstriction), and 
by findings in patients with naturally occurring mutations that result in 
decreased HIF degradation [Smith, 2006; Formenti, 2011].
There have been no histopathologic findings suggestive of PAH in pre-
clinical safety studies with daprodustat up to 13 weeks duration in 
dogs, up to 2 years in rats and mice, and up to 39 weeks in monkeys.
Acute hypoxic challenge (rats):  Daprodustat produced increases in 
peak right ventricular pressure (PRVP) during acute hypoxia that were 
slightly higher than the vehicle control group. However, these hypoxia-
induced PRVP changes were within the range of PRVP changes noted 

Unblinded monitoring of safety data by an 
IDMC in-stream throughout the study.


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among untreated rats.
Results from a clinical study of acute hypoxic challenge in healthy 
volunteers demonstrated that short-term (5 days) therapy with 
daprodustat 5mg or 100mg has no clinically significant effect on 
transthoracic echocardiographic (ECHO) estimates of pulmonary 
artery systolic pressure (PASP) under either normoxic or hypoxic 
conditions.
ECHO assessments performed in Phase 2b studies (24 weeks 
treatment duration) did not identify any clinically meaningful changes in 
PASP in subjects not on dialysis for daprodustat. In hemodialysis 
subjects, mean absolute change from baseline in PASP was similar for 
both treatment groups; however, there was a numeric imbalance 
(Daprodustat: 8 [7%]; Control 0) in subjects reaching the PASP PCI 
(>20 mmHg increase from baseline). Regarding this imbalance, there 
were a number of confounding factors in the study, most notably a 
4.5:1 randomization scheme and inconsistency in timing of ECHOs 
relative to dialysis day.  Additionally, 2 of 3 subjects with resolution of 
PASP on safety follow-up ECHOs had confounding conditions that 
could contribute to resolution other than discontinuation of study 
treatment; and there was no dose relationship for subjects meeting the 
PASP PCI criterion. Overall, there is insufficient evidence to conclude 
a relationship to treatment with daprodustat.
Following review of clinical data received to date, this has not been 
identified as a safety concern for daprodustat.  
Cardiomyopathy
Published data suggest that cardiac effects of HIF stabilization are 
likely a function of the mechanism, extent, and duration of the effects, 
and can range from protective to detrimental depending upon the 
specific model and experimental conditions utilized.
With lifetime exposure to daprodustat in a 2-year rat oral 
carcinogenicity study, an exacerbation of rat spontaneous, progressive 
cardiomyopathy (PCM)(focal myofiber degeneration/necrosis with 

Unblinded monitoring of safety data by an 
IDMC in-stream throughout the study.


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inflammatory infiltrates) was observed at doses of 0.8 mg/kg/day and 
above, although total incidence and severity distribution within any 
daprodustat-group were within historical control ranges.  This is 
consistent with an equivocal threshold for exacerbation of 
spontaneous, progressive cardiomyopathy at 0.8 mg/kg/day which is 
also the threshold dose for observing increased Hct values in 
individual rats.  Cardiomyopathy has not been associated with 
naturally occurring mutation in man which results in increased HIF 
stabilization.
ECHO assessments performed in phase 2b studies (24 weeks 
treatment duration) did not identify any clinically meaningful changes in 
LVEF for daprodustat.
Following review of clinical data received to date, this has not been 
identified as a safety concern for daprodustat.
Proliferative retinopathy, macular edema, choroidal 
neovascularization
Increases in local (ocular) VEGF production with retinal 
neovascularization and macular edema observed in diabetic 
retinopathy and to choroidal leakage, edema and neovascularization 
seen in age-related macular degeneration [Campochiaro, 2006].
Administration of 60 mg/kg daprodustat to mice caused minimal 
increases in circulating VEGF while significant EPO increases were 
observed.
Aside from congestion of retinal vessels and optic disc hyperemia 
secondary to markedly increased red cell mass, there were no ocular 
abnormalities observed in non-clinical studies.
In clinical studies up to 4 weeks duration, a dose-ordered increase in 
VEGF plasma concentrations was observed at doses ranging from 10 
to 150 mg administered once daily and from 10 to 30 mg administered 
three times weekly. In studies up to 24 weeks duration at doses up to 
25 mg, changes in VEGF plasma concentrations were variable but 

Suspected proliferative retinopathy, macular 
edema, choroidal neovascularization or
symptoms consistent with these events should 
be investigated by ophthalmologic consultation 
as clinically warranted.

Unblinded monitoring of safety data by an 
IDMC in-stream throughout the study.


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similar relative to control.
Ophthalmologic assessments performed in phase 2b studies (24 
weeks treatment duration) did not identify any clinically meaningful 
changes in proliferative retinopathy, macular edema, or choroidal 
neovascularization with daprodustat.
Following review of clinical data with daprodustat received to date, this 
has not been identified as a safety concern for daprodustat.
Exacerbation of rheumatoid arthritis
In inflamed rheumatic joints, activation of HIF- related genes 
secondary to decreased oxygen and pro-inflammatory cytokines has 
been postulated to contribute to the neo-angiogenesis, proliferation 
and infiltration of rheumatoid synovial fibroblasts [Westra, 2010; Muz, 
2009].
No abnormalities seen in non-clinical studies conducted to date for 
daprodustat.
Following review of clinical data received to date, this has not been 
identified as a safety concern for daprodustat.

Unblinded monitoring of safety data by an 
IDMC in-stream throughout the study.


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Potential Risk of Clinical Significance
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Drug-drug interactions
Daprodustat is a substrate of CYP2C8:  Co-administration of 
daprodustat with a strong CYP2C8 inhibitor (gemfibrozil) increased the 
Cmax and AUC of daprodustat, 4- and 19-fold, respectively, while co-
administration of a weak inhibitor (trimethoprim) increased the Cmax 
and AUC of daprodustat by 1.3- and 1.5-fold, respectively. Population 
PK analysis from completed Phase 2 studies suggests that co-
administration of daprodustat with a moderate CYP2C8 inhibitor 
(clopidogrel), leads to a ~ 2-fold increase in AUC, with no clinically-
significant increase in the measured Hgb response. Although CYP2C8 
induction studies were not performed, co-administration of daprodustat 
with an inducer of CYP2C8 (e.g., rifampin/rifampicin) may decrease 
the exposure of daprodustat.
Even though co-administration of daprodustat with strong inhibitors 
and inducers of CYP2C8 is prohibited, inadvertent co-administration 
may occur. Due to the known time delay in enhancing erythropoiesis 
by daprodustat, co-administration with strong CYP2C8 inhibitors for up 
to 14 days is not anticipated to lead to immediate marked increases in 
hemoglobin levels. Therefore, there is adequate time to change to 
alternate therapy that does not inhibit CYP2C8.
Additionally, as the time for maximum induction of CYP2C8 occurs 
after approximately 10-14 days of dosing with rifampin (Brodie, 2013 
and Ohnhaus, 1989), daprodustat systemic exposure will decrease 
over time which will result in a lag period before an effect on Hgb is 
recognized and is of clinical concern.
Daprodustat is an inhibitor of CYP2C8:  A clinical drug interaction 
study between 25mg and 100mg daprodustat with a CYP2C8 
substrate (i.e., pioglitazone) showed that there is no PK interaction at 
these doses of daprodustat.  
Daprodustat is a substrate of BCRP: Population PK analysis from 
Phase 2 studies suggested that while BCRP inhibitors were a 
covariate for daprodustat CL/F (8.6% lower clearance) the predicted 

Co-administration of daprodustat with strong 
CYP2C8 inhibitors (e.g., gemfibrozil) and 
inducers (e.g., rifampin/rifampicin) is not 
permitted as outlined in Section 6.10.2.

Co-administration of daprodustat with 
moderate CYP2C8 inhibitors (i.e., clopidogrel, 
teriflunomide, deferasirox) should be 
performed with caution. If one of these 
medications is started, stopped or the dose is 
changed, Hgb should be monitored every 4 
weeks for 12 weeks as outlined in Section 6.3
and Appendix 6.

Specific guidance on the management of 
potential drug-drug interactions and 
concomitant medications is provided in 
Section 6.10.

Hgb will be closely monitored throughout the 
dosing period as outlined in the Time and 
Events Table Section 7.1.

Specific guidance for dose adjustment, dose 
interruption, or discontinuation of daprodustat 
based on achieved Hgb is provided in Section 
6.3 and Appendix 6.

Unblinded monitoring of safety data by an 
IDMC in-stream throughout the study.


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change in exposure was not considered to be of clinical relevance.  
Daprodustat is an inhibitor of OATP1B1/1B3: A clinical drug interaction 
study between 25mg and 100mg daprodustat with an OATP1B1/1B3 
substrate (rosuvastatin) showed that there is no PK interaction at 
these doses of daprodustat.
Other
rhEPO risks (Control)
See risks outlined in table for daprodustat for excessive erythropoiesis 
(polycythemia) leading to thrombosis and/or tissue ischemia, death, 
MI, stroke, heart failure, thromboembolic events, thrombosis of 
vascular access, and for cancer-related mortality and tumor 
progression.
Uncontrolled hypertension
Pure red cell aplasia

See mitigation strategies outlined in table for 
daprodustat for excessive erythropoiesis 
(polycythemia) leading to thrombosis and/or 
tissue ischemia; death, MI, stroke, heart 
failure, thromboembolic events, thrombosis of 
vascular access; and for cancer-related 
mortality and tumor progression.

Specific eligibility criteria related to current 
uncontrolled hypertension are outlined in 
Section 5.2.

Specific eligibility criteria related to personal 
history of pure red cell aplasia are outlined in 
Section 5.2.


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


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


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


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12.6.
Appendix 6: Randomized Treatment Dose Adjustment 
Schemes
HemoCue Hgb (g/dL) 
at current study visit1
HemoCue Hgb change since last 
study visit1
Randomized Treatment Dose 
Adjustment5
<7.52
Any change
Repeat Hgb and average values6; if 
confirmed, increase to the next higher 
dose step
7.5 to <9.5
Decreasing or No change7
Increase to the next higher dose step   
7.5 to <9.5
Increasing8
Maintain dose 
≥9.5 to <10 at two 
consecutive visits 
Decreasing or No change
Increase to the next higher dose step
≥9.5 to ≤11.5 
Any change 
Maintain dose 
>11 to ≤11.5 at two 
consecutive visits 
Increasing or No change
Decrease to the next lower dose step
>11.5 to <12 
Decreasing 
Maintain dose
>11.5 to <12
Increasing or No change
Decrease to the next lower dose step
123
Any change  
Repeat Hgb and average values6; if 
confirmed, temporary hold the dose and 
re-check Hgb at next study visit1; restart at 
one dose step lower when Hgb <11.5 g/dL 
and provided it has been at least 2 weeks 
from the prior study visit.
Any 
>2 g/dL increase over 4 weeks
(>1 g/dL increase over 2 weeks4)
Repeat Hgb and average values6; if 
confirmed, decrease to the next lower 
dose step
Any
>2 g/dL decrease over 4 weeks
(>1 g/dL decrease over 2 weeks4)
Repeat Hgb and average values6, if 
confirmed, increase to the next higher 
dose step
1.“Study visit” refers to mandated study visits (every 4 weeks through Week 52; then every 12 weeks).  From Week 52 
onwards, additional study visits to check Hgb and dispense randomized treatment (where directed by the IRT system)
are required under the following circumstances (additional visits have a visit window of ±1 week):

When Hgb at last study visit is outside of the target range, i.e., <10 or >11 g/dL:  Visit 4 weeks later to assess for 
dose adjustment.

When the dose of randomized treatment is changed or restarted in the previous 12 weeks ±1 week: Visits every 4 
weeks for 12 weeks. 

When a medication that is a moderate CYP2C8 inhibitor (i.e., clopidogrel, teriflunomide, deferasirox) is started, 
stopped, or the dose is changed: Visits every 4 weeks for 12 weeks.

When the investigator determines it clinically necessary to evaluate a subject sooner than 12 weeks later: Visit 4 
weeks later to assess for dose adjustment. 

For subjects changing dialysis modality from HD to PD:  Visits every 4 weeks for 12 weeks. 
2.This rule applies to any mandated visit or unscheduled visit, provided it has been at least 2 weeks from the prior 
study visit.
3.This rule applies to any mandated or unscheduled visit.
4.This rule applies to Week 2 and Week 4 visits only.
5.Those receiving the highest dose of randomized treatment who require a dose increase will maintain the same dose,
while those receiving the lowest dose of randomized treatment that require a dose decrease will have doses withheld.
6.Repeat HemoCue Hgb at the same study visit to confirm Hgb (using the same sample) and take average.
7.No change may be redefined as an increase of <0.5 g/dL based on the review of blinded instream aggregate Hgb 
data.
8.Increasing may be redefined as an increase of ≥0.5 g/dL based on the review of blinded instream aggregate Hgb 
data.


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12.7.
Appendix 7: Definition of and Procedures for Recording, 
Evaluating, Follow-Up and Reporting of Adverse Events
12.7.1.
Definition of Adverse Events
Adverse Event Definition:

An AE is any untoward medical occurrence in a patient or clinical investigation 
subject, temporally associated with the use of a medicinal product, whether or not 
considered related to the medicinal product.

NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a medicinal product.
Events meeting AE definition include:

Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) 
or other safety assessments (e.g., ECGs, radiological scans, SBP, DBP or HR 
measurements), including those that worsen from baseline, and felt to be clinically 
significant in the medical and scientific judgment of the investigator.

Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition.

New conditions detected or diagnosed after placebo run-in or randomized treatment 
administration even though it may have been present prior to the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected interaction.

Signs, symptoms, or the clinical sequelae of a suspected overdose of either placebo 
run-in, randomized treatment or a concomitant medication (overdose per se will not
be reported as an AE/SAE unless this is an intentional overdose taken with possible 
suicidal/self-harming intent.  This should be reported regardless of sequelae).

"Lack of efficacy" or "failure of expected pharmacological action" per se will not be 
reported as an AE or SAE.  However, the signs and symptoms and/or clinical 
sequelae resulting from lack of efficacy will be reported if they fulfill the definition 
of an AE or SAE.
Events NOT meeting definition of an AE include:

Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the subject’s condition.

The disease/disorder being studied or expected progression, signs, or symptoms of 
the disease/disorder being studied, unless more severe than expected for the subject’s 
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
Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that 
leads to the procedure is an AE.

Situations where an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).

Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present 
or detected at the start of the study that do not worsen.
12.7.2.
Definition of Serious Adverse Events
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met (e.g., hospitalization for signs/symptoms of the disease under study, 
death due to progression of disease, etc).
Serious Adverse Event (SAE) is defined as any untoward medical occurrence that, 
at any dose:
a.
Results in death
b.
Is life-threatening
NOTE:
The term 'life-threatening' in the definition of 'serious' refers to an event in which the 
subject was at risk of death at the time of the event.  It does not refer to an event, which 
hypothetically might have caused death, if it were more severe.
c.
Requires hospitalization or prolongation of existing hospitalization
NOTE:

In general, hospitalization signifies that the subject has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for 
observation and/or treatment that would not have been appropriate in the physician’s 
office or out-patient setting.  Complications that occur during hospitalization are 
AEs.  If a complication prolongs hospitalization or fulfills any other serious criteria, 
the event is serious.  When in doubt as to whether “hospitalization” occurred or was 
necessary, the AE should be considered serious.

Hospitalization for elective treatment of a pre-existing condition that did not worsen 
from baseline is not considered an AE.
d.
Results in disability/incapacity
NOTE:

The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.

This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 


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and accidental trauma (e.g. sprained ankle) which may interfere or prevent everyday 
life functions but do not constitute a substantial disruption
e.
Is a congenital anomaly/birth defect
f.
Other situations:

Medical or scientific judgment should be exercised in deciding whether reporting is 
appropriate in other situations, such as important medical events that may not be 
immediately life-threatening or result in death or hospitalization but may jeopardize 
the subject or may require medical or surgical intervention to prevent one of the 
other outcomes listed in the above definition.  These should also be considered 
serious.

Examples of such events are invasive or malignant cancers, intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse
g.
Is associated with liver injury and impaired liver function defined as:

ALT 3xULN and total bilirubin* 2xULN (>35% direct), or

ALT 3xULN and INR** >1.5.
* Serum bilirubin fractionation should be performed if testing is available.  If 
fractionation is unavailable and ALT 3xULN and total bilirubin 2xULN, then the 
event is still to be reported as an SAE.
** INR testing not required per protocol and the threshold value does not apply to 
subjects receiving anticoagulants.  If INR measurement is obtained, the value is to be 
recorded on the SAE form.
12.7.3.
Recording of AEs and SAEs
AEs and SAE Recording:

When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (e.g., hospital progress notes, laboratory, and diagnostics reports) 
relative to the event.

The investigator will then record all relevant information regarding an AE/SAE in 
the eCRF

It is not acceptable for the investigator to send photocopies of the subject’s medical 
records to PPD in lieu of completion of the GSK, AE/SAE eCRF page.

There may be instances when copies of medical records for certain cases are 
requested by PPD.  In this instance, all subject identifiers, with the exception of the 
subject number, will be blinded on the copies of the medical records prior to 
submission of to PPD.

The investigator will attempt to establish a diagnosis of the event based on signs, 


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symptoms, and/or other clinical information.  In such cases, the diagnosis will be 
documented as the AE/SAE and not the individual signs/symptoms.

Subject-completed Patient Reported Outcomes questionnaires and the collection of 
AE data are independent components of the study.
12.7.4.
Evaluating AEs and SAEs
Assessment of Intensity
The investigator will make an assessment of intensity for each AE and SAE reported 
during the study and will assign it to one of the following categories:

Mild:  An event that is easily tolerated by the subject, causing minimal discomfort 
and not interfering with everyday activities.

Moderate:  An event that is sufficiently discomforting to interfere with normal 
everyday activities

Severe:  An event that prevents normal everyday activities. - an AE that is assessed 
as severe will not be confused with an SAE. Severity is a category utilized for rating 
the intensity of an event; and both AEs and SAEs can be assessed as severe.

An event is defined as ‘serious’ when it meets at least one of the pre-defined 
outcomes as described in the definition of an SAE.
Assessment of Causality

The investigator is obligated to assess the relationship between placebo run-in or 
randomized treatment and the occurrence of each AE/SAE.

A "reasonable possibility" is meant to convey that there are facts/evidence or 
arguments to suggest a causal relationship, rather than a relationship cannot be ruled 
out.

The investigator will use clinical judgment to determine the relationship.

Alternative causes, such as natural history of the underlying diseases, concomitant 
therapy, other risk factors, and the temporal relationship of the event to the placebo 
run-in or randomized treatment will be considered and investigated.

The investigator will also consult the IB and/or Product Information, for marketed 
products, in the determination of his/her assessment.

For each AE/SAE the investigator must document in the medical notes that he/she 
has reviewed the AE/SAE and has provided an assessment of causality.

There may be situations when an SAE has occurred and the investigator has minimal 
information to include in the initial report to PPD.  However, it is very important 
that the investigator always make an assessment of causality for every event 


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prior to the initial transmission of the SAE data to PPD.

The investigator may change his/her opinion of causality in light of follow-up 
information, amending the SAE data collection tool accordingly.

The causality assessment is one of the criteria used when determining regulatory 
reporting requirements.
Follow-up of AEs and SAEs

The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as may be indicated or as requested by PPD to 
elucidate as fully as possible the nature and/or causality of the AE or SAE.

The investigator is obligated to assist.  This may include additional laboratory tests 
or investigations, histopathological examinations or consultation with other health 
care professionals.

New or updated information will be recorded in the originally completed eCRF.

The investigator will submit any updated SAE data to PPD within the designated 
reporting time frames.
12.7.5.
Reporting of SAEs to PPD
SAE reporting to PPD via electronic data collection tool

Primary mechanism for reporting SAEs to PPD will be the electronic data collection 
tool

If the electronic system is unavailable for greater than 24 hours, the site will use the 
paper SAE data collection tool and fax it to the Medical Monitor

Site will enter the serious adverse event data into the electronic system as soon as it 
becomes available.

The investigator will be required to confirm review of the SAE causality by ticking 
the ‘reviewed’ box at the bottom of the eCRF page within 72 hours of submission of 
the SAE.

After the study is completed at a given site, the electronic data collection tool (e.g., 
InForm system) will be taken off-line to prevent the entry of new data or changes to 
existing data

If a site receives a report of a new SAE from a study subject or receives updated data 
on a previously reported SAE after the electronic data collection tool has been taken 
off-line, the site can report this information on a paper SAE form or to the Medical 
Monitor by telephone.

Contacts for SAE receipt can be found at the beginning of this protocol on the 
Sponsor/Medical Monitor Contact Information page.


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


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Phase 3-4 liver chemistry stopping criteria and required follow up assessments 
Liver Chemistry Stopping Criteria - Liver Stopping Event
ALT-absolute
ALT 8xULN
ALT Increase
ALT 5xULN but <8xULN  persists for 2 weeks
ALT 3xULN but <5xULN  persists for 4 weeks
Bilirubin1, 2
ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin) 
INR2
ALT 3xULN and INR>1.5, if INR measured
Cannot 
Monitor
ALT 5xULN but <8xULN and cannot be monitored weekly for 2 weeks
ALT 3xULN but <5xULN and cannot be monitored weekly for 4 weeks
Symptomatic3
ALT  3xULN associated with symptoms (new or worsening) believed to be 
related to  liver injury or hypersensitivity
Required Actions and Follow up Assessments following ANY Liver Stopping Event
Actions
Follow Up Assessments

Immediately discontinue randomized 
treatment

Report the event to PPD within 24 hours

Complete the liver event eCRF and complete 
an SAE data collection tool if the event also 
meets the criteria for an SAE2

Perform liver event follow up assessments 

Monitor the subject until liver chemistries 
resolve , stabilize, or return to within baseline 
(see MONITORING below)

Do not restart subject with randomized 
treatment unless allowed per protocol and 
GSK Medical Governance approval is 
granted (refer to Appendix 9)

If restart not  allowed or not granted, 
permanently discontinue randomized 
treatment and may continue subject in the 
study for any protocol specified follow up 
assessments

Viral hepatitis serology4

Only in those with underlying chronic 
hepatitis B at study entry (identified by 
positive hepatitis B surface antigen) 
quantitative hepatitis B DNA and hepatitis 
delta antibody5.

Blood 
sample for PK analysis, obtained within 24 
hour after last dose6

Serum creatine phosphokinase (CPK) and 
lactate dehydrogenase (LDH).

Fractionate bilirubin, if total 
bilirubin2xULN

Obtain complete blood count with 
differential to assess eosinophilia

Record the appearance or worsening of 
clinical symptoms of liver injury, or 
hypersensitivity, on the AE report form

Record use of concomitant medications on 
the concomitant medications report form 


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MONITORING:
For bilirubin or INR criteria:

Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin) and perform 
liver event follow up assessments within  24 
hours

Monitor subjects twice weekly until liver 
chemistries resolve, stabilize or return to 
within baseline

A specialist or hepatology consultation is 
recommended
For All other criteria:

Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin) and perform 
liver event follow up assessments within  24-
72 hours 

Monitor subjects weekly until liver 
chemistries resolve, stabilize or return to 
within baseline
including acetaminophen, herbal 
remedies, other over the counter 
medications.

Record alcohol use on the liver event 
alcohol intake case report form
For bilirubin or INR criteria:

Anti-nuclear antibody, anti-smooth muscle 
antibody, Type 1 anti-liver kidney 
microsomal antibodies, and quantitative 
total immunoglobulin G (IgG or gamma 
globulins).

Serum acetaminophen adduct HPLC 
assay (quantifies potential acetaminophen 
contribution to liver injury in subjects with 
definite or likely acetaminophen use in the 
preceding week [James, 2009]). 

Liver imaging (ultrasound, magnetic 
resonance, or computerised tomography) 
and /or liver biopsy to evaluate liver 
disease; complete Liver Imaging and/or 
Liver Biopsy eCRF forms.
1.
Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin fractionation is not 
immediately available, discontinue randomized treatment for that subject if ALT 3xULN and bilirubin 2xULN. 
2.
All events of ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin) or ALT 3xULN and INR>1.5, if INR 
measured which may indicate severe liver injury (possible ‘Hy’s Law’), must be reported as an SAE (excluding 
studies of hepatic impairment or cirrhosis); INR measurement is not required and the threshold value stated 
will not apply to subjects receiving anticoagulants
3.
New or worsening symptoms believed to be related to liver injury (such as fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, or jaundice) or believed to be related to hypersensitivity (such as fever, rash or 
eosinophilia)   
4.
Includes: Hepatitis A IgM antibody; Hepatitis B surface antigen and Hepatitis B Core Antibody (IgM); Hepatitis C 
RNA; Cytomegalovirus IgM antibody;  Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, obtain 
heterophile antibody or monospot testing);  Hepatitis E IgM antibody 
5.
If hepatitis delta antibody assay cannot be performed, it can be replaced with a PCR of hepatitis D RNA virus 
(where needed) Le Gal, 2005].
6.
PK sample may not be required for subjects known to be receiving placebo or non-GSK comparator treatments.  
Record the date/time of the PK blood sample draw and the date/time of the last dose of randomized treatment 
prior to blood sample draw on the eCRF. If the date or time of the last dose is unclear, provide the subject’s best 
approximation. If the date/time of the last dose cannot be approximated OR a PK sample cannot be collected in 
the time period indicated above, do not obtain a PK sample. Instructions for sample handling and shipping are in 
the SRM.  


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Phase 3-4 liver chemistry increased monitoring criteria with continued therapy
Liver Chemistry Increased Monitoring Criteria – Liver Monitoring Event
Criteria
Actions
ALT 5xULN and <8xULN and
bilirubin <2xULN without symptoms 
believed to be related to liver injury or 
hypersensitivity, and who can be 
monitored weekly for 2 weeks.
OR
ALT 3xULN and <5xULN and
bilirubin <2xULN without symptoms 
believed to be related to liver injury or 
hypersensitivity, and who can be 
monitored weekly for 4 weeks.

Notify the PPD medical monitor within 24 hours
of learning of the abnormality to discuss subject 
safety. 

Subject can continue randomized treatment 

Subject must return weekly for repeat liver 
chemistries (ALT, AST, alkaline phosphatase, 
bilirubin) until they resolve, stabilise or return to 
within baseline 

If at any time subject meets the liver chemistry 
stopping criteria, proceed as described above

If ALT decreases from ALT 5xULN and <8xULN 
to ≥3xULN but <5xULN, continue to monitor liver 
chemistries weekly. 

If, after 4 weeks of monitoring, ALT <3xULN and 
bilirubin <2xULN, monitor subjects twice monthly 
until liver chemistries normalize or return to within 
baseline.
References
James LP, Letzig L, Simpson PM, Capparelli E, Roberts DW, Hinson JA, Davern TJ, Lee 
WM. Pharmacokinetics of acetaminophen-adduct in adults with acetaminophen overdose 
and acute Liver failure. Drug Metab Dispos 2009; 37:1779-1784.
Le Gal F, Gordien E, Affolabi D, Hanslik T, Alloui C, Dény P, Gault E.  Quantification 
of hepatitis delta virus RNA in serum by consensus real-time PCR indicates different 
patterns of virological response to interferon therapy in chronically infected patients J 
Clin Microbiol. 2005; 43(5):2363–2369. 


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12.9.
Appendix 9: Liver Safety Drug Restart Guidelines
If subject meets liver chemistry stopping criteria do not restart randomized treatment 
unless there is a clear underlying cause for the liver stopping event other than drug-
induced liver injury and:

GSK Medical Governance approval is granted (as described below),

Ethics and/or IRB approval is obtained, if required, and

Separate consent for randomized treatment restart is signed by the subject

If GSK Medical Governance approval to restart subject with randomized treatment is 
not granted, then subject must permanently discontinue randomized treatment and 
requested to continue in the study for protocol-specified follow up assessments.
Restart Following Transient Resolving Liver Stopping Events Not Related to 
Randomized Treatment
Restart refers to resuming randomized treatment following liver stopping events in which 
there is a clear underlying cause (other than DILI) of the liver event (e.g. biliary 
obstruction, pancreatic events, hypotension, acute viral hepatitis). Furthermore, there 
should be no evidence of alcoholic hepatitis or hypersensitivity, and the randomized 
treatment should not be associated with HLA markers of liver injury.
Approval by GSK for randomized treatment restart can be considered where:

Investigator  requests consideration for randomized treatment restart if liver 
chemistries have a clear underlying cause (e.g., biliary obstruction, hypotension and 
liver chemistries have improved to normal or are within 1.5 x baseline and ALT 
<3xULN).

Restart risk factors (e.g. fever, rash, eosinophilia, or hypersensitivity, alcoholic 
hepatitis, possible randomized treatment-induced liver injury) or randomized 
treatment has an HLA genetic marker associated with liver injury (e.g. lapatinib, 
abacavir, amoxicillin/clavulanate) are reviewed and excluded.

Ethics Committee or Institutional Review Board approval of randomized treatment 
restart must be obtained, as required.

If restart of randomized treatment is approved by GSK Medical Governance in 
writing, the subject must be provided with a clear description of the possible benefits 
and risks of randomized treatment administration, including the possibility of 
recurrent, more severe liver injury or death.  

The subject must also provide signed informed consent specifically for the 
randomized treatment restart.  Documentation of informed consent must be recorded
in the study chart.  

Randomized treatment must be administered at the dose specified by GSK.

Subjects approved by GSK Medical Governance for restarting randomized treatment 
must return to the clinic once a week for liver chemistry tests until stable liver 


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


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12.10.
Appendix 10: Collection of Pregnancy Information

Investigator will collect pregnancy information on any female subject who becomes 
pregnant while participating in this study.

Information will be recorded on the appropriate form and submitted to PPD within 
24 hours of learning of a subject's pregnancy.

The subject will be followed to determine the outcome of the pregnancy. The 
investigator will collect follow up information on mother and infant, which will be 
forwarded to PPD.  Generally, follow-up will not be required for longer than 6 to 8 
weeks beyond the estimated delivery date. 

Any termination of pregnancy will be reported, regardless of fetal status (presence or 
absence of anomalies) or indication for procedure.

While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy will be reported as an AE or 
SAE.

A spontaneous abortion is always considered to be an SAE and will be reported as 
such.  

Any SAE occurring as a result of a post-study pregnancy which is considered by the 
investigator reasonably related to the randomized treatment, will be reported to PPD 
as described in Appendix 7. While the investigator is not obligated to actively seek 
this information in former study participants, he or she may learn of an SAE through 
spontaneous reporting.
Any female subject who becomes pregnant while participating must permanently 
discontinue randomized treatment. Subjects will be asked to attend an Early 
Treatment Discontinuation visit and expected to attend study visits through the End 
of Study visit, according to the study visit schedule, unless consent is actively 
withdrawn. 


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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12.14.
Appendix 14: Country Specific Requirements
12.14.1.
French Administrative Considerations and Specifics
Requirements
This appendix includes all the requirements of the French law (n2004-806 of 9th August 
2004), and identifies, item per item, the mandatory modifications or additional 
information to the study protocol and includes specific GSK requirements.
1.
Concerning the « STUDY POPULATION»
In line with the local regulatory requirements, the following text in section «OTHER 
STUDY ELIGIBILITY CRITERIA CONSIDERATIONS » is added: A subject will 
be eligible for inclusion in this study if he /she is either affiliated to or beneficiary of a 
social security category.
It is the investigator’s responsibility to ensure and to document (in source document -
patient notes) that the patient is either affiliated to or beneficiary of a social security 
category.
2.
Concerning the “DATA ANALYSIS AND STATISTICAL 
CONSIDERATIONS” and specially in the “SAMPLE SIZE ASSUMPTION”
The expected number of patients to be recruited in France is declared to the French 
regulatory authority.
3. Concerning the “STUDY CONDUCT CONSIDERATIONS” 
In section “Regulatory and Ethical Considerations, Including the Informed Consent 
Process”
Concerning the process for informing the patient or his/her legally authorized 
representative, the following text is added: 
French Patient Informed Consent form is a document which summarizes the main 
features of the study and allows collection of the patient's written consent in duplicate. It 
also contains a reference to the authorization of L'Agence nationale de sécurité du 
médicament et des produits de santé (ANSM) and the approval from the French Ethics 
committee.
Concerning the management of the Patient Informed Consent forms, the following 
text is added: 
The first copy of the Patient Informed Consent form is kept by the investigator. The 
second is given to the patient or his/her legally authorized representative

In section concerning the “NOTIFICATION TO THE HOSPITAL DIRECTOR”
the following text is added:
In accordance with Article L1123-13 of the Public Health Code, the Hospital 
Director is informed of the commitment to the trial in his establishment. The 
Hospital Director is supplied with the protocol and any information needed for the 


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


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


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


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


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


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


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


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


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


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


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


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Section 7.1 Time and Events Table; Table 7 Schedule of Assessments Year 1 to End of Study; hospitalization line; kidney transplant 
added.
Protocol activity (visits ±1 week)
All assessments pre-dialysis unless otherwise specified
(Note: All visit timings are relative to Day 1)
Day 1 through Week 52
Screen
Week -8
Run-in
Week -4
Day 113
Week 2
Full study visit
Week 4, 16, 28, 
40
Abbreviated study visit
Week 8, 12, 20, 24, 32, 36, 
44, 48  
Week 52
Unscheduled10
Hospitalization 3 , kidney transplant3
X
X
X
X
X
Year 2
Year 3
Year 4
Unscheduled10
End of 
Study15
Follow-up
(4-6 weeks after 
stopping 
randomized 
treatment)
Protocol activity (visits ±1 week)
All assessments pre-dialysis unless 
otherwise specified
(Note: All visit timings are relative to Day 
1)
Week 
64
Week 
76
Week 
88
Week 
100
Week 
112
Week 
124
Week 
136
Week 
148
Week 
160
Week 
172
Week 
184
Week 
196
Week 
20814
Hospitalization3 , kidney transplant3
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Section 7.1 Time and Events Table; Table 7 Schedule of Assessments Year 1 to End of Study; footnote16.
16.  Ultrasound of the kidneys and adrenal glands will be performed between the Week -4 and Day 1 visits. A documented ultrasound of 
the kidneys within the 6 months prior to screening may be used to assess entry criteria, provided the size and cyst category has been 
reported.  If a more sensitive imaging study [e.g., magnetic resonance imaging (MRI), computed tomography (CT)] has been 
performed within this timeframe and a report is available, this may be used in place of the ultrasound. See Section 7.4.10.
Section 7.1 Time and Events Table; Table 7 Schedule of Assessments Year 1 to End of Study; footnote17.
17  Treatment will be dispensed every 41 weeks. IRT call will be required every 4 weeks. 


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


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


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


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


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


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


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


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Section 12.6; Appendix 6: Randomized Treatment Dose Adjustment Scheme; line 9 
column 3 of table; word visit added for clarity.
HemoCue Hgb (g/dL) 
at current study visit1
HemoCue Hgb change since last 
study visit1
Randomized Treatment Dose 
Adjustment5
123
Any change  
Repeat Hgb and average values6; if 
confirmed, temporary hold the dose and 
re-check Hgb at next study visit1; restart 
at one dose step lower when Hgb <11.5 
g/dL and provided it has been at least 2 
weeks from the prior study visit.
Section 12.6; Appendix 6: Randomized Treatment Dose Adjustment Scheme; footnote 1; 
last bullet point.

For subjects transitioning to dialysis changing dialysis modality from HD to PD:  
Visits every 4 weeks for 12 weeks.
Section 12.6; Appendix 6: Randomized Treatment Dose Adjustment Scheme; footnote 2; 
word visit added for clarity.
2.
This rule applies to any mandated visit or unscheduled visit, provided it has been 
at least 2 weeks from the prior study visit.
Appendix 11 Definition of Darbepoetin Alfa Pre-filled Syringe Incidents. Section deleted 
as darbepoetin alfa pre-filled syringes are not subject to device reporting requirements.
Definition:

Incident – Any malfunction or deterioration in the characteristics and/or performance 
of the pre-filled syringe, as well as any inadequacy in the labeling or the instructions 
for use which, directly or indirectly, might lead to or might have led to the death of a 
patient/user/other persons or to a serious deterioration in their state of health.

Not all incidents lead to death or serious deterioration in health.  The non-occurrence 
of such a result might have been due to other fortunate circumstances or to the 
intervention of health care personnel.
It is sufficient that:
-
an incident associated with a pre-filled syringe happened and
-
the incident was such that, if it occurred again, might lead to death or a serious 
deterioration in health.
A serious deterioration in state of health can include:
-
life-threatening illness
-
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-
a condition necessitating medical or surgical intervention to prevent one of the 
above 
-
fetal distress, fetal death or any congenital abnormality or birth defects
Examples of incidents

a patient, user, care giver or professional is injured as a result of failure or misuse of 
the pre-filled syringe 

a patient’s treatment is interrupted or compromised by failure of the pre-filled syringe

a patient’s health deteriorates due to failure of the pre-filled syringe
Appendix 12; Section 12.12.3.3 Study Assessments; Week 28 Study Visit; sentence 3. 
Wording change for clarity.
The time and date of study medication administration, before and while on wearing the 
ABPM device, will be recorded
Appendix 14 Country Specific Requirements. Text deleted as country specific 
requirements added.
No county specific requirements exist
Appendix 14 Country Specific Requirements; new Section 12.14.1  French Administrative 
Considerations and Specifics Requirements 
This appendix includes all the requirements of the French law (n2004-806 of 9th August 
2004), and identifies, item per item, the mandatory modifications or additional 
information to the study protocol and includes specific GSK requirements.
1.
Concerning the « STUDY POPULATION»
In line with the local regulatory requirements, the following text in section «OTHER 
STUDY ELIGIBILITY CRITERIA CONSIDERATIONS » is added: A subject will 
be eligible for inclusion in this study if he /she is either affiliated to or beneficiary of a 
social security category.
It is the investigator’s responsibility to ensure and to document (in source document -
patient notes) that the patient is either affiliated to or beneficiary of a social security 
category.
Concerning the “DATA ANALYSIS AND STATISTICAL CONSIDERATIONS” 
and specially in the “SAMPLE SIZE ASSUMPTION”
The expected number of patients to be recruited in France is declared to the French 
regulatory authority.
9.
Concerning the “STUDY CONDUCT CONSIDERATIONS” 


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In section “Regulatory and Ethical Considerations, Including the Informed Consent 
Process”
Concerning the process for informing the patient or his/her legally authorized 
representative, the following text is added: 
French Patient Informed Consent form is a document which summarizes the main 
features of the study and allows collection of the patient's written consent in duplicate. It 
also contains a reference to the authorization of L'Agence nationale de sécurité du 
médicament et des produits de santé (ANSM) and the approval from the French Ethics 
committee.
Concerning the management of the Patient Informed Consent forms, the following 
text is added: 
The first copy of the Patient Informed Consent form is kept by the investigator. The 
second is given to the patient or his/her legally authorized representative

In section concerning the “NOTIFICATION TO THE HOSPITAL DIRECTOR”
the following text is added:
In accordance with Article L1123-13 of the Public Health Code, the Hospital 
Director is informed of the commitment to the trial in his establishment. The 
Hospital Director is supplied with the protocol and any information needed for the 
financial disposition, the name of the investigator(s), the number of sites involved in 
his establishment and the estimated time schedule of the trial (R.1123-63).

In section concerning the “INFORMATION TO THE HOSPITAL 
PHARMACIST” the following text is added:
In accordance with Article R.1123-64 of the Public Health Code, the Hospital 
Pharmacist is informed of the commitment to the trial in his establishment. The 
Pharmacist is supplied with a copy of the protocol (which allows him to dispense the 
drug(s) of the trial according to the trial methodology), all information concerning 
the product(s) of the trial (e.g. included in the CIB), the name of the investigator(s), 
the number of sites involved in his establishment and the estimated time schedule of 
the trial.

In section “DATA MANAGEMENT” the following text is added:
Within the framework of this clinical trial, data regarding the identity of the 
investigators and/or co-investigators and/or the pharmacist if applicable, involved in 
this clinical trial, and data regarding the patients recruited in this clinical trial (patient 
number, treatment number, patient status with respect to the clinical trial, dates of 
visit, medical data) will be collected and computerized in GSK data bases by 
GlaxoSmithKline Laboratory or on its behalf, for reasons of follow up, clinical trial 
management and using the results of said clinical trial. According to the Act n° 78-17 
of 6th January 1978 further modified, each of these people aforesaid has a right of 
access, correction and opposition on their own data through GlaxoSmithKline 
Laboratory (Clinical Operations Department).


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10. Monitoring visits
The Health Institution and the Investigator agree to receive on a regular basis a Clinical 
Research Assistant of GLAXOSMITHKLINE or of a service provider designated by 
GLAXOSMITHKLINE. The Health Institution and the Investigator agree to be available 
for any phone call and to systematically answer to all correspondence regarding the Study 
from GLAXOSMITHKLINE or from a service provider designated by 
GLAXOSMITHKLINE. In addition, the Health Institution and the Investigator agree that 
the CRA or the service provider designated by GLAXOSMITHKLINE have direct access 
to all the data concerning the Study (test results, medical record, etc.). This consultation 
of the information by GLAXOSMITHKLINE is required to validate the data registered in 
the electronic eCRF, in particular by comparing them directly to the source data. In 
accordance with the legal and regulatory requirements, the strictest confidentiality will be 
respected.
11. Data entry into the eCRF
The Health Institution and the Investigator agree to meet deadlines, terms and conditions 
of the Study’s eCRF use here below:
The Health Institution and the Investigator undertake:
1) That the Investigator and the staff of the investigator center make themselves 
available to attend the training concerning the computer system dedicated to the 
electronic eCRF of the Study provided by GLAXOSMITHKLINE or by a 
company designated by GLAXOSMITHKLINE.
2) That the Investigator and the staff of the investigator center use the IT Equipment 
loaned and/or the access codes only for the purpose of which they are intended 
and for which they have been entrusted to them, namely for the Study 
achievement, to the exclusion of any other use.
3) That the Investigator and the staff of the investigator center use the IT Equipment 
loaned according to the specifications and manufacturer’s recommendations 
which will have been provided by GLAXOSMITHKLINE.
4) To keep the IT Equipment and/or access codes in a safe and secure place and to 
only authorize the use of this IT Equipment by investigator center staff designated 
by the principal investigator to enter the data of the Study.
5) That the Investigator and the staff of the investigator center enter the data of the 
electronic eCRF related to a patient visit in the 3 days following the date of the 
patient visit or, for the patient test results, in the 3 days following the reception of 
the results of such tests.
6) That the Investigator resolves and returns to GLAXOSMITHKLINE the data 
queries issued by GLAXOSMITHKLINE or a service provider designated by 
GLAXOSMITHKLINE within 7 days after the reception of the request of 
clarification or in a period of one (1) day during the final stage of clarification of 
the data base or in such other period as provided by GLAXOSMITHKLINE 
and/or a company designated by GLAXOSMITHKLINE.
7) To be responsible for the installation and payment of the required Internet 
connections needed for the use of the IT Equipment, Computer systems and/or 
access codes.


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8) To return at the end of the Study the IT Equipment and/or access codes to 
GLAXOSMITHKLINE or to any company designated by GLAXOSMITHKLINE 
and any training material and documentation. The IT Equipment cannot under any 
circumstances be kept by the Health Institution or the Investigator for any reason 
whatsoever. 
12. CTR publication
It is expressly specified that GLAXOSMITHKLINE and/or the Sponsor can make 
available to the public the results of the Study by the posting of the said results on a 
website of the GLAXOSMITHKLINE GROUP named Clinical Trial Register (CTR) 
including the registration of all the clinical trials conduct by the GLAXOSMITHKLINE 
Group and this before or after the publication of such results by any other process.
13. Data Protection French Law of 6 January 1978 (CNIL)
In accordance with the Data Protection French Law of 6 January 1978 as modified, 
computer files used by GLAXOSMITHKLINE to monitor and follow the implementation 
and the progress of the Study are declared with the Commission Nationale de 
I'Informatique et des Libertés (CNIL) by GLAXOSMITHKLINE. The Investigator has 
regarding the processing data related to him a right of access, of rectification and of 
opposition with GLAXOSMITHKLINE in accordance with the legal provisions. This 
information can be transferred or be accessed to other entities of GLAXOSMITHKLINE 
Group in France, Britain or United States, what the Investigator agrees by the signature of 
the present Protocol.
Appendix 15 Country Specific Requirements; new Section 12.15.2  Country-Specific 
Requirements for the Czech Republic; addition of text relating to acceptable
contraceptive methods for the Czech Republic.
Purpose and Justification:
The purpose of this Czech Republic country-specific requirement is to specify acceptable
contraceptive methods for use during participation in the study 200807. This is as a result 
of recent Czech Republic legislative requirements of CA directive KLH 22 dated 
22Mar2016 for contraception methods.
Czech Republic Specific Contraception Requirements will apply in addition to the list of 
methods stated in Appendix 5:
Men and women able to have children and sexually active, must use acceptable methods 
of birth control from 30 days prior to the first dose of randomized treatment and until 
completion of the Follow-up visit (4-6 weeks after the end of randomized treatment).

Methods of birth control include, one highly reliable method (such as intrauterine 
device, sterilisation of one of the partners, hormonal birth control methods) plus 
one supplementary barrier method (such as condom, diaphragm) with a 
spermicide. 


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
Two barrier methods used in combination with spermicide, are considered 
as reliable contraception methods. 
The study doctor will discuss with the subject the methods of birth control that should be 
used while he/she is in this study and will help the subject to select the methods that are 
appropriate for him/her.


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


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


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
This is a randomized, open-label (sponsor blind), active-controlled, parallel-group, 
multi-center, event-driven study in dialysis subjects with anemia associated with 
CKD who are currently treated with erythropoietinerythropoiesis-stimulating agents 
(ESAs1).
ESA
ErthropoetinErythropoiesis-stimulating agent
Section 1. Protocol Synopsis for Study 200807; Analysis 1st paragraph. Revised analysis 
provided.
The study’s co-primary endpoints will each be tested for non-inferiority using a one-
sided 2.5% significance level and the relevant confidence bound from a two-sided 95% 
confidence interval (CI) (upper bound for MACE and lower bound for the Hgb co-
primary endpoint) for each test. 
Section 3 Objectives and Endpoints; safety endpoint.  Changed “study treatment” to 
“randomized treatment” to more correctly describe endpoint.  
Safety 

To compare the safety and tolerability of 
daprodustat to rhEPO

Incidence and severity of AEs and serious adverse 
events (SAEs) including AEs of special interest1

Reasons for discontinuation of studyrandomized
treatment

Absolute values and changes from baseline in 
laboratory parameters, BP and heart rate (HR)
Section 4.1. Overall Design; 7th bullet. Clarified how stratification factors are considered 
prognostically important.

Subjects will be stratified by dialysis type [HD* or PD], by region (see Appendix 3), 
and by participation in the ABPM sub-study. Dialysis type and region are considered 
to be stratification factors that areconsidered to be potentially prognostically 
important, i.e., predictive of study endpoints while participation in the ABPM sub-
study is an administrative stratification factor intended solely to ensure a similar 
number of sub-study subjects in each of the two randomized groups.  
Section 4.5.2. Benefit Assessment; 1st paragraph. Clarifited other ESAs.
In clinical trials of up to 24 weeks in duration, in subjects with anemia associated with 
CKD, daprodustat has been shown to treat Hgb to target range. Daprodustat may present 
several important advantages over rhEPO and other ESAs its analogs.  It is an oral 
medication and does not require cold-chain storage as does rhEPO, thus increasing ease 
of use for patients and health care providers. After administration of daprodustat, data 
suggest that the increases in Hgb are achieved with EPO exposure lower than those 
observed with rhEPO.  Treatment of anemia of CKD with rhEPO is associated with 
increased CV risk which is postulated to be related to the associated increases in EPO 
exposure with rhEPO [Szczech, 200]; therefore, daprodustat has the potential to raise 
Hgb without the same CV risk associated with rhEPO and its analogs.


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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Section 7.4.1. Events Referred to the Clinical Events Committee; 1st paragraph.  Added 
reference to CEC Site Manual for scope of reporting requirements.
Investigators should refer any event suspected to be one of the following events below to 
the Clinical Events Committee for adjudication:.  See CEC Site Manual for full scope 
of reporting requirements.  
Section 7.4.1. Events Referred to the Clinical Events Committee; 2nd paragraph after 
bullets.  Added clarity where to find description of source documentation required to 
support adjudication of events.  
Source documentation required to support the adjudication of the events is described in 
the SRM CEC Site Manual.
Section 7.4.4. Adverse Events of Special Interest; revised last sentence for clarity.
The results of any investigation should be recorded inon the AE page and the relevant 
AE of special interest page of the subject’s eCRF.
Section 7.4.7. Height and Weight; 3rd sentence; corrected spelling of center.
For in-centercentre HD subjects, weight will be measured pre and post-dialysis. For 
HHD subjects, weight will be done at study visits between dialysis sessions.  For PD 
subjects, this assessment will be done at study visits, as per standard of care. For
HHD and PD subjects these assessments will be done between treatments.
Section 7.4.8. Blood Pressure and Heart Rate; new text.  Added clarity for PD subjects as 
to the timing of the assessments and for the ordering of the various assessments. 
For in-centercentre HD subjects, SBP, DBP and HR will be measured pre and post-
dialysis. For HHD and PD subjects, these assessments will be done at study visits
between dialysis sessions.  For PD subjects, this assessment will be done at study 
visits, as per standard of care.
SBP, DBP, and HR will be performed before collection of blood samples for 
laboratory testing, where applicable (e.g., would not apply for post-HD 
measurement).
Section 7.4.9. Electrocardiogram (ECG); new text 2nd and 4th paragraphs.  Additional 
clarity provided about Day 1 ECG requirements. 
For At the Day 1 visit when an ECG is performed, two additional ECGs are required if 
the initial ECG indicates prolonged QTc (see Section 5.2) using the automated or 
manually calculated QTcB value.  
ECG data will be read locally by a physician with experience in reading and 
interpreting ECGs.  The over-read of the Day 1 ECG is required to confirm 
eligibility. Additional details are provided in the SRM.


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


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


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


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


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


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


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


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


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Section 12.4. Appendix 4: Risk Assessment. Updates included throughout to align with version 8 of the Investigator’s Brochure.
Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Daprodustat 
Excessive erythropoiesis (polycythemia) leading to 
thrombosis and/or tissue ischemia
In animal studies, excessive erythropoiesis attributed to daprodustat 
was associated with vascular congestion/inflammation, microthrombi, 
and tissue ischemia in a number of organs.
Following review of clinical data received to date, this has not been 
identified as a safety concern for daprodustat.
Phase 2 dose-ranging studies, and associated statistical and exposure 
response modelling has informed Phase 3 dose rationale, starting 
doses, dose steps, and dose adjustment scheme to optimize Hgb 
management.

Specific eligibility criteria related to 
requirements for entry Hgb are detailed in 
Section 5.1.

Hgb will be closely monitored throughout the 
dosing period as outlined in the Time and 
Events Table Section 7.1.

Specific guidance for dose adjustment, dose 
interruption, or discontinuation of daprodustat 
based on achieved Hgb (including rate of 
change) is provided in Section 6.3 and 
Section 6.12.

Unblinded monitoring of safety data by an 
IDMC in-stream throughout the study.
Death, MI, stroke, congestive HFheart failure,
thromboembolic events venous thromboembolism, 
thrombosis of vascular access at Hgb levels which are 
within the normal range (i.e. not polycythemic 
conditions)
Marketed rhEPO and its analogs/ESAs have been associated with an 
increased risk for death and serious cardiovascular events when used 
in patients with anemia of CKD.
In non-clinical studies conducted to date, not observed at 
tolerated doses when hemoglobin/hematocrit within normal range 
for species.
The clinical data received to date are insufficient to conclude or 
refute this risk. Following review of clinical data received to date, this 
has not been identified as a safety concern for daprodustat.

Specific eligibility criteria related to CV risk are 
outlined in Section 5.2.

Hgb will be closely monitored throughout the 
dosing period as outlined in the Time and 
Events Table Section 7.1.

Unblinded monitoring of safety data by an 
IDMC in-stream throughout the study.

Planned formal interim analyses with stopping 
guidelines for evidence of increased CV risk 
as outlined in Section 9.4.5.


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Esophageal and gastric erosions
In animal studies, undesirable GI effects including emesis, abnormal 
feces and/or decreased food consumption/body weight loss and 
stomach erosions/ ulcers with hemorrhage were observed with 
daprodustat.  
In rodentsrats, stomach erosions were observed with intravenous and 
oral administration of daprodustat.
Stomach erosions/ulcers also reported in rats with some 
marketed rhEPO/ and its analogs.Gender-averaged systemic 
exposure (AUC) at the no observed adverse effect levels (NOAEL) are 
3.3 -fold (monkeys) and 737 -fold (rats) above human exposure (25 
mg daprodustat).
In clinical trials to date with daprodustat, mild-moderate GI signs and 
symptoms represent the most frequently reported adverse event, 
however causal association has not been established.
Following review of clinical data received to date, GI erosions have not 
been identified as a safety concern for daprodustat.

Suspected GI bleeding or significant 
symptoms consistent with erosions or ulcers
should be investigated diagnostically (i.e. 
endoscopic examination) as clinically 
warranted.

Unblinded monitoring of safety data by an 
IDMC in-stream throughout the study.
Cancer-related mortality and tumor progression and 
recurrence
Marketed rhEPOs and its analogs have been associated with 
increased risk of cancer related morbidity and mortality when used in 
patients with cancer.
Administration of 60mg/kg daprodustat to mice caused minimal 
increases in circulating VEGF while significant EPO increases were 
observed.
There were no test article-related neoplastic findings in a 2-year 
rat (oral daprodustat) or mouse (daprodustat + subcutaneous 
injection of the 3 major human metabolites; M2, M3 and M13) 
carcinogenicity studies.
In clinical studies conducted to date, administration of 

Specific eligibility criteria related to personal 
history of malignancy or subjects with 
complex kidney cyst are outlined in Section 
5.2.

Stopping criteria for subjects with treatment 
emergent malignancy are outlined in Section 
5.5.

Unblinded monitoring of safety data by an 
IDMC in-stream throughout the study.


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daprodustat has been associated with:
Once daily administration:

In studies up to 4 weeks duration, a dose-ordered increase in
VEGF plasma concentrations was observed at doses ranging 
from 10 to 150 mg. 

In studies up to 24 weeks duration at doses up to 25mg, 
changes in VEGF plasma concentration were variable but 
similar relative to control.

Systemic EPO concentrations within the physiologic range.
Three times weekly administration:

In studies up to 4 weeks duration at doses of 10 to 30 mg:
o
Dose dependent increases in plasma VEGF and 
EPO concentrations were observed.
o
Pre-dose concentrations of EPO and VEGF were 
near or below baseline indicating no accumulation 
of EPO or VEGF after three times weekly dosing.
Following review of clinical data received to date, this has not been 
identified as a safety concern for daprodustat. 
Pulmonary artery hypertension (PAH)
A role for HIF-regulated pathways in the pathophysiology of PAH has 
been suggested based on well established effects of acute and chronic 
hypoxia in man on the pulmonary vasculature (vasoconstriction), and 
by findings in patients with naturally occurring mutations that result in 
decreased HIF degradation [Smith, 2006; Formenti, 2011].
There have been no histopathologic findings suggestive of PAH in pre-
clinical safety studies with daprodustat up to (13 weeks duration in 
mice and dogs, up to 26 weeks2 years in rats and mice, and up to 39 
weeks in monkeys.

Unblinded monitoring of safety data by an 
IDMC in-stream throughout the study.


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Acute hypoxic challenge (rats):  Daprodustat produced increases in 
peak right ventricular pressure (PRVP) during acute hypoxia that were 
slightly higher than the vehicle control group. However, Tthese
hypoxia-induced PRVP changes fallwere within the range of PRVP 
differences changes noted among non-untreated rats.
Results from a clinical study of acute hypoxic challenge in healthy 
volunteers demonstrated that short-term (5 days) therapy with 
daprodustat 5mg or 100mg has no clinically significant effect on 
transthoracic echocardiographically (ECHO) estimatesd of systolic
pulmonary artery systolic pressure (sPASP) under either normoxic or 
hypoxic conditions.
ECHO assessments performed in Phase 2b studies (24 weeks 
treatment duration) did not identify any clinically meaningful changes in 
PASPsPAP in subjects not on dialysis for daprodustat. In hemodialysis 
subjects, mean absolute change from baseline in sPAPPASP was 
similar for both treatment groups; however, there was a numeric 
imbalance (Daprodustat: 8 [7%]; Control 0) in subjects reaching the 
sPAPPASP PCI (>20 mmHg increase from baseline). Regarding this 
imbalance, there were a number of confounding factors in the study, 
most notably a 4.5:1 randomization scheme and inconsistency in 
timing of ECHOs relative to dialysis day.  Additionally, 2 of 3 subjects 
with resolution of sPAPPASP on safety follow-up ECHOs had 
confounding conditions that could contribute to resolution other than 
discontinuation of study treatment; and there was no dose relationship 
for subjects meeting the sPAPPASP PCI criterion. Overall, there is 
insufficient evidence to conclude a relationship to treatment with 
daprodustat.
Following review of clinical data received to date, this has not been 
identified as a safety concern for daprodustat.  
Cardiomyopathy
Published data suggest that cardiac effects of HIF stabilization are 
likely a function of the mechanism, extent, and duration of the effects, 
and can range from protective to detrimental depending upon the 

Unblinded monitoring of safety data by an 
IDMC in-stream throughout the study.


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specific model and experimental conditions utilized.
With lifetime exposure to daprodustat in a 2-year rat oral 
carcinogenicity study, an exacerbation of rat spontaneous, 
progressive cardiomyopathy (PCM)(focal myofiber 
degeneration/necrosis with inflammatory infiltrates) was
observed at doses of 0.8 mg/kg/day and above, although total 
incidence and severity distribution within any daprodustat-group 
were within historical control ranges.  This is consistent with an 
equivocal threshold for exacerbation of spontaneous, 
progressive cardiomyopathy at 0.8 mg/kg/day which is also the 
threshold dose for observing increased Hct values in individual 
rats. Small increases in cardiac troponin in 6 month rat study with 
daprodustat were consistent with the background finding of 
spontaneous rodent cardiomyopathy.  There were no elevations 
observed in cardiac troponin in 9 month monkey study with 
daprodustat
Cardiomyopathy has not been associated with naturally occurring 
mutation in man which results in increased HIF stabilization.
ECHO assessments performed in phase 2b studies (24 weeks 
treatment duration) did not identify any clinically meaningful changes in 
LVEF for daprodustat.
Following review of clinical data received to date, this has not been 
identified as a safety concern for daprodustat.
Proliferative retinopathy, macular edema, choroidal 
neovascularization
Increases in local (ocular) VEGF production with retinal 
neovascularization and macular edema observed in diabetic 
retinopathy and to choroidal leakage, edema and neovascularization 
seen in age-related macular degeneration [Campochiaro, 2006].
Administration of 60 mg/kg daprodustat to mice caused minimal 
increases in circulating VEGF while significant EPO increases were 
observed.

Suspected proliferative retinopathy, macular 
edema, choroidal neovascularization or
symptoms consistent with these events should 
be investigated by ophthalmologic consultation 
as clinically warranted.

Unblinded monitoring of safety data by an 
IDMC in-stream throughout the study.


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Aside from congestion of retinal vessels and optic disc 
hyperemia secondary to markedly increased red cell mass, there 
were no ocular abnormalities observed in non-clinical studies.
No ocular abnormalities with daprodustat were seen in non-clinical 
studies of up to 13 weeks duration in mice and dogs, 26 weeks in rats, 
and 39 weeks in monkeys.  
In clinical studies up to 4 weeks duration, a dose-ordered increase in 
VEGF plasma concentrations was observed at doses ranging from 10 
to 150 mg administered once daily and from 10 to 30 mg 
administered three times weekly. In studies up to 24 weeks duration 
at doses up to 25 mg, changes in VEGF plasma concentrations were 
variable but similar relative to control.
Ophthalmologic assessments performed in phase 2b studies (24 
weeks treatment duration) did not identify any clinically meaningful 
changes in proliferative retinopathy, macular edema, or choroidal 
neovascularization with daprodustat.
Following review of clinical data with daprodustat received to date, this 
has not been identified as a safety concern for daprodustat.
Exacerbation of rheumatoid arthritis
In inflamed rheumatic joints, activation of HIF- related genes 
secondary to decreased oxygen and pro-inflammatory cytokines has 
been postulated to contribute to the neo-angiogenesis, proliferation 
and infiltration of rheumatoid synovial fibroblasts [Westra, 2010; Muz, 
2009].
No abnormalities seen in non-clinical studies conducted to date for 
daprodustat.
Following review of clinical data received to date, this has not been 
identified as a safety concern for daprodustat.

Unblinded monitoring of safety data by an 
IDMC in-stream throughout the study.


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Drug-drug interactions
Daprodustat is a substrate of CYP2C8:  Co-administration of 
daprodustat with a strong CYP2C8 inhibitor (gemfibrozil) increased 
the Cmax and AUC of daprodustat, 4- and 19-fold, respectively, while 
co-administration of a weak inhibitor (trimethoprim) increased the 
Cmax and AUC of daprodustat by 1.3- and 1.5-fold, respectively. 
Population PK analysis from completed Phase 2 studies suggests that 
co-administration of daprodustat with a moderate CYP2C8 inhibitor 
(clopidogrel), leads to a ~ 2-fold increase in AUC, with no clinically-
significant increase in the measured Hgb response. Although 
CYP2C8 induction studies were not performed, co-administration 
of daprodustat with an inducer of CYP2C8 (e.g., 
rifampin/rifampicin) may decrease the exposure of daprodustat.
Even though co-administration of daprodustat with strong 
inhibitors and inducers of CYP2C8 is prohibited, inadvertent co-
administration may occur. Due to the known time delay in 
enhancing erythropoiesis by daprodustat, co-administration with 
strong CYP2C8 inhibitors for up to 14 days is not anticipated to 
lead to immediate marked increases in hemoglobin levels. 
Therefore, there is adequate time to change to alternate therapy 
that does not inhibit CYP2C8.
Additionally, as the time for maximum induction of CYP2C8 
occurs after approximately 10-14 days of dosing with rifampin 
(Brodie, 2013 and Ohnhaus, 1989), daprodustat systemic 
exposure will decrease over time which will result in a lag period 
before an effect on Hgb is recognized and is of clinical concern.
Daprodustat is an inhibitor of CYP2C8: in vitro, with an IC50 value of 21 
µM.  A clinical drug interaction study between 25mg and 100mg 
daprodustat with a CYP2C8 substrate (i.e., pioglitazone) showed 
that there is no PK interaction at these doses of daprodustat.  
Population PK analysis from completed Phase 2 studies suggests that 
co-administration of daprodustat with clopidogrel (a moderate CYP2C8

Co-administration of daprodustat with strong 
CYP2C8 inhibitors (e.g., gemfibrozil) and 
inducers (e.g., rifampin/rifampicin) is not 
permitted as outlined in Section 6.10.2.

Co-administration of daprodustat with 
moderate CYP2C8 inhibitors (i.e., clopidogrel, 
teriflunomide, deferasirox) should be 
performed with caution. If one of these 
medications is started, stopped or the dose is 
changed, Hgb should be monitored every 4 
weeks for 12 weeks as outlined in Section 6.3
and Appendix 6.

Specific guidance on the management of 
potential drug-drug interactions and 
concomitant medications is provided in 
Section 6.10.

Hgb will be closely monitored throughout the 
dosing period as outlined in the Time and 
Events Table Section 7.1.

Specific guidance for dose adjustment, dose 
interruption, or discontinuation of daprodustat 
based on achieved Hgb is provided in Section 
6.3 and Appendix 6.

Unblinded monitoring of safety data by an 
IDMC in-stream throughout the study.


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inhibitor) leads to a ~ 2-fold increase in AUC, with no clinically-
significant increase in the measured Hgb response. Co-administration 
of daprodustat with moderate CYP2C8 inhibitors (i.e., clopidogrel, 
teriflunomide, deferasirox) should be performed with caution.
Co-administration of daprodustat with potent BCRP inhibitors has the 
potential to increase exposure of daprodustat. Use of BCRP inhibitors 
(mostly weak) was found to result in a small change in metabolite 
exposure (20% increase in AUC).
Daprodustat is a substrate of BCRP: Population PK analysis from 
Phase 2 studies suggested that while BCRP inhibitors were a 
covariate for daprodustat CL/F (8.6% lower clearance) the 
predicted change in exposure was not considered to be of clinical 
relevance.  
Daprodustat is an inhibitor of OATP1B1/1B3: in vitro, with IC50 values 
of 6 µM and 11 µM, respectively. A clinical drug interaction study 
between 25mg and 100mg daprodustat with either a CYP2C8 
substrate or an OATP1B1/1B3 substrate (rosuvastatin) showed that 
there is no PK interaction at these doses of daprodustat.


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Other
rhEPO risks (Control)
See risks outlined in table for daprodustat for excessive erythropoiesis 
(polycythemia) leading to thrombosis and/or tissue ischemia, death, 
MI, stroke, heart failure, venous thromboembolismthromboembolic 
events, thrombosis of vascular access, and for cancer-related 
mortality and tumor progression.
Uncontrolled hypertension
Pure red cell aplasia

See mitigation strategies outlined in table for 
daprodustat for excessive erythropoiesis 
(polycythemia) leading to thrombosis and/or 
tissue ischemia; death, MI, stroke, heart 
failure, venous thromboembolism
thromboembolic events, thrombosis of 
vascular access; and for cancer-related 
mortality and tumor progression.

Specific eligibility criteria related to current 
uncontrolled hypertension are outlined in 
Section 5.2.

Specific eligibility criteria related to personal 
history of pure red cell aplasia are outlined in 
Section 5.2.


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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Non-inferiority will be established if the upper limit of the two-sided 95% CI is less than 
the margin of 1.250.
Sensitivity and Supportive Analyses: Sensitivity analysesA sensitivity analysis will be 
performed to address potential effects of drop outs and to evaluate the robustness of the 
co-primary MACE analysis. These will include aA sensitivity “tipping point” analysis 
utilizing multiple imputation for randomized subjects who have withdrawn consent or are 
lost to follow upfrom the study will be performed, as well; and as a supportive “on-
drug” analysis to evaluate the comparative treatment effect during the time that subjects 
remain on randomized treatment (plus a window of 28 days). Full details will be provided 
in the RAP.
Section 9.4.1.2. Primary Efficacy Analysis (co-primary), Analysis of the hemoglobin co-
primary endpoint was updated based on FDA feedback.
Mean change in Hgb between baseline and the EP (Weeks 28 to 52): The primary 
efficacy estimand is the effect of daprodustat relative to rhEPO on the change in Hgb 
from baseline to the average of all values in the EP, regardless of adherence to 
treatment including interruptions and discontinuation, the use of non-randomized 
ESA medication for any reason including rescue therapy, or the use of blood 
transfusions, in subjects on dialysis currently treated with an ESA with anemia 
secondary to CKD and assuming subjects do not die before the end of the EP. to 
compare the effect of treatment for the evaluation of mean change from baseline in Hgb 
during a 24 week evaluation period (Weeks 28 to 52 inclusive) in all ITT subjects with at 
least one Hgb during the EP. The analysis will use an ANCOVA model. For each 
subject, baseline Hgb will be the value obtained on Day 1, prior to taking randomized 
treatment, and Hgb during EP will be determined by calculating the mean of all available 
and imputed Hgb values between Weeks 28 to 52 inclusive regardless of adherence to 
randomized treatment. The ANCOVA model will include prognostic randomization 
stratification factors (dialysis type and region), baseline hemoglobin and treatment. It will 
provide a point estimate and two-sided 95% CI for the treatment effect together with the 
one-sided non-inferiority test p-value. Non-inferiority will be established if the lower 
limit of the two-sided 95% CI is greater than the margin of -0.75 g/dL. There will be no 
imputation for missing data but imputation will be explored via sensitivity analyses 
Imputation will be used for missing Hgb data; further details will be provided in the 
RAP.
Sensitivity and Supportive Analyses: Sensitivity analyses for the primary estimand will 
include a multiple imputation-based “tipping point” analysis where assumptions are 
adjusted until non-inferiority is lost by imputing data for subjects who did not fully 
complete the EP. A furthersupportive analysis will evaluate efficacy in those subjects 
who adhere to randomized treatment, defined as ITT subjects with at least one on-
treatment Hgb during the EP (this approach corresponds to evaluating an efficacy 
estimand). A similarsupportive “tipping point” analysis as that described above for the 
primary analysis will be performed for this “on-drug” analysis. In addition, a per-protocol 
sensitivitysupportive analysis will estimate the treatment effect in subjects who strongly 
adhere to the protocol, and sensitivitysupportive analyses to explore a shorter EP (Weeks 
28 to 36) will be performed for the co-primary effectiveness estimand and “on-drug” 


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


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


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

SAP_001.pdf: 
 
CONFIDENTIAL 
 
The GlaxoSmithKline group of companies 
 
200807 
 
1 
 
Division 
: Worldwide Development 
Information Type 
: Reporting and Analysis Plan (RAP) 
 
Title 
: Reporting and Analysis Plan for A phase 3, randomized, 
open-label (sponsor-blind), active-controlled, parallel-group, 
multi-center, event driven study in dialysis subjects with 
anemia associated with chronic kidney disease to evaluate the 
safety and efficacy of daprodustat compared to recombinant 
human erythropoietin, following a switch from 
erythropoiesis-stimulating agents. 
Compound Number  
: GSK1278863 
Effective Date  
: Refer to Document Date 
 
Description : 
• 
The purpose of this RAP is to describe the planned analyses and output to be 
included in the Clinical Study Report for the study Protocol: GlaxoSmithKline 
Document Number 2015N226659_07. 
RAP Author(s):  
(Method: E-mail) 
Author 
Date 
Lead 
 
Principal Statistician 
(Specialty Biostatistics) 
N/A 
Co-Authors 
 
Director Clinical Statistics  
(Specialty Biostatistics) 
02-March-2021 
 
Statistics Leader 
(Specialty Biostatistics) 
02-March-2021 
 
Statistician 
(Specialty Biostatistics) 
03-March-2021 
 
Director Clinical Pharmacology Modelling and Simulation  
(Clinical Pharmacology and Experimental Medicine) 
02-March-2021 
 
Copyright 2021 the GlaxoSmithKline group of companies. All rights reserved.  
Unauthorized copying or use of this information is prohibited. 
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CONFIDENTIAL 
 
The GlaxoSmithKline group of companies 
 
200807 
 
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RAP Team Reviews:  
RAP Team Review Confirmations  
(Method: E-mail) 
Reviewer 
Date 
 
Sr. Director 
Clinical Development Lead 
(Clinical Sciences Respiratory and Specialty) 
03-March-2021 
 
Programming Leader  
(Specialty Biostatistics) 
02-March-2021 
 
Clinical Statistics and Clinical Programming Line Approvals: 
Clinical Statistics & Clinical Programming Line Approvals  
(Method: Pharma TMF eSignature) 
Approver 
Date 
Approval Method 
 
Statistics Director  
(Specialty Clinical Statistics) 
Refer to 
Document Date 
E-signature, 
eTMF 
 
Programming Leader 
(Specialty Clinical Programming) 
Refer to 
Document Date 
E-signature, 
eTMF 
 
 
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TABLE OF CONTENTS 
PAGE 
1. 
REPORTING & ANALYSIS PLAN SYNOPSIS ......................................................... 6 
2. 
SUMMARY OF KEY PROTOCOL INFORMATION .................................................. 9 
2.1. 
Changes to the Protocol Defined Statistical Analysis Plan ............................ 9 
2.2. 
Study Objective(s) and Endpoint(s)............................................................. 10 
2.3. 
Study Design .............................................................................................. 14 
2.4. 
Statistical Hypotheses................................................................................. 15 
2.4.1. 
Hgb efficacy Co-Primary Hypothesis ............................................ 15 
2.4.2. 
CV Safety (MACE) Co-Primary Hypothesis .................................. 15 
3. 
PLANNED ANALYSES .......................................................................................... 16 
3.1. 
Interim Analyses ......................................................................................... 16 
3.1.1. 
Additional Considerations at the Interim Analysis Not 
Specified in the Protocol .............................................................. 17 
3.2. 
Final Analyses ............................................................................................ 17 
4. 
ANALYSIS POPULATIONS ................................................................................... 17 
4.1. 
Protocol Deviations and Study Population Exclusions ................................ 18 
5. 
CONSIDERATIONS FOR DATA ANALYSES AND DATA HANDLING 
CONVENTIONS ..................................................................................................... 19 
6. 
STUDY POPULATION ANALYSES ....................................................................... 19 
6.1. 
Overview of Planned Analyses ................................................................... 19 
6.2. 
Display Details ............................................................................................ 21 
6.2.1. 
Populations Analyzed .................................................................. 21 
6.2.2. 
Subject Disposition ...................................................................... 21 
6.2.3. 
Protocol Deviations ...................................................................... 24 
6.2.4. 
Demographic & Baseline Characteristics ..................................... 24 
6.2.5. 
Prior and Concomitant Medications ............................................. 25 
6.2.6. 
Exposure and Randomized Treatment Compliance ..................... 25 
6.2.7. 
COVID-19 Impacted Visits ........................................................... 26 
7. 
PRIMARY STATISTICAL ANALYSES .................................................................... 26 
7.1. 
Hgb Efficacy Co-Primary Analysis .............................................................. 26 
7.1.1. 
Overview of Planned Hgb Efficacy Co-Primary and 
Supportive Analyses .................................................................... 26 
7.1.2. 
Planned Hgb Efficacy Co-Primary Statistical Analyses ................ 27 
7.2. 
CV Safety (MACE) Co-Primary Analysis ..................................................... 33 
7.2.1. 
Overview of Planned CV Safety (MACE) Co-Primary and 
Supportive Analyses .................................................................... 33 
7.2.2. 
Planned CV Safety (MACE) Co-Primary Statistical 
Analyses ...................................................................................... 34 
8. 
OTHER STATISTICAL ANALYSES ....................................................................... 38 
8.1. 
Efficacy Analyses ........................................................................................ 38 
8.1.1. 
Principal Secondary Efficacy Analyses ........................................ 38 
8.1.2. 
Additional Secondary Efficacy Analyses ...................................... 39 
8.1.3. 
Exploratory Efficacy Analyses ...................................................... 43 
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8.1.4. 
Other Efficacy Analyses ............................................................... 51 
8.2. 
Safety Analyses .......................................................................................... 51 
8.2.1. 
Principal Secondary Safety Analyses ........................................... 51 
8.2.2. 
Additional Secondary Safety Analyses ......................................... 53 
8.2.3. 
Exploratory Safety Analyses ........................................................ 59 
8.2.4. 
Adverse Event Safety Analyses ................................................... 61 
8.2.5. 
Clinical Laboratory Safety Analyses ............................................. 67 
8.2.6. 
Vital Signs Analyses .................................................................... 71 
8.2.7. 
Electrocardiograms ...................................................................... 72 
8.2.8. 
Pregnancies ................................................................................. 72 
8.2.9. 
Other Safety Analyses ................................................................. 73 
8.3. 
Patient Reported Outcomes Analyses ........................................................ 75 
8.3.1. 
Overview of Planned Patient Reported Outcomes 
Analyses ...................................................................................... 75 
8.3.2. 
Planned Patient Reported Outcomes Statistical Analyses ........... 76 
8.4. 
Biomarker Analyses .................................................................................... 79 
8.5. 
Pharmacogenetics Analyses ....................................................................... 79 
8.6. 
Analyses Excluding Sites with Suspected Fraud ......................................... 79 
9. 
REFERENCES ....................................................................................................... 81 
10. APPENDICES ........................................................................................................ 83 
10.1. 
Appendix 1: Protocol Deviation Management and Definitions for 
Per-Protocol Population .............................................................................. 84 
10.1.1. 
Exclusions from Per-Protocol Population ..................................... 84 
10.2. 
Appendix 2: Time & Events ......................................................................... 85 
10.2.1. 
Protocol Defined Time & Events .................................................. 85 
10.3. 
Appendix 3: Assessment Windows ............................................................. 93 
10.4. 
Appendix 4: Treatment States and Phases ................................................. 94 
10.4.1. 
Treatment States ......................................................................... 94 
10.5. 
Appendix 5: Data Display Standards & Handling Conventions .................... 98 
10.5.1. 
Study Treatment & Sub-group Display Descriptors ...................... 98 
10.5.2. 
Baseline Definition & Derivations ................................................. 98 
10.5.3. 
Reporting Process & Standards ................................................. 101 
10.6. 
Appendix 6: Derived and Transformed Data ............................................. 104 
10.6.1. 
General ...................................................................................... 104 
10.6.2. 
Study Population ........................................................................ 107 
10.6.3. 
Efficacy ...................................................................................... 121 
10.6.4. 
Safety ........................................................................................ 139 
10.6.5. 
Patient Reported Outcomes ....................................................... 155 
10.7. 
Appendix 7: Premature Withdrawals & Handling of Missing Data ............. 157 
10.7.1. 
Premature Withdrawals .............................................................. 157 
10.7.2. 
Handling of Missing Data ........................................................... 157 
10.8. 
Appendix 8: Values of Potential Clinical Importance ................................. 161 
10.8.1. 
Laboratory Values ...................................................................... 161 
10.8.2. 
Vital Signs .................................................................................. 161 
10.9. 
Appendix 9: Multicenter Studies ................................................................ 163 
10.9.1. 
Methods for Handling Centres ................................................... 163 
10.10. Appendix 10: Examination of Covariates, Subgroups & Other Strata ........ 164 
10.10.1. Handling of Covariates, Subgroups & Other Strata .................... 164 
10.10.2. Randomization Stratification ...................................................... 176 
10.11. Appendix 11: Multiple Comparisons & Multiplicity ..................................... 177 
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10.11.1. Handling of Multiple Comparisons & Multiplicity ......................... 177 
10.12. Appendix 12: Model Checking and Diagnostics for Statistical 
Analyses ................................................................................................... 180 
10.12.1. Statistical Analysis Assumptions ................................................ 180 
10.13. Appendix 13: Pharmacokinetic Sub-study Analysis Plan ........................... 182 
10.13.1. Overview of Planned Pharmacokinetic Analyses ....................... 182 
10.13.2. Drug Concentration Measures ................................................... 182 
10.13.3. Pharmacokinetic Parameters ..................................................... 183 
10.13.4. Pharmacokinetic / Pharmacodynamic Analyses ......................... 185 
10.14. Appendix 14: ABPM Sub-study Analysis Plan ........................................... 187 
10.14.1. Summary of Key Protocol Information ........................................ 187 
10.14.2. Planned Analyses ...................................................................... 191 
10.14.3. Analysis Populations .................................................................. 191 
10.14.4. Considerations for Data Analyses and Data Handling 
Conventions ............................................................................... 192 
10.14.5. Study Population Analyses ........................................................ 193 
10.14.6. Efficacy Analyses ....................................................................... 194 
10.14.7. Safety Analyses ......................................................................... 196 
10.15. Appendix 15 – Abbreviations & Trade Marks ............................................ 198 
10.15.1. Abbreviations ............................................................................. 198 
10.15.2. Trademarks ............................................................................... 200 
 
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1. 
REPORTING & ANALYSIS PLAN SYNOPSIS 
Overview 
Key Elements of the RAP 
Purpose 
• 
This RAP describes the planned analyses and outputs required for the final 
Clinical Study Report (CSR) for study 200807. 
Protocol 
• 
This RAP is based on the fifth  protocol amendment of study 200807 
[GlaxoSmithKline Document Number 2015N226659_07, 30JUL2020]. While 
there is also a France-specific fifth protocol amendment [GlaxoSmithKline 
Document Number 2015N226659_08, 30JUL2020], the analyses described in 
the France-specific amendment are consistent with the analyses described in 
the global protocol amendment. 
Co-Primary 
Objectives 
• 
To compare daprodustat to rhEPO for hemoglobin (Hgb) efficacy (non-
inferiority) 
• 
To compare daprodustat to rhEPO for cardiovascular (CV) safety (non-
inferiority) 
Co-Primary 
Endpoints 
• 
Mean change in Hgb between baseline and evaluation period (EP, mean over 
Weeks 28 to 52) 
• 
Time to first occurrence of adjudicated major adverse cardiovascular event 
(MACE); [composite of all-cause mortality, non-fatal myocardial infarction (MI) 
or non-fatal stroke] 
Study 
Design 
• 
This is a randomized, open-label (sponsor blind), active-controlled, parallel-
group, multi-center, event-driven study in dialysis subjects with anemia 
associated with chronic kidney disease (CKD) who are currently treated with 
erythropoiesis stimulating agents (ESAs). ESAs refer to any rhEPO or methoxy 
PEG-epoetin beta. 
• 
This study will comprise 4 study periods:  a 4-week screening period, a 4-week 
placebo run-in period, a treatment period, and a follow-up period. Prior ESA 
therapy continues during the screening and run-in periods.  
• 
The total duration of the study is dependent upon the accumulation of at least 
664 adjudicated first MACE (i.e., it is event-driven) unless review of interim data 
by the Independent Data Monitoring Committee (IDMC) recommends bringing 
the study to an earlier close.  
• 
Subjects will be stratified by dialysis type, by region and by participation in the 
ambulatory blood pressure monitoring (ABPM) sub-study. Dialysis type and 
region are considered to be stratification factors that are 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. 
• 
Following stratification, subjects will be randomized 1:1 to receive oral 
daprodustat or rhEPO [intravenous (IV) epoetin alfa or subcutaneous (SC) 
darbepoetin alfa]. 
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Overview 
Key Elements of the RAP 
• 
Both treatment arms (daprodustat and rhEPO) will follow a protocol-specified 
randomized treatment dose adjustment algorithm to achieve and/or maintain 
Hgb within the target range of 10-11 g/dL inclusive. Dose changes will be made 
programmatically by the Interactive Response Technology (IRT) system for 
both randomized treatment arms. 
Planned 
Analyses 
• 
It is planned that study unblinding will occur after at least 664 first MACE have 
occurred (see Section 3.2). Planned final analyses will be performed after study 
unblinding. 
• 
An IDMC will review safety and efficacy data periodically from ongoing clinical 
trials in the daprodustat clinical development program for the treatment of 
subjects with anemia associated with chronic kidney disease.  
• 
In addition, an interim analysis is planned for this study which will assess 
whether the daprodustat program has met criteria for futility or harm and 
whether the study should be stopped. The IDMC will review the interim analysis 
results and will provide a recommendation regarding early stopping to the 
sponsor. 
Key 
Analysis 
Populations 
• 
The primary population for the Hgb efficacy and MACE safety analyses will be 
the All Randomized Intent-to-Treat (ITT) population. Subjects will be analyzed 
according to the treatment to which they were randomized. 
Co-Primary 
Hypotheses 
• 
The co-primary Hgb efficacy objective will assess the estimand defined as the 
effect of daprodustat treatment relative to rhEPO on the change in Hgb from 
baseline to the average of all values in the EP, regardless of adherence to 
treatment including interruptions and discontinuations, the use of non-
randomized ESA medication for any reason including rescue therapy, or the 
use of blood transfusions in subjects on dialysis currently treated with an ESA 
with anemia secondary to CKD and assuming subjects do not die before the 
end of the EP. The analysis will test whether daprodustat is non-inferior to 
rhEPO according to the following statistical hypotheses: 
• Null: The difference in mean change in Hgb between baseline and EP, 
between treatment arms (daprodustat -rhEPO), is less than or equal to 
-0.75 g/dL. 
• Alternative: The difference in mean change in Hgb between baseline 
and EP, between treatment arms (daprodustat -rhEPO), is greater than 
-0.75 g/dL. 
• 
The co-primary CV safety objective will assess the estimand of time to first 
occurrence (in days) of adjudicated MACE from randomization to the end of 
study in all randomized subjects regardless of what treatment(s) they go on to 
receive. The primary analysis will test for non-inferiority of treatment with 
daprodustat relative to rhEPO, expressed by the following statistical 
hypotheses:  
• Null: daprodustat is inferior to rhEPO, with at least a 25% increased relative 
risk of first MACE (i.e. the hazard ratio is 1.25). 
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Overview 
Key Elements of the RAP 
• Alternative: daprodustat is non-inferior to rhEPO (i.e. the hazard ratio is 
<1.25). 
Co-Primary 
Analyses 
• 
For the Hgb efficacy analysis, an analysis of covariance (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% confidence interval (CI) for the treatment difference 
(daprodustat-rhEPO) and generate the 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. 
• 
For the CV safety analysis, 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 for the 
MACE endpoint. Non-inferiority will be achieved if the upper limit of the two-
sided 95% CI is below the margin of 1.25. 
Key 
Secondary 
Analyses 
Principal Secondary Endpoints (multiplicity adjusted endpoints, tested for superiority; 
for other endpoints see Section 2.2) 
• 
Time to first occurrence of adjudicated  
• MACE 
• MACE or an adjudicated thromboembolic event (vascular access 
thrombosis, deep vein thrombosis or pulmonary embolism)  
• MACE or an adjudicated hospitalization for heart failure (HF) 
• 
Average monthly IV iron dose (mg)/subject to Week 52 
Safety 
Endpoints 
• Incidence and severity of adverse events (AEs) and serious adverse events 
(SAEs) including AEs of special interest (AESI) 
• Reasons for discontinuation of randomized treatment 
• 
Absolute values and changes from baseline in laboratory parameters, blood 
pressure (BP) and heart rate (HR) 
 
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2. 
SUMMARY OF KEY PROTOCOL INFORMATION 
2.1. 
Changes to the Protocol Defined Statistical Analysis Plan 
Changes to the originally planned statistical analysis specified in the fourth protocol 
amendment (Dated: 30JUL2020) are detailed as follows: 
Table 1 
Changes to Protocol Defined Analysis Plan 
Protocol 
Reporting & Analysis Plan 
Statistical Analysis Plan 
Statistical Analysis Plan 
Rationale for Changes 
• 
None 
• 
New displays related to 
COVID-19 pandemic have 
been added 
• 
Assessing the impact of the 
COVID-19 pandemic 
• 
None 
• 
Number of RBC whole 
blood and transfusion event 
is included in the 
exploratory efficacy 
analysis of RBC and Whole 
Blood Transfusions 
• 
Number of RBC whole 
blood and transfusion event 
has been defined and 
included in the exploratory 
endpoints 
• 
None 
• 
Time to first RBC and whole 
blood transfusion is 
included in the exploratory 
efficacy analysis of RBC 
and Whole Blood 
Transfusions 
• 
Time to first RBC and whole 
blood transfusion has been 
included in the exploratory 
endpoints 
• 
None 
• 
Phosphate Binder analyses 
have been added 
• 
Assessing the effect of 
Phosphate Binder co-
administration. 
• 
None 
• 
Clopidogrel analyses have 
been added 
• 
Assessing the effect of 
Clopidogrel co-
administration. 
PK Sub-study Statistical Analysis 
Plan 
PK Sub-study Statistical 
Analysis Plan 
Rationale for Changes 
• 
PK sub-study endpoints 
described as dose normalized 
• 
PK sub-study endpoints 
described as dose 
extrapolated 
• 
Terminology clarification 
following discussion with 
regulatory agencies 
PK sub-study endpoints include: 
• 
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. 
PK sub-study endpoints 
modified as follows: 
• 
Endpoints removed: 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 
while in target Hgb range  
vs. percent time in range 
during EP. 
• 
Removed as these 
endpoints do not provide 
additional information for 
efficacy explorations than 
what will be available from 
remaining endpoints. 
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Protocol 
Reporting & Analysis Plan 
Statistical Analysis Plan 
Statistical Analysis Plan 
Rationale for Changes 
• 
Scatter plots of daprodustat PK 
parameters (Ctau and Cmax) dose 
normalized to 1 mg vs. change 
from baseline of Hgb during EP. 
• 
Boxplots of daprodustat PK 
parameters (Ctau and Cmax) 
dose normalized to 1 mg by 
subjects with or without MACE 
or combined safety endpoint 
• 
Scatter plots of daprodustat 
PK parameters (Ctau and 
Cmax) dose normalized to 
average dose during EP 
while in target Hgb range  
vs. percent time in range 
during EP. 
• 
Endpoints removed: Scatter 
plots of daprodustat PK 
parameters (Ctau and Cmax) 
dose normalized to 1 mg 
vs. change from baseline of 
Hgb during EP. 
• 
Endpoints removed: 
Boxplots of daprodustat PK 
parameters (Ctau and 
Cmax) dose normalized to 
1 mg by subjects with or 
without MACE or combined 
safety endpoint 
ABPM Sub-study Statistical 
Analysis Plan 
ABPM Sub-study Statistical 
Analysis Plan 
Rationale for Changes 
• 
Statistical analyses planned. 
• 
No statistical analysis will 
be conducted for this sub-
study due to the small 
number of subjects 
recruited. Instead all data 
will either be summarized or 
listed. 
• 
Small number of subjects 
recruited. 
 
2.2. 
Study Objective(s) and Endpoint(s) 
Objectives 
Endpoints 
Co-Primary Objectives 
Co-Primary Endpoints 
• 
To compare daprodustat to rhEPO for 
CV safety (non-inferiority) 
• 
Time to first occurrence of adjudicated MACE 
(composite of all-cause mortality, non-fatal MI and non-
fatal stroke) 
• 
To compare daprodustat to rhEPO for 
Hgb efficacy(non-inferiority) 
• 
Mean change in Hgb between baseline and EP (mean 
over Weeks 28 to 52) 
Principal Secondary Objectives 
Principal Secondary Endpoints (tested for 
superiority, adjusted for multiplicity) 
• 
To compare daprodustat to rhEPO on 
CV safety endpoints 
• 
Time to first occurrence of adjudicated 
• 
MACE 
• 
MACE or a thromboembolic event (vascular access 
thrombosis, symptomatic deep vein thrombosis or 
symptomatic pulmonary embolism)  
• 
MACE or a hospitalization for heart failure (HF) 
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Objectives 
Endpoints 
• 
To compare daprodustat to rhEPO on 
the use of intravenous (IV) iron 
• 
Average monthly IV iron dose (mg)/subject to Week 52  
Secondary Objectives 
Secondary Endpoints (tested for superiority1, no 
multiplicity adjustment) 
• 
To compare daprodustat to rhEPO on 
additional CV safety endpoints  
 
• 
All-cause mortality, CV mortality, fatal or non-fatal MI, 
fatal or non-fatal stroke2 
• 
MACE or hospitalization for HF2 (recurrent events 
analysis) 
• 
CV mortality or non-fatal MI2 
• 
All-cause hospitalization 
• 
All cause hospital re-admission within 30 days 
• 
MACE or hospitalization for HF or thromboembolic 
events2 
• 
Hospitalization for HF2 
• 
Thromboembolic events2 
• 
To compare daprodustat to rhEPO on 
Hgb variability 
• 
Hgb change from baseline to Week 521 
• 
N (%) responders, defined as mean Hgb within the Hgb 
analysis range 10-11.5  g/dL during EP 
• 
% time Hgb in analysis range (10-11.5 g/dL) during the 
evaluation period (EP, Week 28 to 52) and during the 
maintenance period (MP; Week 28 to end of trial) (non-
inferiority analysis that will use a margin of 15% less time 
in range) 1 
• 
To compare daprodustat to rhEPO on 
BP 
• 
Change from baseline in SBP, DBP and MAP at Week 
52 and at end of treatment  
• 
Number of BP exacerbation events per 100 patient years 
• 
N (%) with at least one BP exacerbation event during 
study 
• 
To compare daprodustat to rhEPO on 
the time to rescue (defined as 
permanently stopping randomized 
treatment due to meeting rescue 
criteria). 
• 
Time to stopping randomized treatment due to meeting 
rescue criteria 
• 
To compare daprodustat to rhEPO on 
HRQoL and Utility score 
• Mean change in SF-36 HRQOL scores (Physical 
Component Score (PCS), Mental Component Score 
(MCS) and 8 health domains) between baseline and 
Weeks 8, 12, 28, 52, of particular interest are the changes 
from baseline in the vitality and physical functioning 
domains at Wk 28 and 52 
• Change from baseline in Health Utility (EQ-5D-5L) score 
at Week 52  
• Change from baseline in EQ VAS at Week 52 
• 
To compare daprodustat to rhEPO on 
the symptom severity and change 
• Change from Baseline at Wk 8,12, 28, 52 in PGI-S 
Exploratory Objectives 
Exploratory Endpoints (statistical testing not 
planned) 
• 
To further compare daprodustat and 
rhEPO on Hgb variability 
• 
Hgb observed and change from baseline across all visits 
to end of treatment 
• 
% of time Hgb is above, within and below the range of 
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Objectives 
Endpoints 
10-11.5 g/dL during EP and MP 
• 
Number (%) of subjects with mean Hgb above, within 
and below the Hgb analysis range during EP and at the 
end of treatment  
• 
Number (%) of subjects with a Hgb <7.5 g/dL during the 
EP and MP 
• 
Number of times Hgb < 7.5 g/dL during the EP and MP 
• 
Number (%) of subjects with a >1g/dL increase in Hgb 
over 2 weeks (assessed at Week 2 and Week 4) or a >2 
g/dL increase in Hgb within any 4 week period from 
Week 4 to Week 52 
• 
Number (%) of subjects with a >1g/dL decrease in Hgb 
over 2 weeks (assessed at Week 2 and Week 4) or a >2 
g/dL decrease in Hgb within any 4 week period from 
Week 4 to Week 52 
• 
N (%) of subjects with a Hgb value ≥ 12 g/dL during the 
EP and MP 
• 
Number of times Hgb ≥ 12 g/dL during the EP and MP 
• 
% of time Hgb ≥ 12 g/dL during the EP and MP 
• 
To compare daprodustat to rhEPO on 
measures of iron parameters 
• 
Observed and change from baseline in hepcidin, ferritin, 
TSAT, total iron, TIBC across all visits to end of 
treatment 
• 
Average quarterly ferritin 
• 
Average quarterly TSAT 
• 
Average quarterly IV iron dose/subject 
• 
N (%) of subject who met iron management criteria 
• 
N (%) of subjects who reduced IV iron supplementation 
relative to baseline (defined as total iron (mg) over 4 
weeks prior to randomization) during EP (defined as 
average monthly IV iron dose (mg) over Weeks 28 to 52) 
• 
To further  compare daprodustat to 
rhEPO on BP and BP medication 
changes   
• 
Observed and change from baseline in SBP, DBP and 
MAP by visit 
• 
Number of BP medications per subject by visit 
• 
Change from baseline in the number of BP medications 
per subject by visit 
• 
N (%) of subjects who had no change, an increase or a 
decrease in the dosage or number of BP medications 
from baseline by visit 
• 
To compare daprodustat to rhEPO on 
the need for RBC and whole blood 
transfusions 
• 
Number (%) of subjects who receive at least one RBC or 
whole blood transfusions by Week 52 and by end of 
treatment 
• 
Number of RBC and whole blood transfusions per 100 
patient years  
• 
Number of RBC and whole blood units per 100 patient 
years 
• 
To compare daprodustat to rhEPO on 
lipid parameters.  
• 
Observed and % change from baseline in lipid 
parameters by visit [total cholesterol, direct low density 
lipoprotein cholesterol (LDL-C), high density lipoprotein 
cholesterol (HDL-C)] 
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Objectives 
Endpoints 
• 
To compare the effect of daprodustat 
to rhEPO on delayed graft function 
(DGF) after deceased donor kidney 
transplantation 
• 
Number (%) of subjects experiencing DGF after 
deceased donor kidney transplantation (where DGF is 
defined as the use of dialysis within 7 days of the 
transplant) 
• 
Length of time that subjects experience DGF after 
deceased donor kidney transplantation 
• 
Evaluate the dose adjustment 
schemes 
• 
Assigned dose by visit and at Day 1, Week 28, Week 52, 
and yearly 
• 
Most recent dose prior to Week 28, Week 52, yearly and 
End of Treatment 
• 
Number (%) of patients with 0, 1, 2, or >2 dose 
adjustments during the following periods: 
o Day 1 - < Week 28 
o Week 28 - < Week 52 
o Day 1 - < End of Treatment 
• 
Number of dose adjustments during the following 
periods: 
o Day 1 - < Week 28 
o Week 28 - < Week 52 
o Day 1 - < End of Treatment 
• 
Number of dose adjustments per year during Day 1 - < 
End of Treatment 
• 
Time dose held for Hgb≥12 g/dL 
• 
To further compare daprodustat to 
rhEPO on HRQoL and Utility score 
• 
Change from baseline in Health Utility I (EQ-5D-5L) 
score at Weeks 8,12, 28, 52, yearly, EOS 
• 
Change from baseline in EQ VAS at Weeks 8, 12, 28, 
52, yearly, EOS 
• 
To further compare daprodustat to 
rhEPO on the symptom severity and 
change 
• 
Shift tables (Baseline to Weeks 8, 12, 28, and 52) in 
PGI-S 
• 
N(%) of patients within each PGI-C symptom change 
level at Weeks 8, 12, 28, 52. 
Safety Objective 
Safety Endpoints 
• 
To compare the safety and tolerability 
of daprodustat to rhEPO 
• 
Incidence and severity of AEs and serious adverse 
events (SAEs) including AEs of special interest3 
• 
Reasons for discontinuation of randomized treatment 
• 
Absolute values and changes from baseline in laboratory 
parameters, BP and heart rate (HR) 
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. 
3. 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 
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2.3. 
Study Design 
Overview of Study Design and Key Features 
 
 
Design Features 
• This is a randomized, open-label (sponsor blind), active-controlled, 
parallel-group, multi-center, event-driven study in dialysis subjects 
with anemia associated with CKD who are currently treated with 
ESAs. 
Dosing and 
Randomized 
Treatment 
Assignment 
• A central randomization approach will be used to protect against 
potential selection bias due to the open-label design. The 
randomization schedule will be generated by PPD, and PPD’s IRT 
system will be used for treatment allocation. 
• Subjects will be stratified by dialysis type [hemodialysis (HD*) or 
peritoneal dialysis (PD)], by region (see Section 10.9.1) and by 
participation in the ABPM sub-study. Dialysis type and region are 
stratification factors considered to be potentially prognostically 
important, i.e., predictive of study endpoints, while participation in the 
ABPM sub-study is an administrative stratification factor intended 
solely to ensure a similar number of sub-study subjects in each of the 
two randomized groups. 
* In addition to HD this group also includes combination methods 
such as hemodiafiltration (HDF) or hemofiltration (HF). 
• Following stratification, subjects will be randomized 1:1 to receive 
oral daprodustat or rhEPO (IV epoetin alfa or SC darbepoetin alfa). 
• Please refer to the protocol for starting doses, dose steps and 
elements of the dose adjustment scheme. 
Interim Analysis 
• 
An IDMC will review safety and efficacy data periodically from 
ongoing clinical trials in the daprodustat clinical development 
program for the treatment of subjects with anemia of chronic kidney 
disease.  
• In addition, a formal interim analysis is planned for this study which 
will assess whether the daprodustat program has met criteria for 
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Overview of Study Design and Key Features 
futility or harm and should be stopped. The IDMC will review the 
interim analysis results and will provide a recommendation regarding 
early stopping to the sponsor. See Section 3.1 for further details. 
2.4. 
Statistical Hypotheses 
2.4.1. 
Hgb efficacy Co-Primary Hypothesis 
The co-primary Hgb efficacy objective will assess the estimand defined as the effect of 
daprodustat treatment relative to rhEPO on the change in Hgb from baseline to the 
average of all values in the EP, regardless of adherence to treatment including 
interruptions and discontinuations, the use of non-randomized ESA medication for any 
reason including rescue therapy, or the use of blood transfusions, in subjects on dialysis 
currently treated with an ESA with anemia secondary to CKD and assuming subjects do 
not die before the end of the EP. The analysis will test whether daprodustat is non-
inferior to rhEPO according to the following statistical hypotheses:  
• 
Null: The difference in mean change in Hgb between baseline and EP, between 
treatment arms (daprodustat -rhEPO), is less than or equal to -0.75 g/dL. 
• 
Alternative: The difference in mean change in Hgb between baseline and EP, 
between treatment arms (daprodustat -rhEPO), is greater than -0.75 g/dL  
The non-inferiority margin is pre-defined as -0.75 g/dL; determined based upon a 
combination of clinical judgment, statistical reasoning and regulatory guidance for 
designing non-inferiority trials.  
Statistical significance of non-inferiority will be assessed at the one-sided 2.5% level. An 
ANCOVA model including prognostic randomization stratification factors (dialysis type 
and region), baseline Hgb and treatment will be used to obtain a point estimate and two-
sided 95% CI for the treatment difference (daprodustat -rhEPO) and generate the p-value 
for the non-inferiority test. The non-inferiority p-value will show strength of evidence 
against the null hypothesis. Non-inferiority will be established if the lower limit of the 
two-sided 95% CI for the treatment difference is greater than -0.75 g/dL. 
2.4.2. 
CV Safety (MACE) Co-Primary Hypothesis 
The co-primary CV safety objective will assess the estimand of time to first occurrence 
(in days) of adjudicated MACE from randomization to the end of study in all randomized 
subjects regardless of what treatment(s) they go on to receive. The primary analysis will 
test for non-inferiority of treatment with daprodustat relative to rhEPO, expressed by the 
following statistical hypotheses:  
• 
Null: daprodustat is inferior to rhEPO, with at least a 25% increased relative risk 
of first MACE (i.e. the hazard ratio is 1.25) 
• 
Alternative: daprodustat is non-inferior to rhEPO (i.e. the hazard ratio is <1.25) 
The non-inferiority margin is pre-defined as the hazard ratio of 1.25; supported by a 
review of evidence reported in historical randomized trials of rhEPO in dialysis and non-
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dialysis CKD subjects and after consideration of the largest point estimate that, by 
design, would meet the statistical criterion for non-inferiority.  
Statistical significance of non-inferiority will be assessed at the one-sided 2.5% level. A 
Cox-Proportional Hazards-Regression model, adjusting for treatment and prognostic 
randomization stratification factors (dialysis type and region), will be used to estimate the 
hazard-ratio, its two-sided 95% CI and to generate the p-value for the non-inferiority test. 
Non-inferiority will be achieved if the upper limit of the two-sided 95% CI is below the 
margin of 1.25. 
The co-primary endpoints will be tested first. Non-inferiority needs to be established for 
both co-primaries to proceed to evaluate MACE for superiority as well as the principal 
secondary endpoints for superiority. Principal secondary endpoints include prioritized 
composites for MACE (including thromboembolic events and hospitalizations for HF) 
and IV iron utilization (defined as the average monthly IV iron dose used to Week 52). 
Statistical testing of MACE for superiority as well as the principal secondary endpoints 
will be adjusted for multiplicity (Section 10.11.1). 
3. 
PLANNED ANALYSES 
3.1. 
Interim Analyses 
The IDMC will periodically receive unblinded safety reports containing, at a minimum, 
clinical endpoints (whether adjudicated or pending adjudication) and SAEs, from an 
independent Statistical Data Analysis Center (SDAC) while the study is ongoing.  The 
IDMC may recommend stopping the study for safety at any time.  
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 blood pressure, 
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.   
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. 
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3.1.1. 
Additional Considerations at the Interim Analysis Not Specified 
in the Protocol 
If the study stops because of results of an interim analysis, subjects will be brought to the 
investigational sites for the final study visits (end of study visit and follow-up visit) as 
soon as possible. 
If the trial is stopped for increased MACE risk, futility or other safety concerns, point 
estimates, two-sided 95% confidence intervals, and one-sided p-values will be generated 
for the primary and principal secondary endpoints. One-sided p-values will be compared 
to 0.025 to assess nominal significance, and will be provided for descriptive purposes 
only. 
3.2. 
Final Analyses 
The final planned primary analyses will be performed after the completion of the 
following sequential steps: 
1. It is projected that the target number of events has been attained as defined in the 
protocol, and final study clinic visits have occurred. 
2. All required database cleaning activities have been completed and final database 
release and database freeze has been declared by PPD Data Management. 
3. All criteria for unblinding the randomization codes have been met.  
4. Randomization codes have been distributed according to GSK and PPD procedures. 
4. 
ANALYSIS POPULATIONS 
Inclusion in any analysis population is contingent on a subject signing informed consent. 
Population 
Definition / Criteria 
Analyses Evaluated 
Screened 
• All screened subjects. 
• Study Population 
• Safety 
Intent-To-Treat 
(ITT) 
• All randomized subjects. 
• Subjects will be analyzed according to the 
treatment to which they were randomized. 
• Study Population 
• Efficacy 
• Safety 
Enrolled 
• All randomized subjects. 
• Subjects will be analyzed according to the 
treatment to which they were randomized. 
• Use of the enrolled population is required for 
some displays; for this study, the enrolled and 
ITT populations will be identical. 
• Study Population 
Per-Protocol (PP) 
• All ITT subjects without PP population 
exclusions. 
• Exclusions from the PP population are defined 
• Efficacy 
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Population 
Definition / Criteria 
Analyses Evaluated 
in Section 4.1 (Protocol Deviations and Study 
Population Exclusions) and Section 10.1 
(Protocol Deviation Management and 
Definition for Per-Protocol Population). 
• Subjects will be analyzed according to the 
treatment received.1 
Safety 
• All randomized subjects who receive at least 
one dose of randomized treatment. 
• Subjects will be analyzed according to the 
treatment received.1 
• Safety 
Sub-study Populations 
Please see sub-study analysis plans for definitions of sub-study analysis populations. 
[1]: Only subjects receiving incorrect randomized treatment for the duration of their study participation will be analyzed 
according to the treatment received. Otherwise, subjects will be analyzed according to the treatment to which they 
were randomized. 
4.1. 
Protocol Deviations and Study Population Exclusions 
• 
Significant protocol deviations  will be summarized and listed. 
• 
Exclusions from the main study populations described above will also be 
summarized and listed. Please refer to Appendix 1: Protocol Deviation Management 
and Definitions for Per-Protocol Population for further details of Per-Protocol 
population exclusions. 
• 
Protocol deviations and study population exclusions will be tracked by the study 
team throughout the conduct of the study in accordance with PPD’s Deviation 
Management Plan and Study Deviation Rules Document. 
o Data will be reviewed prior to unblinding the database to ensure all significant 
deviations and deviations which may lead to exclusion from the analysis are 
captured and categorized on the protocol deviations dataset.  
o This dataset will be the basis for the summaries and listings of protocol 
deviations. 
• 
A separate summary and listing of all inclusion/exclusion criteria deviations will also 
be provided. This summary will be based on data as recorded on the 
inclusion/exclusion page of the electronic case report form (eCRF). 
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5. 
CONSIDERATIONS FOR DATA ANALYSES AND DATA 
HANDLING CONVENTIONS 
Table 2 provides an overview of appendices within the RAP for outlining general 
considerations for data analyses and data handling conventions.  
Table 2 
Overview of Appendices 
Section Component 
10.1 
Appendix 1: Protocol Deviation Management and Definitions for Per-Protocol 
Population 
10.2 
Appendix 2: Time & Events 
10.3 
Appendix 3: Assessment Windows 
10.4 
Appendix 4: Treatment States and Phases 
10.5 
Appendix 5: Data Display Standards & Handling Conventions 
10.6 
Appendix 6: Derived and Transformed Data 
10.7 
Appendix 7: Premature Withdrawals & Handling of Missing Data 
10.8 
Appendix 8: Values of Potential Clinical Importance 
10.9 
Appendix 9: Multicenter Studies 
10.10 
Appendix 10: Examination of Covariates, Subgroups & Other Strata 
10.11 
Appendix 11: Multiple Comparisons & Multiplicity 
10.12 
Appendix 12: Model Checking and Diagnostics for Statistical Analyses 
6. 
STUDY POPULATION ANALYSES 
6.1. 
Overview of Planned Analyses 
The study population analyses will be based on the ITT population and will include a 
total column, unless otherwise specified. 
Table 3 provides an overview of the planned study population analyses. 
Table 3 
Overview of Planned Study Population Analyses 
Parameter 
Analysis 
Population 
Data Displays Generated 
Table 
Figure 
Listing 
Populations Analyzed 
Study Populations 
Screened 
Y 
 
 
Screening Status and Reasons for Screen 
Failure 
Screened 
Y 
 
Y 
Screening Attempts 
Screened 
Y 
 
 
Exclusions from Study Populations 
ITT 
Y 
 
Y 
Subject Disposition 
Subjects Who Were Rescreened 
Screened 
 
 
Y 
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Parameter 
Analysis 
Population 
Data Displays Generated 
Table 
Figure 
Listing 
Subject Status and Reasons for Study 
Withdrawal at Wk28, Wk52 and End of Study 
ITT 
Y 
Y 
Y 
Subject Status and Reasons for Study 
Withdrawal at Wk28, Wk52 and End of Study by 
Region 
ITT 
Y 
 
 
Subject Status and Reasons for Study 
Withdrawal at Wk28, Wk52 and End of Study by 
Country 
ITT 
Y 
 
 
Treatment Status and Reasons for 
Discontinuation of Randomized Treatment at 
Wk28, Wk52 and End of Study 
ITT 
Y 
Y 
Y 
Treatment Status and Reasons for 
Discontinuation of Randomized Treatment at 
Wk28, Wk52 and End of Study by Region 
ITT 
Y 
 
 
Treatment Status and Reasons for 
Discontinuation of Randomized Treatment at 
Wk28, Wk52 and End of Study by Country 
ITT 
Y 
 
 
Number of Subjects by Region, Country and Site 
ID 
Enrolled 
Y 
 
 
Type of Subject Contact at Wk28, Wk52 and End 
of Study 
ITT 
Y 
 
 
End of Study Contact 
ITT 
Y 
 
 
Subject Follow-up Time 
ITT 
Y 
 
 
Subject Completion Status 
ITT 
Y 
 
 
Subject Survival Status 
ITT 
Y 
 
 
Planned and Actual Treatments 
ITT 
 
 
Y 
Protocol Deviations 
Significant Protocol Deviations 
ITT 
Y 
 
Y 
Subjects with Inclusion/Exclusion Criteria 
Deviations 
ITT 
Y 
 
Y 
Demographic & Baseline Characteristics 
Demographic & Baseline Characteristics 
ITT & Safety 
Y 
 
Y 
Demographic & Baseline Characteristics for 
Hyporesponders 
ITT 
Y 
 
 
Demographic & Baseline Characteristics by 
Baseline Dialysis Type 
ITT 
Y 
 
 
Age Ranges 
Enrolled 
Y 
 
 
Race and Racial Combinations 
ITT 
Y 
 
Y 
Smoking History 
ITT 
Y 
 
 
Medical Conditions 
ITT 
Y 
 
 
Dialysis Modality and Frequency 
ITT 
Y 
 
 
Dialysis Modality Changes 
ITT 
Y 
 
 
Prior and Concomitant Medications 
Pre-Treatment Medications 
ITT 
Y 
 
 
On-Treatment Medications 
ITT 
Y 
 
Y 
Post-Treatment Medications 
ITT 
Y 
 
 
Non-randomized ESA Use During Treatment 
Period 
Safety 
Y 
 
Y 
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Parameter 
Analysis 
Population 
Data Displays Generated 
Table 
Figure 
Listing 
Exposure and Randomized Treatment Compliance 
Extent of Exposure to Randomized Treatment 
Safety 
Y 
 
Y 
Randomized Treatment Compliance Categories 
Safety 
Y 
 
 
Randomized Treatment Compliance 
Safety 
Y 
 
 
IRT and eCRF Dose and Frequency 
Discrepancies 
Safety 
Y 
 
 
NOTES: 
• 
Y = Yes display generated. 
6.2. 
Display Details 
6.2.1. 
Populations Analyzed 
The number of subjects in the Screened, Safety, ITT, Enrolled, PP and relevant sub-study 
populations will be summarized by treatment group and overall. 
The number and percentage of subjects by screening status (enrolled/randomized, screen 
failed) and associated reasons for screen failure will be summarized for the screened 
population. 
A summary of all screening attempts and associated reasons for screen failure will be 
provided for the screened population. This summary will count each screening attempt 
individually, regardless of whether or not there was a subsequent re-screen. 
A listing of screen failure records will be provided for all subjects who failed screening, 
including site ID, unique subject ID, date of screen failure, and reason(s) for screen 
failure. 
The number and percentage of subjects excluded from the Safety and PP populations will 
be summarized by reason, treatment group and overall in individual displays for each 
study population.  
A listing of subjects excluded from the Safety and PP populations will be provided. The 
listing will include the treatment arm, site ID, unique subject ID, date of deviation, study 
day of deviation, category, coded term, criteria which lead to exclusion, and the 
populations from which the subject was excluded. 
6.2.2. 
Subject Disposition 
The summary of subject status and reasons for study withdrawal will include: 
• the number and percentage of subjects ongoing at the Week 28 visit and Week 52 
visit, the associated randomized treatment status (on randomized treatment or in 
follow-up), the number and percentage of subjects withdrawing early before the 
Week 28 visit and the Week 52 visit, the associated reasons/subreasons for 
withdrawal, and the number and percentage of subjects that died before the Week 
28 visit and Week 52 visit, summarized by treatment group and overall. For 
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subjects with an adverse event leading to withdrawal of consent, the outcome 
(fatal, non-fatal) of the adverse event will be summarized. 
• the overall number and percentage of subjects who completed the study, the 
overall number and percentage of subjects withdrawing early from the study and 
the associated reasons/subreasons for withdrawal summarized by treatment group 
and overall. For subjects with an adverse event leading to withdrawal of consent, 
the outcome (fatal, non-fatal) of the adverse event will be summarized. 
The summary of subject status and reasons for study withdrawal will be repeated by 
region and by country. The overall only summary of subject status and reasons for study 
withdrawal will be repeated by relationship to COVID-19 pandemic. 
A listing of reasons for study withdrawal will be provided for all subjects who were 
withdrawn from the study. This listing will include treatment, site ID, unique subject ID, 
date of withdrawal, study day of withdrawal, primary reason for withdrawal, subreason 
for withdrawal, was a follow-up phone contact attempted 3 times, and was a follow-up 
certified letter mailed. 
A listing of screening status will be provided for all subjects who were rescreened for the 
study. The listing will include unique subject ID, subject ID, screening status, date of 
screen failure, and reason for screen failure.  
The summary of treatment status and reasons for discontinuation of randomized 
treatment will include: 
• the number and percentage of subjects who never received randomized treatment 
at the Week 28 and Week 52 visits, the number and percentage of subjects 
ongoing on randomized treatment at the Week 28 and Week 52 visits, and the 
number and percentage of subjects who discontinued randomized treatment, 
including the breakdown of the number and percentage of subjects who died 
while taking randomized treatment and those that did not die while taking 
randomized treatment, and the associated reasons/subreasons for randomized 
treatment discontinuation overall and separately for subjects who did not die 
while taking randomized treatment and for subjects who died while taking 
randomized treatment at the Week 28 and Week 52 visits summarized by 
treatment group and overall. 
• the overall number and percentage of subjects who never received randomized 
treatment, the overall number and percentage of subjects who prematurely 
discontinued randomized treatment during the study, including the breakdown of 
the number and percentage of subjects who died while taking randomized 
treatment and those that did not die while taking randomized treatment, and a 
summary of the reasons and subreasons for randomized treatment discontinuation 
overall and separately for subjects who died while taking randomized treatment 
and for subjects who did not die while taking randomized treatment, and the 
overall number and percentage of subjects who did not prematurely discontinue 
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randomized treatment during the study summarized by treatment group and 
overall. 
The summary of treatment status and reasons for discontinuation of randomized 
treatment will be repeated by region and by country. The overall only summary of subject 
status and reasons for discontinuation of randomized treatment will be repeated by 
relationship to COVID-19 pandemic. 
A listing of the randomized treatment discontinuation record will be provided for all 
subjects who prematurely discontinued randomized treatment. This listing will include 
treatment, site ID, unique subject ID, date of last dose, study day of discontinuation, 
primary reason for discontinuation, and subreasons for discontinuation.  
A Kaplan-Meier plot of time to early withdrawal from the study will be produced by 
treatment group.  
Two Kaplan-Meier plots of time to permanent randomized treatment discontinuation by 
treatment group will be produced. For both of the plots, the risk set will include all 
subjects who started taking randomized treatment. The first plot will consider an event as 
subjects who discontinued randomized treatment and the second plot will consider an 
event as subjects who discontinued randomized treatment and did not die while on 
treatment. If a subject discontinued treatment due to death, that subject will not count 
towards the event, and will be censored instead. 
The number and percentage of subjects by region, country, site ID and investigator name 
will be summarized by treatment group and overall for the enrolled population. 
The type of subject contact at the Week 28, Week 52 visit and End of Study visit will be 
provided by treatment group and overall. 
A summary of the timing of the end of study contact will be provided by subject status, 
type of contact, treatment group and overall. 
A summary of the total follow-up time and percentage of total possible follow-up time 
during time periods of the study (i.e., time period for follow-up of CV endpoints, time 
period for vital status, and time period for on-treatment CV endpoints) will be provided 
by treatment group and overall (see Section 10.6.2 and Section 10.6.4 for definitions). 
Cardiovascular Endpoint Follow-up Among All Randomized Subjects will be presented 
by a figure. 
A summary of the subject completion status, including the number and percentage of 
subjects included in the co-primary Hgb analysis, by CV endpoint status (known and 
unknown at the end of study) and by vital status (known and unknown at the end of 
study) will be provided by treatment group and overall. 
A summary of the subject survival status by study completion status will be provided by 
treatment group and overall. 
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A listing of planned and actual treatments will be provided. This listing will include 
region, country, site ID, investigator name, subject number, randomization number, 
randomization date, randomized treatment, actual treatment flag. 
6.2.3. 
Protocol Deviations 
The number and percentage of subjects who had significant protocol deviations (defined 
in PPD’s Study Deviation Rules Document) will be summarized by category and by 
treatment group and overall. It will be repeated by relationship to COVID-19 pandemic. 
A listing of significant protocol deviations will be provided. The listing will include 
treatment, site ID, unique subject ID, date of deviation, study day of deviation, protocol 
deviation category, protocol deviation coded term, and protocol deviation description. 
The number and percentage of subjects who had inclusion/exclusion criteria deviations 
will be summarized by inclusion/exclusion type, criteria description and by treatment 
group and overall. 
A listing of subjects with inclusion/exclusion criteria deviations will be provided. The 
listing will include treatment, site ID, unique subject ID, inclusion/exclusion type, and 
criteria description. 
6.2.4. 
Demographic & Baseline Characteristics 
The number and percentage of subjects or summary statistics will be provided by 
treatment group and overall for the demographic and baseline characteristics listed in 
Section 10.10. This table will be repeated for the primary definition of a hyporesponder 
outlined in Section 10.6.2 and by baseline dialysis type (HD/PD). 
A listing of demographic characteristics will be produced. This listing will include 
treatment, site ID, unique subject ID, year of birth, age, sex, and ethnicity and may 
include additional demographic characteristics. 
The number and percentage of subjects in the following age ranges: Adult (18-64 years), 
 65 – 84 years, and  85 years will be provided by treatment group and overall. 
A summary of race and racial combinations will be provided by treatment group and 
overall. 
A listing of race will be provided. This listing will include treatment, site ID, unique 
subject ID, race, and race detail. 
A summary of smoking history will be provided by treatment group and overall. 
A summary of medical conditions will be provided by treatment group and overall. 
A summary of dialysis modality and frequency at randomization, Week 28, Week 52 and 
End of Study will be provided by treatment group and overall. This summary will include 
the number and percentage of subjects who have temporarily or permanently stopped 
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dialysis at these time points, as well as summary statistics for total residual urine volume 
for subjects on hemodialysis and peritoneal dialysis separately. 
The number and percentage of subjects with dialysis modality changes at any point in the 
study will be provided by treatment group and overall. 
6.2.5. 
Prior and Concomitant Medications 
The number and percentage of subjects reporting the use of each concomitant medication 
will be summarized by treatment group and overall, anatomical therapeutic chemical 
(ATC) Level 1, 2, 3, and Ingredient. Summaries of pre-treatment, on-treatment, and post-
treatment medication will be provided separately. See Section 10.4.1 for a summary of 
treatment states for concomitant medications. 
A listing of on-treatment concomitant medication records will be provided with details of 
the on-treatment concomitant medication use. 
The number and percentage of subjects with any non-randomized ESA use in addition to 
randomized treatment during the treatment period (see Section 10.6.2) will be provided 
by treatment group and overall. Similarly, the number and percentage of subjects with 
any non-randomized ESA used instead of randomized treatment during the treatment 
period (see Section 10.6.2) will be provided by treatment group and overall.  
Additionally, the duration of the non-randomized ESA use during the treatment period 
will be summarized using mean, standard deviation, minimum, P25, median, P75, and 
maximum by treatment group and overall, as well as by the number and percentage of 
subjects in the following duration categories: < 5 days,  5 days - < 14 days,  14 days - 
< 28 days,  28 days. 
A listing of subjects who have non-randomized ESA use will be provided with details of 
the ESA use. 
6.2.6. 
Exposure and Randomized Treatment Compliance 
Months of exposure (see Section 10.6.2) will be summarized using mean, standard 
deviation, minimum, P25, median, P75, and maximum by treatment group and overall. 
Additionally, the number and percentage of subjects in each 6-monthly exposure category 
( 6 months, >6 -  12 months, > 12 -  18 months, etc.) will be provided by treatment 
group and overall. 
A listing of exposure data will be provided. This listing will include treatment, site ID, 
unique subject ID, dose start date, dose stop date, duration of time on dose, dose, dose 
units, dose form, route of administration, and dosing frequency. 
The number and percentage of subjects in each randomized treatment compliance 
category (see Section 10.6.2) during the study will be summarized by treatment group for 
the following time periods: Day 1 < Week 28, Week 28 - < Week 52, Week 28 - < End of 
Treatment, and Day 1 - < End of Treatment (Overall Compliance). 
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The percentage of time that subjects spend in each of the three compliance categories, 
(i.e., under compliant, compliant and over compliant) will be summarized by treatment 
group for the following time periods: Day 1 < Week 28, Week 28 - < Week 52, Week 28 
- < End of Treatment, and Day 1 - < End of Treatment (Overall Compliance). 
The number and percentage of subjects with no dose discrepancy, and at least one dose 
any discrepancy and the number of discrepancies between the IRT-assigned dose and the 
dose recorded in the eCRF will be summarized by treatment group for the following time 
periods: Day 1 < Week 28, Week 28 - < Week 52, Week 28 - < End of Treatment, and 
Day 1 - < End of Treatment (Overall Compliance). For subjects with at least one dose 
discrepancy, the number and percentage of subjects with 1, 2-3, 4-5 and ≥6 discrepancies 
will be summarized by treatment group for the same time periods.  
A visit schedule will be produced that will be utilized in merging eCRF data with IRT 
data. This Visit schedule will generally be based on the actual visits and dates found in 
the IRT. Supplemental information (to account for items such as skipped visits, 
unscheduled visits, and kit replacements) will be provided by means of a protocol-
defined visit schedule, whereby scheduled visit dates and visit windowing will be based 
on the intervals from randomization to each scheduled visit, as specified in the protocol. 
6.2.7. 
COVID-19 Impacted Visits 
A summary of the number and percentage of subjects with any visit impacted by COVID-
19 pandemic and each visit impacted by COVID-19 pandemic may be produced.  The 
summary will include the impact and the reason for impact overall (any visit) and at each 
impacted visit. 
A listing of all subjects with visits and assessments impacted by the pandemic will be 
produced.  
A figure of COVID-19 pandemic visit impacts may be produced.  The figure is a stacked 
bar chart for each impacted visit.  The stack bar is color coded by impact.    
7. 
PRIMARY STATISTICAL ANALYSES 
7.1. 
Hgb Efficacy Co-Primary Analysis 
7.1.1. 
Overview of Planned Hgb Efficacy Co-Primary and Supportive 
Analyses 
Table 4 provides an overview of the planned Hgb efficacy co-primary and supportive 
analyses. 
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Table 4 
Overview of Planned Hgb Efficacy Co-Primary and Supportive 
Analyses 
Endpoint 
Analysis 
Population 
Absolute 
Change from Baseline 
Summary 
Individual 
Stats 
Analysis 
Summary 
Individual 
T 
F 
F 
L 
T 
F 
L 
T 
F 
F 
L 
Mean Change in Hgb between Baseline and EP 
Co-Primary 
Analysis 
ITT 
[all available observed 
and imputed (on and 
off treatment) Hgb 
values] 
Y 
Y 
 
 
Y 
Y 
 
Y 
Y 
 
Y 
Supportive 
While On 
Treatment 
Analysis 
ITT 
[evaluable Hgb values 
only] 
Y 
Y 
 
 
Y 
Y 
 
Y 
Y 
 
 
Supportive 
Analysis PP 
PP 
[evaluable Hgb values 
only] 
Y 
Y 
 
 
Y 
Y 
 
Y 
Y 
 
 
Sensitivity & 
Supportive 
Tipping Point 
Analyses1 
ITT 
 
 
 
 
Y 
Y 
 
 
 
 
 
Supportive 
Analyses 
Alternative EP1 
ITT 
Y 
 
 
 
Y 
Y 
 
Y 
 
 
 
By Subgroup1 
ITT 
 
 
 
 
Y 
Y 
 
Y 
 
 
 
Supportive 
Analysis: 
Observed 
Values only 
ITT 
[all available observed 
(on and off treatment) 
Hgb values] 
Y 
Y 
 
 
Y 
Y 
 
Y 
Y 
 
 
 
NOTES: 
• 
T = Table, F = Figure, L = Listing, Y = Yes display generated. 
• 
Stats Analysis = Represents TFL related to any formal statistical analyses (i.e. modelling) conducted. 
• 
Summary = Represents TFL related to any summaries (i.e. descriptive statistics) of the observed raw data. 
• 
Individual = Represents FL related to any displays of individual subject observed raw data. 
[1] Analysis will be performed using all available observed and imputed (on and off-treatment) Hgb values and 
separately using evaluable Hgb values only (see Section 10.6.3). 
7.1.2. 
Planned Hgb Efficacy Co-Primary Statistical Analyses 
The co-primary efficacy estimand is the effect of daprodustat relative to rhEPO on the 
change in Hgb from baseline to the average of all values in the EP, regardless of 
adherence to treatment including interruptions and discontinuations, the use of non-
randomized ESA medication for any reason including rescue therapy, or the use of blood 
transfusions, in subjects on dialysis currently treated with an ESA with anemia secondary 
to CKD and assuming subjects do not die before the end of the EP. 
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7.1.2.1. 
Endpoint / Variables 
Mean change in Hgb between baseline and over the evaluation period (EP, mean over 
Week 28 and 52).  
7.1.2.2. 
Summary Measure 
Model-adjusted mean treatment difference (LS mean difference) in Hgb change between 
baseline and over the evaluation period.  
7.1.2.3. 
Population of Interest  
The target population is defined by the study’s inclusion and exclusion criteria.   
The analysis population included in the co-primary efficacy analyses will be based on the 
ITT population, unless otherwise specified. 
7.1.2.4. 
Strategy for Intercurrent (Post-Randomization) Events 
The following are the intercurrent events for the co-primary efficacy analyses: 
• Death prior to the end of the EP (i.e. before Week 52 visit) 
• Randomized treatment interruption or discontinuation prior to the end of the EP  
• Use of non-randomized ESA medications for any reason including rescue prior to 
the end of the EP 
• Receipt of blood transfusions prior to the end of the EP 
Except for the intercurrent event of death prior to the end of the EP, a treatment policy 
strategy will be used in which all Hgb data recorded during the EP (Weeks 28-52) will be 
included in the co-primary efficacy analysis, regardless of discontinuation or interruption 
of study medication due to any reasons, and regardless of receipt of non-randomized ESA 
medications for any reason including rescue, or blood transfusions. For deaths, a 
hypothetical strategy will be used as described in Section 7.1.2.5. 
The following are causes of missing Hgb data affecting the co-primary efficacy endpoint 
that are not due to intercurrent events: 
• Study withdrawal prior to the end of the EP 
• Permanent switching from clinic visits to remote visits prior to the end of the EP 
• Intermittent missing Hgb values at one or more visits with the EP 
Missing data will be imputed as described in Section 7.1.2.5. 
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7.1.2.5. 
Statistical Analyses/Methods 
Hgb Efficacy Co-Primary Statistical Analyses 
Endpoint(s) 
• Mean change in Hgb between baseline and EP 
Model Specification 
• Hgb during the EP will be defined as the mean of all available post-randomization Hgb values 
(on and off-treatment) during the EP (Week 28-52). 
• The ANCOVA model used to quantify the difference in mean Hgb change will adjust for the 
following baseline values: 
o Treatment 
o Baseline Hgb (see Section 10.5.2) 
o Dialysis type (as randomized, see Section 10.10.2) 
o Region (as randomized, see Section 10.9 & Section 10.10.2) 
Multiple Imputation Analysis 
• Multiple imputation analysis will be performed using all available Hgb values (on and off-
treatment) and conducted under a set of assumptions about missing Hgb values (see Section 
10.6.3). 
o Intermittent missing post-baseline scheduled Hgb data in both arms through Week 52 
will be imputed using PROC MI procedure with NIMPUTE = 200 and MCMC IMPUTE 
= monotone to generate 200 datasets with only monotone missing patterns. Burn in 
iterations (NBITER) and maximum iteration (MAXITER) will both be set to 500. The 
seed for reproducibility is set to 200807. The imputations will be done by randomized 
treatment, dialysis type, and region.  
o For each of the monotone missing dataset (out of the 200 imputed as indicated 
above), the missing scheduled Hgb values through Week 52 will be imputed based on 
the MAR assumption and will be performed using PROC MI by treatment, dialysis 
type, and region. The monotone regression will have baseline Hgb, prior scheduled 
(possibly imputed) Hgb values, and may include dialysis type and region as covariates 
(see Model Checking & Diagnostics, below).  The seed for reproducibility is set to 
200807.  
o The low and high cutoffs at Hgb values of 6 g/dL and 15 g/dL will be applied to all 
imputed Hgb values. 
o EP Hgb values will be computed and compared across treatment groups using the co-
primary ANCOVA model described above. Rubin’s rules [Rubin, 1987] will be used to 
combine results of the imputed datasets using SAS PROC MIANALYZE procedure. As 
a result, a single estimated treatment difference and its standard error will be 
produced, with which a 95% CI will be calculated. 
Model Checking & Diagnostics 
• Refer to Appendix 12: Model Checking and Diagnostics for Statistical Analyses. 
Model Results Presentation 
• All available observed Hgb values (on and off-treatment) will be summarized using mean, 
standard deviation, minimum, P25, median, P75 and maximum at each visit by treatment 
group. In addition to scheduled visits, the baseline value and mean MP, mean EP, mean Alt 
EP, and end of treatment values will be included (see Section 10.6.3). This summary is 
repeated by dialysis type at randomization. 
o This summary of Hgb will also be repeated for visits up to and including Week 52, 
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using the data used for the primary Hgb analysis (i.e., including imputed values). 
(see Section 10.6.3)), and by dialysis type at randomization. 
• All available observed Hgb change from baseline values (on and off-treatment) will also be 
summarized using mean, standard deviation, minimum, P25, median, P75, and maximum at 
each post-baseline visit, including the mean MP, mean EP, mean Alt EP, and end of treatment 
values (see Section 10.6.3). This summary is repeated by dialysis type at randomization. 
o This summary of Hgb will also be repeated for visits up to and including Week 52, 
using the data used for the primary Hgb analysis (i.e., including imputed values). 
(see Section 10.6.3)), and by dialysis type at randomization. 
• The number and percentage of subjects with imputed data in the primary Hgb analysis will be 
provided by treatment group. The number and percentage of subjects by reason for data 
imputation will be provided. Reasons include: intermittent missing Hgb values, death before 
Week 28, death during Week 28 – 52, investigator site closed before Week 28, investigator site 
closed during Weeks 28-52, lost to follow-up before Week 28, lost to follow-up during Week 28 
– 52, consent withdrawn before Week 28, consent withdrawn during Week 28 – 52, and other 
monotone missing Hgb values. Subjects will be further classified as either having observed all 
7 scheduled EP Hgb values, having observed a partial schedule of EP Hgb values, having 
observed no scheduled EP Hgb values with at least one unscheduled EP Hgb value, or having 
observed no EP Hgb values, scheduled or unscheduled. For subjects with partial scheduled 
EP Hgb values, both the pattern of imputed data (intermittent, monotone) and the amount of 
imputed data (1 – 6 scheduled Hgb values missing) will be summarized. For subjects with 
partial scheduled EP Hgb values and a monotone imputed data pattern, the reason for the 
monotone imputed scheduled EP Hgb values will be provided. Reasons include: death during 
Week 28-52, investigator site closed during Weeks 28-52, lost to follow-up during Week 28 – 
52, consent withdrawn during Week 28 – 52, and other monotone imputed Hgb values. And for 
summaries of the amount of missing scheduled EP Hgb values, the presence or absence of 
additional unscheduled EP Hgb values will be summarized. 
• The least square (LS) mean estimates and standard errors by treatment group, LS mean 
difference, two-sided 95% CI and one-sided non-inferiority p-value for the difference in the co-
primary Hgb endpoint between the daprodustat and rhEPO arms from the ANCOVA model will 
be presented. The number of subjects contributing to the analysis and the associated mean 
and standard deviation of the baseline and EP Hgb values will also be displayed with the 
results of the ANCOVA model. 
• The LS mean difference and associated two-sided 95% CI will be displayed on a forest plot 
together with supportive analysis results (excluding the Tipping Point Analysis).  
• All available observed Hgb values (on and off-treatment (see Section 10.6.3)) will be displayed 
graphically for each scheduled study visit using a line plot. The line plot of mean values and 
95% CIs by time will include horizontal reference lines to depict the Hgb analysis range (10-
11.5 g/dL), vertical reference lines to identify the EP (weeks 28-52), and the number of 
subjects by treatment group contributing to each mean value. The plot will be repeated by 
dialysis type at randomization. 
o This figure will also be repeated for visits up to and including Week 52, using the 
data used for the primary Hgb analysis (i.e., including imputed values). (see 
Section 10.6.3)). 
• All available observed Hgb change from baseline values (on and off-treatment (see Section 
10.6.3)) will be displayed graphically for each scheduled study visit using a line plot. The line 
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plot of mean values and 95% CIs by time will include vertical reference lines to identify the EP 
(Weeks 28-52), and the number of subjects by treatment group contributing to each mean 
value. The plot will be repeated by dialysis type at randomization. 
o This figure will also be repeated for visits up to and including Week 52, using the 
data used for the primary Hgb analysis (i.e., including imputed values). (see 
Section 10.6.3)). 
• A listing of all hemoglobin values will be provided, including treatment, most recent dose, site 
ID, unique subject ID, visit, assessment date, select demographic information and central 
laboratory and HemoCue Hgb values. 
Model Results Interpretation 
• Non-inferiority will be achieved if the lower limit of the two-sided 95% CI of the treatment 
difference is greater than the pre-specified non-inferiority margin of -0.75 g/dL. 
 
Sensitivity Statistical Analyses 
Tipping Point (Multiple Imputation) Analysis 
• Tipping point analysis will be performed using all available Hgb values (on and off-treatment) 
as a sensitivity for the co-primary estimand. 
• Tipping point analyses will be conducted under a range of missing data assumptions to 
determine how extreme assumptions need to be for non-inferiority conclusions to change. 
Assumptions about missing Hgb values on the daprodustat and rhEPO arms will vary 
independently and will include scenarios where subjects with missing data on daprodustat 
have worse outcomes than subjects with missing data on rhEPO.  
o Intermittent missing scheduled Hgb data in both arms through Week 52 will be 
imputed using PROC MI procedure with NIMPUTE = 200 and MCMC IMPUTE = 
monotone to generate 200 datasets with only monotone missing patterns. Burn in 
iterations (NBITER) and maximum iteration (MAXITER) will both be set to 500. 
The seed for reproducibility is set to 200807. The imputations will be done by 
randomized treatment, baseline dialysis type, and region. 
o For each of the monotone missing dataset (out of the 200 imputed as indicated 
above), the missing scheduled Hgb values in both arms through Week 52 will be 
imputed based on the MAR assumption and will be performed using PROC MI by 
treatment, baseline dialysis type, and region. The monotone regression will include 
baseline Hgb, prior scheduled (possibly imputed) Hgb values, and may have 
region, and baseline dialysis type as covariates (see Model Checking & 
Diagnostics, below). The seed for reproducibility is set to 200807.  
o For each treatment arm separately, the imputed monotone missing Hgb values will 
vary from the MAR scenario by a multiple of delta, where delta represents a 
change in Hgb over a 4-week interval. No delta adjustments will be done for 
intermittent missing values. Beginning with the first missed visit (which could occur 
before Week 28), for every 4-week interval, the imputed Hgb value would shift an 
additional delta. For example, the first missed visit will use delta, the second 
missed visit will use 2*delta, etc. The deltas explored for each treatment arm will 
range from -4 g/dL to 4 g/dL per 4-week interval with a 0.1 g/dL increment 
respectively. Delta scenarios which are known ahead of time to not possibly 
represent the tipping point may not be explored. 
o The low and high cutoffs at Hgb values of 6 g/dL and 15 g/dL will be applied to all 
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Sensitivity Statistical Analyses 
imputed Hgb values. 
o EP Hgb values will be computed for each pair of deltas and compared across 
treatment groups using the co-primary ANCOVA model described above (including 
unscheduled visit). Rubin’s rules [Rubin, 1987] will be used to combine results of 
the imputed datasets using SAS PROC MIANALYZE procedure. As a result, for 
each pair of delta values, a single estimated treatment difference and its standard 
error will be produced, with which a 95% CI will be calculated. 
Model Checking & Diagnostics 
• Refer to Appendix 12: Model Checking and Diagnostics for Statistical Analyses. 
Model Results Presentation 
• The delta pairs, their corresponding model-adjusted mean Hgb change from baseline to EP in 
the two treatment arms, the model-adjusted treatment difference, and two-sided 95% CI will be 
presented. The non-inferiority conclusion will be drawn if the lower confidence limit of the two-
sided 95% CI is greater than -0.75, which will also be presented in the tables.  
• Graphics depicting treatment difference and non-inferiority surfaces will be produced using an 
enhanced tipping point approach [Liublinska, 2014]. A colored heat map that illustrates the 
gradual change of treatment difference will be produced. Colored borders will be used to 
highlight the delta combinations that result in rejecting the null hypothesis (i.e., non-inferiority 
established). 
 
Supportive Statistical Analyses 
While On-Treatment Evaluable Hgb Analysis 
• This estimand utilizes the same endpoint, summary measure and target population as the co-
primary Hgb estimand. For the intercurrent events of death, randomized treatment 
discontinuation, use of non-randomized ESA medication for any reason including rescue, and 
blood transfusions, a ‘while on-treatment’ strategy will be used. 
• This estimand reflects the effect of daprodustat treatment relative to rhEPO, while on-treatment 
and without the use of non-randomized ESA medication or blood transfusions. 
• For this analysis, the co-primary Hgb analyses and summaries described above will be 
performed using evaluable Hgb values (see Section 10.6.3).  
• No data will be imputed in this analysis, so a summary of missing data will be provided. 
• The LS mean treatment difference and associated two-sided 95% CI from this analysis will be 
included on a forest plot with the co-primary Hgb analysis results. 
• The number and percentage of subjects meeting each evaluable Hgb (see Section 10.6.3) 
exclusion criterion will be summarized by scheduled visit.  
• A tipping point analysis similar to the one described above will be performed as a sensitivity 
analysis for this estimand using evaluable Hgb values only. 
PP Population Analysis 
• The while on treatment evaluable Hgb analysis and summaries described above (with the 
exception of the missing data summary) will also be performed using the PP population and 
evaluable Hgb values (see Section 10.6.3). 
• The LS mean treatment difference and associated two-sided 95% CI from this analysis will be 
included on a forest plot with the co-primary Hgb analysis results. 
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Supportive Statistical Analyses 
Alternative EP (Week 28-36) Analysis 
• The following analyses will be repeated using an alternative EP from Week 28-36: 
o The co-primary analysis and summaries (using on- and off-treatment, observed 
and imputed Hgb values (see Section 10.6.3))  
o Supportive analysis and summaries of the alternative estimand that uses 
evaluable Hgb values and a while on-treatment strategy for handling intercurrent 
events will be repeated using an alternative EP from Week 28-36. 
• Summaries of imputed/missing Hgb values will not be repeated. 
• The LS mean treatment difference and associated two-sided 95% CI from these analyses will 
be included on a forest plot with the co-primary Hgb analysis results. 
Subgroup Analysis 
• Subgroup analysis will be performed using all available observed and imputed Hgb values (on 
and off-treatment), Rubin’s rules [Rubin, 1987] will be used to combine results of the imputed 
datasets using SAS PROC MIANALYZE procedure.  
• Subgroup analysis will also be performed separately using evaluable Hgb values only (see 
Section 10.6.3). 
• Subgroup analysis details are discussed in Section 10.10.1. 
Observed Values Only Analysis 
• The co-primary analysis will be performed using available observed Hgb values (on and off-
treatment) only for post-randomization hemoglobin. There will be no imputation in this 
approach. 
• The LS mean treatment difference and associated two-sided 95% CI from this analysis will be 
included on a forest plot with the co-primary Hgb analysis results. 
7.2. 
CV Safety (MACE) Co-Primary Analysis 
7.2.1. 
Overview of Planned CV Safety (MACE) Co-Primary and 
Supportive Analyses 
Table 5 provides an overview of the planned CV safety (MACE) co-primary, and 
supportive analyses. 
Table 5 
Overview of Planned CV Safety (MACE) Co-Primary and Supportive 
Analyses 
Endpoint 
Analysis 
Population 
Absolute 
Stats Analysis 
Summary 
Individual 
T 
F 
L 
T 
F 
F 
L 
Time to First Occurrence of Adjudicated MACE 
Co-Primary Analysis 
ITT 
Y 
Y 
 
Y 
 
 
Y 
Supportive Analysis 
While On-treatment 
ITT 
Y 
Y 
 
Y 
 
 
 
Sensitivity Analysis 
Tipping Point 
ITT 
Y 
Y 
 
 
 
 
 
COVID-19 Supportive 
Analyses  
ITT 
Y 
Y 
 
Y 
 
 
 
Events Until 664th 
MACE Supportive 
ITT 
Y 
Y 
 
Y 
 
 
 
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Endpoint 
Analysis 
Population 
Absolute 
Stats Analysis 
Summary 
Individual 
T 
F 
L 
T 
F 
F 
L 
Analysis 
By Subgroup 
ITT 
Y 
Y 
 
Y 
 
 
 
 
NOTES: 
• 
T = Table, F = Figure, L = Listing, Y = Yes display generated. 
• 
Stats Analysis = Represents TFL related to any formal statistical analyses (i.e. modelling) conducted. 
• 
Summary = Represents TFL related to any summaries (i.e. descriptive statistics) of the observed raw data. 
• 
Individual = Represents FL related to any displays of individual subject observed raw data. 
 
7.2.2. 
Planned CV Safety (MACE) Co-Primary Statistical Analyses 
CV Safety (MACE) Co-Primary Statistical Analyses 
Endpoint(s) 
• Time to first occurrence of adjudicated MACE 
Model Specification 
• The Cox Proportional Hazards model will adjust for the following baseline categorical values: 
o Treatment 
o Dialysis type (as randomized, see Section 10.10.2) 
o Region (as randomized, see Section 10.9 & Section 10.10.2) 
• Confidence intervals for the rate per 100 person-years will also be reported. For within-group 
rates, the two-sided 95% CI will be obtained using an exact Poisson method. For difference in 
rates between treatments, the two-sided 95% CI will be constructed with a Normal 
approximation using Wald’s method [Liu, 2006]. 
• The co-primary analysis will use only adjudicated safety endpoints as determined by the 
clinical endpoint committee (CEC) within the time period for follow-up of CV endpoints defined 
in Section 10.6.4. 
• Calculation of time-to-event or censoring is described in further detail in Section 10.6.4. 
• First occurrence of adjudicated MACE for a subject is defined as the first adjudicated event, 
determined by the event date, that is indicated as all-cause mortality, non-fatal MI or non-fatal 
stroke with further details in Section 10.6.4. 
Model Checking & Diagnostics 
• Refer to Appendix 12: Model Checking and Diagnostics for Statistical Analyses. 
Model Results Presentation 
• A summary of the number and percentage of subjects having first-occurrence MACE will be 
provided by treatment group. The number and percentage of the types of events that make up 
the first occurrence of MACE will also be provided by treatment group. 
• A summary of all MACE including the number and percentage of subjects and number of 
events (including first and subsequent MACE) by type of event will be provided by treatment 
group. Subjects experiencing MACE will be further broken down into subjects who experienced 
exactly one MACE, subjects who experienced exactly two MACE, and subjects who 
experienced more than two MACE. The number and percentage of subjects in each of these 
categories by event type combinations will be provided by treatment group.  
• The hazard ratio, two-sided 95% CI, one-sided p-value for the statistical non-inferiority test, 
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CV Safety (MACE) Co-Primary Statistical Analyses 
and one-sided p-value for the superiority test will be presented for the comparison of 
daprodustat vs. rhEPO using the Cox Proportional Hazards model. The number and 
percentage of subjects with a MACE event and the number censored at the end of the study, 
the MACE incidence rate per 100 person-years, and the absolute rate difference per 100 
person-years and associated two-sided 95% CI will be displayed with the results of the Cox 
proportional hazards regression model.  
• To inform on the validity of the adjusted Cox proportional hazards model, the proportional 
hazards assumption will be assessed by plotting the logarithm of the negative logarithm of the 
estimated survivor function against the logarithm of time, for each treatment group. If the 
hazards are proportional, the lines should be approximately parallel. 
• The hazard ratio, two-sided 95% CIs and one-sided non-inferiority and superiority p-values will 
be displayed on a forest plot together with supportive analysis results (i.e., excluding the 
Tipping Point Analysis).  
• Time from Randomization to first adjudicated MACE event or end of trial will be evaluated 
using Kaplan-Meier (KM) methodology and displayed graphically for the comparison of 
daprodustat vs. rhEPO. 
• A listing of all MACE events occurring during the study will be provided and will include 
treatment, site ID, unique subject ID, select demographic information, event type, event date, 
and study day. 
Model Results Interpretation 
• Non-inferiority will be achieved if the upper limit of the two-sided 95% CI for the hazard ratio is 
below the pre-specified non-inferiority margin of 1.25. For evaluation of MACE superiority, a 
principal secondary analysis, see Section 10.11.1. 
 
Sensitivity Statistical Analyses 
Tipping Point (Multiple Imputation) Analysis 
• Tipping point sensitivity analyses will be conducted under a range of missing data assumptions 
to determine how extreme assumptions need to be for non-inferiority conclusions to change. 
Assumptions about missing outcomes on the daprodustat and rhEPO arms will vary 
independently and will include scenarios where subjects with missing data on daprodustat 
have worse outcomes than subjects with missing data on rhEPO. Missing data that occurs 
before the end of the study (i.e., due to withdrawal from the study) will be imputed across a 
range of scenarios using multiple imputation with treatment, dialysis type (as randomized, see 
Section 10.10.2) and region (as randomized, see Section 10.9 & Section 10.10.2) as strata in 
the imputation model and to generate the bootstrap samples. For each treatment arm 
separately, the assumed event rates will range from assuming that all prematurely censored 
subjects have a MACE at the time of censoring (corresponding to an infinite event rate for 
subjects who drop out), to assuming that all prematurely censored subjects complete the study 
without experiencing the event (corresponding to zero event rate for subjects who drop out). 
Event rates between the 0 and infinite scenarios, including a censored at random scenario, will 
be explored by varying the log-hazard rate [Jackson, 2014]. The resulting time to first 
occurrence of MACE data will be compared across treatment groups using the co-primary Cox 
proportional hazards model described above, and Rubin’s rules [Rubin,1987] will be used to 
combine results of the imputed datasets. 
o Graphics depicting hazard ratio and one-sided NI p-value surfaces will be 
produced using an enhanced tipping point approach [Liublinska, 2014]. 
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Supportive Statistical Analyses 
While On-Treatment Analysis 
• The while on-treatment MACE analysis will use a structure identical to that described for the 
co-primary MACE analysis and will use the time to the first occurrence of while on-treatment 
adjudicated MACE endpoint (excluding those MACE occurring after subjects permanently 
discontinued IP). This analysis will use the time period for on-treatment CV endpoints as 
described in Section 10.6.4.  
• The HR, associated two-sided 95% CI, and one-sided non-inferiority and superiority p-values 
from this supportive analysis will be included on a forest plot with the co-primary MACE results. 
• Cumulative time from Randomization to first adjudicated while on-treatment MACE event or 
end of trial will be evaluated using KM methodology and displayed graphically for the 
comparison of daprodustat vs. rhEPO. 
COVID-19 Supportive Analyses 
• COVID-19 MACE are identified by the CEC through one of the following statements: 
o Definitive death due to COVID-19 
o Possible death due to COVID-19 
o Definite COVID-19 related hospitalization (for MIs and strokes) 
o Possible COVID-19 related hospitalization (for MIs and strokes) 
• A summary of the number and percentage of subjects having first-occurrence adjudicated 
COVID-19 MACE will be provided by treatment group. The number and percentage of the 
types of events that make up the first occurrence of adjudicated COVID-19 MACE will also be 
provided by treatment group.  
• The additional supportive analysis of MACE excluding adjudicated COVID-19 MACE, will use a 
structure identical to that described for the co-primary MACE analysis and will exclude those 
adjudicated COVID-19 MACE. This analysis will use the time period for follow-up of CV 
endpoints defined in (see Section 10.6.4). 
• The HR, associated two-sided 95% CI, and one-sided non-inferiority and superiority p-values 
from this supportive analysis will be included on a forest plot with the co-primary MACE results. 
• Cumulative first adjudicated MACE hazard ratio and the upper bound of the 95%CI (Dapro vs 
Darbe) will be estimated using the same Cox Proportional Hazards model specified in the co-
primary MACE analysis (See Section 7.2.2). They will be displayed graphically by calendar 
date, at every half year mark, starting from Jan2018 or later when the Cox Proportional 
Hazards model could converge. At each half year mark, subjects who have not had their first 
MACE will be censored at the date of the half year mark. The graph will also show the 
cumulative number of first adjudicated MACE by calendar date. A vertical reference line will be 
used to represent the date the pandemic measures begin in the majority of the countries. 
Events Until Date of 664th MACE Supportive Analysis 
• The fourth protocol amendment changed the target number of adjudicated first MACE from 945 
to 664. At the time of protocol amendment approval, the new target 664th adjudicated first 
MACE had already occurred. The additional MACE that occur before study closeout will be 
included in the co-primary MACE analysis. This supportive analysis will only include 
adjudicated first MACE that occurred on or before the date of the 664th adjudicated first MACE. 
• A summary of the number and percentage of subjects having first-occurrence adjudicated 
MACE on or before the date of the 664th adjudicated first MACE will be provided by treatment 
group. The number and percentage of the types of events that make up the first occurrence of 
adjudicated MACE will also be provided by treatment group.  
• This supportive analysis of adjudicated first MACE occurring on or before the date of the 664th 
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Sensitivity Statistical Analyses 
adjudicated first MACE will use a structure identical to that described for the co-primary MACE 
analysis and will use the earlier of (the date of the 664th MACE, and the end of the time period 
for follow-up of CV endpoints as described in Section 10.6.4) for censoring.  
• The HR, associated two-sided 95% CI, and one-sided non-inferiority and superiority p-values 
from this supportive analysis will be included on a forest plot with the co-primary MACE results. 
• Cumulative time from Randomization to first adjudicated MACE event or end of trial will be 
evaluated using KM methodology and displayed graphically for the comparison of daprodustat 
vs. rhEPO. 
Subgroup Analysis 
• Subgroup analysis details are discussed in Section 10.10.1. 
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8. 
OTHER STATISTICAL ANALYSES 
8.1. 
Efficacy Analyses 
8.1.1. 
Principal Secondary Efficacy Analyses 
8.1.1.1. 
Overview of Planned Principal Secondary Efficacy Analyses 
Table 6 provides an overview of the planned principal secondary efficacy analyses. 
Table 6 
Overview of Planned Principal Secondary Efficacy Analyses 
Endpoint 
Analysis 
Population 
Absolute 
Stats Analysis 
Summary 
Individual 
T 
F 
L 
T 
F 
F 
L 
Iron Use 
Average monthly IV iron dose 
(mg)/subject  to Week 52 
ITT 
Y 
 
 
Y 
Y 
 
Y 
Supportive analysis: Average 
monthly IV iron dose (mg)/subject 
to Week 52 using on and off-
treatment IV iron records 
ITT 
Y 
 
 
Y 
Y 
 
 
By subgroup 
ITT 
Y 
Y 
 
 
 
 
 
NOTES: 
• 
T = Table, F = Figure, L = Listing, Y = Yes display generated. 
• 
Stats Analysis = Represents TFL related to any formal statistical analyses (i.e. modelling) conducted. 
• 
Summary = Represents TFL related to any summaries (i.e. descriptive statistics) of the observed raw data. 
• 
Individual = Represents FL related to any displays of individual subject observed raw data. 
 
8.1.1.2. 
Planned Principal Secondary Efficacy Statistical Analyses 
Principal Secondary Efficacy Statistical Analyses: Average Monthly IV Iron Dose 
Endpoint(s) 
• 
Average monthly IV iron dose (mg)/subject to Week 52 
Model Specification 
• Average monthly IV iron dose (mg)/subject from baseline to Week 52 will be determined by 
calculating the total IV iron dose per subject from treatment start date + 1 to the earliest of 
(Week 52 visit date, first blood (RBC or whole blood) transfusion date, and treatment stop date 
+ 1 day) which corresponds to the time while the subject was on randomized treatment and 
before receiving a blood transfusion. This total IV iron dose will be divided by (the number of 
days from treatment start date + 1 to the earliest of (Week 52 visit date, first blood transfusion 
date (RBC or whole blood), and treatment stop date +1) /30.4375 days). See Section 10.4.1 for 
the definition of on-treatment IV iron. 
• An ANCOVA model will be used to compare the difference in average monthly IV iron dose per 
subject between arms, adjusting for:  
o Treatment 
o Baseline monthly IV iron dose (see Section 10.5.2) 
o Dialysis type (as randomized, see Section 10.10.2) 
o Region (as randomized, see Section 10.9 & Section 10.10.2) 
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Principal Secondary Efficacy Statistical Analyses: Average Monthly IV Iron Dose 
Model Results Presentation 
• The number and percentage of subjects with baseline IV iron use, on-treatment EP IV iron use, 
and on-treatment IV iron use to Week 52 will be summarized by treatment. 
• Average monthly IV iron dose at baseline, while on treatment during the EP, and while on 
treatment to Week 52 will be summarized by treatment group using mean, standard deviation, 
minimum, P25, median, P75, and maximum. 
• The least square (LS) mean estimates and standard errors by treatment group, LS mean 
difference, two-sided 95% CI and one-sided superiority p-value for the difference in average 
monthly IV iron dose/subject to Week 52 between the daprodustat and rhEPO arms from the 
ANCOVA model will be presented. The number of subjects contributing to the analysis and the 
associated mean and standard deviation of the baseline and Week 52 values will also be 
displayed with the results of the ANCOVA model. 
• A listing of average monthly IV iron dose will be provided including treatment, site ID, unique 
subject ID, time period, and average monthly IV iron dose at Week 52. 
Model Results Interpretation 
• See Section 10.11.1. 
 
Supportive Statistical Analyses 
Average monthly IV iron dose (mg)/subject to Week 52 using on and off treatment IV iron 
records, regardless of transfusion 
• The summaries and analysis described above for the principal secondary average monthly IV 
iron dose/subject to Week 52 will be repeated using all available IV iron records during the Day 
1 – Week 52 visits, regardless of whether or not a subject was on treatment or transfusion. 
• The average monthly IV iron dose (mg)/subject to Week 52 for this analysis will be determined 
by calculating the total IV iron dose per subject from Day 1 to the earliest of Week 52 visit date, 
study completion/withdrawal date) and dividing by (earliest of the (Week 52 visit date, study 
completion/withdrawal date) – Randomization date + 1 day/30.4375 days). 
Subgroup Analysis 
• Subgroup analysis details are discussed in Section 10.10.1. 
8.1.2. 
Additional Secondary Efficacy Analyses 
8.1.2.1. 
Overview of Planned Additional Secondary Efficacy Analyses 
Table 7 provides an overview of the planned additional secondary efficacy analyses. 
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Table 7 
Overview of Planned Additional Secondary Efficacy Analyses 
Endpoint 
Analysis 
Popula-
tion 
Absolute 
Change from Baseline 
Stats 
Analysis 
Summary Individual 
Stats 
Analysis 
Summary Individual 
T 
F 
L 
T 
F 
F 
L 
T 
F 
L 
T 
F 
F 
L 
Hgb Variability 
Hgb change 
from baseline 
to Week 521, 2 
ITT 
 
 
 
 
 
 
 
Y 
Y 
 
Y 
 
 
 
Hgb change 
from baseline 
to Week 52 by 
subgroup1,2,3 
ITT 
 
 
 
 
 
 
 
Y 
Y 
 
 
 
 
 
Hgb respon-
ders2 
ITT 
Y 
 
 
Y 
 
 
 
 
 
 
 
 
 
 
Hgb 
responders by 
subgroup2,3 
ITT 
Y 
Y 
 
 
 
 
 
 
 
 
 
 
 
 
% of time Hgb 
in analysis 
range2 
ITT 
Y 
 
 
Y 
 
 
 
 
 
 
 
 
 
 
% of time Hgb 
in analysis 
range by 
subgroup2,3 
ITT 
Y 
Y 
 
 
 
 
 
 
 
 
 
 
 
 
Time to Rescue 
Time to 
stopping 
randomized 
treatment due 
to meeting 
rescue criteria 
ITT 
Y 
Y 
 
Y 
 
 
 
 
 
 
 
 
 
 
Time to 
stopping 
randomized 
treatment due 
to meeting 
rescue criteria 
by 
hyporesponder 
subgroup 
ITT 
Y 
 
 
 
 
 
 
 
 
 
 
 
 
 
NOTES: 
• 
T = Table, F = Figure, L = Listing, Y = Yes display generated. 
• 
Stats Analysis = Represents TFL related to any formal statistical analyses (i.e. modelling) conducted. 
• 
Summary = Represents TFL related to any summaries (i.e. descriptive statistics) of the observed raw data. 
• 
Individual = Represents FL related to any displays of individual subject observed raw data. 
[1] Analysis will be performed using all available (on and off-treatment) Hgb values. 
[2] Analysis will be performed using evaluable Hgb values only (see Section 10.6.3). 
[3] Subgroup analysis will only use the region and hyporesponder subgroups defined in Section 10.10.1. 
 
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8.1.2.2. 
Planned Secondary Efficacy Statistical Analyses 
Hgb Variability 
Secondary Efficacy Statistical Analyses: Hgb Variability 
Endpoint(s) 
• Hgb change from baseline to Week 52 
• N (%) responders, defined as mean Hgb within the Hgb analysis range 10-11.5 g/dL during EP 
• % time Hgb in analysis range (10-11.5 g/dL) during the evaluation period (EP, Week 28 to 52) 
and during the maintenance period (MP; Week 28 to end of trial) (non-inferiority analysis that 
will use a margin of 15 percentage points less time in range)  
Model Specification 
• For the secondary analysis of Hgb change from baseline to Week 52, a mixed model repeated 
measures (MMRM) approach will be used with an unstructured covariance matrix to compare 
the difference in means between arms. The model will be fitted to Hgb data collected after 
baseline up to Week 52, excluding values collected during the stabilization period 
(Randomization date + 1 day to <Week 28). The model will include factors for treatment, time, 
prognostic randomization stratification factors (as randomized, see Section 10.10.2), baseline 
Hgb and the baseline Hgb by time and treatment by time interaction terms. Analyses will be 
done with the MIXED procedure in SAS, using the Kenward-Roger option to estimate 
denominator degrees of freedom and standard errors. This analysis will be performed using all 
available Hgb values (on and off-treatment) and separately using evaluable Hgb values only 
(see Section 10.6.3). In the analysis using all available Hgb values, subjects who withdraw 
from the study before Week 52 are considered to be missing at random and in the analysis 
using evaluable Hgb values, subjects who permanently discontinue randomized treatment 
before Week 52 are assumed to be missing at random. 
• For the Hgb responder analysis, mean Hgb during the EP will be defined as in the while on-
treatment supportive analysis (Section 10.6.3). Responders will be subjects with a mean Hgb 
during the EP that falls within the Hgb analysis range of 10-11.5 g/dL. A Cochran-Mantel-
Haenszel (CMH) chi-squared test, adjusting for treatment and the prognostic randomization 
stratification factors (as randomized, see Section 10.10.2), will be used to compare the number 
and % of responders between the treatment groups. 
• For the analysis of % time in range, the method by Rosendaal [Rosendall, 1993] will be used to 
calculate the percentage of time (days) a subject’s Hgb is below, within and above the Hgb 
analysis range of 10 to 11.5 g/dL during the EP (Weeks 28-52) and separately during the MP 
(Week 28 – end of study) (See Section 10.6.3). A van Elteren test (stratified Wilcoxon rank 
sum test) will be used to compare the percentage of time in range between treatment arms, 
adjusting for treatment and the prognostic randomization stratification factors (see Section 
10.10.2). This analysis will be performed using evaluable Hgb values only. Hodges-Lehmann 
estimate of the treatment difference will be used to assess non-inferiority in % time in range. 
Model Results Presentation 
• For the MMRM analysis of change from baseline in Hgb, an LSMEANS statement will provide 
adjusted treatment group means and standard errors and a point estimate and two-sided 95% 
confidence interval for the adjusted mean treatment difference (daprodustat - rhEPO) at Week 
52. The one-sided non-inferiority p-value for this test will be calculated. 
• For the responder analysis, the number and percentage of subjects with mean EP Hgb, mean 
MP Hgb, and end of treatment Hgb above, within and below the Hgb analysis range will be 
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Secondary Efficacy Statistical Analyses: Hgb Variability 
summarized by treatment group. 
• For the responder analysis, the number and % of responders by treatment group, difference in 
response rate (daprodustat vs – rhEPO) and two-sided 95% CI using Wald method will be 
provided along with the one-sided CMH p-value for the treatment group comparison. If the 
CMH adjusted treatment difference is positive, then the one-sided p-value is p/2, and if the 
adjusted treatment difference is negative, then the one-sided p-value is 1-p/2, where p is the 
two-sided p-value from the CMH test. 
• The % time Hgb is above, in and below the Hgb analysis range (10-11.5 g/dL) during the MP 
and the EP will be summarized using mean, standard deviation, minimum, P25, median, P75, 
and maximum by treatment group. 
• The percent time in range for each treatment group, the stratified Mann-Whitey estimate of the 
treatment difference (daprodustat – rhEPO) and associated two-sided 95% CI [Kawaguchi, 
2011] will be presented in addition to the one-sided superiority p-value from the van Elteren 
test. Hodges-Lehmann estimate of the treatment difference (daprodustat-rhEPO) and 
associated two-sided 95% CI will be presented. 
Model Results Interpretation 
• For the MMRM analysis of change from baseline in Hgb, the NI margin used in the co-primary 
analysis of Hgb (-0.75 g/dL) will be used for reference in this comparison, thus generating 
support for non-inferiority if the lower bound of the two-sided 95% CI is above -0.75 g/dL. 
• For the responder analysis, the one-sided CMH p-value will be compared to 0.025 to assess 
nominal significance. 
• For the percent time in range analysis, a NI margin of -15% will be used as a reference in this 
comparison, thus generating support for non-inferiority if the lower limit of the two-sided 95% CI 
of Hodges-Lehmann estimate is above -0.15. If non-inferiority is established, nominal 
superiority will be achieved if the the one-sided p-value is < 0.025. 
 
Supportive Statistical Analyses 
Subgroup Analysis 
• Subgroup analyses will be performed for all Hgb variability endpoints, using the region and 
hyporesponder subgroups only (described in Section 10.9.1 & Section 10.10), in a method 
similar to that described for the subgroup analyses of the co-primary and principal secondary 
analyses. 
 
Time to Rescue 
Secondary Efficacy Statistical Analyses: Time to Rescue 
Endpoint(s) 
• Time to stopping randomized treatment due to meeting rescue criteria 
Model Specification 
• Analysis of the endpoint above will be performed using an analysis model identical to that 
described for the co-primary MACE analysis. 
• Analysis will include only those efficacy endpoints occurring within the time period for treatment 
discontinuation. Calculation of time-to-event or censoring is described in further detail in 
Section 10.6.3. 
• Time to stopping study medication due to meeting rescue criteria is defined as the time from 
Randomization until the date on which a subject permanently stops study medication due to 
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meeting criteria for rescue. 
Model Results Presentation 
• Summaries will include (see Section 10.6.3):  
o the number and percentage of subjects meeting evaluation criteria for rescue and 
the number of occurrences (events),  
o the number and percentage of subjects unable to be evaluated for rescue, and  
o the number and percentage of subjects meeting rescue. 
• The analysis model results presentation will be identical to the co-primary MACE model results, 
with the following exceptions: 
o The one-sided p-value presented will be for the test of superiority of daprodustat 
vs. rhEPO. 
o The forest plot figure will not be created for the time to stopping study medication 
due to meeting rescue criteria endpoint. 
Model Results Interpretation 
• One-sided p-values will be compared to 0.025 to assess nominal significance. 
 
Supportive Statistical Analyses 
Subgroup Analysis 
• Subgroup analyses will be performed for the time to rescue endpoint using the hyporesponder 
subgroup only (described in Section 10.10), in a method similar to that described for the 
subgroup analyses of the co-primary MACE analysis. 
8.1.3. 
Exploratory Efficacy Analyses 
8.1.3.1. 
Overview of Planned Exploratory Efficacy Analyses 
Table 8 provides an overview of the planned exploratory efficacy analyses. 
Table 8 
Overview of Planned Exploratory Efficacy Analyses 
Endpoint 
Analysis 
Population 
Absolute 
Change from Baseline 
Summary 
Individual 
Summary 
Individual 
T 
F 
F 
L 
T 
F 
F 
L 
Hgb Variability 
Hgb observed 
(including imputed) and 
change from baseline 
(CFB) at all visits 
ITT 
Included with Hgb co-primary and supportive analyses (Section 
7.1) 
% of time Hgb is above, 
within and below Hgb 
analysis range during 
EP and MP 
ITT 
Included with Hgb secondary analyses (Section 8.1.2) 
Number (%) of subjects 
with mean Hgb above, 
within and below Hgb 
analysis range during 
EP and at the end of 
treatment 
ITT 
Included with Hgb secondary analyses (Section 8.1.2) 
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Endpoint 
Analysis 
Population 
Absolute 
Change from Baseline 
Summary 
Individual 
Summary 
Individual 
T 
F 
F 
L 
T 
F 
F 
L 
Number (%) of subjects 
with Hgb < 7.5 g/dL 
during EP and MP1 
ITT 
Y 
 
 
 
 
 
 
 
Number of times Hgb < 
7.5 g/dL during EP and 
MP1 
ITT 
Y 
 
 
 
 
 
 
 
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 521 
ITT 
Y 
 
 
 
 
 
 
 
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 521 
ITT 
Y 
 
 
 
 
 
 
 
N (%) of subjects with a 
Hgb value  12 g/dL 
during the EP and MP1 
ITT 
Y 
 
 
 
 
 
 
 
Number of times Hgb  
12 g/dL during the EP 
and MP1 
ITT 
Y 
 
 
 
 
 
 
 
% of time Hgb  12 
g/dL during the EP and 
MP1 
ITT 
Y 
 
 
 
 
 
 
 
Iron Parameters 
Hepcidin, ferritin, TSAT, 
total iron, TIBC 
observed and CFB at 
all visits 
ITT 
Y 
Y 
 
 
Y 
Y 
 
 
Average quarterly IV 
iron dose/subject 
ITT 
Y 
Y 
 
 
 
 
 
 
Average quarterly 
TSAT 
ITT 
Y 
Y 
 
 
 
 
 
 
Average quarterly 
ferritin 
ITT 
Y 
Y 
 
 
 
 
 
 
Subjects who met iron 
management criteria 
ITT 
Y 
 
 
 
 
 
 
 
Subjects who reduced 
IV iron during EP 
ITT 
Y 
 
 
 
 
 
 
 
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Endpoint 
Analysis 
Population 
Absolute 
Change from Baseline 
Summary 
Individual 
Summary 
Individual 
T 
F 
F 
L 
T 
F 
F 
L 
relative to Baseline 
RBC and Whole Blood Transfusions 
Number (%) of subjects 
receiving at least one 
RBC or whole blood 
transfusion by Week 52 
and by end of treatment 
ITT 
Y 
 
 
 
 
 
 
 
Number of RBC and 
whole blood transfusion 
events per 100 patient 
years 
ITT 
Y 
 
 
 
 
 
 
 
Number of RBC and 
whole blood 
transfusions per 100 
patient years 
ITT 
Y 
 
 
 
 
 
 
 
Number of RBC and 
whole blood units per 
100 patient years 
ITT 
Y 
 
 
 
 
 
 
 
Time to first RBC or 
whole blood transfusion 
ITT 
Y 
Y 
 
 
 
 
 
 
DGF 
Number (%) of subjects 
experiencing DGF 
ITT 
Y 
 
 
 
 
 
 
 
Duration of DGF 
ITT 
Y 
 
 
 
 
 
 
 
Dose Adjustment Scheme Evaluation 
Assigned dose by visit 
ITT 
Y 
Y 
 
 
 
 
 
 
Most recent dose by 
visit 
ITT 
 
Y 
 
 
 
 
 
Y 
Number (%) of patients 
with 0,1,2…, 10, or >10 
dose adjustments 
during the following 
periods: Day 1 - <Week 
28, Week 28 – <Week 
52, Day 1 – < end of 
treatment 
ITT 
Y 
 
 
 
 
 
 
 
Number of dose 
adjustments during the 
following periods: Day 1 
- <Week 28, Week 28 – 
<Week 52, Day 1 – < 
end of treatment 
ITT 
Y 
 
 
 
 
 
 
 
Time dose held for Hgb 
 12 g/dL 
ITT 
Y 
 
 
 
 
 
 
 
Dosing algorithm 
update1 
ITT 
Y2 
Y2 
 
 
 
 
 
 
 
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NOTES: 
• 
T = Table, F = Figure, L = Listing, Y = Yes display generated. 
• 
Summary = Represents TFL related to any summaries (i.e. descriptive statistics) of the observed raw data. 
• 
Individual = Represents FL related to any displays of individual subject observed raw data. 
[1] Summaries will be presented using evaluable Hgb values only (see Section 10.6.3). 
[2] Summary tables and figures will contain the results of a statistical model. 
 
8.1.3.2. 
Planned Exploratory Efficacy Display Details 
Hgb Variability 
The number and percentage of subjects with a Hgb value < 7.5g/dL and the number of 
times a Hgb value < 7.5 g/dL occurs during the EP and the MP will be summarized by 
treatment group using central laboratory Hgb values and separately using HemoCue Hgb 
values. This summary will be presented using evaluable Hgb values only (see Section 
10.6.3). The central laboratory summary will be considered the primary summary of this 
data. 
The number and percentage of subjects with a >1 g/dL 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 will be summarized by visit and overall at Week 52 by 
treatment group using HemoCue Hgb values. This summary will be presented using 
evaluable Hgb values only (see Section 10.6.3). 
The number and percentage of subjects with a >2 g/dL increase in Hgb within any 4-
week period from Week 4 to Week 52 will be summarized by visit and overall at Week 
52 by treatment group using central laboratory Hgb values. This summary will be 
presented using evaluable Hgb values only (see Section 10.6.3). The central laboratory 
summary will be considered the primary summary of this data. 
The number and percentage of subjects with a >1 g/dL decrease in Hgb over 2 weeks 
(assessed at Week 2 and Week 4) or a >2 g/dL increase in Hgb within any 4-week period 
from Week 4 to Week 52 will be summarized by visit and overall at Week 52 by 
treatment group using HemoCue Hgb values. This summary will be presented using 
evaluable Hgb values only (see Section 10.6.3). 
The number and percentage of subjects with a >2 g/dL decrease in Hgb within any 4-
week period from Week 4 to Week 52 will be summarized by visit and overall at Week 
52 by treatment group using central laboratory Hgb values. This summary will be 
presented using evaluable Hgb values only (see Section 10.6.3). The central laboratory 
summary will be considered the primary summary of this data. 
The number and percentage of subjects with a Hgb value  12 g/dL and the number of 
times a Hgb value  12 g/dL occurs during the EP and the MP will be summarized by 
treatment group using central laboratory Hgb values and separately using HemoCue Hgb 
values. This summary will be presented using evaluable Hgb values only (see Section 
10.6.3). The central laboratory summary will be considered the primary summary of this 
data. 
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The percentage of time Hgb is  12 g/dL and the percentage of time Hgb is  12 g/dL for 
subjects with at least one Hgb  12 g/dL during the MP and the EP will be calculated 
using the Rosendaal method as described in Section 8.1.2. The percentage of time Hgb is 
 12 g/dL during the MP and the EP will be summarized using mean, standard deviation, 
minimum, P25, median, P75, and maximum by treatment group. This summary will be 
presented using evaluable Hgb values only (see Section 10.6.3). 
Iron Parameters 
Hepcidin, ferritin, and total iron on-treatment values will be log-transformed (see Section 
10.5.2) and summarized using geometric mean, coefficient of variation, minimum, P25, 
median, P75, and maximum for each scheduled visit by treatment group. Graphical 
summaries will be provided. 
TSAT and TIBC on-treatment values will be summarized using mean, standard deviation, 
minimum, P25, median, P75, and maximum for each scheduled visit by treatment group. 
Graphical summaries will be provided. 
Percent change from baseline in log-transformed (see Section 10.5.2) hepcidin , ferritin, 
and total iron on-treatment values will be summarized using geometric mean, 95% 
confidence interval, minimum, P25, median, P75, and maximum for each scheduled visit 
by treatment group. Graphical summaries will be provided. 
Change from baseline in TSAT and TIBC on-treatment values will be summarized using 
mean, standard deviation, minimum, P25, median, P75, and maximum for each scheduled 
visit by treatment group. Graphical summaries will be provided. 
Average quarterly IV iron dose/subject while on treatment will be summarized by 
presenting average monthly IV iron dose by quarter (see Section 10.6.3). Summaries will 
include mean, standard deviation, minimum, P25, median, P75, and maximum by 
treatment group. Graphical summaries will be provided. 
Average quarterly TSAT while on treatment will be summarized by presenting average 
TSAT values for the quarters used to generate IV iron dose by quarter (see Section 
10.6.3). Summaries will include mean, standard deviation, minimum, P25, median, P75, 
and maximum by treatment group. Graphical summaries will be provided. 
Average quarterly ferritin while on treatment will be summarized by presenting average 
ferritin values by quarter (see Section 10.6.3). Summaries will include geometric mean, 
coefficient of variation, minimum, P25, median, P75, and maximum by treatment group. 
Graphical summaries will be provided. 
The number and percentage of subjects that met the iron management criteria during the 
study while on treatment will be summarized by treatment group for each 3-month period 
of the study, the first year and across the entire study. There are two types of iron 
management thresholds: the first type requires that iron therapy be administered if 
subjects have ferritin and/or TSAT values that are too low; the second type requires that 
all iron (excluding multivitamins) must be stopped if ferritin and/or TSAT values are too 
high. It is also possible for a subject to meet starting and stopping criteria on the same 
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day with a low ferritin and a high TSAT. These subjects will also be summarized (see 
Section 10.6.3). Assessment of meeting iron management thresholds will be made based 
on central laboratory data values at the scheduled visits for ferritin and TSAT 
assessments, according to the schedule outlined in the Time and Events table (see Section 
10.2.1). Further, the subjects who met the threshold requiring iron administration to start 
or stop while on IV iron will be grouped by the action taken with IV iron therapy in the 8 
weeks following the date the threshold was met (i.e., starting or increasing iron therapy, 
maintaining existing iron therapy, receiving no iron therapy, stopping or decreasing iron 
therapy with no increase, Section 10.6.3) according to concomitant medication records 
for IV iron. 
The number and percentage of subjects that reduced IV iron supplementation relative to 
baseline during the EP while on treatment will be summarized by treatment group (see 
Section 10.6.3). 
RBC and Whole Blood Transfusions 
Summary and analysis tables will use the ITT population. 
The total number of on-treatment RBC and whole blood transfusion events, transfusions 
and units for each subject will be derived as described in Section 10.6.3. 
The number of on-treatment RBC and whole blood transfusion events per subject, the 
number of subjects with at least one RBC and whole blood transfusion event, and total 
number of RBC and whole blood transfusion events will be summarized.  
The number of on-treatment RBC and whole blood transfusions events per 100 patient 
years will be summarized by treatment group. 
The number of on-treatment RBC and whole blood transfusions per 100 patient years will 
be summarized by treatment group.  
The number of on-treatment RBC and whole blood units per 100 patient years will be 
summarized by treatment group.  
The reason for transfusion events will be summarized. 
The above summaries will be produced for the Evaluation Period, Week 52 and End of 
Treatment. 
An analysis of time to first RBC or whole blood transfusion will be performed as 
described in Section 10.6.3, including a Kaplan-Meier plot. 
All transfusion summaries will be repeated for the primary definition of ESA 
hyporesponder subgroups (see Section 10.6.2). 
DGF 
Delayed graft function after deceased donor kidney transplantation is defined in Section 
10.6.3. 
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The number and percentage of patients experiencing DGF after deceased donor kidney 
transplantation will be summarized by treatment group. 
The length of time in days that subjects experience DGF after deceased donor kidney 
transplantation will be summarized using mean, standard deviation, minimum, P25, 
median, P75, and maximum by treatment group. 
Dose Adjustment Scheme 
See Section 10.6.3 for additional details of dose adjustment scheme endpoints. 
For exploratory summaries of dose levels, subjects in the rhEPO arm will be further 
divided into subjects receiving epoetin alfa and subjects receiving darbepoetin alfa. The 
total weekly dose of epoetin alfa will be summarized and the total 4-weekly dose of 
darbepoetin alfa will be summarized (see Section 10.6.3). Since it is possible for subjects 
to switch from epoetin alfa to darbepoetin alfa during the study, subjects who receive 
both treatments during the study will be counted in each group. 
The assigned dose by visit will be summarized using mean, standard deviation, 
minimum, P25, median, P75, and maximum by treatment group.  
The assigned dose by visit will also be summarized by treatment group using the number 
and percentage of subjects assigned to each dose level. Stacked bar graphs displaying 
assigned dose at all scheduled visits starting with Day 1 will be provided by treatment 
group. 
The median assigned dose by treatment and visit will be displayed graphically for each 
scheduled study visit using a line plot. The line plot of median assigned dose along with 
the first and the third quartiles by time will include vertical reference lines to identify the 
EP as well as the number of subjects by treatment group contributing to each median 
value. 
The following summaries of dose adjustments will be produced twice – the first time 
counting all dose adjustments, including adjustments related to periods of dose holds (i.e., 
IRT assignment of a 0-dose), the second time excluding dose adjustments related to 
periods of dose hold. 
The number and percentage of patients with 0, 1, 2…,  10, or >10 dose adjustments will 
be summarized by treatment group. Summaries will be presented for the following 
categories of time: Day 1 – < Week 28, Week 28 – <Week 52, and Day 1 – < end of 
treatment. 
The number of dose adjustments per subject will be summarized using mean, standard 
deviation, minimum, P25, median, P75, and maximum by treatment group. Summaries 
will be presented for the following categories of time: Day 1 – < Week 28, Week 28 – 
<Week 52, and Day 1 – < end of treatment. For the period of time from Day 1 - < end of 
treatment, the number of dose adjustments per year will be summarized as well. 
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The time (in days) that study treatment was withheld for Hgb values  12 g/dL per 
subject will be summarized for all subjects and for subjects who had a dose hold using 
mean, standard deviation, minimum, P25, median, P75, and maximum by treatment 
group. Summaries will be presented for the following categories of time: Day 1 – < Week 
28, Week 28 – <Week 52, Day 1 – < end of treatment, Week 28 - < end of treatment. 
Summary tables for the dose adjustment scheme endpoints will also be repeated for the 
following subgroups (see Section 10.10.1 for subgroup definitions): 
• rhEPO hyporesponders (primary definition) 
• Region 
• Race group 
• Dialysis type at randomization 
• Baseline weight quartiles 
The median most recent dose by treatment and visit will be displayed graphically for each 
scheduled study visit using a line plot. The line plot of median most recent dose along 
with the first and the third quartiles by time will include vertical reference lines to 
identify the EP as well as the number of subjects by treatment group contributing to each 
median value. This plot will be created by treatment group separately for subjects 
receiving epoetin alfa and darbepoetin alfa and these plots will also be overlaid on a 
graph of corresponding Hgb values by visit. 
Protocol Amendment 3 updated the dosing algorithm used to assign doses of randomized 
treatment to subjects in both treatment arms. In order to assess the impact of the dosing 
algorithm update, Hgb profiles will be created by dosing algorithm category (original 
algorithm, updated algorithm) and by treatment group. Subjects who were randomized 
under the original algorithm but switched to the updated algorithm will only have their 
original dosing algorithm Hgb values included. Hgb values from subjects who were 
randomized under the updated algorithm will be included in the updated algorithm group 
(see Section 10.6.3). Only evaluable Hgb values will be used.  
Evaluable Hgb data will be fit in an MMRM model with an unstructured covariance 
matrix using the Kenward-Roger option for PROC MIXED in SAS to estimate 
denominator degrees of freedom and standard errors. The model will adjust for dialysis 
type, region, baseline Hgb, baseline Hgb by time, and algorithm by treatment by time. 
The model will be run without main effects (treatment, time, and algorithm) and without 
two-way interaction terms (algorithm by time, treatment by time, and algorithm by 
treatment) for computational ease since in SAS, the main effects and two-way interaction 
terms are included within the three-way interaction term, thus giving equivalent results. 
In the event of model convergence issues, the steps outlined in Section 10.10.1 will be 
followed. 
A summary of adjusted mean evaluable Hgb values, standard errors, 95% confidence 
intervals, and 95% predictions intervals (see Section 10.6.3) for each scheduled study 
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visit will be provided for each algorithm (original, updated) overall and by treatment 
group. A corresponding figure will plot the adjusted mean Hgb values in a line plot and 
the 95% confidence intervals and 95% prediction intervals with shaded regions for each 
visit for each algorithm group by treatment (including overall), as long as the 
algorithm/treatment group combination contains at least 20 subjects at the visit. 
8.1.4. 
Other Efficacy Analyses 
Phosphate Binder Analyses 
The following analyses will be conducted to confirm the effect of phosphate binder co-
administration. 
Evaluable Hgb values will be summarized using mean, standard deviation, minimum, 
P25, median, P75 and maximum at week 4 by treatment group and by baseline phosphate 
binder use (see Section 10.6.3). 
The number and percentage of subjects with evaluable Hgb above, within and below the 
Hgb analysis range (10-11.5g/dL) at week 28 and week 52 will be summarized by 
treatment group and by phosphate binder use at week 28 and week 52 respectively(see 
Section 10.6.3). 
The assigned dose by visit will be summarized using mean, standard deviation, 
minimum, P25, median, P75, and maximum at week 28 and week 52 by treatment group 
and by baseline phosphate binder use (see Section 10.6.3). 
The median assigned dose by treatment, by baseline phosphate binder use (see Section 
10.6.3) will be displayed graphically for each scheduled study visit from day 1 to week 
52 using a line plot. The line plot of median assigned dose along with the first and the 
third quartiles by time will include vertical reference lines to identify the EP as well as 
the number of subjects by treatment group contributing to each median value. This plot 
will be created by treatment group separately for subjects receiving epoetin alfa and 
darbepoetin alfa and these plots will also be overlaid on a graph of corresponding mean 
evaluable Hgb values by visit. Since it is possible for subjects to switch from epoetin alfa 
to darbepoetin alfa during the study, subjects who receive both treatments during the 
study will be counted in each group.  
8.2. 
Safety Analyses 
8.2.1. 
Principal Secondary Safety Analyses 
8.2.1.1. 
Overview of Planned Principal Secondary Safety Analyses 
Table 9 provides an overview of the planned principal secondary safety analyses. 
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Table 9 
Overview of Planned Principal Secondary Safety Analyses 
Endpoint 
Analysis 
Population 
Absolute 
Stats Analysis 
Summary 
Individual 
T 
F 
L 
T 
F 
F 
L 
CV Safety Endpoints 
Time to First Occurrence of 1 
• 
MACE2 
• 
MACE + 
thromboembolic events 
(vascular access 
thrombosis, deep vein 
thrombosis, pulmonary 
embolism) 
• 
MACE + hospitalization 
for HF 
ITT 
Y 
Y 
 
Y 
 
 
 
Supportive Analysis While On-
treatment 
ITT 
Y 
Y 
 
 
 
 
 
By subgroup 
ITT 
Y 
Y 
 
 
 
 
 
NOTES: 
• 
T = Table, F = Figure, L = Listing, Y = Yes display generated. 
• 
Stats Analysis = Represents TFL related to any formal statistical analyses (i.e. modelling) conducted. 
• 
Summary = Represents TFL related to any summaries (i.e. descriptive statistics) of the observed raw data. 
• 
Individual = Represents FL related to any displays of individual subject observed raw data. 
[1] Separate displays produced for each event - adjudicated events used. 
[2] Displays to assess MACE superiority will be included with the co-primary MACE displays. 
8.2.1.2. 
Planned Principal Secondary Safety Statistical Analyses 
Principal Secondary Safety Statistical Analyses: Additional Cardiovascular Safety 
Endpoints 
Endpoint(s) 
• Time to first occurrence of 
• 
MACE 
• 
MACE or a thromboembolic event (vascular access thrombosis, deep vein thrombosis or 
pulmonary embolism)  
• 
MACE or hospitalization for HF 
Model Specification 
• Analysis of each of the endpoints above will be performed individually using an analysis model 
identical to that described for the co-primary MACE analysis (Section 7.2.2) for the evaluation 
of superiority. 
• Analysis will include only those safety endpoints occurring within the time period for follow-up 
of CV endpoints as described in Section 10.6.4. 
• For those endpoints or components of endpoints intended to go through the adjudication 
process, only the adjudicated results will be used. 
Model Results Presentation 
• The summary displays of time-to-event endpoints will include a summary of the number and 
percentage of subjects having events. The number and percentage of the type of first 
occurrence will also be provided for the composite endpoints by treatment group. 
• A summary of all MACE or thromboembolic events including the number and percentage of 
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Endpoints 
subjects and number of events (including first and subsequent MACE or thromboembolic 
event) by type of event will be provided by treatment group.  
• A summary of all MACE or hospitalization for HF events including the number and percentage 
of subjects and number of events (including first and subsequent MACE or hospitalization for 
HF) by type of event will be provided by treatment group. Subjects experiencing MACE or 
hospitalization for HF events will be further classified into subjects who experienced exactly 
one MACE or hospitalization for HF event, subjects who experienced exactly two MACE or 
hospitalization for HF events, and subjects who experienced more than two MACE or 
hospitalization for HF events. The number and percentage of subjects in each of these 
categories by event type combinations will be provided by treatment group. 
• The model results presentation will be identical to the co-primary MACE model results, with the 
following exception: 
o A single one-sided p-value for the test of superiority of daprodustat vs. rhEPO will 
be presented (i.e. there will be no test for non-inferiority). 
Model Results Interpretation 
• See Section 10.11.1. 
 
Supportive Statistical Analyses 
While On-Treatment Analysis 
• While on-treatment analyses will be produced for superiority comparisons of the principal 
secondary CV safety endpoints in a method that is identical to the while on-treatment 
supportive analysis of the MACE co-primary endpoint described in Section 7.2.2, using events 
that occur during the time period for on-treatment CV endpoints (see Section 10.6.4). 
Subgroup Analysis 
• Subgroup analysis details are discussed in Section 10.10.1. 
8.2.2. 
Additional Secondary Safety Analyses 
8.2.2.1. 
Overview of Planned Additional Secondary Safety Analyses 
Table 10 provides an overview of the planned additional secondary safety analyses. 
Table 10 
Overview of Planned Additional Secondary Safety Analyses 
Endpoint 
Analysis 
Popula-
tion 
Absolute 
Change from Baseline 
Stats 
Analysis 
Summary Individual 
Stats 
Analysis 
Summary Individual 
T 
F 
L 
T 
F 
F 
L 
T 
F 
L 
T 
F 
F 
L 
Additional CV Safety Endpoints1 
All-cause 
mortality 
ITT 
Y 
Y 
 
Y 
 
 
Y 
 
 
 
 
 
 
 
CV mortality 
ITT 
Y 
Y 
 
Y 
 
 
 
 
 
 
 
 
 
 
MI (non-fatal 
and fatal) 
ITT 
Y 
Y 
 
Y 
 
 
 
 
 
 
 
 
 
 
Stroke (non-fatal 
and fatal) 
ITT 
Y 
Y 
 
Y 
 
 
 
 
 
 
 
 
 
 
MACE or 
ITT 
Y 
 
 
Y 
 
 
 
 
 
 
 
 
 
 
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Endpoint 
Analysis 
Popula-
tion 
Absolute 
Change from Baseline 
Stats 
Analysis 
Summary Individual 
Stats 
Analysis 
Summary Individual 
T 
F 
L 
T 
F 
F 
L 
T 
F 
L 
T 
F 
F 
L 
hospitali-zation 
for HF (recurrent 
events) 
CV mortality or 
non-fatal MI 
ITT 
Y 
Y 
 
Y 
 
 
 
 
 
 
 
 
 
 
All-cause 
hospitalization 
ITT 
Y 
Y 
 
Y 
 
 
 
 
 
 
 
 
 
 
All-cause 
hospital re-
admission within 
30 days 
ITT 
Y 
Y 
 
Y 
 
 
 
 
 
 
 
 
 
 
MACE or 
hospitali-zation 
for HF or 
thrombo-embolic 
events 
ITT 
Y 
Y 
 
Y 
 
 
 
 
 
 
 
 
 
 
Hospitalization 
for HF 
ITT 
Y 
Y 
 
Y 
 
 
 
 
 
 
 
 
 
 
Thromboembolic 
events 
ITT 
Y 
Y 
 
Y 
 
 
 
 
 
 
 
 
 
 
Blood Pressure 
SBP, DBP and 
MAP changes 
from Baseline2,3 
ITT 
 
 
 
Y 
Y 
 
 
Y 
 
 
Y 
Y 
 
 
Number of BP 
exacerbation 
events per 100 
patient years3 
ITT 
Y 
 
 
Y 
 
 
 
 
 
 
 
 
 
 
Patients 
experiencing at 
least one BP 
exacerbation 
event during 
study3 
ITT 
Y 
 
 
Y 
 
 
 
 
 
 
 
 
 
 
NOTES: 
• 
T = Table, F = Figure, L = Listing, Y = Yes display generated. 
• 
Stats Analysis = Represents TFL related to any formal statistical analyses (i.e. modelling) conducted. 
• 
Summary = Represents TFL related to any summaries (i.e. descriptive statistics) of the observed raw data. 
• 
Individual = Represents FL related to any displays of individual subject observed raw data. 
[1] Adjudicated events used where available. 
[2] Analysis will be performed using all available (on and off treatment) BP values. 
[3] Analysis will be performed using on-treatment BP values only. 
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8.2.2.2. 
Planned Additional Secondary Safety Statistical Analyses 
Additional CV Safety Endpoints 
Secondary Safety Statistical Analyses: Additional CV Safety Endpoints 
Endpoint(s) 
• All-cause mortality, CV mortality, fatal or non-fatal MI, fatal or non-fatal stroke 
• MACE or hospitalization for HF (recurrent events analysis) 
• CV mortality or non-fatal MI 
• All-cause hospitalization (see Section 10.6.4) 
• All-cause hospital re-admission within 30 days (see Section 10.6.4) 
• MACE or hospitalization for HF or thromboembolic events  
• Hospitalization for HF 
• Thromboembolic events 
Model Specification 
• Analysis of the endpoints above (except the recurrent event analysis) will be performed 
individually using an analysis model identical to that described for the co-primary MACE 
analysis for the evaluation of superiority, using the event dates defined in Section 10.6.4. 
Additionally, supportive summaries and analyses for the following endpoints will be generated 
including fatal events which are identified only through the death endpoint page and do not 
have a corresponding positively adjudicated endpoint event (see Section 10.6.4): 
o MI 
o Stroke 
o Thromboembolic events: Pulmonary Embolism 
• For purposes of time-to-event models, subjects who have never been hospitalized will be right-
censored (i.e., are still considered to be at-risk) for an all-cause hospital re-admission within 30 
days. 
• The recurrent event analysis of MACE or hospitalization for HF events will use the Prentice, 
Williams, Peterson (PWP) model [Prentice, 1981], based on the Cox proportional hazards 
model, to analyze the multiple event data. This model analyzes the time to first, second, etc. 
events while accounting for the correlation of events within an individual subject. Subjects are 
at risk for a kth event only if they survived a (k-1)st event. For the models described below, if 
there are not at least 15 kth events per arm, the treatment effect associated with the kth, (k+1)th, 
etc. events will not be estimated. All event times will be relative to randomization, as opposed 
to intra-event time (i.e. total times rather than gap times will be used). 
 
Three models will be used. The first model will estimate a common treatment effect, regardless 
of the number of events experienced by subjects. A second model will be run that allows the 
treatment effects to differ depending on the number of events experienced by subjects. A third 
model will be run that allows the treatment effect associated with the time to 1st MACE or 
hospitalization for HF to differ from a common treatment effect estimated for time to 2nd, 3rd, 4th, 
etc. MACE or hospitalization for HF. The common treatment effect associated with the time to 
2nd, 3rd, 4th, etc. in the third model would provide support for a treatment effect on time to 
subsequent MACE or hospitalization for HF. 
 
It is possible for a patient to die in conjunction with experiencing a series of events in a short 
time frame. Ultimately, the CEC will identify the primary cause of death. For the purposes of 
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analysis of time to first and subsequent MACE or hospitalization for HF, only those events 
occurring prior to and including the ‘fatal’ event will be included. For example, suppose a 
subject has an MI, followed by a stroke, and dies within a short time frame. If the CEC 
attributes the death to the MI, only the MI will be used in the analysis. If the CEC attributes the 
death to the stroke, both the MI and stroke would be used. If the CEC attributes the death to 
some cause other than the MI and stroke, all three events would be used.  
• Analyses will include only those safety endpoints occurring within the time period for follow-up 
of CV endpoints, with the exception of all-cause mortality, which will use the time period for 
vital status (see Section 10.6.4). 
• For those endpoints or components of endpoints intended to go through the adjudication 
process, only the adjudicated results will be used. 
Model Checking & Diagnostics 
• Refer to Appendix 12: Model Checking and Diagnostics for Statistical Analyses. 
Model Results Presentation 
• The summary displays of time-to-event endpoints will include a summary of the number and 
percentage of subjects having events. Summaries of composite endpoints will include the 
number and percentage of the type of first occurrence by treatment group. 
• A summary of all time-to-event endpoints including the number and percentage of subjects and 
number of events (including first and subsequent events) by type of event will be provided by 
treatment group. 
• Summaries of adjudication details of all-cause mortality will include the number and percentage 
of subjects by cause of death. 
• Summaries of adjudication details of MI will include the number and percentage of events by 
outcome of MI (fatal or non-fatal), type of MI, increased cardiac markers (y/n), ST segment 
classification [ST-elevation myocardial infarction (STEMI), non-ST-elevation myocardial 
infarction (NSTEMI), ECG not interpretable, ECG not available], and Q wave classification (Q 
wave MI, Non Q wave MI, ECG not interpretable, ECG not available). 
• Summaries of adjudication details of stroke will include the number and percentage of events 
by outcome of stroke (fatal or non-fatal), type of stroke (ischemic, hemorrhagic, or 
undetermined) and ischemic details (with/without hemorrhagic transformation) and location if 
hemorrhagic (intraparenchymal, intraventricular, subarachnoid, retinal, unknown location). 
• Summaries of adjudication details of heart failure will include the number of events by type: 
hospitalization for heart failure, heart failure requiring urgent ER/ED visit, heart failure requiring 
urgent office/practice visit, and fatal heart failure events identified by cause of death only. 
• Summaries of adjudication details of thromboembolic events will include the number and 
percentage of events by type of thromboembolic event (DVT, PE, VAT).  
o Summaries of PEs will include outcome of PE (fatal or non-fatal). 
o Summaries of VATs will include type of VAT (AV fistula, AV graft, central venous 
catheter, other), method of diagnosis (ultrasound/Doppler, AV imaging, CVC 
imaging, other), and treatment (thrombolytic therapy, thrombectomy, angioplasty, 
stent, surgical intervention, not specified). 
• The model results presentation for the endpoints above (except the recurrent event analysis) 
will be identical to the co-primary MACE model results, with the single exception being the one-
sided p-value presented will be for the test of superiority of daprodustat vs. rhEPO. 
• For the recurrent events analysis, hazard ratios, two-sided 95% CIs and one-sided chi-squared 
p-values associated with treatment effects (daprodustat vs. rhEPO) will be presented for the 
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three models described above.  
• Summaries that partition the investigator-reported events as (adjudicated to the same event, 
adjudicated to a different event, adjudicated as a non-event) will be presented. Summaries of 
investigator/adjudicator agreement by type of event reported by investigators may also be 
reported. 
• A summary of all-cause hospitalization will be provided by treatment group including 
summaries of the number of hospitalizations per subject, average length of stay per 
hospitalization and primary diagnosis at discharge by system organ class and lower level term.. 
• A summary of all-cause hospital re-admission within 30 days will be provided by treatment 
group including summaries of the number of re-admissions within 30 days per subject and the 
primary diagnosis at re-admission discharge by system organ class and lower level term. 
• A listing of all all-cause mortality events that occur during the study will be provided. This listing 
will include treatment, site ID, unique subject ID, select demographic information, event date, 
study day, and cause of death. 
Model Results Interpretation 
• One-sided p-values will be compared to 0.025 to assess nominal significance. 
Blood Pressure 
Secondary Safety Statistical Analyses: Blood Pressure 
Endpoint(s) 
• 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 (%) of subjects with at least one BP exacerbation event during study 
Model Specification 
• The difference in change from baseline in BP (SBP, DBP, and MAP) at Week 52 will be 
analyzed with a mixed model repeated measures (MMRM) approach with an unstructured 
covariance matrix to compare the difference in means between arms. The models will be fitted 
to scheduled BP data collected after baseline up to Week 52. Models will be run two times: 
o On-treatment BP values only, excluding values collected during the stabilization 
period (Randomization date + 1 day to <Week 28). 
o On-treatment BP values only, including values collected during the stabilization 
period. 
• The models will include factors for treatment, time, prognostic randomization stratification 
factors (see Section 10.10.2), baseline BP parameter and the baseline BP parameter by time 
and treatment by time interaction terms. Analyses will be done with the MIXED procedure in 
SAS, using the Kenward-Roger option to estimate denominator degrees of freedom and 
standard errors. For analyses using on- and off-treatment values, subjects who withdraw from 
the study before Week 52 are considered to be missing at random and in the analysis using 
on-treatment values only, subjects who permanently discontinue randomized treatment before 
Week 52 are assumed to be missing at random. 
• The difference in change from baseline in BP (SBP, DBP, and MAP) at the derived end of 
treatment (see Section 10.6.4) will be analyzed with an ANCOVA model including terms for 
treatment, prognostic randomization stratification factors (see Section 10.10.2) and the 
corresponding baseline BP parameter. This analysis will be performed using on-treatment BP 
values only. 
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Secondary Safety Statistical Analyses: Blood Pressure 
• The number of on-treatment BP exacerbation events per 100 patient years will be calculated 
(see Section 10.6.4). Confidence intervals for the rate per 100 patient years will also be 
reported. For within group rates and the ratio of model estimated exacerbation rates, the point 
estimates. two-sided 95% confidence intervals, and one-sided p-value for the treatment group 
comparison will be obtained using a negative binomial model with treatment and the prognostic 
randomization strata as covariates and the logarithm of time on-treatment as an offset variable. 
Model Results Presentation 
• BP parameter values (SBP, DBP, and MAP) will be summarized using mean, standard 
deviation, minimum, P25, median, P75, and maximum at each visit by treatment group. In 
addition to scheduled visits, the derived baseline value and end of treatment values will be 
summarized (see Section 10.6.4). Summaries of on-treatment BP values only and on- and off-
treatment BP values together will be produced. A summary of on-treatment BP values by 
baseline dialysis type will be produced. On-treatment BP parameter values will be plotted by 
visit using a line plot. 
• BP parameter change from baseline values (SBP, DBP, and MAP) will be summarized using 
mean, standard deviation, minimum, P25, median, P75, and maximum at each post-baseline 
visit by treatment group. In addition to scheduled visits, the derived end of treatment values will 
be summarized (see Section 10.6.4). Summaries of on-treatment BP values only and on- and 
off-treatment BP values together will be produced. A summary of change from baseline in on-
treatment BP parameter values by baseline dialysis type will be produced. On-treatment BP 
parameter change from baseline values will be plotted by visit using a line plot. 
• For the MMRM analyses of change from baseline in BP parameters to Week 52, an LSMEANS 
statement will provide adjusted treatment group means and standard errors and a point 
estimate and two-sided 95% confidence interval for the adjusted mean treatment difference 
(daprodustat - rhEPO) and a one-sided superiority p-value for this test. 
• For the ANCOVA analyses of change from baseline in BP parameters to the derived end of 
treatment, the adjusted mean estimates and standard errors by treatment group, adjusted 
mean difference, two-sided 95% CI and one-sided superiority p-value for the difference in BP 
parameter between the daprodustat and rhEPO arms from the ANCOVA model will be 
presented. The number of subjects contributing to the analysis and the associated mean and 
standard deviation of the baseline and end of treatment values will also be displayed with the 
results of the ANCOVA model. 
• The model estimated on-treatment BP exacerbation rates per 100 patient years and associated 
95% confidence intervals will be provided by treatment group. The ratio of model estimated on-
treatment BP exacerbation rates and associated two-sided 95% confidence interval and one-
sided p-value will also be provided for the comparison of daprodustat vs. rhEPO.  
• On-treatment BP exacerbations will be summarized as follows: The number and percent of 
subjects with 0, 1, 2, 3, 4, 5 and >5 on-treatment BP exacerbations will be provided by 
treatment group. Additionally, the number and percent of subjects with on-treatment BP 
exacerbations and number of on-treatment BP exacerbation events will be provided by 
treatment group, in total and by BP exacerbation type (see Section 10.6.4). The total treatment 
exposure in years and overall on-treatment BP exacerbation rate per 100 PY will be provided 
by treatment group. 
o The BP exacerbation summary above will be repeated for the following groups and 
BP values: 
▪ All subjects, on-treatment post-dialysis BP values only 
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Secondary Safety Statistical Analyses: Blood Pressure 
▪ All subjects, on-treatment pre-dialysis BP values only 
▪ Hemodialysis subjects, all on-treatment BP values 
▪ Hemodialysis subjects, on-treatment post-dialysis BP values only 
▪ Peritoneal dialysis subjects, on-treatment post-dialysis BP values only 
 
Model Results Interpretation 
• One-sided p-values will be compared to 0.025 to assess nominal significance. 
8.2.3. 
Exploratory Safety Analyses 
8.2.3.1. 
Overview of Planned Exploratory Safety Analyses 
Table 11 provides an overview of the planned exploratory safety analyses. 
Table 11 
Overview of Planned Exploratory Safety Analyses 
Endpoint 
Analysis 
Population 
Absolute 
Change from Baseline 
Summary 
Individual 
Summary 
Individual 
T 
F 
F 
L 
T 
F 
F 
L 
BP and BP Medication Changes 
SBP, DBP and MAP by 
visit 
ITT 
Included with BP secondary analyses (Section 8.2.2) 
SBP, DBP, and MAP 
change from baseline to 
last record prior to 
change in BP 
medications1 
ITT 
 
 
 
 
Y 
 
 
 
Number of BP 
medications per subject 
by visit1 
ITT 
Y 
 
 
 
 
 
 
 
CFB in number of BP 
medications per subject 
by visit1 
ITT 
 
 
 
 
Y 
 
 
 
Number (%) of subjects 
who had no change, an 
increase or a decrease 
in dosage or number of 
BP medications from 
baseline by visit1 
ITT 
Y 
 
 
 
 
 
 
 
Lipid Parameters 
Lipid parameters by 
visit (TC, LDL-C, HDL-
C) 
ITT 
Y 
Y 
 
 
Y 
 
 
 
NOTES: 
• 
T = Table, F = Figure, L = Listing, Y = Yes display generated. 
• 
Summary = Represents TFL related to any summaries (i.e. descriptive statistics) of the observed raw data. 
• 
Individual = Represents FL related to any displays of individual subject observed raw data. 
[1]: Summary will include on-treatment BP values or BP medications taken while the subject was on treatment only. 
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8.2.3.2. 
Planned Exploratory Safety Display Details 
Blood Pressure 
The last on-treatment BP parameter change from baseline value (SBP, DBP, and MAP) 
recorded prior to the first change in BP medications will be summarized using mean, 
standard deviation, minimum, P25, median, P75, and maximum by treatment group. The 
first change in blood pressure medication occurs at the earliest time a new anti-
hypertensive medication is administered or if the dose or frequency of an existing blood 
pressure medication is changed for any reason (increased, decreased, discontinued, or 
switched to another agent) in any anti-hypertensive medication, except medication 
records with frequencies of “Once only” and “PRN.” 
Number of BP medications per subject while the subject was on treatment will be 
summarized using mean, standard deviation, minimum, P25, median, P75, and maximum 
for each scheduled visit by treatment group. Number of BP medications for each subject 
at baseline is defined as the number of medications taken on the day before randomized 
treatment start date.  For end of treatment, it is defined as the number of medications 
taken on last non-zero dose date + 1 day.  The number of BP medications at all other 
nominal visits is defined as the number of medications taken on the day of the visit.  
Medication records with frequencies of “Once only” and “PRN” will be excluded from 
this summary. 
Change from baseline in the number of BP medications per subject while the subject was 
on treatment will be summarized using mean, standard deviation, minimum, P25, median, 
P75, and maximum for each scheduled visit by treatment group. The number of BP 
medications at baseline, end of treatment and all other nominal visits will be defined as 
described in the previous paragraph. Medication records with frequencies of “Once only” 
and “PRN” will be excluded from this summary. 
Additionally, the number and percentage of subjects who had no change, at least one 
change, an increase, a decrease or a switch in the dosage or number of BP medications 
from baseline while the subject was on treatment will be summarized for each scheduled 
post-baseline visit by treatment group (see Section 10.6.4 for details of classifying BP 
medication changes). Medication records with frequencies of “Once only” and “PRN” 
will be excluded from this summary. 
Cumulative number of changes in on-treatment BP medications from baseline to Week 
52 and End of Treatment will be summarized by treatment group. For all records except 
with frequencies “Once only” and “PRN,” the cumulative number of changes will be 
summarized using mean, standard deviation, minimum, P25, median, P75, and 
maximum. The number of percentage of subjects with no change and at least one 
medication change will be displayed excluding “Once only” and “PRN” records.  For 
subjects with at least one change, the number and percentage of subjects for each reason 
(increase, decrease, and switch) will be displayed (see Section 10.6.4 for details of 
counting BP medication cumulative changes) by treatment group. Number and 
percentage of subjects for each reason of BP medication change will be displayed by 
treatment group. Cumulative number of changes in on-treatment BP medication from 
baseline to Week 52 and End of Treatment for “Once only” records only will be 
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summarized using mean, standard deviation, minimum, P25, median, P75, and maximum 
(see Section 10.6.4 for details of counting BP medication cumulative changes) by 
treatment group. 
Number and percentage of subjects with at least one PRN record at baseline and on-
treatment BP medication during the period from randomized treatment start date to Week 
52 and End of Treatment will be displayed by treatment group.  
Number and percentage of subjects with any BP medication taken at baseline (the day 
before randomized treatment start date) and any on-treatment BP medication during the 
period from randomized treatment start date to Week 52 and End of Treatment will be 
displayed by treatment group.  
Lipid Parameters 
Lipid parameter values for this study include total cholesterol, LDL-C (direct) and HDL-
C. These values are collected according to the schedule outlined in the Time and Events 
table (see Section 10.2.1). Lipid parameter values follow the derivation guidelines for 
laboratory values outlined in Section 10.6.4. The summaries described below will include 
summaries in both SI units and conventional units for each of the lipid parameters and 
will summarize log-transformed values. 
Total cholesterol, LDL-C (direct), and HDL-C on-treatment values will be log-
transformed and summarized using geometric mean, CV, minimum, P25, median, P75, 
and maximum for each scheduled visit by treatment group.  
Percent change from baseline in log-transformed total cholesterol, LDL-C (direct), and 
HDL-C on-treatment values will be summarized using geometric mean, 95% confidence 
interval, minimum, P25, median, P75, and maximum for each scheduled visit by 
treatment group.  
8.2.4. 
Adverse Event Safety Analyses 
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) coding dictionary. 
The reporting of the CEC-adjudicated CV endpoint events has been described in Section 
7.2, Section 8.2.1, and Section 8.2.2. However, AE summaries and analysis will also 
include the AEs and SAEs associated with the adjudicated events listed below: 
• 
All-cause mortality (CV and non-CV mortality) 
• 
Non-fatal MI 
• 
Non-fatal stroke 
• 
Hospitalization for HF 
• 
Thromboembolic events (vascular access thrombosis, deep vein 
thrombosis, pulmonary embolism) 
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For the purpose of AE summaries and analysis, the investigator-reported AE details will 
be used, regardless of the adjudication outcome of the event. 
Adopting recommendations from the Pharmaceutical Research and Manufacturers of 
America (PhRMA) Safety Planning, Evaluation and Reporting Team (SPERT) [Crowe, 
2009], the first two tiers of the three-tier system will be used for the evaluation of AEs to 
examine the level of statistical evidence for differences between treatment groups. 
• Tier 1 events in this study are defined as treatment emergent AEs of special 
interest (AESI). Tier 1 events will include AEs which meet criteria for inclusion 
as an AESI (see Section 10.6.4). Statistical comparisons will be made to compare 
the number and % of AESIs between the treatment groups, using the CMH chi-
square test. A nominal statistical association will be declared if the unadjusted 
two-sided p-value for an event is less than 0.05. 
• Tier 2 events in this study are defined as the most common treatment emergent 
AEs (those occurring in  5% of subjects in any treatment group). Tier 2 events 
are mutually exclusive of the Tier 1 AESI events. Any statistical comparisons for 
Tier 2 events will be made to compare treatment groups with multiplicity 
adjustment, using a CMH chi-square test, and the double false discovery rate 
(FDR, see Section 10.6.4) [Mehrota, 2012]. The double FDR multiplicity 
procedure is designed to limit the number of false positive signals identified to no 
more than two-sided 10% (the false discovery rate). 
Unless otherwise specified, all other AE and SAE summaries will include all AEs. 
See Section 10.4.1 for AE treatment state definitions. 
The adverse event safety analyses will be based on the Safety population, unless 
otherwise specified. 
8.2.4.1. 
Overview of Planned Adverse Event Analyses 
Table 12 provides an overview of the planned adverse event safety analyses. 
Table 12 
Overview of Planned Adverse Event Safety Analyses 
Parameter 
Absolute 
Summary 
Individual 
T 
F 
F 
L 
AESIs & PhRMA SPERT Adverse Event Analyses 
Analysis of AESIs 
Y 
Y 
 
 
Analysis of Common ( 5%) AEs 
Y 
Y 
 
 
Adverse Events 
All AEs by System Organ Class (SOC) and 
Preferred Term 
Y 
 
 
Y 
All AEs by System Organ Class (SOC) and 
Preferred Term (subjects and occurrences) 
Y 
 
 
 
All AEs by SOC and Preferred Term by 
Y 
 
 
 
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Parameter 
Absolute 
Summary 
Individual 
T 
F 
F 
L 
Subgroups 
All AEs by Overall Frequency 
Y 
 
 
 
Common AEs by Overall Frequency 
Y 
Y1 
 
 
All AEs by Maximum Intensity 
Y 
 
 
 
All Drug-Related AEs by Maximum Intensity 
Y 
 
 
 
All Drug-Related AEs by SOC and Preferred 
Term 
Y 
 
 
 
Common Non-Serious AEs by SOC and 
Preferred Term (subjects and occurrences) 
Y 
 
 
 
Subject Numbers for Individual AEs 
 
 
 
Y 
Relationship Between AE SOCs, Preferred Term 
& Verbatim Text 
 
 
 
Y 
Serious and Other Significant Adverse Events 
SAEs by SOC and Preferred Term (subjects and 
occurrences) 
Y 
 
 
 
SAEs by Maximum Intensity 
Y 
 
 
 
Reasons for Considering as a SAE 
 
 
 
Y 
Drug-Related SAEs by SOC and Preferred Term 
(subjects and occurrences) 
Y 
 
 
 
Fatal SAEs by SOC and Preferred Term 
(subjects and occurrences) 
Y 
 
 
Y 
Non-Fatal SAEs by SOC and Preferred Term 
(subjects and occurrences) 
Y 
 
 
Y 
Drug-Related Fatal SAEs by SOC and Preferred 
Term (subjects and occurrences) 
Y 
 
 
 
AEs Leading to Permanent Discontinuation of 
Randomized Treatment by SOC and Preferred 
Term 
Y 
 
 
Y 
BP Exacerbation Events 
Y 
 
 
 
BP Exacerbation SAEs 
Y 
 
 
 
Other Significant AEs 
 
 
 
Y 
Other CV Events 
Other CV Events2 
 
 
 
 
NOTES: 
• 
T = Table, F = Figure, L = Listing, Y = Yes display generated. 
• 
Summary = Represents TFL related to any summaries (i.e. descriptive statistics) of the observed raw data. 
• 
Individual = Represents FL related to any displays of individual subject observed raw data. 
[1]: Plot of common AEs and relative risk will be generated. 
[2]: Electronically generated patient profiles will be produced and used in the preparation of SAE summaries as a part 
of the study report. 
8.2.4.2. 
Planned Adverse Event Safety Statistical Analyses 
AESIs & PhRMA SPERT Adverse Event Analyses 
Adverse events of special interest are described in Section 10.6.4.  
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Summaries of AESIs will include the number, percentage and rate per 100 person-years 
of subjects having at least one occurrence, the number of events, the number of subjects 
by number of occurrence, the characteristics of the AE (serious, drug-related, etc.), 
outcome, maximum intensity, time to first onset/worsening, and action taken summarized 
by treatment group. For each count, a subject will be summarized as follows: 
• Serious/drug-related/severe/fatal: If any specific AE falls in the respective 
category, the subject will be counted in that category. 
• Outcome: The subject will be counted within a category if there is at least one 
specific AE in that category. 
• Maximum intensity: The specific AE with the maximum intensity will be counted 
for this purpose. For example, a subject will be counted in the ‘severe’ category if 
there is at least one specific AE with severe intensity. A subject will be counted in 
the ‘moderate’ category if there is at least one specific AE with moderate intensity 
and there is no specific AE with severe intensity. 
• Time to first onset/worsening (days): The earliest of onset dates for the specific 
AE – treatment start + 1 
If the AE onset date/AE worsening and/or resolution date is missing or incomplete in the 
database for any occurrence of the specific AE, time to first onset/worsening will be left 
missing for the subject. These summaries of special interest AEs will be provided for 
those AEs classified as treatment emergent. 
Cumulative incidence function (CIF) plots may be produced for each AESI summarizing 
the time to first occurrence of the AESI by treatment group. If there are less than 20 
subjects total for both the daprodustat and rhEPO arm, then these plots will not be 
created. Competing risks for the AESI cumulative incidence plots include: 
AE of Special Interest (Event of interest) 
Competing Risk Events 
Thrombosis and/or tissue ischemia secondary 
to excessive erythropoiesis 
Death due to any cause prior to the AESI 
Cardiomyopathy 
Death due to any cause prior to the AESI 
Pulmonary artery hypertension 
Death due to any cause prior to the AESI 
Cancer-related mortality and tumor progression 
and recurrence 
All other non-cancer-related death prior to the 
AESI (use death date as the competing risk 
date) 
Esophageal and gastric erosions 
Death due to any cause prior to the AESI 
Proliferative retinopathy, macular edema, 
choroidal neovascularization 
Death due to any cause prior to the AESI 
Exacerbation of rheumatoid arthritis 
Death due to any cause prior to the AESI 
Worsening of hypertension 
Death due to any cause prior to the AESI 
Additionally, as a part of the PhRMA SPERT analyses described in Section 8.2.4, 
treatment emergent AE of special interest are considered Tier 1 events. The relative risk, 
corresponding two-sided 95% confidence intervals and two-sided p-values comparing 
daprodustat vs. rhEPO for these Tier 1 AEs will be provided.  
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The number, percentage and rate per 100 person-years for subjects reporting Tier 2 AEs 
will be summarized by system organ class, preferred term and treatment group. 
Additionally, as a part of the PhRMA SPERT analyses described in Section 8.2.4, the 
most common treatment emergent AEs that are not Tier 1 AEs are considered to be Tier 2 
AEs. The relative risk will be calculated for these Tier 2 AEs and a corresponding two-
sided 95% confidence interval comparing daprodustat vs. rhEPO. Two two-sided p-
values will be displayed: one that makes no adjustment for multiplicity and one that 
makes the double FDR adjustment. 
Dot plots displaying the incidence of the event will be provided for the Tier 1 and Tier 2 
events by AESI term (Tier 1)/ preferred term (Tier 2) and treatment group. The incidence 
rate in each treatment group and corresponding two-sided 95% confidence interval for the 
relative risk of the daprodustat group compared to the rhEPO group will be provided. 
Adverse Events 
The number and percentage of subjects reporting at least one AE will be provided for 
each treatment group. These events will be summarized by treatment group, primary 
system organ class, and preferred term. Pre-treatment and treatment emergent AEs will 
be summarized separately. 
The number and percentage of subjects and the number of occurrences of all treatment 
emergent AEs will be summarized by primary system organ class, and preferred term. 
Summaries of all treatment emergent AEs will be produced for the age group, gender, 
race group, baseline dialysis type, weight quartile subgroups. Summaries of treatment 
emergent AEs by subgroup will be produced twice: by system organ class and preferred 
term and separately by overall frequency. 
A listing of AE records for all subjects who reported AEs will be produced. 
Summaries of all treatment emergent AEs will be provided by maximum intensity. For 
AEs reported more than once by a subject, the most severe intensity will be included in 
summaries where applicable. The max intensity will be presented as “Unknown” if 
Missing and/or N/A are the only available severity values. Analysis will be repeated for 
all drug-related treatment emergent AEs. 
The number and percentage of subjects reporting the most common treatment emergent 
AEs (those occurring in  5% of subjects in any treatment group) will be summarized by 
preferred term and treatment group.  
The number and percentage of subjects reporting treatment emergent AEs assessed by the 
investigator to be related to the study drug will be summarized by treatment group, 
primary system organ class, and preferred term and separately by overall frequency.  
The number and percentage of subjects and the number of occurrences of common non-
serious treatment emergent adverse events (those occurring in  5% of subjects in any 
treatment group) will be summarized by primary system organ class, preferred term, and 
treatment group and separately by overall frequency. 
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A listing of which subjects reported specific adverse events will be produced. 
The hierarchical relationship between MedDRA SOCs, PTs and verbatim text will be 
listed for all adverse events. 
Serious and Other Significant Adverse Events 
The number and percentage of subjects and the number of occurrences of treatment 
emergent SAEs will be provided for each treatment group. These events will be 
summarized by treatment group, primary system organ class, and preferred term. 
Treatment emergent SAE preferred terms will also be summarized by treatment group 
and overall frequency. 
Summaries of treatment emergent SAEs will be provided by maximum intensity. 
A listing of reasons for considering as a SAE will be produced for all treatment emergent 
SAEs. 
The number and percentage of subjects and the number of occurrences of treatment 
emergent drug-related SAEs, fatal SAEs, non-fatal SAEs, and drug-related fatal SAEs 
will be summarized by treatment group: by primary system organ class and preferred 
term and separately by overall frequency. 
A listing of treatment emergent fatal SAE records and a listing of treatment emergent 
non-fatal SAE records will be provided. 
The number and percentage of subjects reporting treatment emergent AEs leading to 
discontinuation of randomized treatment will be summarized by treatment group, primary 
system organ class, and preferred term. 
A listing of treatment emergent AEs leading to discontinuation of randomized treatment 
will be provided. 
BP events and BP-related SAEs are defined in Section 10.6.4. 
The number and percentage of subjects with at least one on-treatment BP event will be 
provided for each treatment group. In addition, this summary will include the number and 
percentage of subjects with at least one on-treatment BP event that is considered 
clinically significant and the number and percentage of subjects with at least one on-
treatment BP event that is considered to be symptomatic. 
The number and percentage of subjects reporting at least one treatment emergent BP-
related SAE will be provided for each treatment group. In addition, the number of 
treatment emergent BP-related SAEs will be summarized by treatment group, primary 
system organ class, and preferred term. 
A listing of other significant adverse events will be produced. Other significant adverse 
events are events that are not reported as fatal or serious but represent ICH-defined 
‘Other significant adverse events’ (i.e., marked haematological and other laboratory 
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abnormalities and any adverse events that led to an intervention, including withdrawal of 
drug treatment, dose reduction, or significant additional concomitant therapy). For this 
study, other significant AEs will be defined as non-fatal non-serious AEs resulting in an 
action taken with study treatment of either ‘dose interrupted/delayed’ or ‘dose reduced’. 
Other CV Events 
GSK has identified other CV events of interest for all clinical studies. In this study, 
investigators will be required to fill out the specific CV event page of the eCRF for the 
following CV AEs and SAEs or any event that may potentially be one of the categories 
listed: 
• Arrhythmias 
• Pulmonary hypertension 
• Valvulopathy 
• Revascularization 
Electronically generated patient profiles for subjects reporting these events will not be 
prospectively created. 
8.2.5. 
Clinical Laboratory Safety Analyses 
Clinical chemistry, hematology and other laboratory tests are assessed in this study 
according to the schedule outlined in the Time and Events table (see Section 10.2.1). The 
following tests will be summarized in clinical laboratory displays: 
Clinical 
Chemistry 
Potassium (serum) 
Aspartate 
aminotransferase (AST) 
Albumin  
Calcium (albumin 
corrected) 
Alanine 
amintotransferase (ALT) 
Blood Urea Nitrogen (BUN) 
Phosphate 
Bilirubin (total and 
direct/indirect) 
 
 
Hematology 
Platelet count 
RBC indices: 
Leukocyte (white blood cell) 
count with Differential 
Erythrocyte (red blood 
cell) count 
Mean corpuscular 
volume (MCV) 
Neutrophils (absolute and 
segmented) 
Reticulocyte count 
Mean corpuscular 
hemoglobin (MCH) 
Lymphocytes 
Hematocrit 
Mean corpuscular 
hemoglobin 
concentration (MCHC) 
Monocytes 
 
Erythrocytes (red cell) 
distribution width (RDW) 
Eosinophils 
 
 
Basophils 
 
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Other 
laboratory 
tests 
Intact parathyroid 
hormone (iPTH) 
Hemoglobin A1c (HbA1c) 
in diabetic subjects 
High-sensitivity C-reactive 
protein (hs-CRP) 
Summaries of central laboratory Hgb values, HemoCue Hgb values, iron parameter 
values (serum iron, ferritin, hepcidin, TIBC, TSAT), and lipid parameter values (total 
cholesterol, direct LDL-C, HDL-C) are included in earlier efficacy and safety sections 
and will not be included with clinical laboratory displays. However, these parameters 
may be included in PCI summaries. 
The clinical chemistry tests performed in this study include ALT, AST and bilirubin. In 
addition to being summarized with the clinical chemistry values, these laboratory values 
will be included in some of the Hepatobiliary (liver) displays. 
In addition to the visits listed for the laboratory assessments in the Time and Events table 
(see Section 10.2.1), any of these assessments can be performed at an unscheduled/retest 
visit or at the follow-up visit at the discretion of the investigator. See Section 10.5.3 for 
handling of unscheduled values. The laboratory’s normal range values will be provided 
by the central laboratory and potential clinical importance thresholds are defined in 
Section 10.8.1. 
All of the tabular summaries described below will include summaries in SI units; 
conventional units will also be provided for the following laboratory tests: MCHC, 
albumin corrected calcium, phosphate, albumin, BUN, total cholesterol, LDL-C, and 
HDL-C. Conversions from SI units to conventional units are included in Section 10.6.4. 
Hemoglobin summaries will only use conventional mg/dL units. Summaries of 
reticulocytes will be provided for the total count and percent of total erythrocytes and 
summaries of neutrophils, lymphocytes, monocytes, eosinophils, and basophils will be 
provided for total counts and differentials (percent of total leukocytes). 
The clinical laboratory safety analyses will be based on the Safety population, unless 
otherwise specified. 
8.2.5.1. 
Overview of Planned Clinical Laboratory Safety Analyses 
Table 13 provides an overview of the planned clinical laboratory safety analyses. 
Table 13 
Overview of Planned Clinical Laboratory Safety Analyses 
Parameter 
Absolute 
Change from Baseline 
Summary 
Individual 
Summary 
Individual 
T 
F 
F 
L 
T 
F 
F 
L 
Chemistry 
Chemistry Values by 
Visit 
Y 
 
 
 
Y 
 
 
 
Worst Case Chemistry 
Results by PCI Criteria 
Post-Baseline Relative 
to Baseline 
Y 
 
 
 
 
 
 
 
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Parameter 
Absolute 
Change from Baseline 
Summary 
Individual 
Summary 
Individual 
T 
F 
F 
L 
T 
F 
F 
L 
Hematology 
Hematology Values by 
Visit 
Y 
 
 
 
Y 
 
 
 
Worst Case 
Hematology Results by 
PCI Criteria Post-
Baseline Relative to 
Baseline 
Y 
 
 
 
 
 
 
 
Other Laboratory Tests 
Other Laboratory 
Values by Visit 
Y 
 
 
 
Y 
 
 
 
Worst Case Other 
Laboratory Results by 
PCI Criteria Post-
Baseline Relative to 
Baseline 
Y 
 
 
 
 
 
 
 
Hepatobiliary (Liver) 
Liver 
Monitoring/Stopping 
Event Reporting 
Y 
 
 
 
 
 
 
 
Hepatobiliary 
Laboratory 
Abnormalities 
Y 
 
 
 
 
 
 
 
Medical Conditions for 
Subjects with Liver 
Stopping Events 
 
 
 
Y 
 
 
 
 
Substance Use for 
Subjects with Liver 
Stopping Events 
 
 
 
Y 
 
 
 
 
Scatter Plot of 
Maximum vs. Baseline 
for ALT 
 
Y 
 
 
 
 
 
 
Scatter Plot of 
Maximum ALT vs. 
Maximum Total 
Bilirubin 
 
Y 
 
 
 
 
 
 
All Laboratory 
All Laboratory Data for 
Subjects with Any 
Value of PCI 
 
 
 
Y 
 
 
 
 
All Laboratory Data 
 
 
 
Y 
 
 
 
 
Iron 
Worst Case Iron 
Results by PCI Criteria 
Post-Baseline Relative 
to Baseline 
 
 
 
Y 
 
 
 
 
 
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NOTES: 
• 
T = Table, F = Figure, L = Listing, Y = Yes display generated. 
• 
Summary = Represents TFL related to any summaries (i.e. descriptive statistics) of the observed raw data. 
• 
Individual = Represents FL related to any displays of individual subject observed raw data. 
8.2.5.2. 
Planned Clinical Laboratory Safety Display Details 
Clinical Chemistry 
Continuous on-treatment values (see Section 10.4.1) will be summarized using mean, 
standard deviation, minimum, P25, median, P75, and maximum for each scheduled visit 
and for baseline and end of treatment (see Section 10.6.4) by treatment group.. 
Continuous on-treatment change from baseline values will be summarized using mean, 
standard deviation, minimum, P25, median, P75, and maximum for each scheduled visit 
and for end of treatment (see Section 10.6.4) by treatment group.  
The number and percentage of subjects with on-treatment or worst case laboratory results 
relative to PCI criteria (see Section 10.8.1) which are post-baseline relative to baseline 
will be summarized by laboratory test, category and treatment group. See Section 10.6.4 
for additional information on worst case values and PCI categories. 
Hematology 
The displays presented for clinical chemistry laboratory values will also be presented for 
the hematology laboratory tests listed in Section 8.2.5. 
Other Laboratory Tests 
The displays presented for clinical chemistry laboratory values will also be presented for 
the other laboratory tests listed in Section 8.2.5.  
On-treatment hsCRP values will be log-transformed (see Section 10.5.2) and summarized 
using geometric mean, coefficient of variation, minimum, P25, median, P75, and 
maximum for each scheduled visit by treatment group. 
Percent change from baseline in log-transformed (see Section 10.5.2) on-treatment 
hsCRP values will be summarized using geometric mean, 95% confidence interval, 
minimum, P25, median, P75, and maximum for each scheduled visit by treatment group. 
Hepatobiliary (Liver) 
Please refer to the protocol for details of liver chemistry stopping criteria. 
Liver monitoring/stopping events will be summarized by treatment group. 
Hepatobiliary laboratory abnormalities will be summarized by treatment group. 
Medical conditions for subjects with liver stopping events and substance use for subjects 
with liver stopping events will be listed. 
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A scatter plot of maximum on-treatment ALT values versus baseline ALT values will be 
produced. 
A scatter plot of maximum on-treatment total bilirubin (xULN) versus maximum on-
treatment ALT (xULN) values will be produced. 
All Laboratory 
A listing of all laboratory data for subjects with on-treatment laboratory values outside of 
PCI criteria will be provided. 
A listing of all laboratory data will be provided. 
Iron parameters 
The number and percentage of subjects with on-treatment or post-treatment worst case 
laboratory results relative to PCI criteria (see Section 10.8.1) which are post-baseline 
relative to baseline will be summarized by laboratory test, category and treatment group. 
See Section 10.6.4 for additional information on worst case values and PCI categories. 
8.2.6. 
Vital Signs Analyses 
Vital signs are assessed in this study according to the schedule outlined in the Time and 
Events table (see Section 10.2.1) and include the following assessments: 
• Height 
• HR 
• Weight 
• Estimated Dry Weight 
Summaries and analyses of BP values are described in earlier safety sections and will not 
be included with vital signs summaries. However, BP values will be included in PCI 
summaries. 
The vital signs analyses will be based on the Safety population, unless otherwise 
specified. 
8.2.6.1. 
Overview of Planned Vital Signs Analyses 
Table 14 provides an overview of the planned vital signs analyses. 
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Table 14 
Overview of Planned Vital Signs Analyses 
Parameter 
Absolute 
Change from Baseline 
Summary 
Individual 
Summary 
Individual 
T 
F 
F 
L 
T 
F 
F 
L 
Vital Signs 
Vital Signs by Visit 
Y 
 
 
 
Y 
 
 
 
Summary of Worst 
Case Vital Signs 
Results by PCI Criteria 
Y 
 
 
 
 
 
 
 
All Vital Signs for 
Subjects with Any 
Value of Potential 
Clinical Importance 
 
 
 
Y 
 
 
 
 
NOTES: 
• 
T = Table, F = Figure, L = Listing, Y = Yes display generated. 
• 
Summary = Represents TFL related to any summaries (i.e. descriptive statistics) of the observed raw data. 
• 
Individual = Represents FL related to any displays of individual subject observed raw data. 
8.2.6.2. 
Planned Vital Signs Display Details 
Vital sign values will be summarized using mean, standard deviation, minimum, P25, 
median, P75, and maximum for each scheduled visit and for baseline and end of 
treatment by treatment group.  
Vital sign change from baseline values will be summarized using mean, standard 
deviation, minimum, P25, median, P75, and maximum for each scheduled visit and for 
end of treatment by treatment group.  
The number and percentage of subjects with on-treatment or post-treatment worst case 
vital sign results relative to PCI criteria (see Section 10.8.1) which are post-baseline 
relative to baseline will be summarized by test, category and treatment group. See 
Section 10.6.4 for additional information on worst case values and PCI categories. The 
difference between on-treatment post-dialysis weight and estimated dry weight will be 
summarized using mean, standard deviation, minimum, P25, median, P75, and maximum 
for each scheduled visit and for baseline and end of treatment by treatment group. A 
corresponding line plot will be provided to display this data graphically. 
A listing of all vital signs data for subjects with on-treatment vital signs values outside of 
PCI criteria will be provided. 
8.2.7. 
Electrocardiograms 
Electrocardiograms (ECGs) will be read locally and ECG data will not be included in 
summary tables or individual subject listings.  
8.2.8. 
Pregnancies 
A listing of all subjects who became pregnant during the study will be included. 
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8.2.9. 
Other Safety Analyses 
Clopidogrel Analyses 
The following analyses will be conducted to confirm the effect of clopidogrel co-
administration. 
The treatment emergent AEs and SAEs will be summarized with the number, percentage 
and rate per 100 person-years, by clopidogrel co-administration, treatment group, and 
system organ class and preferred term. Clopidogrel co-administration is defined as 
subjects who use clopidogrel once or more during the on-treatment state for concomitant 
medications (see Section 10.4.1). 
The number and percentage of subjects with a >1 g/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, will be summarized by visit by clopidogrel co-administration, 
and by treatment group using HemoCue Hgb values. This summary will be presented 
using evaluable Hgb values only (see Section 10.6.3).  
The number and percentage of subjects with a >2 g/dL increase in Hgb within any 4-
week period from Week 4 to Week 52, will be summarized by visit by clopidogrel co-
administration, and by treatment group using central laboratory Hgb values. This 
summary will be presented using evaluable Hgb values only (see Section 10.6.3).  
For the above two tables, the Clopidogrel co-administration groups are baseline 
clopidogrel users, new clopidogrel users, and clopidogrel non-users during the first year 
of the study. Baseline clopidogrel users, defined as subjects who use clopidogrel at 
randomization, will be summarized only at Week 2 and Week 4 for the HemoCue Hgb 
table, and only at week 4 in the central laboratory Hgb table. New clopidogrel users are 
defined as subjects who started clopidogrel after randomization during the on-treatment 
state for concomitant medications (see Section 10.4.1) in the first year of the study. If 
they started clopidogrel within two weeks of a scheduled visit (i.e. visit date - 2w < 
clopidogrel start date visit date + 2w), they will only be summarized in the following 
scheduled visit. Clopidogrel non-users are subjects who do not use clopidogrel neither at 
randomization nor anytime during the on-treatment state for concomitant medications 
(see Section 10.4.1) in the first year of the study. 
The number and percentage of subjects with a Hgb value  12 g/dL during the study will 
be summarized by clopidogrel co-administration, and by treatment group using evaluable 
Hgb values (see Section 10.6.3). Clopidogrel co-administration is defined as subjects who 
use clopidogrel once or more either at randomization or during the on-treatment state for 
concomitant medications (see Section 10.4.1). 
The number and percentage of subjects who had dose adjustments (decreases, increases, 
no change) will be summarized at Week 2 and Week 4 by baseline clopidogrel co-
administration, and by treatment group. The number of dose decreases per subject will be 
summarized for baseline clopidogrel users, using mean, standard deviation, minimum, 
P25, median, P75, and maximum by baseline clopidogrel use, and by treatment group, for 
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Day 1 to Week 12. Baseline clopidogrel co-administration is defined as subjects who use 
clopidogrel at randomization. 
The number and percentage of subjects had dose adjustments (decreases, increases, no 
change) will be summarized for new clopidogrel users, who started clopidogrel after 
randomization, during the on-treatment state for concomitant medications (see Section 
10.4.1), by treatment group. If they started clopidogrel within two weeks of a scheduled 
visit (i.e. visit date - 2w < clopidogrel start date  visit date + 2w), they will be 
summarized in the following scheduled visit. The number of dose decreases per subject 
will also be summarized for these new clopidogrel users using mean, standard deviation, 
minimum, P25, median, P75, and maximum by clopidogrel use, and by treatment group, 
for clopidogrel use start date to clopidogrel use + Week 12. 
The median assigned dose by treatment, by clopidogrel co-administration, and visit will 
be displayed graphically for each scheduled study visit from day 1 to week 52 using a 
line plot. The line plot of median assigned dose along with the first and the third quartiles 
by time will include vertical reference lines to identify the EP as well as the number of 
subjects by treatment group contributing to each median value. This plot will be created 
by treatment group separately for subjects receiving epoetin alfa and darbepoetin alfa and 
these plots will also be overlaid on a graph of corresponding mean evaluable Hgb values 
by visit. Since it is possible for subjects to switch from epoetin alfa to darbepoetin alfa 
during the study, subjects who receive both treatments during the study will be counted in 
each group. Clopidogrel co-administration here is defined as subjects who use 
clopidogrel once or more, at randomization, or during the on-treatment state for 
concomitant medications (see Section 10.4.1) in the first year of the study. 
A box plot of evaluable Hgb change at Week 2 from baseline, by baseline clopidogrel co-
administration and treatment group will be produced. Hemocue Hgb will be used in this 
figure, since only Hemocue Hgb is available at Week 2. Baseline clopidogrel co-
administration is defined as subjects who use clopidogrel at randomization. This box plot 
will be repeated at Week 4 using evaluable Hgb, by baseline clopidogrel co-
administration and treatment group.  
A box plot of 4-week changes in evaluable Hgb after starting clopidogrel will also be 
produced by treatment for new clopidogrel users, who started clopidogrel after 
randomization, during the on-treatment state for concomitant medications (see Section 
10.4.1). The 4-week change in evaluable Hgb will be estimated by calculating the change 
at the first visit after starting clopidogrel, from the previous visit at least 4 weeks before. 
The first visit after starting clopidogrel is defined as the first visit (scheduled or 
unscheduled) after clopidogrel start that was at least two weeks after the start date of 
clopidogrel. 
COVID-19 Analyses 
The following COVID-19 related displays will be provided. 
A summary of the number and percentage of subjects for the following assessments will 
be produced: Case Diagnosis, COVID-19 Test performed, and Results of the COVID-19 
test. 
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Summaries of characteristics of COVID-19 AEs will include the number, percentage of 
subjects having at least one occurrence, the outcome, maximum intensity, and the 
duration of the AE summarized by treatment group. For each count, a subject will be 
summarized as follows: 
• Outcome: The subject will be counted within a category if there is at least one 
specific AE in that category. 
• Maximum intensity: The specific AE with the maximum intensity will be counted 
for this purpose. For example, a subject will be counted in the ‘severe’ category if 
there is at least one specific AE with severe intensity. A subject will be counted in 
the ‘moderate’ category if there is at least one specific AE with moderate intensity 
and there is no specific AE with severe intensity. 
• Duration of the occurrence (days): AE resolution date – AE onset date/AE 
worsening date + 1 for the occurrence 
A summary of the number and percentage of subjects with COVID-19 symptoms will be 
produced. 
A summary of exposure adjusted incidence rates over time (see Section 10.6.4) will be 
produced by treatment group for any treatment emergent AE, any treatment emergent 
SAE, and any treatment emergent Severe AE, for two periods – pre COVID-19 pandemic 
and during COVID-19 pandemic. The summary will be produced overall, by Country, 
Region, Sex, and by Age at randomization (Grouping 2) (see Section 10.10.1). A 
summary of exposure adjusted incidence rates by treatment group will also be produced 
for Common (>5%) AEs for two periods – pre COVID-19 pandemic and during COVID-
19 pandemic. 
8.3. 
Patient Reported Outcomes Analyses 
This study includes the following patient reported outcomes (PROs) that are assessed 
according to the schedule in the Time and Events table in Section 10.2.1: 
• SF-36 
• EQ-5D-5L & EQ-VAS 
• PGI-S 
• PGI-C 
Additional details on these questionnaires can be found in Section 10.6.5. All analyses 
will use on-treatment values only unless otherwise specified. 
8.3.1. 
Overview of Planned Patient Reported Outcomes Analyses 
Table 15 provides an overview of the planned patient reported outcomes analyses. 
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Table 15 
Overview of Planned Patient Reported Outcomes Analyses 
Endpoint 
Analysis 
Popula-
tion 
Absolute 
Change from Baseline 
Stats 
Analysis 
Summary Individual 
Stats 
Analysis 
Summary Individual 
T 
F 
L 
T 
F 
F 
L 
T 
F 
L 
T 
F 
F 
L 
HRQoL and Utility Scores  
SF-36 domain 
and 
component 
scores 
ITT 
 
 
 
Y 
 
 
 
Y 
Y 
 
Y 
 
 
 
EQ-5D-5L & 
EQ-VAS 
ITT 
 
 
 
Y 
 
 
 
Y 
Y 
 
Y 
 
 
 
Hyporesponder 
SF-36 
subgroup 
analyses 
ITT 
 
 
 
 
 
 
 
Y 
 
 
 
 
 
 
Symptom Severity 
PGI-S score 
ITT 
 
 
 
Y 
 
 
 
Y 
Y 
 
Y 
 
 
 
PGI-S 
categories 
ITT 
 
 
 
 
 
 
 
 
 
 
Y 
 
 
 
PGI-C 
categories 
ITT 
 
 
 
Y 
 
 
 
 
 
 
 
 
 
 
NOTES: 
• 
T = Table, F = Figure, L = Listing, Y = Yes display generated. 
• 
Stats Analysis = Represents TFL related to any formal statistical analyses (i.e. modelling) conducted. 
• 
Summary = Represents TFL related to any summaries (i.e. descriptive statistics) of the observed raw data. 
• 
Individual = Represents FL related to any displays of individual subject observed raw data. 
8.3.2. 
Planned Patient Reported Outcomes Statistical Analyses 
8.3.2.1. 
HRQoL and Utility Score 
Patient Reported Outcomes Statistical Analyses: HRQoL and Utility Score 
Secondary Endpoints Endpoint(s) 
• Mean change in SF-36 HRQoL scores (PCS, MCS and 8 health domains) between baseline 
and Wk 8, 12, 28, 52, of particular interest are the changes from baseline in the vitality and 
physical functioning domains at Wk 28 and 52. 
• Change from baseline in Health Utility (EQ-5D-5L) score at Week 52 
• Change from baseline in EQ VAS at Week 52 
Exploratory Endpoint(s) 
• Change from baseline in Health Utility (EQ-5D-5L) score at Weeks 8, 12, 29, 52, yearly, EOS 
• Change from baseline in EQ VAS at Weeks 8, 12, 28, 52, yearly, EOS 
Model Specification 
• Scoring for the SF-36 parameters and EQ-5D parameters is outlined in Section 10.6.5. 
• The mean change from baseline in SF-36 HRQoL scores (PCS, MCS, and 8 health domains), 
EQ-5D-5L score, and EQ-VAS score will be analyzed using an MMRM approach with an 
unstructured covariance matrix to compare the difference in means between arms. The models 
will be fitted to QoL data collected after baseline up to Week 52. The model will include factors 
for treatment, time, prognostic randomization stratification factors, baseline QoL parameter 
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Patient Reported Outcomes Statistical Analyses: HRQoL and Utility Score 
value and the baseline QoL parameter by time and treatment by time interaction terms. 
Analyses will be done with the MIXED procedure in SAS, using the Kenward-Roger option to 
estimate denominator degrees of freedom and standard errors. 
Model Results Presentation 
• SF-36 domain scores (PCS, MCS, and 8 health domains) will be summarized using mean, 
standard deviation, minimum, P25, median, P75, and maximum by treatment group at all 
scheduled visits. 
• Change from baseline in SF-36 domain scores (PCS, MCS, and 8 health domains) will be 
summarized using mean, standard deviation, minimum, P25, median, P75, and maximum by 
treatment group at all scheduled visits. 
• Bar graphs displaying mean change from baseline for the Week 8, 12, 28, and 52 visits for the 
SF-36 PCS, MCS, and 8 health domains will be provided by treatment group. 
• EQ-5D-5L responses will be summarized by dimension at all scheduled visits, including the 
derived end of treatment visit. 
• EQ-5D-5L and EQ-VAS scores will be summarized using mean, standard deviation, minimum, 
P25, median, P75, and maximum by treatment group at all scheduled visits, including the 
derived end of treatment visit. 
• Change from baseline in EQ-5D-5L and EQ-VAS scores will be summarized using mean, 
standard deviation, minimum, P25, median, P75, and maximum by treatment group at all 
scheduled visits, including the derived end of treatment visit. 
• Bar graphs displaying mean baseline and Week 52 visit scores for the EQ-5D-5L will be 
provided by treatment group. 
• For the MMRM analyses of change from baseline in HRQoL parameters, an LSMEANS 
statement will provide adjusted treatment group means and standard errors and a point 
estimate and two-sided 95% confidence interval for the adjusted mean treatment difference 
(daprodustat - rhEPO) and a one-sided superiority p-value for this test at Weeks 8, 12, 28, and 
52 for the SF-36 component scores and domains, and at Week 52 for the EQ-5D-5L and EQ 
VAS.  
Model Results Interpretation 
• One-sided p-values will be compared to 0.025 to assess nominal significance. 
• Clinically meaningful effects for PRO assessments focused on metrics that would be needed 
for a reimbursement agency or health technology assessment agency will be specified in a 
separate reimbursement RAP. 
 
Supportive Statistical Analyses 
Subgroup Analysis 
• Subgroup analyses will be performed for the change from baseline in the SF-36 PCS, MCS, 
vitality and physical functioning domains at Week 28 and 52 using the age, gender and 
hyporesponder subgroups only (described in Section 10.10), in a method similar to that 
described for the subgroup analysis of the secondary Hgb change from baseline analyses. 
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8.3.2.2. 
Symptom Severity & Change 
Patient Reported Outcomes Statistical Analyses: Symptom Severity & Change 
Secondary Endpoint(s) 
• Change from Baseline at Wk 8,12, 28, 52 in PGI-S 
Exploratory Endpoint(s) 
• Shift tables (Baseline to Weeks 8, 12, 28, and 52) in PGI-S 
• N (%) of patients within each PGI-C symptom change level at Weeks 8, 12, 28, 52 
Model Specification 
• Scoring for the PGI-S and PGI-C parameters is outlined in Section 10.6.5. 
• The mean change from baseline in PGI-S score will be analyzed using an MMRM approach 
with an unstructured covariance matrix to compare the difference in means between arms. The 
models will be fitted to data collected after baseline up to Week 52. The model will include 
factors for treatment, time, prognostic randomization stratification factors, baseline PGI-S score 
value and the baseline PGI-S score by time and treatment by time interaction terms. Analyses 
will be done with the MIXED procedure in SAS, using the Kenward-Roger option to estimate 
denominator degrees of freedom and standard errors. 
Model Results Presentation 
• PGI-S scores will be summarized using mean, standard deviation, minimum, P25, median, 
P75, and maximum by treatment group at all scheduled visits. 
• Change from baseline in PGI-S values will be summarized using mean, standard deviation, 
minimum, P25, median, P75, and maximum by treatment group at all scheduled visits. 
• For the MMRM analyses of change from baseline in PGI-S, an LSMEANS statement will 
provide adjusted treatment group means and standard errors and a point estimate and two-
sided 95% confidence interval for the adjusted mean treatment difference (daprodustat - 
rhEPO) and a one-sided superiority p-value for this test at Weeks 8, 12, 28, and 52. 
• Additionally, shift tables by treatment group will be generated that display the number and 
percentage of subjects in each PGI-S category at baseline and the resulting PGI-S category at 
each scheduled visit. 
• Stacked bar charts will be produced by treatment group that display the percentage of subjects 
with each PGI-S response at baseline and Weeks 8, 12, 28 and 52. 
• The number and percentage of subjects in each PGI-C category at each scheduled visit will be 
summarized. 
Model Results Interpretation 
• One-sided p-values will be compared to 0.025 to assess nominal significance. 
• Clinically meaningful effects for PRO assessments will be specified in a separate 
reimbursement RAP. 
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8.4. 
Biomarker Analyses 
Blood samples will be collected as outlined in the Time and Events Table in Section 
10.2.1 for potential future analysis of CV risk, inflammation and iron metabolism. If 
biomarker analysis is pursued, details will be included in a separate RAP. 
8.5. 
Pharmacogenetics Analyses 
Blood samples will be collected as outline in the Time and Events Table in Section 10.2.1 
for potential future pharmacogenetics (PGx) analysis of the response to daprodustat 
(GSK1278863). If PGx analysis is pursued, details will be included in a separate RAP. 
8.6. 
Analyses Excluding Sites with Suspected Fraud 
During the conduct of the study, 3 sites were closed due to GCP issues including 
suspected fraud at the site. The data from these sites will be included in the study 
displays, however in order to assess the impact of these sites on overall study 
conclusions, a subset of the displays created for the study will be repeated, excluding the 
data from these 3 sites with ID: 
 and 
. 
The list of displays to be repeated is below: 
Display Type 
Display 
Number 
Display Title 
Study Population Table 
1.001 
Summary of Study Populations 
Study Population Table 
1.005 
Summary of Subject Status and Reasons for Study Withdrawal 
at Week 28, Week 52 and Overall 
Study Population Table 
1.008 
Summary of Randomized Treatment Status and Discontinuation 
of Randomized Treatment at Week 28, Week 52, and Overall 
Study Population Table 
1.017 
Summary of Subject Follow-up Time 
Study Population Table 
1.019 
Summary of Subject Survival Status 
Study Population Table 
1.021 
Summary of Demographic and Baseline Characteristics for the 
Intent-to-Treat Population 
Study Population Table 
1.035 
Summary of Extent of Exposure to Study Treatment 
Study Population Table 
1.036 
Summary of Randomized Treatment Compliance Categories 
Study Population Table 
1.037 
Summary of Randomized Treatment Compliance 
Study Population Table 
1.038 
Summary of IRT and eCRF Dose Comparison 
Efficacy Table 
2.001 
Summary of Post-randomization Hemoglobin (g/dL) Data 
Efficacy Table 
2.003 
Summary of Post-randomization Hemoglobin (g/dL) Change 
from Baseline Data 
Efficacy Table 
2.006 
Summary of Co-primary Analysis of Post-randomization 
Hemoglobin Change from Baseline to the Evaluation Period 
Safety Table 
3.001 
Summary of First Occurrence Adjudicated MACE During the 
Time Period for Follow-up of Cardiovascular Events 
Safety Table 
3.002 
Summary of Analysis of Time to First Occurrence of Adjudicated 
MACE During the Time Period for Follow-up of Cardiovascular 
Events 
Safety Table 
3.003 
Summary of All Adjudicated MACE During the Time Period for 
Follow-up of Cardiovascular Events 
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Display Type 
Display 
Number 
Display Title 
Safety Table 
3.004 
Summary of First and Subsequent Adjudicated MACE During the 
Time Period for Follow-up of Cardiovascular Events 
Safety Table 
3.005 
Supportive Analysis: Summary of First Occurrence of 
Adjudicated MACE During the Time Period for On-treatment 
Cardiovascular Events 
Safety Table 
3.006 
Supportive Analysis: Summary of Analysis of Time to First 
Occurrence of Adjudicated MACE During the Time Period for 
On-treatment Cardiovascular Events 
Safety Figure 
3.002 
Kaplan-Meier Plot of Time to First Occurrence of Adjudicated 
MACE During the Time Period for Follow-up of Cardiovascular 
Events 
Safety Figure 
3.003 
Kaplan-Meier Plot of Time to First Occurrence of Adjudicated 
MACE During the Time Period for On-treatment Cardiovascular 
Events 
 
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9. 
REFERENCES 
Agarwal RJ. Blood pressure and mortality among hemodialysis patients.  Hypertension. 
2010;55:762-768. 
Anker SD et al. Development and validation of cardiovascular risk scores for 
haemodialysis patients.  International Journal of Cardiology. 2016; 216:68–77. 
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. 
Crowe BJ, Xia HA, Berlin JA, Watson DJ, Shi H, Lin SL, et al. Recommendations for 
safety planning, data collection, evaluation and reporting during drug, biologic and 
vaccine development: a report of the safety planning, evaluation, and reporting team. 
Clinical Trials. 2009; 6 (5): 430-440. 
Francq BG, Lin D, Hoyer W. Confidence, prediction, and tolerance in linear mixed 
models. Statistics in Medicine. 2019; 38 (30): 5603 – 5622. 
Fine JP, Gray RJ. A proportional hazards model for the subdistribution of a competing 
risk. Journal of the American Statistical Association. 1999; 94:496–509. 
GlaxoSmithKline Document Number 2015N226659_07, 200807, A phase 3 randomized, 
open-label (sponsor-blind), active-controlled, parallel-group, multi-center, event driven 
study in dialysis subjects with anemia associated with chronic kidney disease to evaluate 
the safety and efficacy of daprodustat compared to recombinant human erythropoietin, 
following a switch from erythropoietin-stimulating agents, 30JUL2020. 
GlaxoSmithKline Document Number 2015N226659_08, 200807, A phase 3 randomized, 
open-label (sponsor-blind), active-controlled, parallel-group, multi-center, event driven 
study in dialysis subjects with anemia associated with chronic kidney disease to evaluate 
the safety and efficacy of daprodustat compared to recombinant human erythropoietin, 
following a switch from erythropoietin-stimulating agents, 30JUL2020. 
Holm S. A simple sequential rejective multiple test procedure. Scandinavian Journal of 
Statistics. 1979; 6: 65-70. 
Iverson C, Christiansen S, Flanagin A, et al. AMA Manual of Style: A Guide for Authors 
and Editors. 10th ed. New York, NY: Oxford University Press; 2007. 
Jackson D, White IR, Seaman S, Evans H, Baisley K, Carpenter J. Relaxing the 
independent censoring assumption in the Cox proportional hazards model using multiple 
imputation. Statistics in Medicine. 2014; 33: 4681-4694. 
Kawaguchi A, Koch GG, Wang X. Stratified multivariate Mann-Whitey estimators for 
the comparison of two treatments with randomization based covariance adjustment. 
Statistics in Biopharmaceutical Research. 2011; 3 (2): 217-231. 
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Liu GF, Wang J, Liu K, Snavely DB. Confidence intervals for an exposure adjusted 
incidence rate difference with applications to clinical trials. Statistics in Medicine 2006; 
25: 1275-1286. 
Liublinska V, Rubin DB. Sensitivity analysis for a partially missing binary outcome in a 
two-arm randomized clinical trial. Statistics in Medicine 2014; 33(24): 4170-4185. 
Mehrota DV, Adewale AJ. Flagging clinical adverse experiences: Reducing false 
discoveries without materially compromising power for detecting true signals. Statistics 
in Medicine. 2012; 31: 1918-1930. 
Peters SA, Huxley RR, Woodward 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 (9): 2394 – 2401. 
Prentice RL, Williams BJ, Peterson AV. On the regression-analysis of multivariate 
failure time data. Biometrika 1981; 68: 373-379. 
Rosendall FR, Cannegieter SC, Van der Meer, FJM, and Briet, E. A Method to 
Determine the Optimal Intensity of Oral Anticoagulant Therapy. Thrombosis and 
Haemostasis. 1993; 69 (3): 236 – 239. 
Rubin DB. Multiple Imputation for Nonresponse in Surveys.  John Wiley & Sons, 1987. 
 
 
 
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10. 
APPENDICES 
Section 
Appendix 
RAP Section 4 : Analysis Populations 
Section 10.1 
Appendix 1: Protocol Deviation Management and Definitions for Per-Protocol 
Population 
RAP Section 5 : General Considerations for Data Analyses & Data Handling Conventions 
Section 10.2 
Appendix 2: Time and Events 
Section 10.3 
Appendix 3: Assessment Windows 
Section 10.4 
Appendix 4: Treatment States & Phases 
Section 10.5 
Appendix 5: Data Display Standards & Handling Conventions 
• Study Treatment & Sub-group Display Descriptors 
• Baseline Definitions & Derivations 
• Reporting Process & Standards 
Section 10.6 
Appendix 6: Derived and Transformed Data 
• General 
• Study Population 
• Efficacy 
• Safety 
• Patient Reported Outcomes 
Section 10.7 
Appendix 7: Premature Withdrawals & Handling of Missing Data 
• Premature Withdrawals 
• Handling of Missing Data 
Section 10.8 
Appendix 8: Values of Potential Clinical Importance 
• Laboratory Values 
• Vital Signs 
Section 10.9 
Appendix 9: Multicentre Studies 
Section 10.10 
Appendix 10: Examination of Covariates and Subgroups 
Section 10.11 
Appendix 11: Multiple Comparisons and Multiplicity 
Section 10.12 
Appendix 12: Model Checking and Diagnostics for Statistical Analyses 
Section 10.13 
Appendix 13: Pharmacokinetic Sub-study Analysis Plan 
Section 10.14 
Appendix 14: ABPM Sub-study Analysis Plan 
Other RAP Appendices 
Section 10.15 
Appendix 15: Abbreviations & Trade Marks 
 
 
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10.1. 
Appendix 1: Protocol Deviation Management and Definitions 
for Per-Protocol Population 
10.1.1. 
Exclusions from Per-Protocol Population 
Exclusions from the PP population include events that, if they should occur, might: 
• 
Directly impact the hemoglobin efficacy endpoint; or 
• 
Lead to permanent discontinuation of study treatment or study withdrawal and hence 
indirectly impact the efficacy endpoint by causing data to be missing. 
The following criteria define the events which, if they occur prior to the end of the EP, 
may lead to exclusion of a subject from the PP population. Exclusions from the PP 
Population will be subject to blinded review by the study team. The study team will also 
review the listing of unique concomitant medication terms to identify the prohibited 
medications. These reviews will occur before database has been unblinded for analysis. 
A subject meeting any of the following criteria may be excluded from the Per-Protocol 
population: 
Number 
Exclusion Description 
01 
Baseline HemoCue Hgb value outside of Randomization (Day 1) Hgb entry criteria 
range 
02 
Less than 5 out of 7 scheduled evaluable1 Hgb values2 from the EP 
03 
Non-compliance with randomized treatment (compliance category of under compliant 
or over compliant) during the EP, based on eCRF randomized medication exposure 
and compliance forms 
04 
Inadequate iron status during EP, defined as ferritin  100 ng/mL on two consecutive 
scheduled visits or TSAT  20% on two consecutive scheduled visits 
05 
Subject received prohibited medication3 for more than two weeks during EP 
NOTES: 
1. See Section 10.6.3. 
2. Based on central laboratory Hgb values. If central laboratory Hgb value is missing, a non-missing 
HemoCue Hgb value will be used.  
3. Prohibited medications include strong inhibitors of CYP2C8 (e.g., gemfibrozil) and strong inducers of 
CYP2C8 (e.g., rifampin/rifampicin). 
 
 
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10.2. 
Appendix 2: Time & Events 
10.2.1. 
Protocol Defined Time & Events 
10.2.1.1. 
Schedule of Assessments Year 1 to End of Study 
Protocol activity (visits ±1 week, except Weeks 2 and 4 
which are ±3 days) 
All assessments pre-dialysis unless otherwise specified 
(Note: All visit timings are relative to Day 1) 
 
Day 1 through Week 52 
Screen 
Week -8 
Run-in 
Week -4 
Day 113 
Week 2 
Full study visit 
Week 4, 16, 28, 
40 
Abbreviated study visit 
Week 8, 12, 20, 24, 32, 36, 
44, 48   
Week 52 Unscheduled10 
Informed consent (main study) 
X22 
 
 
 
 
 
 
 
IRT system transaction17 
X 
X 
X 
X 
X 
X 
X 
X 
Subject reminder, inform site staff of changes in health1 
 
 
X 
 
 
 
X 
 
Check/confirm entry criteria 
X 
 
X 
 
 
 
 
 
History: medical, hospitalization, transfusion 
demography, height 
X 
 
 
 
 
 
 
 
Weight (pre- and post-dialysis for in-center HD subjects; 
between treatments for HHD; at study visits per standard of 
care for PD) and EDW 
X 
X 
X 
X 
X 
X 
X 
X 
SBP/DBP, HR (pre- and post-dialysis for in-center HD 
subjects; between treatments for HHD; at study visits per 
standard of care for PD) (single readings unless otherwise 
indicated) 
X 
X 
X (triplicate) 
X 
X 
X 
X (triplicate) 
X 
Kt/Vurea 18 
 
 
X 
 
X 
 
X 
 
ECG 2 
 
 
X2 
 
 
 
X 
 
Ultrasound of kidneys and adrenal glands  
 
X16 
 
 
 
 
 
 
Placebo run-in or randomized treatment dispensing (start 
administration on date treatment dispensed)19 
 
X 
(placebo) 
X 
X9 
X 
X 
X 
X9 
Placebo run-in or randomized treatment compliance19 
 
 
X (placebo) 
X11 
X 
X 
X 
X11 
Iron therapy, transfusions3 
X 
X 
X 
X 
X 
X 
X 
X 
Rescue medication(s) for Initial Intervention3 ,4  
 
 
 
 
X 
X 
X 
 
Females only: estradiol and FSH (if required)  
X 
 
 
 
 
 
 
 
FRP only:  Serum pregnancy test 5,20 
 
X 
X 
 
X 
 
X 
 
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Protocol activity (visits ±1 week, except Weeks 2 and 4 
which are ±3 days) 
All assessments pre-dialysis unless otherwise specified 
(Note: All visit timings are relative to Day 1) 
 
Day 1 through Week 52 
Screen 
Week -8 
Run-in 
Week -4 
Day 113 
Week 2 
Full study visit 
Week 4, 16, 28, 
40 
Abbreviated study visit 
Week 8, 12, 20, 24, 32, 36, 
44, 48   
Week 52 Unscheduled10 
HemoCue Hgb 
X 
X 
X 
X 
X 
X 
X 
X 
Hematology6   
X 
X 
X 
 
X 
Hgb only  
X 
X 
Clinical chemistry6 
X 
 
X 
 
X 
 
X 
X 
Ferritin, total iron, UIBC 6 
X 
 
X 
 
X 
 
X 
 
Hepcidin   
 
 
X 
 
X 
 
X 
 
HbA1c7, lipids (non-fasting) 
 
 
X 
 
 
 
X 
 
hsCRP, iPTH 
 
 
X 
 
Wk 28 
 
X 
 
Storage biomarkers21  
 
 
X 
 
Wk 28 
 
X 
 
Hospitalization 3, kidney transplant3 
 
 
 
X 
X 
X 
X 
X 
Non-serious AEs, SAEs, AEs of special interest, clinical 
events  
X8 
X 
X 
X 
X 
X 
X 
X 
Review concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
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Schedule of Assessments Year 1 to End of Study (Continued) 
 
Year 2 
Year 3 
Year 4 
Unscheduled10,12 End of  
Study15 
Follow-up 
(4-6 weeks after 
stopping 
randomized 
treatment)  
Protocol activity (visits ±1 week) 
All assessments pre-dialysis unless 
otherwise specified 
(Note: All visit timings are relative to Day 
1) 
Week 
64 
Week 
76 
Week 
88 
Week 
100 
Week 
112 
Week 
124 
Week 
136 
Week 
148 
Week 
160 
Week 
172 
Week 
184 
Week 
196 
Week 
20814 
IRT system transaction17 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Weight (pre- and post-dialysis for in-center 
HD subjects; between treatments for 
HHD; at study visits per standard of care 
for PD) and EDW 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
SBP/DBP, HR (pre- and post-dialysis for 
in-center HD subjects; between 
treatments for HHD; at study visits per 
standard of care for PD) (single readings 
unless otherwise indicated) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
(triplicate)
X 
Kt/Vurea 18 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
ECG 2 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
 
Randomized treatment dispensing (start 
administration on day of dispensing)17,19 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X9 
 
 
Randomized treatment compliance17,19 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X11 
X 
 
Iron therapy, transfusions3 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Rescue medication(s) for Initial 
Intervention 3,4  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
FRP only: serum pregnancy test5,20 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
HemoCue Hgb 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Hematology6 
X 
Hgb 
only 
X 
Hgb 
only 
X 
Hgb 
only 
X 
Hgb 
only 
X 
Hgb 
only 
X 
Hgb 
only 
X 
X 
X 
X 
Clinical chemistry6 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
Ferritin, total iron, UIBC6  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
Hepcidin, HbA1c7, lipids (non-fasting), 
hsCRP 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
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Year 2 
Year 3 
Year 4 
Unscheduled10,12 End of  
Study15 
Follow-up 
(4-6 weeks after 
stopping 
randomized 
treatment)  
Protocol activity (visits ±1 week) 
All assessments pre-dialysis unless 
otherwise specified 
(Note: All visit timings are relative to Day 
1) 
Week 
64 
Week 
76 
Week 
88 
Week 
100 
Week 
112 
Week 
124 
Week 
136 
Week 
148 
Week 
160 
Week 
172 
Week 
184 
Week 
196 
Week 
20814 
iPTH 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Hospitalization3, kidney transplant3 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Non-serious AEs, SAEs, AEs of special 
interest, clinical events  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Review concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
x 
X 
X 
X 
iPTH, intact parathyroid hormone; FSH, follicle stimulating hormone; UIBC, unsaturated iron binding capacity; HbA1c, glycated hemoglobin; hsCRP, high sensitivity C-reactive 
protein; SBP, systolic blood pressure; DBP, diastolic blood pressure; ECG, electrocardiogram; EDW, estimated dry weight 
 
1. 
Health changes include new symptoms or medical problems (e.g., pregnancy, hospitalizations) and changes in medication. 
2. 
Day 1 ECG may be performed as early as the Week -4 visit through the Day 1 visit on a dialysis day (if 3 times/week dialysis, cannot be done on the first dialysis session of the 
week).  If performed on Day 1, it must be pre-dialysis and over-read prior to randomization. All other ECGs assessments may be recorded pre or post dialysis and require over-
reading.  
3. 
Record in eCRF, if applicable. 
4. 
See details on Rescue in Protocol 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 Protocol Appendix 5) during the study pregnancy tests are no longer required. 
6. 
See details on hematology and clinical chemistry in Protocol Section 7.4.11. 
7. 
HbA1c assessment only in subjects with diabetes on Day 1 or diagnosed during the study. 
8. 
Only SAEs assessed as related to study participation or a GSK product are collected at this visit. See Protocol Section 7.4.3.1 for additional details. 
9. 
If dose does not change, then randomized treatment is returned to subject. 
10. If a subject lost their placebo run-in or randomized treatment, it is not necessary to perform the unscheduled visit assessments other than dispensing placebo run-in or randomized 
treatment.  
11. Required only if dose is changed or randomized treatment is dispensed.  Compliance checking will be required when a dose of randomized treatment is changed. 
12. Additional visits to check Hgb and dispense randomized treatment (where directed by the IRT system) are required under the circumstances described in Protocol Appendix 6.  
Hematology and chemistry samples are not required.   
13. All assessments pre-dose. 
14. Further visits every 12 weeks as required. 
15. Investigator will inform subject when to attend this End of Study visit (Protocol Section 6.3.4). 
16. Ultrasound of the kidneys and adrenal glands will be performed as early as 6 weeks prior to the Day 1 visit. If results of kidney and adrenal ultrasound require follow-up testing, 
then the run-in period can be extended by 1 additional week.  A documented ultrasound of the kidneys within the 6 months prior to screening may be used to assess entry criteria, 
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provided the size and cyst category has been reported.  If a more sensitive imaging study [e.g., magnetic resonance imaging (MRI), computed tomography (CT)] has been 
performed within this timeframe and a report is available, this may be used in place of the ultrasound. See Protocol Section 7.4.10. 
17. Treatment will be dispensed every 4±1 weeks; an IRT transaction will be required; perform randomized treatment compliance.  
18. A historical Kt/Vurea measurement within the last 12 weeks can be used.  If a Kt/Vurea measurement is not available, then a urea reduction ratio (URR) measurement is 
acceptable. Kt/Vurea and URR measurements are not required for daily HHD. 
19. In circumstances where the new dose of randomized treatment cannot be dispensed on the day of the study visit, the new dose of randomized treatment can be dispensed at next 
HD treatment. For visits after Day 1, prior randomized treatment should be continued unless on dose hold, Hgb ≥12 g/dL. Compliance is deferred until randomized treatment is 
returned.  
20. For Argentina ONLY:  Pregnancy testing will be performed every 4 weeks for FRP as required by local law. 
21. Biomarker samples will be stored for future analyses for all subjects, except if not permitted by IRB/EC or refused by subject. 
22. Informed consent will be obtained prior to any study procedures.  
 
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10.2.1.2. 
Schedule of Assessments for Patient Reported Outcomes, Genetics and Sub-studies 
Protocol Activity 
(visits ±1 week) 
(Note: All visit timings are relative to 
Day 1) 
Screening 
Day 1 through Week 208 
End of Study 
 
Week -8 Week -4 
Day 1 
Week 4 
Week 8 & 
12 
Week 16, 20 
& 24 
Week 28  
Week 32, 
36, 40, 44, 
48 
Week 52 
Week 100, 
148, 208 
Patient Global Impression of Severity 
(PGI-S)1 
X 
 
X 
 
X 
 
X 
 
X 
 
 
Patient Global Impression of Change 
(PGI-C) 1 
 
 
 
 
X 
 
X 
 
X 
 
 
Short Form 36 (SF-36) 1 
 
 
X 
 
X 
 
X 
 
X 
 
 
EuroQol 5 Dimension 5 Level Health 
Utility Index (EQ-5D-5L) and EuroQol 
Visual Analogue Scale (EQ-VAS) 1, 2 
 
 
X 
 
X 
 
X 
 
X 
X 
X 
Healthcare resource utilization (subject 
reported) 
 
 
  
X 
X 
X 
X 
 
X 
X 
X (& Follow up) 
Genetics sample 3 
 
 
X 
 
 
 
 
 
 
 
 
ABPM sub-study (Appendix 12):  
                           Informed Consent  
X4 
X4 
 
 
 
 
 
 
 
 
 
    Atrial fibrillation/flutter screening 
 
X5 
 
 
 
 
 
 
 
 
 
                               24 hour ABPM 
 
X6 
 
 
 
X (Week 16) 
 
 
 
 
 
    Record awake and sleep times 
 
X7 
 
 
 
X7 (Week 
16) 
 
 
 
 
 
PK sub-study (Appendix 13): 
          Informed Consent 
 
 
X8 
X8 
X8 
X8 
X8 
X8 
X8 
 
 
                             PK assessment 
 
 
 
X9 
X9 
X9 
X9 
X9 
X9 
 
 
1. Subjects who are unable to or require assistance to read must not complete the questionnaires. 
2. Only in selected countries. See Protocol 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 Protocol Section 12.12.3.3) 
6. Baseline ABPM will be performed at any mid-week dialysis visit starting at Week -4 until 1 week prior to randomization (Day 1); the device will be returned at the next visit, which 
ideally is no later than 1 week prior to randomization to allow for QC of the ABPM.  
7. Subject will record sleep and awake times during the ABPM session. 
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8. Informed consent for PK sub-study can be obtained anytime from Day 1 (once the subjects is confirmed to have been randomized to daprodustat) till Week 52, i.e., last study visit 
where PK sampling can be obtained. 
9. Blood samples will be collected at any single study visit from the Week 4 through Week 52 visit (i.e., PK is collected at one visit only, based on convenience for the subject/site).  
 
10.2.1.3. 
Schedule of Assessments for Subjects Permanently Discontinuing Randomized Treatment 
Protocol Activity 
All assessments pre-dialysis unless otherwise specified 
(Note: All visit timings are relative to Day 1) 
Early Treatment Discontinuation 
Visit (within 2 weeks of 
discontinuing randomized 
treatment) 
Day 1 through Week 527 
Week 4, 16, 28, 40, 52 ± 2 weeks 
Unscheduled 
IRT system transaction 
X 
 
 
SBP/DBP, HR (pre- and post-dialysis for in-center HD subjects; 
between treatments for HHD; at study visits per standard of care 
for PD) (single readings unless otherwise indicated) 
X (triplicate) 
X 
X 
ECG 
X 
 
 
Iron therapy, transfusions1 
X 
X 
X 
Serum pregnancy test (FRP only) 
X6 
 
 
HemoCue Hgb 
X 
X 
X 
Hematology3 ,  
X 
X 
Clinical chemistry3  
X 
X 
 
Ferritin, total iron, UIBC, hepcidin, lipids, iPTH 
X 
 
 
Hospitalization1, kidney transplant1 
X 
X 
X 
Non-serious AEs, AEs of special interest, SAEs, clinical events 
X 
X 
X 
Review concomitant medications 
X 
X 
X 
Healthcare resource utilization (subject reported) 
X 
 
 
PGI-S, PGI-C4, 9 
X 
 
 
SF-364, 9 
X 
 
 
EQ-5D-5L& EQ-VAS4, 5, 9 
X 
 
 
ABPM sub-study (Appendix 12):                        24 hour ABPM 
 
X (Week 16) 
 
Record awake and sleep times 
 
X (Week 16)2 
 
Note: see footnotes on next page 
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Schedule of Assessments for Subjects Permanently Discontinuing Randomized Treatment (Continued) 
Protocol activity (visits ± 2 week) 
(Note: All visit timings are relative 
to Day 1) 
Year 27 
Year 37 
Year 47 
Unscheduled
End of  
Study8 
Week 
64 
Week 
76 
Week 
88 
Week 
100 
Week 
112 
Week 
124 
Week 
136 
Week 
148 
Week 
160 
Week 
172 
Week 
184 
Week 
196 
Week 
208 
IRT system call 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
SBP/DBP, HR (pre- and post-
dialysis for in-center HD subjects, 
between treatments for HHD and 
PD subjects) (single readings 
unless otherwise indicated) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
HemoCue Hgb 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Hematology3   
X 
Hgb 
only 
X 
Hgb 
only 
X 
Hgb 
only 
X 
Hgb 
only 
X 
Hgb 
only 
X 
Hgb 
only 
X 
 
X 
Clinical chemistry3  
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Hospitalization1, kidney transplant1 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Non-serious AEs, SAEs, AEs of 
special interest, clinical events  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Review concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
1. Record in eCRF, if applicable. 
2. Subject will record sleep and wake time during the ABPM session. 
3. See details on hematology and clinical chemistry in Protocol Section 7.4.11. 
4. Only completed at Early Treatment Discontinuation visit if the randomized treatment discontinuation occurs on or before Week 52 
5. Only in selected countries. See Protocol Appendix 3. 
6. Additional pregnancy test required at subsequent visit. Must be at least 4 weeks after the end of randomized treatment. 
7. Phone visits are acceptable in exceptional circumstances. 
8. Investigator will inform subject when to attend this End of Study visit.  
9. Subjects who are unable to or require assistance to read must not complete the questionnaires. 
 
 
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10.3. 
Appendix 3: Assessment Windows 
Data for continuous variables that are not related to time-to-event will be summarized 
according to the scheduled visit time period for which they were recorded in the eCRF. 
Unscheduled assessments will not be slotted to a particular time point, but will remain as 
unscheduled if they are either summarized or listed unless otherwise specified (i.e. Hgb 
endpoints described in Section 10.6.3 and BP endpoints described in Section 10.6.4). 
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10.4. 
Appendix 4: Treatment States and Phases 
10.4.1. 
Treatment States 
Assessments and events will be classified according to time of occurrence relative to the 
treatment start and stop dates and last non-zero dose date (see Section 10.6.1). 
10.4.1.1. 
Treatment States for Hgb, Iron Parameters, IV Iron Dose Endpoints, 
Iron Use Summaries, Transfusion and PRO Data 
Treatment State 
Definition 
Pre-Treatment 
Date ≤ Treatment Start Date 
On-Treatment 
Treatment Start Date < Date ≤ Treatment Stop Date + 1 day 
Post-Treatment 
Date > Treatment Stop Date + 1 day 
Post-Randomization 
Randomization Date < Date 
NOTES:  
• 
If the treatment stop date is missing and the treatment start date is non-missing and Date > Treatment Start Date, 
then the assessment will be considered to be On-Treatment 
10.4.1.2. 
Treatment States for CV Endpoint Data 
Treatment State 
Definition 
Pre-Treatment 
Date < Treatment Start Date 
On-Treatment 
Treatment Start Date  Date ≤ Last Non-Zero Dose Date + 28 days 
Post-Treatment 
Date > Last Non-Zero Dose Date + 28 days 
Post-Randomization 
Randomization Date  Date 
NOTES:  
• 
If the last non-zero dose date is missing and the treatment start date is non-missing and Date ≥ Treatment Start 
Date, then the assessment will be considered to be On-Treatment 
• 
Treatment state definitions use the imputed CV endpoint date 
10.4.1.3. 
Treatment States for BP, Lipid Parameters, Clinical Chemistry, 
Hematology, Other Laboratory Tests, Hepatobiliary (Liver) and Vital 
Signs Data 
Treatment State 
Definition 
Pre-Treatment 
Date ≤ Treatment Start Date 
On-Treatment 
Treatment Start Date < Date ≤ Last Non-Zero Dose Date + 1 day 
Post-Treatment 
Date > Last Non-Zero Dose Date + 1 day 
Post-Randomization 
Randomization Date < Date 
NOTES:  
• 
If the last non-zero dose date is missing and the treatment start date is non-missing and Date > treatment start 
date, then the assessment will be considered to be On-Treatment 
10.4.1.4. 
Treatment States for AE Data 
Non-serious AEs and serious AEs are to be recorded on the eCRF starting at the placebo 
run-in phase. Serious AEs assessed as related to study procedures or related to a GSK 
concomitant medication are to be recorded on the eCRF from the time a subject consents 
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to participation in the study. AE of worsening of an on-going event will be counted once 
in a particular treatment state. 
Treatment State 
Definition 
Pre-treatment 
• 
For subjects with a non-missing screen failure date, if AE onset is on or before the 
screen failure date: AE Start Date  Screen Failure Date 
• 
For randomized subjects with a missing treatment start date, all AEs are 
considered pre-treatment 
• 
For randomized subjects with a non-missing treatment start date, if AE onset date 
is before treatment start date: AE Start Date < Treatment Start Date 
Placebo Run-In 
If AE onset date or AE worsening date is on or after placebo run-in treatment start date 
& on or before placebo run-in treatment stop date: 
Placebo Run-in Treatment Start Date  AE Start Date  Placebo Run-in Treatment 
Stop Date 
Placebo Run-in Treatment Start Date  AE Worsening Date  Placebo Run-in 
Treatment Stop Date 
AE worsening during placebo run-in will be defined relative to the maximum intensity of 
AE prior to placebo run-in start date.  
AE worsening date is the first date in the placebo run-in period, when AE intensity 
increased relative to the maximum intensity of the AE prior to placebo run-in start date.  
Post-
randomization 
If AE onset date or AE worsening date is on or after the randomization date 
Randomization date  AE Start Date 
Randomization date  AE Worsening Date 
AE worsening during post-randomization will be defined relative to the maximum 
intensity of AE prior to randomization date.  
AE worsening date is the first date in the post-randomization period, when AE intensity 
increased relative to the maximum intensity of the AE prior to randomization date.  
Treatment 
emergent 
If AE onset date or AE worsening date is on or after treatment start date & on or before 
the last non-zero dose date plus 1 day. 
Treatment Start Date ≤ AE Start Date ≤ Last Non-Zero Dose Date + 1 day 
Treatment Start Date ≤ AE Worsening Date ≤ Last Non-Zero Dose Date + 1 day 
AE worsening during treatment emergent will be defined relative to the maximum 
intensity of AE prior to randomized treatment start date.  
AE worsening date is the first date in the treatment emergent period, when AE intensity 
increased relative to the maximum intensity of the AE prior to randomized treatment 
start date. 
Follow-up 
If AE onset date or AE worsening date is after the last non-zero dose date plus 1 day. 
AE Start Date > Last Non-Zero Dose Date + 1 day 
AE Worsening Date > Last Non-Zero Dose Date + 1 day 
AE worsening during follow-up will be defined relative to the maximum intensity of AE 
prior to randomized treatment start date.  
AE worsening date is the first date in the follow-up period, when AE intensity increased 
relative to the maximum intensity of the AE prior to randomized treatment start date. 
Onset /Worsening 
Time Since 1st 
Dose (Days) 
If Treatment Start Date ˃  AE Onset Date = AE Onset Date - Treatment Start Date 
If Treatment Start Date ≤ AE Onset Date = AE Onset Date - Treatment Start Date +1 
If Treatment Start Date ˃  AE Worsening Date = AE Worsening Date - Treatment Start 
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Treatment State 
Definition 
Date 
If Treatment Start Date ≤ AE Worsening Date = AE Worsening Date - Treatment Start 
Date +1 
Missing otherwise. 
Onset/Worsening 
Time Since Last 
Dose (Days) 
If Last Non-Zero Dose Date  AE onset date: AE onset date – last non-zero dose date 
+1 
If Last Non-Zero Dose Date > AE onset date: AE onset date – last non-zero dose date 
If Last Non-Zero Dose Date  AE worsening date: AE worsening date – last non-zero 
dose date +1 
If Last Non-Zero Dose Date > AE worsening date: AE worsening date – last non-zero 
dose date 
Missing otherwise. 
Duration (Days)  
AE Resolution Date – AE Onset Date/AE Worsening Date + 1 
Drug-related 
If relationship is marked ‘YES’ on eCRF or if the value is missing. 
NOTES:  
• 
AEs that occur or worsen during interruptions of randomized study treatment will be classified as treatment 
emergent and post-randomization. 
• 
If the last non-zero dose date is missing and the treatment start date is non-missing and the AE onset date or AE 
worsening date is on or after the treatment start date, then the AE will be considered to be treatment emergent. 
• 
If AE onset date or AE worsening date is missing and AE resolution date is before the treatment start date, then 
the AE will be classified as Pre-treatment. If the AE resolution date is after the start of placebo run-in, the AE will 
also be considered a Placebo Run-in AE. 
• 
If AE onset date or AE worsening date is missing and AE resolution date is either missing or on or after treatment 
start date, then the AE will be classified as treatment emergent and post-randomization. 
10.4.1.5. 
Treatment States for Concomitant Medications (Other Than IV Iron 
Dose Endpoints and Iron Use Summaries) 
Pre-treatment medications are those taken (i.e., started) before the start date of 
randomized treatment. On-treatment medications are those taken (i.e., started or 
continued) at any time between the randomized treatment start date and the last non-zero 
dose date + 1 day, inclusive. Pre-treatment medications that were continued during this 
on-treatment period are also considered to be on-treatment medications. Post-treatment 
medications are those taken (i.e., started or continued) at any time after the last non-zero 
dose date + 1 day. On-treatment medications that were continued during this post-
treatment period are also considered to be post-treatment medications. Post-
randomization medications are those taken (i.e., started or continued) at any time on or 
after the randomization date. 
It will be assumed that the medication has been taken on the date in which it is reported 
as started or stopped.  Also, for any medication starting on the same date as randomized 
treatment, it will be assumed that the medication was taken after the subject started taking 
randomized treatment. 
Illustrations of the pre-treatment, on-treatment, and post-treatment treatment states are 
included below: 
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Pre-
treatment 
On-treatment 
Post-
treatment 
Pre-
treatment 
medication 
On-
treatment 
medication 
Post-
treatment 
medication 
(a) 
x⎯⎯x 
Randomized Treatment Start Date 
 
Last Non-zero Dose Date + 1 Day 
Last Non-zero Dose Date + 2 Days 
 
Y 
N 
N 
(b) 
x⎯⎯ 
⎯⎯x 
 
Y 
Y 
N 
(c) 
x⎯⎯ 
⎯⎯⎯ 
⎯⎯⎯x 
Y 
Y 
Y 
(d) 
 
x⎯⎯x 
 
N 
Y 
N 
(e) 
 
x⎯⎯ 
⎯⎯⎯x 
N 
Y 
Y 
(f) 
 
 
x⎯⎯x 
N 
N 
Y 
(g) 
?⎯⎯ x 
 
 
Y 
N 
N 
(h) 
?⎯⎯⎯ 
⎯⎯x 
 
Y* 
Y 
N 
(i) 
?⎯⎯⎯ 
⎯⎯⎯ 
⎯⎯⎯x 
Y* 
Y* 
Y 
(j) 
x⎯⎯⎯ 
⎯⎯⎯ 
⎯⎯⎯? 
Y 
Y** 
Y** 
(k) 
 
x⎯⎯ 
⎯⎯⎯? 
N 
Y 
Y** 
(l) 
 
 
x⎯⎯? 
N 
N 
Y 
(m) ?⎯ ⎯⎯ 
 
⎯⎯⎯  
 
⎯⎯⎯? 
Y*** 
Y*** 
Y*** 
(n) 
x⎯⎯⎯ 
x 
 
 
 
 
Y 
Y 
N 
(o) 
?⎯ ⎯⎯ 
x 
 
 
 
 
Y* 
Y 
N 
(p) 
 
x 
⎯⎯x 
 
 
 
N 
Y 
N 
(q) 
 
x 
⎯⎯⎯ 
x 
 
 
N 
Y 
N 
(r) 
 
 
 
x 
⎯ 
⎯⎯⎯x 
N 
Y 
Y 
(s) 
 
 
 
x 
⎯ 
⎯⎯⎯? 
N 
Y 
Y** 
(t) 
 
 
 
 
x 
⎯⎯⎯x 
N 
N 
Y 
(u) 
 
 
 
 
x 
⎯⎯⎯? 
N 
N 
Y 
(v) 
 
 
x⎯⎯ 
⎯ 
x 
 
N 
Y 
Y 
x = start/stop date of medication 
? = missing start/stop date of medication 
* If a medication is stopped On-treatment or Post-treatment and no start date is recorded it will be 
assumed that the medication was ongoing from the Pre-treatment phase 
** If a medication is started Pre-treatment or On-treatment and no stop date is recorded then usage 
will be assumed to be ongoing for the remainder of the study 
*** If a medication has no start or stop date it will be assumed that the medication was ongoing from 
the Pre-treatment phase to the Post-treatment phase 
 
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10.5. 
Appendix 5: Data Display Standards & Handling 
Conventions 
10.5.1. 
Study Treatment & Sub-group Display Descriptors 
Treatment Group Descriptions 
IVWRS  
Data Displays for Reporting  
Code 
Description 
Description 
Order [1] 
A 
Dapro 
Dapro 
1 
B 
rhEPO 
rhEPO 
2 
-- 
-- 
Total 
3 
NOTES: 
1. 
Order represents treatments being presented in TFL, as appropriate. 
10.5.2. 
Baseline Definition & Derivations 
10.5.2.1. 
Baseline Definitions 
For all endpoints (except as noted) the baseline value will be the latest non-missing pre-
dose assessment on or before the randomization date. This is generally expected to be the 
pre-dose value from the Day 1 visit, although such values may be missing. 
Parameter 
Study Assessments Considered As Baseline 
Baseline Used in 
Data Display 
Screen 
Week -8 
Run-in 
Week -4 
Day 1 (Pre-Dose) 
Efficacy 
Hgb 
 
 
X 
Randomization 
Date 
Monthly IV iron1 
 
 
X 
Randomization 
Date 
Iron parameters 
 
 
X 
Randomization 
Date 
Safety 
Subjects who have 
in-clinic HD: dry 
weight, pre-dialysis 
BP parameters, HR, 
and weight 
 
 
X 
Randomization 
Date 
Subjects who have 
in-clinic HD: post-
dialysis BP 
parameters, HR, and 
weight 
 
X 
 
Week -
4/Randomization 
Date 
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Parameter 
Study Assessments Considered As Baseline 
Baseline Used in 
Data Display 
Screen 
Week -8 
Run-in 
Week -4 
Day 1 (Pre-Dose) 
Subjects who do not 
have in-clinic HD: BP 
parameters, HR, 
weight and dry 
weight 
 
 
X 
Randomization 
Date 
Lipid parameters, 
clinical chemistry, 
hematology, other 
laboratory, and 
hepatobiliary (liver) 
tests 
 
 
X 
Randomization 
Date 
PRO 
SF-36 domain and 
component scores 
 
 
X 
Randomization 
Date 
EQ-5D-5L & VAS 
 
 
X 
Randomization 
Date 
PGI-S 
 
 
X 
Randomization 
Date 
NOTES: 
• 
Unless otherwise stated, the mean of replicate assessments at any given time point will be used as the value for 
that time point. 
[1]: Baseline monthly IV iron dose will be defined as total IV iron (mg) over the 16 weeks prior to randomization. See 
Section 10.6.3. 
[2]: Post-dialysis baseline values for subjects with in-clinic dialysis will be defined as the latest non-missing pre-dose 
assessment before the randomization date. This will most often be the value recorded at the Week -4 visit. However, for 
cases where the treatment start date falls after the randomization date, the randomization date will be used as the 
baseline measurement.  
10.5.2.2. 
Derivations and Handling of Missing Baseline Data 
Change from Baseline 
Definition 
Reporting Details 
Change from Baseline 
= Post-Baseline Visit Value – Baseline 
NOTES: 
• 
Unless otherwise specified, the baseline definitions specified in Section 10.5.2 Baseline Definitions will be used 
for derivations for endpoints / parameters and indicated on summaries and listings. 
• 
Unless otherwise stated, if baseline data is missing no derivation will be performed and the change from baseline 
value will be set to missing. 
• 
The baseline definition will be footnoted on all change from baseline displays. 
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Percent Change from Baseline 
Lipid parameters will be log-transformed and the percent change from baseline will be 
reported. Other endpoints may also be log-transformed if deemed appropriate. 
To calculate a geometric mean for baseline measurement or at a specified timepoint, the 
following steps are used: 
1. Log-transform the data points 
2. Calculate the mean and standard error (SE) of the log-transformed data 
3. Exponentiate the mean, (if required, the mean – SE, mean + SE) and the endpoints of 
the confidence interval back to the original scale in order to obtain the geometric 
mean, (the geometric mean – SE, the geometric mean + SE) and the confidence 
interval for the geometric mean. 
4. Coefficient of variation will be calculated as  
1
)
exp(
log
−
=
scale
Var
CV
 100% 
To calculate a geometric mean for the ratio of a specific timepoint to baseline (expressed 
as a percent change from baseline), the following steps are used: 
1. Log-transform the data at both the baseline and the specified timepoint  
2. For each subject, calculate a change from baseline using the log-transformed data 
3. Calculate the mean and standard error (SE) of change from baseline using the log-
transformed data 
4.  Exponentiate the mean, (if required, the mean – SE, the mean + SE), back to the 
original scale and then subtract 1, then multiply everything by 100% in order to 
express the geometric mean, (the geometric mean – SE, the geometric mean + SE) as 
the percent change from baseline. 
So, geometric mean for percent change from baseline = 
     [ Exp(∑ {log(value at specified time point_i) – log(baseline value_i) }/n) – 1 ] x 100, 
Where i = subject, n= total number of subjects, and ∑ represents the sum over all 
subjects. 
To calculate a 95% CI of the geometric mean for the ratio of a specific timepoint to 
baseline (expressed as a percent change from baseline), the following steps are used: 
1. Log-transform the data at both the baseline and the specified timepoint  
2. For each subject, calculate a change from baseline using the log-transformed data 
3. Calculate the mean and standard error (SE) of change from baseline using the log-
transformed data 
4. Calculate the lower and upper limits of the 95% CI of change from baseline using the 
log-transformed data using standardized normal distribution: Mean -/+ z(1- α/2)*SE 
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(z for α=0.05 is obtained through PROBIT function in SAS that is specified as 
PROBIT(0.975)) 
5.  Exponentiate the lower and upper limits of the 95% CI, back to the original scale 
and then subtract 1, then multiply everything by 100% in order to express the 
confidence interval (CI) as the percent change from baseline. 
To calculate the minimum, median and maximum for the ratio of a specific timepoint to 
baseline (expressed as a percent change from baseline), the following steps are used: 
1. Log-transform the data at both the baseline and the specified timepoint  
2. For each subject, calculate a change from baseline using the log-transformed data 
3. Calculate the minimum (median and maximum) of change from baseline using the 
log transformed data. 
4. Exponentiate the minimum (median and maximum), back to the original scale and 
then subtract 1, then multiply everything by 100% in order to express the minimum 
(median and maximum) as the percent change from baseline.  
So, minimum percent change from baseline = 
     [ Exp(min {log(value at specified time point_i) – log(baseline value_i) }) – 1 ] x 100, 
Where i = subject. 
Unless otherwise specified, the baseline definitions specified in Section 10.5.2 will be 
used for derivations for endpoints/parameters and indicated on summaries and listings. 
Unless otherwise specified, if baseline data is missing, no derivation will be performed 
and the % change from baseline value will be set to missing. The baseline definition will 
be footnoted on all change from baseline displays. 
10.5.3. 
Reporting Process & Standards 
Reporting Process 
Software 
• The currently supported versions of SAS software, Version 9.4 (or higher) will be used for all 
analyses unless otherwise specified. Additionally, R Version 3.6.2 or higher may be used for 
analysis and the production of graphics. 
Analysis Datasets  
• Analysis datasets will be created according to clinical data interchange standards consortium 
(CDISC) standards: study data tabulation model (SDTM) implementation guide (IG) Version 
3.1.3 with some updates from Version 3.2, Analysis data model (ADaM) IG Version 1.1, and 
GSK ADaM specification template. 
• For creation of ADaM datasets (ADCM/ADAE), the same version of dictionary datasets will be 
implemented for conversion from system independent (SI) to SDTM. 
Generation of RTF Files 
• Rich text format (RTF) files will be generated. 
 
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Reporting Standards 
General 
• The current GSK Integrated Data Standards Library (IDSL) will be applied for reporting, unless 
otherwise stated: 
o 4.03 to 4.23: General Principles 
o 5.01 to 5.08: Principles Related to Data Listings 
o 6.01 to 6.11: Principles Related to Summary Tables 
o 7.01 to 7.13: Principles Related to Graphics  
Formats 
• GSK IDSL Statistical Principles (5.03 & 6.06.3) for decimal places (DP’s) will be adopted for 
reporting of data based on the raw data collected. 
• Numeric data will be reported at the precision collected on the eCRF. 
• The reported precision from non eCRF sources will follow the IDSL statistical principles but 
may be adjusted to a clinically interpretable number of DP’s.  
Planned and Actual Time 
• Reporting for tables, figures and formal statistical analyses: 
• Planned time relative to randomization will be used in figures, summaries, statistical 
analyses and calculation of any derived parameters, unless otherwise stated. 
• All scheduled visits, regardless of deviation from the planned assessment times and/or 
scheduled visit days will be used in tables, figures and formal statistical analyses unless 
otherwise stated. 
• The derived end of treatment value (see Section 10.6.1) will also be included in displays of 
data by visit. 
• Tables presenting data values by visit will also include values from scheduled visits 
occurring on or before the Day 1 visit, despite the description contained in the title (e.g., 
post-randomization, evaluable, or on-treatment). The description in the title refers to the 
post-randomization values that are included in the table. 
• Reporting for Data Listings:  
• Planned and actual time relative to study drug dosing will be shown in listings (Refer to 
IDSL Statistical Principle 5.05.1). 
• Unscheduled or unplanned readings will be presented within the subject’s listings.  
• Visits outside the protocol defined time-windows (i.e. recorded as protocol deviations) will 
be included in listings. 
Unscheduled Visits 
• Unscheduled visits will not be included in summary tables, with the following exceptions: 
• If the table includes a row for all post-baseline assessments, unscheduled visits will be 
included in this row. 
• Some Hgb endpoints will include unscheduled Hgb values (See Section 10.6.3) 
• Some BP endpoints will include unscheduled BP values (see Section 10.6.4) 
• Unscheduled visits will not be included in figures, with similar exceptions: 
•  If the figure includes a data value for all post-baseline assessments, unscheduled visits will be 
included in this value. 
• Some Hgb endpoints will include unscheduled Hgb values (See Section 10.6.3) 
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Reporting Standards 
• Some BP endpoints will include unscheduled BP values (see Section 10.6.4) 
• All unscheduled visits will be included in listings. 
Descriptive Summary Statistics 
Continuous Data 
Refer to IDSL Statistical Principle 6.06.1 
Categorical Data 
N, n, frequency, % 
Graphical Displays 
• Refer to IDSL Statistical Principals 7.01 to 7.13. 
Adjusted Means 
• SAS option OBSMARGINS will be used to generate all adjusted mean values, e.g. LSMEANS 
statement in relevant SAS procedures will include the OBSMARGINS option (or OM as an 
abbreviation), to weight least square means coefficients of the categorical variables in the 
model to be proportional to those found in the input dataset.  
 
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10.6. 
Appendix 6: Derived and Transformed Data 
10.6.1. 
General 
Multiple Measurements at One Time Point 
• Mean of the measurements will be calculated and used in any derivation of summary statistics 
but if listed, all data will be presented. 
o Triplicate BP and HR measurements are expected at certain time points (See 
Section 10.2.1) 
• Subjects having both High and Low values for Normal Ranges at any post-baseline visits for 
safety parameters will be counted in both the High and Low categories of “Any visit post-
baseline” row of related summary tables. This will also be applicable to relevant Potential 
Clinical Importance summary tables. 
Randomization Date 
• Date subject was randomized 
Treatment Start Date 
• First randomized treatment dose start date 
Last Non-Zero Dose Date 
• Date of last actual dose of randomized study treatment from the IP Discontinuation eCRF form. 
o The dose steps used by the dosing algorithm described in the protocol include a 
dose hold or a zero dose. If subjects are assigned by the algorithm to a zero dose, 
they do not receive randomized treatment for that period. Hence, it would be 
possible for a subject to complete the study, while still following the dosing 
algorithm, but not be actually taking any actual randomized treatment. The last 
non-zero dose date, then captures the latest date in the study that a subject 
physically took a dose of randomized treatment. 
• The eCRF allows for the possibility of partial or missing dates to be recorded for the last actual 
dose of randomized study treatment on the IP Discontinuation form (i.e., missing day, or day 
and month, or day and month and year). In such a case, or in case of subjects who have a 
non-missing treatment start date, but are a missing an IP Discontinuation form, the following 
conventions will be applied in order to impute a last non-zero dose date: 
o Missing day: 
▪ The last day of the month will be used, unless the treatment stop date also 
occurs in the same month; in this case, the treatment stop date will be 
used. 
o Missing day and month; 
▪ ‘31’ will be used for the day and ‘Dec’ will be used for the month, unless 
the treatment stop date also occurs in the same year; in this case the 
treatment stop date will be used. 
o Missing day, month, and year: 
▪ Treatment stop date will be used only for subjects who have a non-
missing treatment start date. 
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Treatment Stop Date 
• Calculated as the latest randomized treatment dose stop date, for subjects who have a non-
missing treatment start date. Note that this date could come from a randomized treatment 
exposure record with a missing or partial dose stop date if the associated dose start date for 
that exposure record is on or after the last non-missing randomized treatment dose stop date. 
• The eCRF allows for the possibility of missing or partial dates to be recorded for the dose stop 
date on the study treatment form (i.e., missing day, or day and month, or day and month and 
year). In such a case, the following conventions will be applied in order to impute a treatment 
stop date: 
o Missing day: 
▪ The last day of the month will be used, unless the study completion or 
withdrawal date also occurs in the same month; in the case, the study 
completion or withdrawal date will be used. 
o Missing day and month: 
▪ ‘31’ will be used for the day and ‘Dec’ will be used for the month, unless 
the study completion or withdrawal date also occurs in the same year; in 
this case, the study completion or withdrawal date will be used. 
o Missing day, month and year: 
▪ The study completion or withdrawal date will be used only for subjects 
who have a non-missing treatment start date. 
End of Treatment Value 
• Only defined for subjects with a non-missing treatment start date 
• Hgb, iron, transfusion and PRO parameters: the latest value on or before the treatment 
stop date + 1 day. 
• Blood pressure, central laboratory, and vital signs parameters: the latest value on or before 
the last non-zero dose date + 1 day. 
Study Completion/Withdrawal Date 
• Date of withdrawal for subjects withdrawing (i.e., subjects who actively withdraw or are 
deemed lost to follow-up) from study or date of completion of study for subjects who 
complete the study. If the date of study withdrawal entered in the eCRF is before the last 
study contact date, the last study contact date will be used as the study withdrawal date for 
analysis. 
 
• Note: Subjects who die while on study are considered as having completed the 
study 
• The eCRF allows for the possibility of missing or partial dates to be recorded for the study 
completion/withdrawal date on the Study Conclusion form (i.e., missing day, or day and 
month, or day and month and year). In such a case, or in case of subjects who are missing 
a Study Conclusion form, the following conventions will be applied in order to impute a 
study completion/withdrawal date: 
• Missing day: 
▪ The last day of the month will be used, unless the last study contact date 
also occurs in the same month; in the case, the last study contact date will 
be used. 
 
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o Missing day and month: 
▪ ‘31’ will be used for the day and ‘Dec’ will be used for the month, unless 
the last study contact date also occurs in the same year; in this case, the 
last study contact date will be used. 
o Missing day, month and year: 
▪ The last study contact date will be used. 
Planned/Actual Visit Dates 
• Planned/actual visit dates will be defined as follows: 
o Week 28 date: Non-missing Week 28 visit start date (from SV domain), otherwise 
randomization date + 28*7 
o Week 36 date: Non-missing Week 36 visit end date (from SV domain), otherwise 
randomization date + 36*7 
o Week 52 date: Non-missing Week 52 visit end date (from SV domain), otherwise 
randomization date + 52*7 
o End of Study date: Non-missing End of Study visit end date (from SV domain), 
otherwise the middle of the End of Study window. 
Stabilization Period 
• Defined as the period between and including the randomization date + 1 day - <Week 28 
visit, using planned/actual dates. 
Alternative Evaluation Period (Alt. EP) 
• Defined as the period between and including Week 28 visit – Week 36 visit, using 
planned/actual dates.  
Evaluation Period (EP) 
• Defined as the period between and including Week 28 visit – Week 52 visit, using 
planned/actual dates. 
Maintenance Period (MP) 
• Defined as the period between and including Week 28 visit – End of Study visit, using 
planned/actual dates. 
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Study Day 
• Calculated as the number of days from randomization date: 
• Ref Date = Missing                       → Study Day = Missing  
• Ref Date < Randomization Date   → Study Day = Ref Date – Randomization Date     
• Ref Date ≥ Randomization Date   → Study Day = Ref Date – (Randomization Date) + 1     
Treatment Day 
• Calculated as the number of days from treatment start date: 
• Treatment Start Date = Missing        → Treatment Day = Missing  
• Ref Date < Treatment Start Date      → Treatment Day = Ref Date – Treatment Start Date    
• Ref Date ≥ Treatment Start Date      → Treatment Day = Ref Date – (Treatment Start 
Date) + 1     
Last Study Contact Date 
• Latest visit date from an unscheduled visit or a clinic, telephone, designated third party, 
healthcare provider or medical records, other, or other contact with subject (mail, email, text, 
social media, etc.) visit. 
Time Definitions (per GSK standard principles) 
• 1 week = 7 days 
• 1 month = 30.4375 days 
• 1 year = 365.25 days 
Production of Two-Sided p-values 
• The majority of the efficacy and safety analyses in this study will use one-sided 2.5% p-values 
to assess statistical significance. Should two-sided p-values be required for publication 
purposes after the study is complete, the corresponding two-sided p-values will be produced at 
that time. 
Last Known Alive Date 
• The last know alive date for a subject in the study will be defined as the latest of the following 
dates: 
o The date of the last visit in the clinic 
o Last date recorded when the subject was last known alive  
o For the non-clinic visit, the last clinic information assessment date 
10.6.2. 
Study Population 
10.6.2.1. 
Subject Disposition 
Subject Disposition 
Screen Failures 
• Screen failures are defined as subjects who consent to participate in the clinical trial but are not 
subsequently randomized.  
o At the time of screening closure, there may have been subjects who had been 
consented but had not been entered into the eCRF. These subjects are not 
included in the clinical database but will be noted in a footnote on the Summary of 
Screening Status and Reasons for Screen Failures. 
• Any subject that consented, was entered into the eCRF, and was not randomized, but is 
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missing a screen failure record will have the following values imputed: 
o Was this subject a screen failure? = Yes 
o Reason for screen failure = Missing 
Randomized Treatment Discontinuation 
• Any randomized subject with a non-missing treatment start date that is missing an IP 
Discontinuation eCRF will have the following values imputed: 
o Date of last dose = See Last Non-Zero Dose Date in Section 10.6.1 
o Was the study treatment stopped permanently before the scheduled end of the 
treatment period? = Yes 
o Primary reason the treatment was stopped = Missing 
Study Completers/Withdrawals 
• Any randomized subject that is missing Study Conclusion eCRF will have the following values 
imputed: 
o Date of subject completion or withdrawal? = See Study Completion/Withdrawal 
Date in Section 10.6.1 
o Was the subject withdrawn from the study? = Yes 
o Primary reason for study withdrawal = Missing 
 
Subjects Completion Status 
Known Cardiovascular Endpoint Status at End of Study 
The following scenarios will be considered as known CV endpoint status at End of Study: 
• Subjects who die during the study 
• Subjects who attend a clinic visit within the EOS window  
• For the following non-clinic EOS visits, eCRF Visit Contact Details page indicates that a clinical 
events assessment was able to be performed and date clinical information was assessed is 
within the EOS window. 
o Telephone contact with subject 
o Other contact with subject (mail, email, text, social media, etc.) 
o Designated third party (e.g. family member, caretaker) 
o Health care provider or medical records 
Unknown Cardiovascular Endpoint Status at End of Study 
The following scenarios will be considered as incomplete CV endpoint status at End of Study: 
• Subjects who withdraw from the study 
• EOS visit type =  
o no contact able to be made for this visit 
o survival status search performed but could not confirm that the subject was alive 
or dead 
o Publicly available sources (e.g., public registry, newspaper)  
o Other, specify 
• For the following non-clinic EOS visits, eCRF Visit Contact Details page indicates that a clinical 
events assessment was not able to be performed or date clinical information was assessed is 
before the EOS window: 
o Telephone contact with subject 
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o Other contact with subject (mail, email, text, social media, etc.) 
o Designated third party (e.g. family member, caretaker) 
o Health care provider or medical records 
• eCRF Visit Contact Details page is missing information to determine if a clinical events 
assessment was performed or the date it was performed. 
Known Vital Status at End of Study 
The following scenarios will be considered as known vital status at End of Study: 
• Subjects who die during the study, or have a death date 
• Subjects who attend a clinic visit within the EOS window  
• For the following non-clinic EOS visits, latest date subject last known to be alive is within or 
after the EOS window. 
o Telephone visit 
o Other contact with subject (mail, email, text, social media, etc.) 
o Designated third party (e.g. family member, caretaker) 
o Health care provider or medical records 
o Publicly available sources (e.g., public registry, newspaper) 
o Other, specify 
• For subjects who withdraw from the study, the latest date subject last known to be alive is 
within or after the EOS window. 
Unknown Vital Status at End of Study 
The following scenarios will be considered as unknown vital status at End of Study: 
• For subjects who withdraw from the study, the latest date subject last known to be alive is 
missing or before the EOS window; 
• EOS visit type = no contact able to be made for this visit (LTFU subjects only); 
• EOS visit type = survival status search performed but could not confirm that the subject was 
alive or dead (LTFU subjects only); 
• For the following non-clinic EOS visits, latest date subject last known to be alive is missing or 
before the EOS window. 
o Telephone visit 
o Other contact with subject (mail, email, text, social media, etc.) 
o Designated third party (e.g. family member, caretaker) 
o Health care provider or medical records 
o Publicly available sources (e.g., public registry, newspaper) 
o Other, specify 
 
10.6.2.2. 
Demographic & Baseline Characteristics 
Demographic & Baseline Characteristics 
Age 
• GSK standard IDSL algorithms will be used for calculating age where birth date will be imputed 
as follows: 
o Any subject with a missing day will have this imputed as day ‘15’.  
o Any subject with a missing date and month will have this imputed as ‘30th June’. 
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• Birth date will be presented in listings as ‘YYYY’. 
High Level Race 
• Geographic ancestry data will be combined into the following high level race categories: 
o American Indian or Alaskan Native 
o Asian (Asian-East Asian Heritage, Asian-Japanese Heritage, Asian-Central/South 
Asian Heritage, Asian-South East Asian Heritage, Mixed Asian Race) 
o Black or African American  
o Native Hawaiian or Other Pacific Islander 
o White (White-Arabic/North African Heritage, White-White/Caucasian/European 
Heritage, Mixed White Race) 
o Mixed Race (Multiple high level races are selected) 
Note: A subject will only be counted in one category. Mixed Asian Race includes subjects who 
have more than one Asian category selected, but no other categories. Mixed White Race includes 
subjects who have more than one White category selected, but no other categories. 
Race Detail 
• Geographic ancestry data will be combined into race detail categories: 
o American Indian or Alaskan Native 
o Asian-Central/South Asian Heritage 
o Asian-East Asian Heritage 
o Asian-Japanese Heritage 
o Asian-South East Asian Heritage 
o Mixed Asian Race (Only display if data exists) 
o Black or African American (African American/African Heritage) 
o Native Hawaiian or Other Pacific Islander 
o White-Arabic/North African Heritage 
o White-White/Caucasian/European Heritage 
o Mixed White Race (Only display if data exists) 
o Mixed Race (Multiple high level races are selected; only display if data exists) 
Note: A subject will only be counted in one category. Mixed Asian Race includes subjects who 
have more than one Asian category selected, but no other categories. Mixed White Race includes 
subjects who have more than one White category selected, but no other categories. 
Dialysis Type at Randomization 
• Dialysis type at randomization will use the subject’s randomization date and the dialysis type 
information recorded on the Dialysis History and Dialysis Changes eCRF pages to determine 
the dialysis type on the randomization date and will be summarized as follows: 
o HD (which includes: HD – conventional and HDF/HF) 
o PD 
o Missing 
Prior ESA Type and Standardized Prior ESA Dose (U/week) at Randomization 
• During the screening period, subjects may be receiving ESAs in multiple ways, including: 
epoetin IV or SC, darbepoetin IV or SC, or methoxy PEG-epoetin beta IV or SC.  
• A subject’s prior ESA type will be determined from the records that contribute to the subject’s 
standardized prior ESA dose. The following categories of prior ESA type will be summarized: 
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o Darbepoetin alfa only 
o Epoetin only 
▪ This group contains subjects using any of the following types of epoetin: 
epoetin alfa, epoetin beta, epoetin lambda, epoetin theta, and epoetin 
zeta. 
o Methoxy PEG-epoetin beta only 
▪ This group contains subjects using methoxy PEG-epoetin beta and 
pegzerepoetin alfa. 
o Multiple 
▪ This group contains subjects using any combination of the ESA types. 
o Missing 
 
• The dose of ESA will be standardized to obtain a continuous single unit prior ESA dose in 
terms of epoetin IV U/week for the period from the Week -8 visit to the day before the 
Randomization date. 
 
• All prior ESA therapy concomitant medication records from screening/run-in will be selected 
and ordered by start date and end date. 
 
• The standardization will be carried with the following formula: 
• For subjects taking epoetin IV: 
o Standardized ESA dose (U/week) = epoetin IV dose (U)*frequency 
• For subjects taking epoetin SC: 
o Standardized ESA dose (U/week) = (161/113)*epoetin SC dose(units)*frequency 
• For subjects taking darbepoetin IV or SC: 
o Standardized ESA dose (U/week) = 250*darbepoetin dose (g)*frequency 
• For subjects taking methoxy PEG-epoetin beta: 
o Standardized ESA dose (U/week) = 208*methoxy PEG-epoetin beta dose 
(g)*frequency 
 
Note: Frequency and Gap Factors defined as follows: 
 
Frequency (from eCRF) 
Frequency 
(for standardization formula) 
Gap Factor 
One time dose 
see below 
n/a 
Four times per week 
4 
0.75 day 
Three times per week 
3 
1.33 days 
Two times per week 
2 
2.5 days 
Every week 
1 
6 days 
Every 10 days 
0.70 
9 days 
Every 2 weeks 
0.50 
13 days 
Every 3 weeks 
0.33 
20 days 
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Every 4 weeks 
0.25 
27 days 
Every 5 weeks 
0.20 
34 days 
Every 6 weeks 
0.167 
41 days 
Every 8 weeks 
0.125 
55 days 
 
• If the frequency of the record is not ‘one time dose’, then duration is calculated as follows: 
o If the concomitant medication record start date  Randomization date, the duration of 
the record is 0. 
o If the concomitant medication record end date + gap factor < Week -8 visit date, the 
duration of the record is 0.  
o If the concomitant medication record end date + gap factor ≥ Week -8 visit date, the 
duration of a record will be calculated as Stop Date – Start Date +1 day, where: 
▪ Start date will be the latest of (concomitant medication record start date and 
the Week -8 visit date). 
▪ Stop date will be the concomitant medication record end date + gap factor. 
• If the frequency of the record is ‘one time dose’, then: 
o If the concomitant medication record start date  Randomization date, the duration of 
the record is 0. 
o If Week -8 visit date ≤ concomitant medication record start date, then: 
▪ Frequency (for standardization formula) = 1 
▪ Duration = 7 days 
o If concomitant medication record start date < Week -8 visit date, then: 
▪ Frequency (for standardization formula): 7/ [earliest of (the day before the next 
sequential prior ESA concomitant medication record start date and the day 
before randomization) – start date of record + 1 day] 
▪ If the earliest non-missing date of (the day before the next sequential prior 
ESA concomitant medication record start date and the day before 
randomization) < Week -8 visit date, the duration of the record is 0. 
▪ If the earliest non-missing date of (the day before the next sequential prior 
ESA concomitant medication record start date and the day before 
randomization)  Week -8 visit date, the duration of the record is calculated as 
Stop Date – Start Date + 1, where: 
• Start date will be the Week -8 visit date. 
• Stop date will be the earliest of (the day before the next sequential 
prior ESA concomitant medication record start date and the day 
before randomization) 
 
• The total dose for each prior ESA record will be: Standardized dose*duration/7days 
 
• A weighted mean will then be used to obtain the prior ESA dose: 
Mean prior ESA dose = [(ESA total doseRecord 1) + ... + (ESA total doseRecord n)]/[( 
Randomization Date – Week -8 Visit Date)/7days] 
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Baseline Erythropoietin Resistance Index (ERI, U/kg/wk/g/L) 
• Calculated by dividing the standardized prior ESA dose (U/week) at randomization by the 
baseline estimated dry weight (in kg) and then dividing by the achieved Day 1 Hgb (in g/L). 
• Note: the central laboratory Hgb value from Day 1 should be used to calculate ERI, however if 
this value is missing and there is a corresponding non-missing HemoCue Hgb value available, 
the Day 1 HemoCue Hgb value will be used. 
rhEPO Hyporesponders 
• A subject will be considered to be a hyporesponder if:  
o ERI ≥ 2.0 U/kg/wk/g/L  
Or 
o Prior ESA dose (U/week) at baseline divided by the baseline estimated dry weight 
(in kg)  450 U/kg/week 
• Note: an ERI ≥ 2.0 U/kg/wk/g/L for epoetin-treated subjects corresponds to an ERI 
≥0.008μg/kg/wk/g/L for darbepoetin-treated subjects and 0.01 g/kg/wk/g/L for methoxy-
PEG-epoetin-treated subjects.  
• Supportive analyses will be used in the summary of demographics and baseline characteristics 
and will use the following alternative hyporesponder definitions:  
1) an ERI cut-point of ≥ 1.5 U/kg/wk/g/L only 
2) subjects with prior ESA dose (U/week) at baseline in the top 20th percentile of the 
randomized study population. 
Baseline Post-Dialysis Body Mass Index (BMI) 
• Calculated as baseline post-dialysis weight (kg) / [height (m)]2 
Dosing Algorithm at Randomization 
• Protocol Amendment 3 updated the dosing algorithm used to assign doses of randomized 
treatment to subjects in both treatment arms. The number of subjects randomized under the 
original algorithm and under the updated algorithm will be summarized. 
• A subject’s randomization date will be compared to the site-specific ethics 
committee/regulatory protocol amendment approval date for their site. This date is stored in the 
IRT system as the Site Level Amendment Flag Date for each site.  
• Subjects randomized before their site’s non-missing Site Level Amendment Flag Date or who 
have a missing Site Level Amendment Flag Date will be considered to have been randomized 
under the original algorithm, and subjects randomized on or after their site’s non-missing Site 
Level Amendment Flag Date will be considered to have been randomized under the updated 
algorithm. 
Cardiovascular Risk Score 
A risk score for two-year cardiovascular mortality and morbidity in a hemodialysis population has 
been developed [Anker, 2016] and will be calculated at baseline for each HD participant. 
 
The following table describes how the published risk score is calculated*: 
 
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*For the intradialytic weight change (kg) parameter, a value of ≥-1.2kg will have a risk score of 0 points. 
 
It should be noted that creatinine is not routinely collected in this study and will be assumed to be 
the same in all HD participants (i.e. <436, resulting in 3 risk score points).   
 
CVD history is defined as having a yes response to any of the following medical history conditions: 
angina pectoris, myocardial infarction, stroke, coronary artery disease, transient ischaemic attack, 
heart failure, atrial fibrillation, cardiac arrest, valvular heart disease. 
 
Intradialytic weight change will be calculated using the Week -4 post-dialysis weight in kg – the 
Week -4 pre-dialysis weight in kg. 
 
Baseline Hgb categories will be defined based on g/dL units (i.e. <10, 10-<12 and ≥12) and will 
use central laboratory Hgb values if available. If a baseline central laboratory Hgb value is not 
available, a baseline HemoCue Hgb value will be used.  
 
Risk score points for CKD aetiology will be determined based on the following approach: 
i. 
Participants with diabetic renal disease are assigned 4 points 
ii. 
All other participants who have hypertensive renal disease are assigned 1 point 
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iii. 
All other participants who have interstitial nephritis are assigned -1 point 
iv. 
All other participants who have a medical history of polycystic kidney, autosomal dominant 
or do not have any of these medical history terms selected are assigned 0 points 
 
The overall CV risk score is determined by summing up the individual risk scores for the 11 risk 
factors. 
History of Diabetes 
• Subjects are considered to have a history of diabetes if they have a yes response to at least 
one record of the medical history terms that contains "Diabetic" or "Diabetes" except anything 
containing non-diabetic or variations relating to it (e.g. nondiabetic and other spellings) and 
also: 
o DIABETES INSIPIDUS,  
o NEPHROGENIC DIABETES INSIPIDUS 
• If subjects have indicated that they do not have any of the listed diabetic medical history 
conditions above, they are considered not to have a history of diabetes. 
• If subjects have not been classified as either having or not having a history of diabetes and are 
missing a response to any of the listed medical history conditions, their diabetes history status 
will be missing. 
History of Stroke 
• Subjects are considered to have a history of stroke if they have a yes response to the stroke 
medical history condition. 
• Subjects who have indicated that they do not have a history of stroke will be summarized 
accordingly. 
• If a subject is missing a response to the stroke medical history condition, their stroke history 
status will be missing. 
History of MI 
• Subjects are considered to have a history of MI if they have a yes response to either of the 
following medical history conditions: myocardial infarction, cardiac arrest. 
• Subjects who have indicated that they do not have a medical history of myocardial infarction or 
cardiac arrest will be considered not to have a history of MI. 
• If subjects have not been classified as either having or not having a history of MI, and are 
missing a response to either the myocardial infarction or cardiac arrest medical condition, their 
MI history status will be missing. 
History of Cancer 
• Subjects are considered to have a history of cancer if they have a yes response to either of the 
following medical history conditions: neoplasms malignant or unknown/unspecified, allogenic 
bone marrow transplant. 
• Subjects who have indicated that they do not have a medical history of neoplasms malignant or 
unknown/unspecified or allogenic bone marrow transplant will be considered not to have a 
history of cancer. 
• If subjects have not been classified as either having or not having a history of cancer and are 
missing a response to either the neoplasms malignant or unknown/unspecified or allogenic 
bone marrow transplant medical condition, their cancer history status will be missing. 
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History of Heart Failure 
• Subjects are considered to have a history of heart failure if they have a yes response to any of 
the following medical history conditions: heart failure, left ventricular systolic dysfunction, left 
ventricular diastolic dysfunction, pulmonary hypertension. 
• Subjects who have indicated that they do not have a medical history of any of the terms listed 
above will be considered not to have a history of heart failure. 
• If subjects have not been classified as either having or not having a history of heart failure and 
are missing a response to any of the medical condition terms listed above, their heart failure 
history status will be missing. 
History of Thromboembolic Events 
• Subjects are considered to have a history of thromboembolic events if they have a yes 
response to any of the following medical history conditions: pulmonary embolism, deep vein 
thrombosis, retinal vein occlusion, arteriovenous graft thrombosis, arteriovenous fistula 
thrombosis, central venous catheter thrombosis. 
• Subjects who have indicated that they do not have a medical history of any of the terms listed 
above will be considered not to have a history of thromboembolic events. 
• If subjects have not been classified as either having or not having a history of thromboembolic 
events and are missing a response to any of the medical condition terms listed above, their 
thromboembolic event history status will be missing. 
History of Cardiovascular Disease 
• Subjects are considered to have a history of cardiovascular disease if they have a yes 
response to any of the following medical history conditions: angina pectoris, myocardial 
infarction, stroke, coronary artery disease, transient ischaemic attack, heart failure, atrial 
fibrillation, cardiac arrest, valvular heart disease. 
• Subjects who have indicated that they do not have a medical history of any of the terms listed 
above will be considered not to have a history of cardiovascular disease. 
• If subjects have not been classified as either having or not having a history of cardiovascular 
disease and are missing a response to any of the medical condition terms listed above, their 
cardiovascular disease history status will be missing. 
Baseline Iron Use & Standardized Baseline IV Iron Dose 
• See Section 10.6.3. 
Dialysis Access Type Used at Randomization 
• Dialysis access type at randomization will use the subject’s randomization date and the dialysis 
access type information recorded on the Dialysis Access History and Dialysis Access Changes 
eCRF pages to determine the dialysis access type on the randomization date and will be 
summarized as follows: 
o Arteriovenous fistula 
o Arteriovenous graft 
o Central venous catheter – tunneled 
o Central venous catheter – non-tunneled 
o Peritoneal catheter 
o Other 
o Missing 
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Phosphate Binder Use at Randomization 
• Phosphate binder use at randomization will be summarized as follows: 
o Iron-based phosphate binders 
o Calcium-based phosphate binders 
o Non-calcium and non-iron based phosphate binders 
o No phosphate binder use 
• Subjects will be counted in each applicable group, based on the concomitant medications they 
are receiving on the day of randomization. 
Concomitant Medication Use at Randomization 
• Concomitant medication records on the day of randomization will be used to determine the 
following classifications of concomitant medication use at randomization: 
o ACEI/ARB 
o Vitamin D 
o Beta blockers 
o SGLT2i 
o Statin 
o Aspirin 
o Vitamin K 
o Insulin 
o Calcimimetics 
o Diabetic medication 
10.6.2.3. 
Randomized Treatment Discontinuation, Study Withdrawal and 
Possible Follow-up Time 
Randomized Treatment Discontinuation, Study Withdrawal, and Possible Follow-up Time 
Randomized Treatment Discontinuation 
• Randomized Treatment Discontinuation Censored Time (days) = Treatment stop date – 
Treatment start date +1 
If the treatment stop date = death date for a subject, the subject will be censored and will not be 
counted as an event for treatment discontinuation summaries that exclude subjects who die while 
on treatment. 
• Time to Randomized Treatment Discontinuation (days) = Treatment stop date – Treatment 
start date +1 
• Randomized Treatment Person Years = (Cumulative total of time to randomized treatment 
discontinuation for subjects who discontinued randomized treatment + Cumulative total of 
randomized treatment discontinuation censoring time for subjects who did not discontinue 
randomized treatment) / 365.25 
• Randomized Treatment Discontinuation Incidence Rate (per 100 person years) = 100* Number 
of subjects who discontinued randomized treatment / randomized treatment person years 
Study Withdrawal 
• Study Censored Time (days) = Study completion date – Randomization date +1 
• Time to Study Withdrawal (days) = Study withdrawal date – Randomization date +1 
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Randomized Treatment Discontinuation, Study Withdrawal, and Possible Follow-up Time 
• Study Person Years = (Cumulative total time to study withdrawal for subjects withdrawing from 
the study + Cumulative total of study censoring time for subjects who did not withdraw from 
study) / 365.25 
• Study Withdrawal Incidence Rate (per 100 person years) = (100 * Number of subjects who 
have withdrawn from study) / Study Person Years 
Possible Follow-up Time 
• Possible follow-up time (days) = Study completion date or date of the middle of the end of 
study window for subjects who did not complete the study – randomization date + 1 
• Total possible follow-up time (person years) = Cumulative total of possible follow-up time 
(days) for all subjects / 365.25 
10.6.2.4. 
Prior and Concomitant Medications 
Prior and Concomitant Medications 
Non-randomized ESA use during treatment period 
• Subjects will be considered to have non-randomized ESA use during the treatment period if 
they have any ESA concomitant medication records with one of the following two reasons for 
medication: 
o Non-randomized ESA treatment in addition to randomized treatment 
o Non-randomized ESA treatment instead of randomized treatment 
Duration of non-randomized ESA use during treatment period 
• If there is only one concomitant medication record of non-randomized ESA use during the 
treatment period, then: 
o Duration (days) = earliest of (concomitant medication record end date, last non-
zero dose date + 1 day) – latest of (concomitant medication start date, treatment 
start date) + 1 day 
• If there are multiple concomitant medication records of non-randomized ESA use during the 
treatment period, then the duration of non-randomized ESA use will add the durations for all 
records, subtracting any overlapping days that may exist between the multiple records. 
Clopidogrel start date for new clopidogrel users 
• New clopidogrel users are subjects who did not use clopidogrel on randomization day, but 
started their clopidogrel use after randomization during the on-treatment state for concomitant 
medications. To determine the start date of clopidogrel for the new users, only the first 
clopidogrel record during the on-treatment state for concomitant medications will be 
considered. The start date will be the first day subjects on both clopidogrel and randomized 
treatment. 
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10.6.2.5. 
Exposure and Compliance 
Exposure and Compliance 
Exposure 
• Exposure (days) = Treatment stop date – treatment start date + 1 day 
Compliance 
• Compliance will be calculated based on data recorded in the Study Treatment Details 
eCRF pages and will only be calculated for subjects with a non-missing treatment start 
date, and will not be calculated after a subject’s treatment stop date, or study conclusion 
date for subjects who have a non-missing treatment start date and a missing treatment 
stop date. 
• A compliance category will be assigned to each randomized treatment exposure record 
according to the following tables. Exposure records corresponding to periods of dose 
hold/zero-dose as assigned by the IRT will be categorized in the compliant category and 
any gaps between exposure records will be categorized in the under compliant category. 
o Daprodustat Doses 
Under Compliant 
Compliant 
Over Compliant 
Compliance for the 
exposure record < 
80% 
Compliance for the 
exposure record  
80% and  120% 
Compliance for the 
exposure record > 
120% 
Where compliance for the exposure record is calculated as 100% * 
[# dispensed – (# returned + # lost)] / # tablets per day / (dose stop 
date – dose start date +1) 
# tablets per day: 
1 tablet per day: 1mg, 2mg, 4mg, 6mg, 8mg, 10mg 
2 tablets per day: 12mg, 16mg 
3 tablets per day: 24mg 
 
o rhEPO Every 4 Week Exposure Records: Based on Number of Doses Given 
Duration of 
Exposure Record 
Under Compliant 
Compliant 
Over Compliant 
1 – 14 days 
< 1 dose 
1 dose 
> 1 dose 
15 – 42 days 
< 1 dose 
1 or 2 doses 
> 2 doses 
43 – 70 days 
< 2 doses 
2 or 3 doses 
> 3 doses 
71 – 98 days 
< 3 doses 
3 or 4 doses 
> 4 doses 
99 – 126 days 
< 4 doses 
4 or 5 doses 
> 5 doses 
Etc. 
 
 
 
 
o rhEPO Every 2 Week Exposure Records: Based on Number of Doses Given 
Duration of 
Exposure Record 
Under Compliant 
Compliant 
Over Compliant 
1 – 7 days 
< 1 dose 
1 dose 
> 1 dose 
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8 – 21 days 
< 1 dose 
1 or 2 doses 
> 2 doses 
22 – 35 days 
< 2 doses 
2 or 3 doses 
> 3 doses 
36 – 49 days 
< 3 doses 
3 or 4 doses 
> 4 doses 
50 – 63 days 
< 4 doses 
4 or 5 doses 
> 5 doses 
64 – 77 days 
< 5 doses 
5 or 6 doses 
> 6 doses 
78 – 91 days 
< 6 doses 
6 or 7 doses 
> 7 doses 
92 – 105 days 
< 7 doses 
7 or 8 doses 
> 8 doses 
Etc. 
 
 
 
 
o rhEPO Every Week Exposure Records: Based on Number of Doses Given 
Duration of 
Exposure Record 
Under Compliant 
Compliant 
Over Compliant 
1 – 3 days 
< 1 dose 
1 dose 
> 1 dose 
4 – 10 days 
< 1 dose 
1 or 2 doses 
> 2 doses 
11 days 
< 1 dose 
1 or 2 or 3 doses 
> 3 doses 
12 – 17 days 
< 2 doses 
2 or 3 doses 
> 3 doses 
18 days 
< 2 doses 
2 or 3 or 4 doses 
> 4 doses 
19 – 24 days 
< 3 doses 
3 or 4 doses 
> 4 doses 
25 days 
< 3 doses 
3 or 4 or 5 doses 
> 5 doses 
26 – 31 days 
< 4 doses 
4 or 5 doses 
> 5 doses 
32 days 
< 4 doses 
4 or 5 or 6 doses 
> 6 doses 
33 – 38 days 
< 5 doses 
5 or 6 doses 
> 6 doses 
39 days 
< 5 doses 
5 or 6 or 7 doses 
> 7 doses 
40 – 45 days 
< 6 doses 
6 or 7 doses 
> 7 doses 
46 days 
< 6 doses 
6 or 7 or 8 doses 
> 8 doses 
47 – 52 days 
< 7 doses 
7 or 8 doses 
> 8 doses 
53 days 
< 7 doses 
7 or 8 or 9 doses 
> 9 doses 
Etc. 
 
 
 
 
o rhEPO TIW Exposure Records: Based on Number of Doses Given 
Duration of 
Exposure Record 
Under Compliant 
Compliant 
Over Compliant 
1 – 2 days 
< 1 dose 
1 dose 
> 1 dose 
3 – 4 days 
< 1 dose 
1 or 2 doses 
> 2 doses 
5 – 6 days 
< 2 doses 
2 or 3 doses 
> 3 doses 
7 days 
< 2 doses 
2 or 3 or 4 doses 
> 4 doses 
8 – 9 days 
< 3 doses 
3 or 4 doses 
> 4 doses 
10 – 11 days 
< 4 doses 
4 or 5 doses 
> 5 doses 
12 – 13 days 
< 5 doses 
5 or 6 doses 
> 6 doses 
14 days 
< 5 doses 
5 or 6 or 7 doses 
> 7 doses 
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Exposure and Compliance 
15 – 16 days 
< 6 doses 
6 or 7 doses 
> 7 doses 
17 – 18 days 
< 7 doses 
7 or 8 doses 
> 8 doses 
19 – 20 days 
< 8 doses 
8 or 9 doses 
> 9 doses 
21 days 
< 8 doses 
8 or 9 or 10 doses 
> 10 doses 
Etc. 
 
 
 
 
• Compliance will be summarized for the following time periods: Day 1 - < Week 28, Week 
28 - < Week 52, Week 28 - < End of Treatment, and Day 1 - < End of Treatment (Overall 
compliance). 
• Within each period, the percentage of time that a subject spent in each of the 3 categories 
above or with missing compliance data will be determined and will be based on the 
durations of each record within the period. 
• A subject’s compliance category will be the category that corresponds to the highest 
percentage of total time. In the unlikely event of a tie, the lower compliance category will 
be chosen (i.e., in a tie between under and compliant, under is chosen; in a tie between 
compliant and over, compliant is chosen; and in a tie between under and over, under is 
chosen; in a tie with missing, missing is chosen). 
10.6.3. 
Efficacy 
10.6.3.1. 
Hemoglobin Endpoints 
Hemoglobin Values 
Central Laboratory and HemoCue Hgb Values 
• When source of Hgb measurement is not specified: 
o For reporting purposes, central laboratory Hgb values will be used, unless 
otherwise specified. However, if a central laboratory Hgb value is missing, a 
corresponding non-missing HemoCue Hgb value will be used. This approach will 
be used for the co-primary Hgb analysis. 
• Some displays may be created for either central laboratory Hgb values only or HemoCue Hgb 
values only. The central laboratory summary will be considered the primary summary in this 
case. 
Evaluable Hemoglobin Values 
• Evaluable Hgb values are on-treatment Hgb values (see Section 10.4.1) that are not taken 
within the 8 weeks following a red blood cell transfusion, a whole blood transfusion, or a non-
randomized ESA treatment which occurs on or after the randomization date. 
• Red blood cell transfusions, whole blood transfusions and non-randomized ESA treatments 
occurring on or after the randomization date are identified by comparing the start and stop date 
of the respective transfusion or ESA concomitant medication record to the randomization date. 
Imputed Hemoglobin Values 
• For each missing value between baseline to Week 52 (inclusive), 200 imputed values will be 
generated using the multiple imputation method (see Section 7.1.2). The average of these 200 
imputed values will be used as the value for this missing value in the summary tables and 
figures. 
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Hemoglobin Values 
• For co-primary efficacy Hgb analysis and the corresponding subgroup analyses using all 
available observed and imputed Hgb values (on and off-treatment), Rubin’s rules [Rubin, 1987] 
will be used to combine results of the imputed datasets using SAS PROC MIANALYZE 
procedure. 
EP Hemoglobin Value for Co-primary Hgb Analysis 
• For each subject, the mean of all available (on and off treatment) Hgb values during the EP 
(See Section 10.6.1) including any imputed and unscheduled Hgb values that were taken 
during this time period. 
• Should the assessment dates for Hgb values from the Early Treatment Discontinuation visit 
and the End of Study visit fall within the EP, then these values will be included as unscheduled 
Hgb values. Hgb values from the Follow-up visit will not be included in the EP mean. 
EP Hemoglobin Value for While On-Treatment Evaluable Hgb Supportive Analysis 
• For each subject, the mean of all evaluable Hgb values during the EP (See Section 10.6.1) 
including any evaluable unscheduled Hgb values that were taken during this time period. 
• Should the assessment dates for Hgb values from the Early Treatment Discontinuation visit 
and the End of Study visit fall within the EP, then these values will be included as unscheduled 
Hgb values. Hgb values from the Follow-up visit will not be included in the EP mean. 
EP Hemoglobin Value for Alternative EP Supportive Analyses 
• For each subject, the mean of all Hgb values during the Alt. EP (See Section 10.6.1) including 
any imputed and unscheduled Hgb values that were taken during this time period. This 
analysis will be conducted using all available (on and off treatment) Hgb values and separately 
using evaluable Hgb values only. 
• Should the assessment dates for Hgb values from the Early Treatment Discontinuation visit 
and the End of Study visit fall within the Alt. EP, then these values will be included as 
unscheduled Hgb values. Hgb values from the Follow-up visit will not be included in the Alt. EP 
mean. 
Use of Unscheduled Hemoglobin Values and Multiple Hgb Values on the Same Date 
• The scenarios outlined below provide guidance on the use of unscheduled Hgb values and 
multiple Hgb values occurring on the same date. Each row represents a single calendar date. 
• Rows outlining scenarios where there is at least one central lab Hgb and at least one 
HemoCue Hgb on the same date apply only for the derivation of Hgb values to be used in the 
co-primary Hgb analysis, where central lab values are used if they are available and if the 
central lab value is missing, then a corresponding non-missing HemoCue Hgb value is used. 
• Rows outlining scenarios involving combinations of scheduled and unscheduled Hgb values of 
the same type apply to all Hgb summaries and analysis. 
Scheduled 
Central Lab 
Hgb Value 
Unscheduled 
Central Lab 
Hgb Value 
Scheduled 
HemoCue 
Hgb Value 
Unscheduled 
HemoCue 
Hgb Value 
Value to Use 
Type/Label 
x 
 
 
 
Scheduled central lab 
Hgb value 
Scheduled visit 
 
x 
 
 
Unscheduled central lab 
Hgb value 
Unscheduled 
 
 
x 
 
Scheduled HemoCue 
Hgb value 
Scheduled visit 
 
 
multiple1 
 
Average of scheduled 
HemoCue Hgb values 
Scheduled visit 
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Hemoglobin Values 
 
 
 
x 
Unscheduled HemoCue 
Hgb value 
Unscheduled 
 
multiple 
 
 
Average of unscheduled 
central lab Hgb values 
Unscheduled 
 
 
 
multiple 
Average of unscheduled 
HemoCue Hgb values 
Unscheduled 
x 
x 
 
 
Average of central lab 
Hgb values 
Scheduled visit 
x 
 
x 
 
Scheduled central lab 
Hgb value 
Scheduled visit 
x 
 
 
x 
Scheduled central lab 
Hgb value 
Scheduled visit 
 
x 
x 
 
Unscheduled central lab 
Hgb value 
Unscheduled 
 
x 
 
x 
Unscheduled central lab 
Hgb value 
Unscheduled 
 
 
x 
x 
Average of HemoCue 
Hgb values 
Scheduled visit 
1: The dose adjustment algorithm will require sites to obtain two HemoCue Hgb values at some visits. 
 
Time In Range 
Time in Range During the EP 
• Number of days that a subject’s evaluable Hgb is within the analysis range of 10-11.5 g/dL 
inclusive during the EP (See Section 10.6.1), including any unscheduled evaluable Hgb values 
that were taken during this time period. 
• Use of unscheduled Hgb values follows the scenarios for unscheduled and multiple Hgb 
values. 
• Linear interpolation is used to estimate Hgb between visits, accounting for any intermittent 
missing values (Rosendall, 1993). 
Percent Time in Range During the EP 
• Time in Range During the EP / [Earlier of (Date of the last evaluable Hgb value, Week 52 visit 
date) – Later of (Date of the first evaluable Hgb value that between Week 16 and Week 52 
inclusive, Week 28 visit date)] 
• Note: Percent time in/below/above range during the EP is only defined for subjects with a 
Treatment Stop Date that is on or after their Week 28 visit date, and have at least two 
evaluable Hgb values on different days, where at least one evaluable Hgb value is contained 
within the EP and another evaluable Hgb value occurs within the range of the Week 16 visit 
through 4 weeks following the Week 52 visit, inclusive.  
Time in Range During the MP 
• Number of days that a subject’s evaluable Hgb is within the analysis range of 10-11.5 g/dL 
inclusive between Weeks 28 and End of Study inclusive, including any unscheduled evaluable 
Hgb values that were taken during this time period. 
• Linear interpolation is used to estimate Hgb between visits, accounting for any intermittent 
missing values (Rosendall, 1993). 
Percent Time in Range During the MP 
• Time in Range During the MP / [Earlier of (Date of the last evaluable Hgb value, End of study 
date)– Later of (Date of the first evaluable Hgb value that is on or after week 16, Week 28 visit 
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Time In Range 
date)] 
• Note: Percent time in/below/above range during the MP is only defined for subjects with a 
Treatment Stop Date that is on or after their Week 28 visit date, and have at least two 
evaluable Hgb values on different days, where at least one evaluable Hgb value is contained 
within the MP and another evaluable Hgb value occurs within the range of the Week 16 visit 
through the Treatment Stop Date + 1 day.  
10.6.3.2. 
Iron Endpoints 
Iron Endpoints 
Iron Medications 
• During the study, subjects may be receiving iron in multiple routes, including: 
o IV iron 
o Oral iron  
o Other iron (including intramuscular, subcutaneous, and hemodialysis/dialysate) 
• Note: The iron route categories above will be determined using the route on the 
Prior/Concomitant Medication – Iron Therapy record. In addition, ferric citrate records recorded 
on the Prior/Concomitant Medication – Metabolic Bone Disease Therapy eCRF form will also 
be summarized as oral iron use. 
Baseline Iron Use 
• The number and percentage of subjects in the following iron use categories at baseline will be 
summarized: 
o IV iron use only 
o Oral iron use only 
o Other iron use only 
o IV and oral iron use only 
o IV and other iron use only 
o Oral and other iron use only 
o IV, oral, and other iron use 
o No iron use 
• When determining baseline iron use, the gap factors mentioned below in the IV iron 
standardization algorithm will be applied to the end date for each iron record, and the baseline 
period of 16 weeks before the Randomization date until the day before the Randomization date 
will also be used. 
Standardized IV Iron Dose (mg/week) to Determine Iron Management Action 
• In order to compare between IV iron records, to determine the action taken with IV iron therapy 
in the 8 weeks following the date the IV management threshold was met, the dose of IV iron in 
each associated record will be standardized in terms of mg/month. 
• IV iron therapy concomitant medication records that occur or are ongoing during the 8 weeks 
following the date the IV management threshold was met (inclusive), will be selected and 
ordered by start and end date. 
o If there is a record has a start date on the date the IV management threshold was 
met, and a prior record has an end date on the day before the IV management 
threshold was met, this prior record will be selected and considered as well. 
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• The standardization will be carried out with the following formula: 
o Standardized IV iron dose (mg/week) = IV iron drug dose (mg) * frequency 
 
Note: Frequency defined as follows: 
Frequency (from eCRF) 
Frequency 
(for standardization formula) 
2 times per week 
2 
3 times per week 
3 
4 times per week 
4 
5 times per week 
5 
BID 
14 
Once daily 
7 
One time dose 
1 
Every 12 Hours 
14 
Every 2 weeks 
0.5 
Every 4 weeks 
0.25 
Once a month 
0.23 
Once a week 
1 
TID 
21 
Standardized Baseline IV Iron Dose (mg/month) 
• In order to calculate the baseline average monthly IV iron dose, the dose of IV iron will be 
standardized to obtain a continuous single unit IV iron dose in terms of mg/month for the period 
from 16 weeks before the Randomization date to the day before the Randomization date. 
• IV iron therapy concomitant medication records that occur or are ongoing during the period 
from (the Randomization date – 16 weeks) to the Randomization date will be selected and 
ordered by start and end date. 
• The standardization will be carried out with the following formula: 
o Standardized IV iron dose (mg/week) = IV iron drug dose (mg) * frequency 
 
Note: Frequency and Gap Factors defined as follows: 
Frequency (from eCRF) 
Frequency 
(for standardization formula) 
Gap Factor 
2 times per week 
2 
2.5 days 
3 times per week 
3 
1.33 days 
4 times per week 
4 
0.75 day 
5 times per week 
5 
0.4 day 
BID 
14 
0 days 
Once daily 
7 
0 days 
One time dose 
1 
n/a 
Every 12 Hours 
14 
0 days 
Every 2 weeks 
0.5 
13 days 
Every 4 weeks 
0.25 
27 days 
Once a month 
0.23 
29 days 
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Once a week 
1 
6 days 
TID 
21 
0 days 
 
• If the frequency of the record is not ‘one time dose’, then duration is calculated as follows: 
o If the concomitant medication record start date  Randomization date, the duration of 
the record is 0. 
o If the concomitant medication record end date + gap factor < (Randomization date – 
16 weeks), the duration of the record is 0. 
o If the concomitant medication record end date + gap factor  (Randomization date – 
16 weeks) or the record is ongoing, the duration of the record will be calculated as 
Stop Date – Start Date +1 day where: 
▪ Start date will be the latest of (concomitant medication record start date and 
the Randomization date – 16 weeks). 
▪ Stop date will be the earliest of (concomitant medication record stop date + 
gap factor and the day before randomization). 
• If the frequency of the record is ‘one time dose’, then: 
o If concomitant medication record start date < Randomization date - 16 weeks, or if 
Randomization date  concomitant medication record start date, then duration of the 
record is 0. 
o If Randomization date -16 weeks  concomitant medication record start date < 
Randomization date, then: 
▪ Frequency (for standardization formula) = 1 
▪ Duration = 7 days 
• The total dose for each IV iron record will be: Standardized dose*duration/7 days 
• A weighted mean will then be used to obtain the baseline monthly IV iron dose: 
Mean baseline monthly IV iron dose = [(IV iron total doseRecord 1) + ... + (IV iron total doseRecord 
n)]/[ (16* 7)/30.4375 days]. 
Standardized IV Iron Dose (mg/month) from Randomization to Week 52 
• In order to calculate the average monthly IV iron dose from Randomization to Week 52, the 
dose of IV iron will be standardized to obtain a continuous single unit IV iron dose in terms of 
mg/month for the period from the Randomization date to the Week 52 visit date while the 
subject is on treatment and before their first RBC or whole blood transfusion.  
o Note: Subjects who are randomized but never treated will not have a value for 
average monthly IV iron from Randomization to Week 52.  
• IV iron therapy concomitant medication records that occur or are ongoing during the period 
from the subject’s Randomization date – 16 weeks to the Week 52 visit date will be selected 
and ordered by start date and end date. 
• The standardization will be carried out with the following formula: 
o Standardized IV iron dose (mg/week) = IV iron drug dose (mg) * frequency 
 
Note: Frequency and Gap Factors defined as follows: 
Frequency (from eCRF) 
Frequency 
(for standardization formula) 
Gap Factor 
2 times per week 
2 
2.5 days 
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3 times per week 
3 
1.33 days 
4 times per week 
4 
0.75 day 
5 times per week 
5 
0.4 day 
BID 
14 
0 days 
Once daily 
7 
0 days 
One time dose 
1 
n/a 
Every 12 Hours 
14 
0 days 
Every 2 weeks 
0.5 
13 days 
Every 4 weeks 
0.25 
27 days 
Once a month 
0.23 
29 days 
Once a week 
1 
6 days 
TID 
21 
0 days 
 
• If the frequency of the record is not ‘one time dose’, then duration is calculated as follows: 
o If the concomitant medication record start date > earliest of (treatment stop date + 1 
and Week 52 visit date), the duration of the record is 0. 
o If the concomitant medication record end date + gap factor < Randomization date, the 
duration of the record is 0. 
o If the concomitant medication record end date + gap factor  Randomization date or 
the record is ongoing, the duration of the record will be calculated as Stop Date – Start 
Date +1 day where: 
▪ Start date will be the latest of (concomitant medication record start date, 
randomization date, treatment start date). 
▪ Stop date will be the earliest of (concomitant medication record stop date + 
gap factor, first transfusion date (RBC or whole blood), treatment stop date + 
1, and the Week 52 visit date). 
• If the frequency of the record is ‘one time dose’, then: 
o If concomitant medication record start date < treatment start date, or if earliest of (first 
transfusion date (RBC or whole blood), treatment stop date +1 and Week 52 visit date) 
< concomitant medication record start date, then duration of the record is 0. 
o If latest of (Randomization date, treatment start date)  concomitant medication record 
start date  earliest of (first transfusion date (RBC or whole blood), treatment stop date 
+ 1 and Week 52 visit date), then: 
▪ Frequency (for standardization formula) = 1 
▪ Duration = 7 days 
• The total dose for each IV iron record will be: Standardized dose*duration/7 days 
• A weighted mean will then be used to obtain the monthly IV iron dose from Randomization to 
Week 52: 
Mean monthly IV iron dose from Randomization to Week 52 while on treatment =  
[(IV iron total doseRecord 1) + ... + (IV iron total doseRecord n)] / {[earliest of (treatment stop 
date + 1, Week 52 Visit Date) – treatment start date + 1] / 30.4375 days}. 
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Standardized Monthly IV Iron Dose (mg/month) from Week 28 to Week 52 (EP Average 
Monthly IV Iron Dose) 
• In order to calculate the average monthly IV iron dose from Week 28 to Week 52, the dose of 
IV iron will be standardized to obtain a continuous single unit IV iron dose in terms of 
mg/month for the period from the Week 28 visit date to the Week 52 visit date while the subject 
is on treatment and before their first RBC or whole blood transfusion. 
o Note: Subjects who are randomized but never treated, who have a RBC or whole 
blood transfusion, or who permanently discontinue randomized treatment on or 
before the Week 28 visit date will not have a value for average monthly IV iron 
from Week 28 to Week 52.  
• IV iron therapy concomitant medication records that occur or are ongoing during the period 
from the subject’s Week 24 visit date to the Week 52 visit date will be selected and ordered by 
start date and end date. 
• The standardization will be carried out with the following formula: 
o Standardized IV iron dose (mg/week) = IV iron drug dose (mg) * frequency 
 
Note: Frequency and Gap Factors defined as follows: 
 
 
Frequency (from eCRF) 
Frequency 
(for standardization formula) 
Gap Factor 
2 times per week 
2 
2.5 days 
3 times per week 
3 
1.33 days 
4 times per week 
4 
0.75 day 
5 times per week 
5 
0.4 day 
BID 
14 
0 days 
Once daily 
7 
0 days 
One time dose 
1 
n/a 
Every 12 Hours 
14 
0 days 
Every 2 weeks 
0.5 
13 days 
Every 4 weeks 
0.25 
27 days 
Once a month 
0.23 
29 days 
Once a week 
1 
6 days 
TID 
21 
0 days 
 
• If the frequency of the record is not ‘one time dose’, then duration is calculated as follows: 
o If the concomitant medication record start date > earliest of (treatment stop date + 1 
and Week 52 visit date), the duration of the record is 0. 
o If the concomitant medication record end date + gap factor < Week 28 visit date, the 
duration of the record is 0. 
o If the concomitant medication record end date + gap factor  Week 28 visit date or the 
record is ongoing, the duration of the record will be calculated as Stop Date – Start 
Date +1 day where: 
▪ Start date will be the latest of (concomitant medication record start date, and 
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the Week 28 visit date). 
▪ Stop date will be the earliest of (concomitant medication record stop date + 
gap factor, first transfusion date (RBC or whole blood), treatment stop date + 
1, and the Week 52 visit date). 
• If the frequency of the record is ‘one time dose’, then: 
o If concomitant medication record start date < Week 28 visit date, or if earliest of (first 
transfusion date (RBC or whole blood), treatment stop date + 1 and Week 52 visit 
date) < concomitant medication record start date, then duration of the record is 0. 
o If Week 28 visit date  concomitant medication record start date  earliest of (first 
transfusion date (RBC or whole blood), treatment stop date +1 and Week 52 visit 
date), then: 
▪ Frequency (for standardization formula) = 1 
▪ Duration = 7 days 
• The total dose for each IV iron record will be: Standardized dose*duration/7 days 
• A weighted mean will then be used to obtain the monthly IV iron dose from Week 28 to Week 
52: 
Mean monthly IV iron dose from Week 28 to Week 52 while on treatment =  
[(IV iron total doseRecord 1) + ... + (IV iron total doseRecord n)] / {[earliest of (treatment stop 
date + 1, Week 52 Visit Date) – Week 28 Visit Date +1 ]/30.4375 days}. 
Iron Use by Quarter 
• The number and percentage of subjects in the following iron use categories defined by route 
will be summarized by quarters listed below for Average Quarterly IV Iron Dose: 
o IV iron use only 
o Oral iron use only 
o Other iron use only 
o IV and oral iron use only 
o IV and other iron use only 
o Oral and other iron use only 
o IV, oral, and other iron use 
o No iron use 
• When determining iron use by quarter, the gap factors mentioned in the IV iron standardization 
algorithm will also be applied to the end date for each iron record. 
• Although baseline iron use is defined based on a period of 16 weeks, it will also be included in 
summaries of iron use by quarter. 
Average Quarterly IV Iron Dose 
• The standardized IV iron (mg/month) dose will be summarized by quarters, where quarters will 
be defined using study visits as follows: 
o Baseline 
o For summaries of on & off treatment IV iron dose: 
▪ Quarter 1 = [Randomization date – Week 12)  
o For summaries of on-treatment IV iron dose: 
▪ Quarter 1 = [Treatment start date + 1 – Week 12)  
▪ Quarter 2 = [Week 12 – Week 24) 
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▪ Quarter 3 = [Week 24 – Week 36) 
▪ Etc. 
• To determine the planned start date and end date of quarters, the visit end date (from the SV 
domain) will be used. If there is not a corresponding visit, or if the subject is missing that visit, 
the planned visit date (Randomization date + 7*x) will be used, where x is the scheduled week 
(e.g., Week 24, x = 24). 
• A subject’s quarterly average IV iron dose will end at the earliest of the following: 
o For summaries of on & off treatment IV iron dose: death date, study 
completion/withdrawal date, and the planned quarter end date. 
o For summaries of on-treatment IV iron dose: death date, first transfusion (RBC or 
whole blood), study completion/withdrawal date, treatment stop date + 1, and the 
planned quarter end date. 
• The standardization algorithm for IV iron described earlier in the table will be used to determine 
the standardized IV iron dose (mg/month) during each quarter. 
• Although the standardized baseline IV iron dose is defined based on a period of 16 weeks, it 
will also be included in summaries of average quarterly IV iron dose. 
Reduction in IV Iron Supplementation 
• A reduction in IV iron supplementation relative to baseline occurs when Baseline average 
monthly IV iron > EP average monthly IV iron, when both baseline IV iron and EP average 
monthly IV iron are non-missing. 
TIBC 
• TIBC will be calculated automatically by the central laboratory using: 
o TIBC = UIBC + total iron 
TSAT 
• TSAT will be calculated automatically by the central laboratory using: 
o TSAT = 100 * (Serum Iron/TIBC) 
Average Quarterly TSAT and Ferritin 
• The average TSAT and Ferritin values will be summarized by quarters, where quarters will be 
defined as they are for Average Quarterly IV Iron Dose, with the following exception: 
o Baseline average quarterly ferritin and TSAT will take the average of all available 
records before or on randomization ferritin and TSAT values. 
 
Note: any unscheduled values falling within these quarters will be used in the calculation of the 
quarterly average value. 
Meeting Iron Management Criteria 
Iron therapy will be administered if at any visit: 
• Ferritin  100 ng/mL and/or TSAT  20% 
All iron must be stopped if at any visit: 
• Ferritin > 800 ng/mL and TSAT >20%, or 
• TSAT > 40% 
Subjects meeting iron management criteria requiring starting and stopping of iron administration on 
the same day: 
• Ferritin  100 ng/mL and TSAT > 40% 
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10.6.3.3. 
Time to Rescue 
Time to Stopping Randomized Treatment Due to Meeting Rescue Criteria 
Meeting Rescue Evaluation Criteria and Rescue Criteria 
• Subjects meeting evaluation criteria for rescue are identified from the Rescue Treatment eCRF. 
Subjects with a record on this form are considered to have met evaluation criteria for rescue. It 
is possible that a subject could be evaluated for rescue more than once, and in that case a 
subject would have multiple records on this form. 
• Subjects unable to be evaluated for rescue are subjects who met evaluation criteria for rescue, 
but were unable to be assessed at the 4 week check (e.g., subjects who died, permanently 
discontinued randomized treatment or withdrew from the study before the 4 week check). The 
outcome of initial intervention eCRF field on the Rescue Treatment eCRF will be blank for these 
subjects. 
• Subjects meeting rescue are identified by the response ‘Met rescue criteria’ to the outcome of 
initial intervention question on the Rescue Treatment eCRF. 
Event Date 
• Treatment stop date when the primary reason and subreason for randomized treatment stop 
are: 
o Primary reason: Subject reached protocol-defined stopping criteria 
o Subreason: Rescue 
General Definitions 
• Time to event (days) = date of event – randomization date +1 
• Censored time (days) = censoring date – randomization date + 1 
• Rescue person years = (cumulative total time to stopping randomized treatment for subjects 
who stopped randomized treatment due to meeting rescue criteria + cumulative total of 
censoring time for subjects who did not stop randomized treatment due to meeting rescue 
criteria) / 365.25 
• Rescue incidence rate (per 100 person years) = (100 * number of subjects who stopped 
randomized treatment due to meeting rescue criteria) / rescue person years 
• Rescue absolute rate difference (per 100 person years) = daprodustat rescue incidence rate 
(per 100 person years) – rhEPO rescue incidence rate (per 100 person years) 
Time Period for Treatment Discontinuation 
The period for treatment discontinuation begins at randomization. The end of this time period is 
defined as follows: 
• For subjects who did not take randomized treatment, use the date of randomization 
• For subjects whose treatment stop date is missing and who took randomized treatment, use 
study conclusion date 
• For subjects either continuing on study past treatment stop date or completing/withdrawing on 
the same day as treatment stop date, use treatment stop date 
 
Any events that occurred before the start of this time period are considered to be prior to the time 
period for treatment discontinuation, and any endpoints that occurred after the end of this time 
period are considered to be post the time period for treatment discontinuation. 
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10.6.3.4. 
RBC and Whole Blood Transfusion Endpoints 
Number of RBC and Whole Blood Transfusions 
• The number of transfusions associated with each RBC and Whole Blood Transfusion record is 
determined by the frequency, start date, end date and number of units, as described below. 
• Only on-treatment transfusions are included. “End date” below refers to the end date defined 
for the transfusion, or the end of the on-treatment period, if sooner (see Section 10.6.3). 
• For records with a frequency of “Once only” or “Continuous infusion”, each record is 
considered to be a single transfusion (regardless of start and end dates or number of units). 
• For records with a frequency of “Once daily”, the number of transfusions will equal the duration 
(end date – start date +1). 
• For records with a frequency of “PRN”, or where the frequency is unknown, the number of 
transfusions for each record will be equal to the number of units recorded. 
• For other transfusion records, the number of transfusions will equal the duration (end date – 
start date +1) times a multiplier, as defined below: The number of transfusions should be 
rounded up to the nearest integer. 
 
Frequency 
Multiplier 
QM 
0.033 
Every 2 weeks 
0.071 
Once a week 
0.14 
Q4D 
0.25 
2 times per week 
0.29 
Q3D 
0.33 
3 times per week 
0.43 
Every other day 
0.5 
4 times per week 
0.57 
5 times per week 
0.71 
BID 
2 
Q12H 
2 
TID 
3 
Q8H 
3 
QID 
4 
Q6H 
4 
5 times per day 
5 
Q4H 
6 
Number of RBC and Whole Blood Transfusion Events 
• RBC and Whole Blood Transfusion Events are defined by grouping together on-treatment 
transfusion records.  
• Transfusion records are grouped into the same Transfusion Event if the transfusion start/end 
dates match with or are contained within an Admission/Discharge period, (based on the 
Hospitalization page in the eCRF) 
• For example, the following transfusion records would be grouped into a single Transfusion 
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Event, because each transfusion is contained within the same hospital admission/discharge 
period:  
 
Dose 
Frequency 
Transfusion Dates 
Hospitalisation 
Comment 
Start Date 
End Date 
Admission 
Discharge 
1 unit 
Once only 
16FEB2019 16FEB2019 15FEB2019 26FEB2019 1 Transufsion 
Event 
1 unit 
Once only 
19FEB2019 19FEB2019 15FEB2019 26FEB2019 
 
• Transfusion records not matching with an Admission/Discharge period are considered to be 
the same Transfusion Event if the gap between transfusions is 5 days or less, with further 
details provided below. For any subject where the frequency is PRN and the transfusion start 
date ≠ end date, the dates of individual transfusions are unknown and the number of 
transfusion events will be counted as one. 
• In the case of a sequence of more than two transfusions, transfusions are considered to be the 
same Transfusion Event if the gap between each transfusion and the start date of the first 
transfusion in the sequence (the “anchor” transfusion) is 5 days or less. The first transfusion 
that is greater than 5 days after the “anchor” transfusion is not included in the Transfusion 
Event, and it becomes the new “anchor” transfusion for a new Transfusion Event. 
• In the example below, transfusion records 1 and 2 would be grouped into a single Transfusion 
Event, because the gap between the transfusions (17JAN2019 to 18JAN2019) was 5 days or 
less. Record 3 falls outside this Transfusion Event because the gap between the start date 
(22JAN2019) and the previous anchor date (16JAN2019) is more than 5 days. Therefore 
22JAN2019 becomes the new “anchor” transfusion used to define the next Transfusion Event. 
This pattern is repeated, if necessary. N.B.  “anchor” transfusions are shown in bold. 
 
# 
Dose 
Frequency 
Transfusion Dates 
Comment 
Start Date 
End Date 
1 
1 unit 
Once only 
16JAN2019 
16JAN2019 
1 Transfusion Event 
2 
1 unit 
Once only 
19JAN2019 
19JAN2019 
3 
1 unit 
Once only 
22JAN2019 
22JAN2019 
1 Transfusion Event 
4 
1 unit 
Once only 
25JAN2019 
25JAN2019 
5 
1 unit 
Once only 
28JAN2019 
28JAN2019 
1 Transfusion Event 
Number of Units 
• The number of RBC and whole blood units are derived from blood transfusion records. The 
number of units associated with each record is determined by the frequency, start date, end 
date and dose (i.e. number of units recorded), as described below: 
• Only units associated with on-treatment transfusions are included. “End date” below refers to 
the end date defined for the transfusion, or the end of the on-treatment period, if sooner (see 
Section 10.4.1). 
• For records with the frequency recorded as “Once only” or “Continuous infusion”, the total 
number of units associated with each record is the number of units recorded (regardless of 
start and end dates) 
• For records with the frequency recorded as “Once daily”, the total number of units associated 
with each record will equal the number of units recorded multiplied by the duration (end date – 
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start date +1) 
• For records with the frequency recorded as “PRN”, the total number of units will be equal to the 
number of units recorded (regardless of start and end dates) 
• For other records, the number of units will be equal to the number of units recorded multiplied 
by the duration (end date – start date +1) times a multiplier, as defined for Number of RBC and 
Whole Blood Transfusions above 
• The table below provides multipliers for converting various reported units to Units (which 
should be rounded up to the nearest integer).  For example, a transfusion of 450ml represents 
a single unit:  
(450 x 0.0025) = 1.125 (rounded up to 2 Units) 
 
Reported Units 
Multiplier 
Units 
1 
Milliliters (ml or CC) 
0.0025 
Milligram (mg) 
0.0025 
Milligrams/milliliters (mg/ml) 
0.0025 
• Where a non-integer number of units has been entered on the eCRF, this will be rounded up to 
the nearest integer prior to any subsequent derivation (if necessary). 
• Where a transfusion record has been entered with a missing number of units, the number of 
units associated with the record will be assumed to be 1 unit. 
Evaluation Period (Weeks 28 to 52) 
• Only transfusion events with a start date from date of week 28 visit to the date of the week 52 
visit will be included 
• Patient Years (PY) = (cumulative total time from date of week 28 visit to the date of the week 
52 visit, for subjects who did not withdraw from randomized treatment during the evaluation 
period + cumulative time from date of week 28 visit to the date of withdrawal from randomized 
treatment, for subjects who withdrew from randomized treatment during the evaluation period) / 
365.25 
• Transfusion Events per 100 PY = (100 * number of on-treatment RBC or whole blood 
transfusion events during the evaluation period) / Patient Years (PY) 
• Transfusions per 100 PY = (100 * number of on-treatment RBC or whole blood transfusions 
during the evaluation period) / Patient Years (PY) 
• Units per 100 PY = (100 * number of on-treatment RBC or whole blood transfusion units during 
the evaluation period) / Patient Years (PY) 
Randomization to Week 52 
• Only transfusion events with a start date from the date of randomization to the date of the week 
52 visit will be included  
• Patient Years (PY) = (cumulative total time from date of randomization to the date of the week 
52 visit, for subjects who did not withdraw from randomized treatment prior to week 52 + 
cumulative time from date of randomization to the date of withdrawal from randomized 
treatment, for subjects who withdrew from randomized treatment prior to week 52) / 365.25 
• Transfusion Events per 100 PY = (100 * number of on-treatment RBC or whole blood 
transfusion events from the date of randomization to the date of the week 52 visit) / Patient 
Years (PY) 
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• Transfusions per 100 PY = (100 * number of on-treatment RBC or whole blood transfusions 
from the date of randomization to the date of the week 52 visit) / Patient Years (PY) 
• Units per 100 PY = (100 * number of on-treatment RBC or whole blood transfusion units from 
the date of randomization to the date of the week 52 visit) / Patient Years (PY) 
Randomization to End of Treatment 
• Person Years (PY) = (cumulative total time from date of randomization to the study conclusion 
date, for subjects who did not withdraw from randomized treatment + cumulative time from 
date of randomization to the date of withdrawal from randomized treatment, for subjects who 
withdrew from randomized treatment) / 365.25 
• Transfusion Events per 100 PY = (100 * number of on-treatment RBC or whole blood 
transfusion events from the date of randomization to the date of study conclusion or withdrawal 
from treatment) / Person Years (PY) 
• Transfusions per 100 PY = (100 * number of on-treatment RBC or whole blood transfusions 
from the date of randomization to the date of study conclusion or withdrawal from treatment) / 
Person Years (PY) 
• Units per 100 PY = (100 * number of on-treatment RBC or whole blood transfusion units from 
the date of randomization to the date of study conclusion or withdrawal from treatment) / 
Person Years (PY) 
Time to First On-Treatment RBC or Whole Blood Transfusion 
• Event Date = Start date for the first on-treatment RBC or whole blood transfusion received after 
treatment start date 
• Censoring Date = date of stopping randomized treatment for subjects who stopped randomized 
treatment, or date of study completion for subjects who did not stop randomized treatment 
• Time to event (days) = date of event – treatment start date +1 
• Censored time (days) = censoring date – treatment start date + 1 
• Person years (PY) = (cumulative total time to event date, for subjects who received at least 
one on-treatment RBC or whole blood transfusion + cumulative total of censoring time for 
subjects who did not receive at least one on-treatment RBC or whole blood transfusion) / 
365.25 
• Incidence rate per 100 PY = (100 * number of subjects who received at least one on-treatment 
RBC or whole blood transfusion) / person years 
Absolute rate difference (per 100 person years) = daprodustat incidence rate (per 100 person 
years) – rhEPO incidence rate (per 100 person years) 
Time Period for On-Treatment Transfusions 
• The period for capturing on-treatment transfusions begins on the treatment start date +1day. 
The end of this time period is defined as follows: 
o For subjects continuing on study past the (treatment stop date + 1day), use 
(treatment stop date + 1day) 
o For subjects whose study withdrawal/completion date is on or before (treatment 
stop date + 1day), use date of study withdrawal/completion 
Model Specification 
• Analysis of time to first RBC or whole blood transfusion will be performed using an analysis 
model identical to that described for the co-primary MACE analysis (Section 7.2.2) for the 
evaluation of superiority. 
• Analysis will include only transfusion occurring during the on-treatment period.. 
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Model Results Presentation 
• The model results presentation will be identical to the co-primary MACE model results, with the 
following exception: 
• A single one-sided p-value for the test of superiority of daprodustat vs. rhEPO will be presented 
(i.e. there will be no test for non-inferiority). 
• A Kaplan-Meier plot will be produced showing the survival function for time to first RBC or 
whole blood transfusion. 
 
10.6.3.5. 
Delayed Graft Function Endpoints 
DGF Endpoints 
DGF Following Deceased Donor Kidney Transplantation 
• DGF following deceased donor kidney transplantation will be identified using the following 
combination of responses to questions on the Kidney Transplant eCRF form: 
o Donor source of transplant = either [‘Deceased donor – donation after cardiac 
death (DCD)’ or ‘Deceased donor – donation after brain death (DBD)’]  
and 
o Did the subject have delayed graft function requiring dialysis within the first 7 days 
= ‘Yes’ 
Duration of DGF 
• The duration of DGF following deceased donor kidney transplantation will be defined as date of 
last dialysis after transplant (from the Kidney Transplant eCRF form) – kidney transplant date + 
1 day 
10.6.3.6. 
Dose Adjustment Scheme Endpoints 
Dose Adjustment Scheme Endpoints 
General 
• The IRT system assigns all randomized treatment doses in accordance with the dose 
adjustment scheme specified in the protocol.  
• During the study, it is possible for subjects to change randomized treatment doses at both 
scheduled and unscheduled visits.  
• Sites are instructed to complete an exposure record every time dosing instruction is received 
from the IRT, with the exception of re-dispensing situations where the subject is instructed to 
continue using the same randomized treatment. 
• Summary tables for some dose adjustment scheme endpoints may summarize subjects by the 
type of rhEPO treatment received (i.e., epoetin alfa, darbepoetin alfa). Since it is possible for 
subjects to switch from epoetin alfa to darbepoetin alfa during the study, these displays will 
include subjects who switch rhEPO treatments in both the epoetin alfa and darbepoetin alfa 
groups. 
Daprodustat Doses 
Sites will enter the dose of daprodustat into exposure records – the daily frequency will be auto-
populated for this randomized treatment. The dose steps of daprodustat are shown below: 
Total Daily Dose 
How Administered 
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1 mg 
single 1 mg tablet 
2 mg 
single 2 mg tablet 
4 mg 
single 4 mg tablet 
6 mg 
single 6 mg tablet 
8 mg 
single 8 mg tablet 
10 mg 
single 10 mg tablet 
12 mg 
two 6 mg tablets 
16 mg 
two 8 mg tablets 
24 mg 
three 8 mg tablets 
Epoetin Alfa Doses 
Sites will enter the dose and frequency of each dose of epoetin alfa into exposure records. The 
dose steps of epoetin alfa (including the corresponding total weekly doses) are shown below: 
Total Weekly Dose 
 Dose and Frequency 
1500 
1500 U once a week 
2000 
2000 U once a week 
3000 
3000 U once a week 
4000 
4000 U once a week 
5000 
5000 U once a week 
6000 
6000 U once a week 
8000 
8000 U once a week 
10000 
10000 U once a week 
12000 
4000 U 3 times a week 
15000 
5000 U 3 times a week 
18000 
6000 U 3 times a week 
21000 
7000 U 3 times a week 
24000 
8000 U 3 times a week 
27000 
9000 U 3 times a week 
30000 
10000 U 3 times a week 
36000 
12000 U 3 times a week 
42000 
14000 U 3 times a week 
48000 
16000 U 3 times a week 
60000 
20000 U 3 times a week 
Darbepoetin Alfa Doses 
Sites will enter the dose and frequency of each dose of darbepoetin alfa into exposure records. 
The dose steps of darbepoetin alfa (including the corresponding total 4-weekly doses) are shown 
below: 
 
 
Total 4-Weekly Dose 
Pre-filled Syringe Dose and Frequency 
20 µg 
20 µg every 4 weeks 
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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 week 
Assigned Dose at A Scheduled Visit 
• The assigned dose at a particular visit refers to the dose the subject received at that visit, as 
recorded in the eCRF. The assigned dose at Visit X is the dose from the earliest exposure 
record with a start date on or after the Visit X date, but before the Visit X+1 date. 
o For example, the assigned dose at the Week 28 visit is the dose from the earliest 
exposure record with a start date on or after the Week 28 visit date, but before the 
Week 32 visit date. 
Most Recent Dose Prior to A Scheduled Visit / End of Treatment 
• The most recent dose prior to a particular visit refers to the dose the subject received in the 
period directly preceding the visit, as recorded in the eCRF. The most recent dose prior to Visit 
X is the dose from the latest exposure record with a start date that is on or after the Visit X-1 
date and before the Visit X date. 
o For example, the most recent dose prior to Week 28 is the dose from the latest 
exposure record with a start date that is on or after the Week 24 visit date and 
before the Week 28 visit date. 
• If a subject permanently stops randomized treatment after Visit X-1 and on or before Visit X, 
the most recent dose prior to Visit X will be the dose from the subject’s final exposure record. 
Two Approaches to Dose Adjustment Summaries 
• The first approach counts all dose adjustments, including dose adjustments related to 
periods of dose holds (i.e., IRT assignment of a 0-dose). 
• The second approach does not count dose adjustments related to periods of dose holds. 
However, should the dose that a subject receives following a period of dose hold be 
different from the dose the subject received before the dose hold, this would still count as a 
dose adjustment in this approach. 
Number of Dose Adjustments per Year During Day 1 - < End of Treatment 
• The number of dose adjustments per year will be determined by dividing the total number of 
dose adjustments between Day 1 and End of Treatment by [(Treatment Stop Date – Day 1 
date + 1 day) / 365.25]. 
Dosing Algorithm Update 
• The dosing algorithm update went into effect on different dates at different sites, due to 
variable approval times. The IRT records the date that each site changed algorithms. Subjects’ 
randomization dates and Hgb assessment dates will be compared to their site’s date of 
algorithm change. Any randomization/Hgb assessment dates before the day of the site’s 
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algorithm change are considered to have occurred under the original algorithm. Any 
randomization/Hgb assessment dates on or after the day of the IRT algorithm change are 
considered to have occurred under the updated algorithm.  
• The 95% prediction interval for Hgb values at a visit provides an estimate of the range where 
future Hgb values would occur, with a probability of 95%. The 95% prediction interval for future 
Hgb values can be calculated using the approach described in (Francq, 2019), where the 
prediction interval at Visit x is calculated using adjusted mean Hgb value at Visit x  1.96 * sqrt 
(standard error2 + total variance at Visit x). Due to the use of an unstructured covariance matrix 
(Section 8.1.3), the total variance at Visit x is found at (x, x) on the diagonal of the R matrix. 
10.6.3.7. 
Phosphate Binder Use 
 Phosphate Binder Use 
Baseline Phosphate Binder Use (Yes/No) 
• Baseline Phosphate binder use will be categorized as either Yes, or No for the phosphate 
binder analyses. 
• Subjects will be counted in each applicable group, based on the concomitant medications they 
are receiving on the day of randomization. 
Phosphate Binder Use at Week 28 (Yes/No) 
• Phosphate binder use at Week 28 will be categorized as either Yes, or No for the phosphate 
binder analyses. 
• Subjects will be counted in each applicable group, based on the concomitant medications they 
are receiving between Week 24 and Week 28. 
Phosphate Binder Use at Week 52 (Yes/No) 
• Phosphate binder use at Week 52 will be categorized as either Yes, or No for the phosphate 
binder analyses. 
• Subjects will be counted in each applicable group, based on the concomitant medications they 
are receiving between Week 48 and Week 52. 
10.6.4. 
Safety 
10.6.4.1. 
CV Safety Endpoints 
 CV Safety Endpoints 
Dates for Investigator Reported CV Safety Endpoints 
• All-cause hospitalization: admission date 
• All-cause hospital re-admission: admission date within 30 days following a discharge date 
 
• Death: date of death from the Death1 eCRF page 
• Myocardial infarction: date of onset of Myocardial Infarction/Unstable Angina symptoms from 
the MI/UA1 eCRF page 
• Stroke: start date of neurological symptoms from the Stroke/TIA eCRF page 
• Hospitalization for HF: Earliest of (ER admission date, Hospital admission date) from Heart 
Failure eCRF page 
• Thromboembolic event: date of onset of thromboembolic event from the Thromboembolic 
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Event eCRF page 
Dates for Adjudicated CV Safety Endpoints 
• Death: event date reported by CEC 
• Myocardial infarction: event date reported by CEC 
o Fatal MI events only identified through a primary cause of death, without a 
corresponding positively adjudicated MI event: death event date reported by CEC 
• Stroke: event date reported by CEC 
o Fatal stroke events only identified through a primary cause of death, without a 
corresponding positively adjudicated stroke event: death event date reported by 
CEC 
• Hospitalization for HF: event date reported by CEC 
o Fatal heart failure/cardiogenic shock events only identified through a primary 
cause of death, without a corresponding heart failure event: death event date 
reported by CEC 
• Thromboembolic event (DVT, PE, VAT): event date reported by CEC 
o Fatal PE events only identified through a primary cause of death, without a 
corresponding positively adjudicated PE event: death event date reported by CEC 
 
Due to the design of the CRF, a fatal MI is reported as both an MI and a death. Both of these 
events will go through the adjudication process. It is possible that the MI could be negatively 
adjudicated, while the death is positively adjudicated with a primary cause of acute MI. The 
rationale for this is that the definition of a positively adjudicated MI (contained in the CEC charter) 
is more explicit than the definition of acute MI as a primary cause of death. Therefore, in analyses 
that include MI events without including all-cause mortality, the primary approach will be to include 
only those fatal MI events that correspond to a positively adjudicated MI event. These analyses 
will then be repeated for supportive purposes using all fatal MI events – including those fatal MI 
events only identified through a primary cause of death (i.e., acute MI) without a corresponding 
positively adjudicated MI event. 
 
Additionally, a fatal MI event could have an event date that differs from the death date because 
the subject may have died as a result of the MI but not on the same day. For analysis of first 
occurrence MACE, MI or any other composite endpoint that includes both MI and death, if both 
the MI and death events are positively adjudicated, the MI date will be used as the event date. For 
analysis of CV mortality only and all-cause mortality only, the death date will be used. 
 
Similarly, fatal stroke events are reported as both a stroke and a death. In analyses that include 
stroke events without including all-cause mortality, the primary approach will be to include only 
those fatal stroke events that correspond to a positively adjudicated stroke event. These analyses 
will be repeated for supportive purposes using all fatal stroke events – including those fatal stroke 
events only identified through a primary cause of death (i.e., stroke) without a corresponding 
positively adjudicated stroke event. For analysis of first occurrence MACE, stroke, or any other 
composite endpoint that includes stroke and death, if both the stroke and death events are 
positively adjudicated, the stroke date will be used as the event date. For analysis of CV mortality 
only and all-cause mortality, the death date will be used. 
 
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Fatal heart failure events are reported as both a heart failure and a death. In analyses that include 
hospitalization for heart failure events without including all-cause mortality, a single approach 
which includes only those fatal hospitalization for heart failure events that correspond to a 
positively adjudicated hospitalization for heart failure event will be used. The definition of the 
hospitalization for heart failure endpoint includes requirements around hospitalization which are 
not captured in the associated primary cause of death (heart failure/cardiogenic shock), so 
identification of hospitalization for heart failure events through only a primary cause of death is not 
possible. However, supportive analyses of the hospitalization for heart failure endpoint may 
include all heart failure events. These supportive analyses would then be able to include fatal 
heart failure events from the death page (i.e. primary cause of death = heart failure/cardiogenic 
shock) that do not correspond to a positively adjudicated heart failure event. For analysis of 
hospitalization for heart failure or any composite endpoint that includes hospitalization for heart 
failure and death, if both the hospitalization for heart failure and death events are positively 
adjudicated, the hospitalization for heart failure date will be used as the event date. For analysis of 
CV mortality only and all-cause mortality, the death date will be used. 
 
Fatal pulmonary embolism events are reported as both a pulmonary embolism and a death. In 
analyses that include pulmonary embolism events (i.e., thromboembolic events) without including 
all-cause mortality, the primary approach will be to include only those fatal pulmonary embolism 
events that correspond to a positively adjudicated pulmonary embolism event. These analyses will 
be repeated for supportive purposes using all pulmonary embolism events – including those fatal 
pulmonary embolism events only identified through a primary cause of death (i.e., pulmonary 
embolism) without a corresponding positively adjudicated pulmonary embolism event. For analysis 
of pulmonary embolism or any composite endpoint that includes pulmonary embolism and death, 
if both the pulmonary embolism and death events are positively adjudicated, the pulmonary 
embolism date will be used as the event date. For analysis of CV mortality only and all-cause 
mortality, the death date will be used. 
 
In the situation that there is a fatal MI (or fatal stroke, hospitalization for heart failure, or pulmonary 
embolism) that does not have both an MI (or stroke, hospitalization for heart failure, or pulmonary 
embolism) endpoint and a death endpoint reported, the date of the event that is reported will be 
used in the analysis of all relevant endpoints. This would additionally apply to situations where the 
MI (or stroke, hospitalization for heart failure, or pulmonary embolism) may occur within an 
analysis period and the death may occur outside of the analysis period; the endpoint with the date 
in the analysis period will be used for all relevant endpoints. 
Missing or Partial Endpoint Dates 
Missing or Partial Event (Start) Dates 
• If event dates are missing or partial and there is not sufficient information to classify the time 
period of the event, the event will be classified as occurring on-treatment and post-
randomization. The event will also be considered to have occurred during the follow-up for 
cardiovascular events as defined in Section 10.6.4. 
• The following rules for missing or partial event dates for events other than death will be 
implemented as long as the imputed date is after the randomization date. If the imputed date 
is prior to the randomization date, then the date of randomization will be imputed for the event 
date. 
o If only the day of the month is missing, impute the first day of the month (e.g., --
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FEB2016 would impute as 01FEB2016) 
o If the month and day of the month are missing, impute 01JAN (e.g., -----2016 
would impute as 01JAN2016) 
o If the year, month, and day of month are missing, impute the randomization date 
• The following rules for missing or partial death dates will be implemented as long as the 
imputed date is after the randomization date. If the imputed date is prior to the randomization 
date, then the date of randomization will be imputed for the death date.  
o The latest clinic visit, telephone visit, other contact with subject visit, CV endpoint 
(other than death), AE or SAE date, or date last known to be alive will be 
determined. If the year, month, and day of month of the death are missing then 
the death date will be imputed as the latest of the dates. 
o If only the day of the month of death is missing, then impute the first day of the 
month (e.g., --FEB2016 would impute as 01FEB2016). However, if this imputed 
date results in a date that is prior to the latest clinic visit, telephone visit, other 
contact with subject visit, CV endpoint (other than death), AE or SAE date, or 
date last known to be alive then impute the missing day of death as equal to this 
date instead. For example: 
▪ If –FEB2016 is given as the death date and there is a non-fatal MI on 
08FEB2016, then the imputed date of death would be 08FEB2016 rather 
than 01FEB2016 such that the death is not before the non-fatal MI. 
▪ If –MAR2016 is give as the death date and the latest date is a non-fatal 
MI on 08FEB2016 then the imputed date of death would be 01MAR2016. 
o If the month and day of the month of death are missing, then impute as 01JAN 
(e.g., -----2016 would impute as 01JAN2016). However, if this imputed date 
results in a date that is prior to the latest clinic visit, telephone visit, other contact 
with subject visit, CV endpoint (other than death), AE or SAE date, or date last 
known to be alive then impute the missing month and day of death as equal to 
this date instead. For example: 
▪ If -----2016 is given as the death date and the latest date is a non-fatal MI 
on 08FEB2016 then the imputed date of death would be 08FEB2016 
rather than 01JAN2016 such that the death is not before the non-fatal MI. 
▪ If -----2017 is given as the death date and the latest date is a non-fatal MI 
on 08FEB2016 then the imputed date of death would be 01JAN2017. 
o For deaths that occur after subjects have prematurely withdrawn from the study, 
missing or partial dates will be imputed as specified above except if the 
imputation places the death prior to or on the premature withdrawal date. In this 
case the death date will be imputed as the premature withdrawal date..  
 
Missing or Partial Hospitalization End Dates 
• If hospitalization end dates are missing or partial, the following rules for missing or partial 
dates will be implemented as long as the imputed date is before the next hospitalization start 
date or study completion/withdrawal date (if there is no next hospitalization start date). If the 
imputed date is after the next hospitalization start date, then the date of the next 
hospitalization start date – 1day will be used as the hospitalization end date. If the imputed 
date is after the study completion/withdrawal date, then the date of the study 
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completion/withdrawal date will be used as the hospitalization end date. 
o If only the day of the month is missing, impute the last day of the month (e.g., --
MAR2016 would impute as 31MAR2016) 
o If the month and day of the month are missing, impute 31DEC (e.g., -----2016 
would impute as 31DEC2016) 
o If the year, month, and day of month are missing, impute the date of study 
completion/withdrawal. 
Order of CV Safety Endpoint Events 
• If multiple events occur on the same day or have imputed dates that place them on the 
same day, but it is not clear which event occurred first, then the following order will be 
applied: 
1. MI 
2. Stroke 
3. Hospitalization for Heart Failure 
4. Thromboembolic Event: DVT 
5. Thromboembolic Event: VAT 
6. Thromboembolic Event: PE 
7. Death 
CV Mortality 
• CV mortality includes all adjudicated deaths indicated as having a cardiovascular primary 
cause of death (including fatal MI and fatal stroke events) as well as deaths with an 
undetermined primary cause of death that are indicated to be either presumed sudden death 
or presumed cardiovascular death. Deaths with an undetermined primary cause of death that 
are indicated to be an unknown death will not be included as a CV mortality event. 
Heart Failure Events 
• The primary heart failure event of interest in this study is hospitalization for heart failure. 
However, investigators are requested to report all potential heart failure events for 
adjudication, even if there was no hospitalization associated with the event. 
• The CEC will categorize heart failure events into one of the following adjudicated event types: 
o Hospitalization for Heart Failure 
o Urgent ER/ED Visit for Heart Failure 
o Urgent Office/Practice Visit for Heart Failure 
o Negative adjudication (i.e., not one of the heart failure events above) 
• For purposes of endpoints that contain hospitalization for heart failure as a component, only 
the events adjudicated by the CEC as Hospitalization for Heart Failure will be included. 
• The concordance table for heart failure events will include the 4 adjudicated event types listed 
above. 
Investigator-reported Endpoint Events for Concordance 
• For purposes of concordance tables, events with an investigator-reported event date  
randomization date during the time period for follow-up of cardiovascular events, that meet the 
following final diagnosis criteria will be considered to be investigator-reported endpoint events: 
 
Endpoint 
Investigator-reported final diagnosis (from eCRF) 
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Myocardial infarction 
Myocardial infarction 
Stroke 
Primary ischemic stroke (with or without hemorrhagic 
transformation), Primary intracranial hemorrhage, Retinal/ocular 
hemorrhage or infarction, Unknown type of stroke 
Hospitalization for 
Heart Failure 
Systolic heart failure, Diastolic heart failure, Heart failure - 
unspecified type 
 
Additional criteria: 
If admission/discharge times are non-missing, at least one of the 
following must be true (1-3):  
1. Time in hospital is ≥24 hours 
2. Time in ED/ER is ≥24 hours 
3. Consecutive time in hospital + time in ED/ER is ≥24 hours 
Or if admission/discharge times are missing, then at least one of 
the following must be true (4-6): 
4. Change in calendar date between hospital admission and 
discharge 
5. Change in calendar date between ED/ER admission and 
discharge 
6. Change in calendar date between consecutive hospital and 
ED/ER admission and discharge 
Thromboembolic 
Event (DVT, PE, VAT) 
Deep Vein Thrombosis (DVT), Pulmonary Embolism (PE), 
Vascular Access Thrombosis 
All-cause mortality 
Any death record 
CV mortality 
Any Cardiovascular primary cause of death 
Non-CV mortality 
Any Non-Cardiovascular primary cause of death 
Unknown (sub-
category of All-cause 
mortality) 
Any Unknown primary cause of death 
 
Events with an adjudication record, but without an investigator reported record, will also be 
included in the concordance summaries. 
All-cause Hospitalization and All-cause Hospital Re-admission within 30 days 
• All-cause hospitalization events are defined to be hospital admissions recorded on the 
Hospitalization eCRF form with a hospitalization duration  24 hours. 
• All-cause hospital re-admissions within 30 days are defined to be hospital admissions 
recorded on the Hospitalization eCRF form with a hospitalization duration of  24 hours and 
an admission date within 30 days following a previous discharge date of an all-cause 
hospitalization event, where the previous hospitalization should be  24 hours as stated 
above. 
• Hospitalization rate (per year) across the study = number of all-cause hospitalization events / 
[follow-up time (days) / 365.25]. 
• All-cause hospital re-admission rate (per year) across the study = number of all-cause hospital 
re-admissions / [follow-up time (days) / 365.25]. 
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General Definitions 
• Time to event (days) = date of event – randomization date +1 
• Censored time (days) = censoring date – randomization date + 1 
• First event person years = (cumulative total time to first event for subjects who have the event 
+ cumulative total of censoring time for subjects without the event) / 365.25 
• First event incidence rate (per 100 person years) = (100 * number of subjects with at least 1 
event) / first event person years 
• First event absolute rate difference (per 100 person years) = daprodustat incidence rate (per 
100 person years) – rhEPO incidence rate (per 100 person years) 
Evaluation Time Periods for CV Endpoints 
Time Period for Follow-up of Cardiovascular Endpoints 
The period for capturing CV safety endpoints begins at randomization. The end of this time period 
is the date of study completion/withdrawal, with the exception that if a death has been reported in 
the clinical database after this time, then the death will be included in the analysis. 
 
Any endpoints that occurred before the start of this time period are considered to be prior to the 
time period for follow-up of cardiovascular safety events, and any endpoints that occurred after the 
end of this time period are considered to be post the time period for follow-up of cardiovascular 
safety endpoints. 
Time Period for Vital Status 
The period for capturing vital status begins at the date of randomization. The end of this time 
period is defined as follows: 
• For all subjects known to have died, use the date of death 
• For all subjects who complete the study, use the study completion date (see Section 10.6.1) 
• For all subjects who withdraw from the study, but vital status has been ascertained, and are 
known to have not died – use the latest date last known to be alive. If vital status has not been 
ascertained following study withdrawal, use the study withdrawal date 
 
Any endpoints that occurred before the start of this time period are considered to be prior to the 
time period for vital status, and any endpoints that occurred after the end of this time period are 
considered to be post the time period for vital status. 
Time Period for On-treatment Cardiovascular Endpoints 
The period for capturing on-treatment CV safety endpoint events begins at the treatment start date. 
The end of this time period is defined as follows: 
• For subjects whose last non-zero dose date is missing and who took randomized treatment, 
use date of study withdrawal/completion 
• For subjects continuing on study past the last non-zero dose date +28 days, use (last non-zero 
dose date + 28) 
• For subjects whose study withdrawal/completion date is on or before (last non-zero dose date 
+28), use date of study withdrawal/completion 
 
If the censoring date as defined above for on-treatment CV safety endpoints is after the censoring 
date as defined for the primary analysis during the time period for follow-up of CV safety endpoints, 
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then use the censoring date for the primary analysis time period. 
 
Any endpoints that occurred before the start of this time period are considered to be prior to the 
time period for on-treatment cardiovascular safety endpoints, and any endpoints that occurred after 
the end of this time period are considered to be post the time period for on-treatment 
cardiovascular safety endpoints. 
10.6.4.2. 
Blood Pressure Endpoints 
Blood Pressure Endpoints 
Pre- and Post- Dialysis BP 
• For subjects undergoing dialysis in-clinic, both pre- and post- dialysis BP values will be 
measured. 
• Unless otherwise specified, for summaries and analyses of BP values, the post-dialysis BP 
values for subjects undergoing dialysis in-clinic will be used.  
End of Treatment BP Value 
• See Section 10.6.1 
Mean Arterial Pressure (MAP) 
• MAP = [(2*DBP) + SBP]/3 
Blood Pressure Exacerbations 
• BP exacerbations will be defined as ( 25 mmHg increase from baseline or SBP  180 mmHg 
or DBP  15 mmHg increase from baseline or DBP  110 mmHg) and grouped by type as 
follows: 
o BP exacerbations 
▪ SBP exacerbations 
• 
 25 mmHg increase from baseline or  
• SBP  180 mmHg 
o SBP  180 mmHg and baseline SBP < 180 mmHg 
(including subjects with a missing baseline SBP) 
o SBP  180 mmHg and baseline SBP ≥ 180 mmHg 
▪ DBP exacerbations 
• 
 15 mmHg increase from baseline or  
• DBP  110 mmHg 
o DBP  110 mmHg and baseline DBP < 110 mmHg 
(including subjects with a missing baseline DBP) 
o DBP  110 mmHg and baseline DBP ≥110 mmHg 
Notes:  
• BP values used to assess BP exacerbations must be on-treatment (see Section 10.4.1), unless 
otherwise specified. 
• BP values used to assess BP exacerbations can be scheduled or unscheduled. 
• For visits where BP is measured in triplicate, the average of the 3 BP values will be used to 
assess BP exacerbations. 
• For subjects who have in-clinic dialysis, BP exacerbations identified using post-dialysis BP 
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values will be used in summaries and analyses of BP exacerbations, unless otherwise 
specified. 
• Subjects with multiple exacerbation events on the same calendar date for each type defined 
above are considered to have one exacerbation event for event counts by type. For example, a 
subject with an SBP and a DBP exacerbation on the same date would count in each of the 
SBP and DBP types, but would only count as one BP exacerbation event in in the total BP 
exacerbation type. 
Blood Pressure Exacerbation Event Date 
• Date of BP exacerbation 
On-Treatment BP Medication 
• See Section 10.4.1 for treatment states for concomitant medications. 
General 
• Censored time (days) = last non-zero dose date– treatment start date + 1 
• BP exacerbation person years = (cumulative total of censoring time for all subjects) / 365.25 
• BP exacerbation event incidence rate (per 100 person years) = (100 * number of BP 
exacerbations) / BP exacerbation person years 
Changes in Blood Pressure Medications 
• No change: no new anti-hypertensive records since baseline (day before randomized 
treatment start date) and no change to anti-hypertensive records since baseline until date 
of visit while on randomized treatment. 
• Increase: addition of new anti-hypertensive records for any reason or a change with a 
primary reason for changing dose/frequency or stopping of ‘increased to…’ since baseline 
until date of visit while on randomized treatment 
• Decrease: discontinuation of an anti-hypertensive record with primary reason for change 
starting with “discontinued” or a change with a reason of ‘Decreased due to…’ since 
baseline until date of visit while on randomized treatment 
• Switch = change with a reason of ‘switched to another agent…’ since baseline until date of 
visit while on randomized treatment 
Cumulative Changes in Blood Pressure Medications 
• For the summary of cumulative changes excluding “Once only” and “PRN” records, 
cumulative change will be counted from the date of first randomized treatment to the Week 
52 visit date while on randomized treatment. If a new anti-hypertensive medication is 
added during this time, it will be counted as one change. If the medication also stops 
during this period, then it will count as two changes (one change due to starting, and one 
change due to stopping). The cumulative number of changes will be calculated by adding 
up the changes for all records during this time period. The same steps will be repeated for 
the period starting from the date of first randomized treatment to End of Treatment 
• For the summary of cumulative changes for “Once only” records only, cumulative change 
will be counted from the date of first randomized treatment to the Week 52 visit date while 
on randomized treatment. Since “Once only” doses will have same start and stop dates, a 
new anti-hypertensive medication record during this period will be counted as one change. 
As “once only” doses are likely administered to control BP during dialysis, so they are 
considered part of a single titration regimen, hence multiple “once only” records on the 
same date will be counted as one change. The same steps will be repeated for the period 
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starting from the date of first randomized treatment to End of Treatment 
 
10.6.4.3. 
Adverse Events 
Adverse Events 
AEs of Special Interest 
Adverse events of special interest are classified as follows: 
• Thrombosis and/or tissue ischemia secondary to excessive erythropoiesis   
• Cardiomyopathy 
• Pulmonary artery hypertension 
• Cancer-related mortality and tumor progression and recurrence  
• Esophageal and gastric erosions 
• Proliferative retinopathy, macular edema, choroidal neovascularization  
• Exacerbation of rheumatoid arthritis 
• Worsening of hypertension 
 
Potential AESIs will be identified through a pre-defined terms of interest process in which pre-
defined lists of AE preferred terms corresponding with each AESI will be used to identify events 
considered to be potential AESIs. Sites will be prompted via query to complete any necessary 
additional information for these AESIs in the eCRF. 
 
For the category of thrombosis and/or tissue ischemia secondary to excessive erythropoiesis, after 
the terms of interest list has been applied, the additional Hgb criteria described below will be 
applied to identify only those events that are considered to be secondary to excessive 
erythropoiesis as meeting the AESI definition for thrombosis and/or tissue ischemia secondary to 
excessive erythropoiesis. 
Thrombosis and tissue ischemia events will be considered to be secondary to excessive 
erythropoiesis if during the window of [AE start date – 30 days, AE start date +15 days] any one of 
the following 3 events occurs: 
• Any Hgb value  13 g/dL (measured pre-dialysis) 
• Hgb increase > 2 g/dL over 2 weeks (+1 week) 
o Note: for programming purposes, a +1 week window is applied, corresponding to 
the allowable visit window, to look for increases > 2 g/dL over 3 weeks 
• Hgb increase > 4 g/dL over 4 weeks (+1 week) 
o Note: for programming purposes, a +1 week window is applied, corresponding to 
the allowable visit window, to look for increases > 4 g/dL over 5 weeks 
To identify Hgb increases that meet the increase criterion above, all Hgb values taken within [AE 
start date – 58 days, AE start date + 15 days] will be identified. This corresponds to identifying Hgb 
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values that occurred 4 weeks before the [AE start date – 30 days, AE start date +15 days] window 
of interest. HemoCue Hgb and central laboratory Hgb values will then be evaluated separately to 
identify increases, so that HemoCue and central laboratory Hgb values are not compared to each 
other to identify an increase. 
For HemoCue Hgb and separately for central laboratory Hgb values, if there is a Hgb value (or 
daily Hgb average) within the [AE start date – 30 days, AE start date +15 days] window and an 
earlier Hgb value (or daily Hgb average) that is within the larger [AE start date – 58 days, AE start 
date + 15 days] window, and the amount of time between the two Hgb values is: 
• Between 1 day and 3 weeks, inclusive, then the Hgb values will be compared to determine 
if there has been a Hgb increase > 2g/dL. 
• Between 15 days and 5 weeks, inclusive, then the Hgb values will be compared to 
determine if there has been a Hgb increase > 4g/dL. 
Unscheduled Hgb values will also be used in the assessment of secondary to excessive 
erythropoiesis following the guidance specified in Section 10.6.3 for unscheduled Hgb values and 
multiple Hgb values on the same date. 
Pre-defined Lists of AE Preferred Terms Corresponding with Each AESI 
Thrombosis and/or tissue ischemia secondary to excessive erythropoiesis 
• Narrow SMQ: Embolic and thrombotic events, arterial 
• Narrow SMQ: Embolic and thrombotic events, venous 
• Narrow SMQ: Embolic and thrombotic events, vessel type unspecified and mixed arterial and 
venous 
• Broad SMQ: Thrombophlebitis 
• Additional Preferred Terms:  
o Vascular access site occlusion 
o Stoma site ischaemia 
o Vascular access site complication 
o Subendocardial ischaemia 
o Retinal vascular occlusion 
o Uterine ischaemia 
o Administration site ischaemia 
o Vaccination site ischaemia 
o Anterior segment ischaemia 
o Vestibular ischaemia 
o Application site ischaemia 
o Cerebral small vessel ischaemic disease 
o Biliary ischaemia 
o Colitis ischaemic 
o Bone marrow ischaemia 
o Delayed ischaemic neurological deficit 
o Brain stem ischaemia 
o Hypoxic-ischeaemic encephalopathy 
o Catheter site ischaemia 
o Ischaemic cardiomyopathy 
o Cerebellar ischaemia 
o Ischaemic cerebral infarction 
o Cerebral ischaemia 
o Ischaemic contracture of the left 
ventricle 
o ECG signs of myocardial ischaemia 
o Ischaemic enteritis 
o Gastrointestinal ischaemia 
o Ischaemic gastritis 
o Graft ischaemia 
o Ischaemic heart disease prophylaxis 
o Hepatic ischaemia 
o Ischaemic hepatitis 
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o Implant site ischaemia 
o Ischaemic limb pain 
o Infusion site ischaemia 
o Ischaemic mitral regurgitation 
o Injection site ischaemia 
o Ischaemic nephropathy 
o Intestinal ischaemia 
o Ischaemic neuropathy 
o Ischaemia 
o Ischaemic pancreatitis 
o Macular ischaemia 
o Ischaemic skin ulcer 
o Medical device site ischaemia 
o Ischaemic stroke 
o Myocardial ischaemia 
o Necrosis ischaemic 
o Peripheral ischaemia 
o Ocular ischaemic syndrome 
o Renal ischaemia 
o Optic ischaemic neuropathy 
o Retinal ischaemia 
o Reversible ischaemic neurological deficit 
o Spinal cord ischaemia 
o Transient ischaemic attack 
 
Cardiomyopathy 
• Narrow SMQ: Cardiomyopathy 
Pulmonary artery hypertension 
• High Level Term: Pulmonary hypertensions 
• Additional Preferred Terms: 
o Right ventricular dilatation 
o Right ventricular enlargement 
o Right ventricular dysfunction 
o Right ventricular failure 
o Right ventricular ejection fraction decreased 
o Right ventricular hypertrophy 
 
Cancer-related mortality and tumor progression and recurrence 
• Narrow SMQs: 
o Biliary malignant tumours 
o Myelodysplastic syndrome 
o Biliary tumours of unspecified malignancy o Oropharyngeal neoplasms 
o Breast malignant tumours 
o Ovarian malignant tumours 
o Breast tumours of unspecified 
malignancy 
o Ovarian tumours of unspecified 
malignancy 
o Liver malignant tumours 
o Prostate malignant tumours 
o Liver tumours of unspecified malignancy 
o Prostate tumours of unspecified 
malignancy 
o Malignancy related conditions 
o Tumour lysis syndrome 
o Haematological malignant tumours 
o Skin malignant tumours 
o Non-haematolgoical malignant tumours 
o Skin tumours of unspecified malignancy 
o Haematological tumours of unspecified 
malignancy 
o Uterine and fallopian tube malignant 
tumours 
o Non-haematological tumours of 
unspecified malignancy 
o Uterine and fallopian tube tumours of 
unspecified malignancy 
o Malignant lymphomas 
 
 
• Additional Preferred Terms: 
o Aplastic anaemia 
o Pancytopenia 
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o Cytopenia 
o Myelosuppression 
o Aplasia pure red cell 
 
Esophageal and gastric erosions 
• High Level Terms: 
o Duodenal ulcers and perforation 
o Oesophageal ulcers and perforation 
o Gastric ulcers and perforation 
o Peptic ulcers and perforation 
o Gastrointestinal ulcers and perforation, site 
unspecified 
 
• Additional Preferred Terms: 
o Haematemesis 
o Helicobacter duodenitis 
o Gastrointestinal haemorrhage 
o Helicobacter gastritis 
o Upper gastrointestinal haemorrhage 
o Melaena 
 
Proliferative retinopathy, macular edema, choroidal neovascularization 
• Broad SMQ: Retinal disorders 
Exacerbation of rheumatoid arthritis 
• High Level Term: Rheumatoid arthropathies 
• Additional Preferred Terms: 
o Rheumatoid factor increased 
o Rheumatoid factor quantatative increased 
o Rheumatoid factor positive 
 
 
Worsening of hypertension 
• Narrow SMQ: Hypertension 
Blood Pressure Events 
BP events will be identified during the study via programmatic sweeps of AE and SAE terms 
entered into the eCRF (using the narrow SMQ for hypertension). AEs identified this way will require 
an additional BP Exacerbation eCRF page to be completed that characterizes the event as 
clinically significant and/or symptomatic.  
In addition, subjects that experience BP values that meet the following criteria at any visit will also 
be considered to have a BP event and be required to complete the Blood Pressure Exacerbation 
eCRF page: 
• SBP: an increase from baseline of  25 mmHg or SBP  180 mmHg 
• DBP: an increase from baseline of  15 mmHg or DBP  110 mmHg 
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BP-related SAEs are those SAEs that have been identified via the BP Exacerbation eCRF page. 
False Discovery Rate (FDR) Method and Procedure 
The FDR method adjusts p-values within a group (SOC or preferred terms (PTs) within a SOC) 
based on the following: 
a) Order p-values from lowest to highest (1... m) 
b) Compute adjusted p-values, p’, as follows 
p’(m) = p(m) i.e., the adjusted p-values for the highest p-value is the same as the 
highest p-value 
p’(j) = min({p’(j+1), m/j*p(j)} for j  m - 1 
The FDR procedure is applied at the system organ class (SOC) level and for each AE preferred 
term (PT) reported as Tier 2 events. The following stops will be undertaken in this procedure: 
1. Compute adjusted p-values for PTs within each SOC using the FDR method. 
2. Order SOCs (small to large) according to the minimum FDR adjusted p-value observed for 
treatment differences across PTs within SOC. 
3. Perform the FDR method on the minimum adjusted p-values from Step 2. 
4. Select SOCs with FDR adjusted p-value from Step 3 <0.10. 
5. Apply a single FDR adjustment to all unadjusted p-values belonging to all PTs from SOCs 
identified in Step 4. with a threshold of FDR adjusted p-values <0.10 will be used to flag 
PTs that warrant further investigation. 
Note that 0.10 is recommended as a reasonable multiplicity adjustment for 0.05. 
General Definitions 
• Post-Randomization last contact date for censoring (subjects not having AE) will be 
defined as the study completion date. 
• Treatment emergent last contact date for censoring (subjects not having AE) will be 
defined as follows: 
o 1 day after the last non-zero dose date (last non-zero dose date + 1) for subjects 
not having treatment emergent AE and continuing on study past (last non-zero 
dose date + 1) 
o Last non-zero dose date for all other subjects 
• AE Patient Years: (Cumulative total of time to AE for subjects who have the AE + 
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Cumulative total of censoring time for subjects without the AE) / 365.25 
o For treatment emergent AEs, the start date of the patient years value for each 
subject should be the treatment start date. 
o For post-randomization AEs, the start date of the patient years value for each 
subject should be the randomization date. 
o For follow-up AEs, the start date of the patient years value for each subject should 
be 2 days after the last non-zero dose date (last non-zero dose date + 2). 
• Incidence Rate (per 100 patient years): (100 * Number of subjects with at least 1 AE) / AE 
person years 
• For the analysis of the time to AE onset/worsening, if the AE onset/worsening date is 
missing then the time to AE onset/worsening will be counted as 1 day. 
10.6.4.4. 
Laboratory Parameters 
Laboratory Parameters 
• If a laboratory value which is expected to have a numeric value for summary purposes, has a 
non-detectable level reported in the database, where the numeric value is missing, but typically 
a character value starting with ‘<x’ or ‘>x’ (or indicated as less than x or greater than x in the 
comment field) is present, the number of significant digits in the observed values will be used 
to determine how much to add or subtract in order to impute the corresponding numeric value.  
o Example 1: 2 Significant Digits = ‘< x’ becomes x – 0.01 
o Example 2: 1 Significant Digit   = ‘> x’ becomes x + 0.1 
o Example 3: 0 Significant Digits = ‘< x’ becomes x – 1     
• If there is more than one laboratory value on the same date for the same laboratory test, then 
the laboratory values associated with scheduled visits will be used. Hgb summaries and 
analyses are an exception and should use the data handling conventions outlined in Section 
10.6.3. 
• For purposes of flagging worst-case post baseline laboratory values: 
o If there are multiple scheduled values on the same day, or only multiple 
unscheduled values on the same day, then the average of the values on that day 
should be used for the purpose of determining the worst-case value. 
• The following will be used to convert laboratory values from SI units to conventional units 
[Iverson, 2007]: 
• MCHC and Albumin: Divide the g/L value by 10 to get the g/dL value. 
• Albumin corrected calcium: Divide the mmol/L value by 0.25 to get the mg/dL value. 
• Phosphate: Divide the mmol/L value by 0.323 to get the mg/dL value. 
• BUN: Divide the mmol/L value by 0.357 to get the mg/dL value. 
• Total cholesterol, LDL-C and HDL-C: Divide the mmol/L value by 0.0259 to get the mg/dL 
value. 
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Normal Range Categories, PCI Criteria Categories and Worst Case Values 
• Normal range categories are: To Low, To Normal or No Change, To High 
• PCI criteria categories are: To Low, To w/in Range or No Change, To High 
• Subjects with a missing baseline value are to be assumed to have a normal/within range 
baseline value. 
• The determination of the worst-case post baseline value takes into account both planned and 
unscheduled assessments. 
• Worst case can be either High or Low.  
o If a subject has both a decrease ‘To Low’ and an increase ‘To High’, then the 
subject is counted in both the ‘To Low’ and ‘To High’ categories.  
o If a subject was High at baseline and decreases to Low during the time interval, 
then the subject is counted in the ‘To Low’ category. Likewise, if a subject was low 
at baseline and increases to high during the time interval, then the subject is 
counted in the ‘To High’ category. 
o Subjects are only counted in the ‘To Normal or No Change’ or ‘To w/in Range or 
No Change’ category if their values are: 
▪ When using normal ranges: Normal at baseline and have no high and no 
low values; When using PCI ranges: Within range at baseline and have no 
high and no low values 
▪ High at baseline and do not change to low 
▪ Low at baseline and do not change to high 
10.6.4.5. 
Vital Signs 
Vital Signs 
Pre- and Post- Dialysis HR & Weight 
• For subjects undergoing dialysis in-clinic, both pre- and post- dialysis HR & weight values will 
be measured. 
• Unless otherwise specified, for summaries of HR & weight values, the post-dialysis HR & 
weight values for subjects undergoing dialysis in-clinic will be used.  
• If there is more than one vital sign value on the same date for the same vital sign value, then 
the vital sign values associated with scheduled visits will be used. 
• If there are multiple values from a scheduled visit on the same date, then the average of the 
scheduled values will be used. 
• For purposes of flagging worst-case post baseline vital sign values: 
o If there are multiple scheduled values on the same day, or only multiple 
unscheduled values on the same day, then the average of the values on that day 
should be used for the purpose of determining the worst-case value. 
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10.6.4.6. 
COVID-19 
COVID-19 
Exposure Duration 
• For subjects who DO NOT experience the event, the exposure duration is calculated as: 
(last non-zero dose date or end date of time block, whichever occurs sooner – treatment start 
date or start date of time block, whichever occurs later + 1)/365.25 
• For subjects who DO experience the event, the exposure duration is calculated as: 
(start date of AE – treatment start date or start date of time block, whichever occurs later + 
1)/365.25 
Exposure Adjusted Incidence Rate 
• Exposure adjusted incidence rate (rate/100 PY) = (number of subjects with the adverse event 
during the time block / total exposure duration across all subjects) * 100 
 
Time Periods  
• Pre COVID-19 pandemic period: the date of interest is prior to the country specific start date of 
COVID-19 pandemic measures. For example, for recruitment and demographic summaries, 
the subject will be counted in the pre COVID-19 period, if the randomization date of the subject 
is prior to the country specific start date of COVID-19 pandemic measures. 
• During COVID-19 period: the date of interest is after the country specific start date of COVID-
19 pandemic measures. For example, for recruitment and demographic summaries, the subject 
will be counted in the during COVID-19 period, if the randomization date of the subject is after 
the country specific start date of COVID-19 pandemic measures. 
• There is currently no post COVID-19 period. 
10.6.5. 
Patient Reported Outcomes 
SF-36 
General Information & Scoring 
• The SF-36 acute version 2 is a 36-item generic quality of life instrument designed to measure a 
subject’s level of performance in the following eight health domains: Physical Functioning, 
Role-Physical (role limitations caused by physical problems), Social Functioning, Bodily Pain, 
Mental Health, Role-Emotional (role limitations caused by emotional problems), Vitality, and 
General Perception of Health. 
• Scoring of the questionnaire data will be performed using Optum PRO CoRE scoring software 
version 1.4 using a norms-based scoring approach using 2009 norms and the maximum data 
recovery mode to handle missing data.  
• The 8 domain scores and scores for the physical and mental component summary measures 
will be provided by the Optum PRO CoRE software. 
 
EQ-5D-5L 
General 
• The EQ-5D-5L is a self-assessment questionnaire, consisting of five items covering five 
dimensions (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression). Each 
dimension is measured by a five-point Likert scale (no problems, slight problems, moderate 
problems, severe problems, and extreme problems). 
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EQ-5D-5L 
General 
• The responses for the five dimensions together form a five-figure description of a health state 
(i.e., the score of 11112 describes the health state of no problems with mobility, self-care, 
usual activities or pain/discomfort, but slight problems with anxiety/depression). EQ-5D-5L 
health states are converted to a single summary index score by applying a country-specific 
value set formula that essentially attaches weights to each of the levels in each dimension. 
• The EuroQol Group’s United Kingdom (UK) crosswalk value set for the health states will be 
used for all subjects, regardless of country. The converted single index using this value set will 
be on a scale from -0.594 to 1, where -0.594 is the 
 and 1 is the 
 
. 
• The EQ-5D-5L will only be assessed in the countries listed in Section 10.9. 
 
EQ-VAS 
General 
• The EQ-VAS is a self-assessment visual analogue scale, ranging from 0=
 – 
100=
.  
• The EQ-VAS will only be assessed in the countries listed in Section 10.9. 
 
PGI-S 
General 
• The PGI-S is a 1-item questionnaire designed to assess a subject’s impression of disease 
severity on a 5-point disease severity scale (absent, mild, moderate, severe, or very severe). 
• Scores range from 
 as follows: 
o 
o 
o 
o 
o 
 
PGI-C 
General 
• The PGI-C is a 1-item questionnaire designed to assess a subject’s impression of change in 
their anemia of CKD on a 7-point Likert-type response scale (very much improved, moderately 
improved, minimally improved, no change, minimally worse, moderately worse, or very much 
worse). 
• Scores range from to
as follows: 
o 
o 
o 
o 
o 
o 
o 
 
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CCI
CCI
CCI
CCI
CCI
CCI
CCI
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Clinical Outcome Assessment 
data collection questionnaires or 
indices, which are protected by 
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10.7. 
Appendix 7: Premature Withdrawals & Handling of Missing 
Data 
10.7.1. 
Premature Withdrawals 
Element 
Reporting Detail 
General 
• Subject study completion (i.e. as specified in the protocol) was defined as 
completing all phases of the study including the End of Study visit, with the 
following exception: subjects who die while on study are also considered as 
having completed the study.  
• Withdrawn subjects will not be replaced in the study. 
• All available data from subjects who were withdrawn from the study will be listed 
and all available planned data will be included in summary tables and figures, 
unless otherwise specified. 
• Per protocol, subjects may prematurely discontinue study drug but are 
encouraged to remain in the study. 
10.7.2. 
Handling of Missing Data 
Element 
Reporting Detail 
General 
• Missing data occurs when any requested data is not provided, leading to blank 
fields on the collection instrument: 
o These data will be indicated by the use of a “blank” in subject listing 
displays, unless all data for a specific visit are missing in which case the 
data is excluded from the table.  
o Answers such as “Not applicable” and “Not evaluable” are not considered to 
be missing data and should be displayed as such. 
Outliers 
• Any subjects excluded from the summaries and/or statistical analyses will be 
documented along with the reason for exclusion in the clinical study report. 
10.7.2.1. 
Handling of Missing and Partial Dates 
Element 
Reporting Detail 
General 
Partial dates will be displayed as captured in subject listing displays. 
Concomitant 
Medications 
• Partial dates for any concomitant medications recorded in the CRF will be 
imputed using the following convention: 
o If the partial date is a start date, a '01' will be used for the day and 'Jan' will 
be used for the month 
o If the partial date is a stop date, a '28/29/30/31' will be used for the day 
(dependent on the month and year) and 'Dec' will be used for the month. 
• The recorded partial date will be displayed in listings. 
Adverse 
Events 
• The eCRF allows for the possibility of partial dates (i.e., only month and year or 
only year) to be recorded for AE start/worsening and end dates. In such a case, 
the following conventions will be applied for calculating the time to onset and 
the duration of the event: 
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Element 
Reporting Detail 
o Imputing a Start/Worsening Date from a Partial Start/Worsening Date:  
o If an imputed worsening date is before the start date, then the start 
date will be used as the imputed worsening date.  
o Completely missing stop date: 
➢ If only the day is missing, the first of the month will be used 
unless the Screen Week -8 visit date, Run-In visit date or 
treatment start date also occurs in the same month.  
• If the treatment start date occurs in the same 
month, then the treatment start date will be used 
as the start/worsening date.  
• Otherwise, if the Run-In visit date occurs in the 
same month (and the treatment start date is not in 
that month), then the Run-In visit date will be used 
as the start/worsening date.  
• Otherwise, if the Screen Week -8 visit date occurs 
in the same month (and the treatment start and 
Run-In visit dates are not in that month), then the 
Screen Week -8 visit date will be used as the 
start/worsening date. 
➢ If the day and month are missing, then ‘01’ will be used for 
the day and ‘Jan’ will be used for the month unless the 
Screen Week -8 visit date, Run-In visit date or treatment 
start date also occurs in the same year. 
• If the treatment start date occurs in the same year, 
then the treatment start date will be used as the 
start/worsening date.  
• Otherwise, if the Run-In visit date occurs in the 
same year (and the treatment start date is not in 
that year), then the Run-In visit date will be used 
as the start/worsening date.  
• Otherwise, if the Screen Week -8 visit date occurs 
in the same year (and the treatment start and Run-
In visit dates are not in that year), then the Screen 
Week -8 visit date will be used as the 
start/worsening date. 
o Partial or non-missing stop date is before the Run-in visit date:  
➢ If only the day is missing, the first of the month will be used 
unless the Screen Week -8 visit date also occurs in the 
same month; in this case the Screen Week -8 visit date will 
be used as the start/worsening date. 
➢ If the day and month are missing, then ‘01’ will be used for 
the day and ‘Jan’ will be used for the month unless the 
Screen Week -8 visit date also occurs in the same year; in 
this case the Screen Week -8 visit date will be used as the 
start/worsening date. 
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Element 
Reporting Detail 
o Partial or non-missing stop date is before treatment start date, and 
either on or after Run-In date or has the same year (or year and 
month) as the Run-In date:  
➢ If only the day is missing, then the first of the month will be 
used unless the Run-In Visit date also occurs in the same 
month; in this case the Run-In Visit date will be used as the 
start/worsening date. 
➢ If the day and month are missing, then '01' will be used for 
the day and 'Jan' will be used for the month unless the 
Run-In Visit date also occurs in the same year; in this case 
the Run-In Visit date will be used as the start/worsening 
date. 
o Stop date is partial with the same year (or year and month) as the 
treatment start date or is on or after the treatment start date:  
➢ If only the day is missing, then the first of the month will be 
used unless the start date of study treatment also occurs in 
the same month; in this case the study treatment start date 
will be used as the start/worsening date. 
➢ If the day and month are missing, then '01' will be used for 
the day and 'Jan' will be used for the month unless the 
start date of study treatment occurs in the same year; in 
this case the study treatment start date will be used as the 
start/worsening date. 
o Imputing a Stop Date from a Partial Stop Date:  
o Latest of (start date and latest worsening date) is on or before the 
treatment stop date or is partial with the same year (or year and 
month) as the treatment stop date:  
➢ If only the day is missing, the last day of the month will be 
used unless the treatment stop date also occurs in the 
same month; in this case the treatment stop date will be 
used at the stop date. 
➢ If the day and month are missing, then '31' will be used for 
the day and 'Dec' will be used for the month, unless the 
stop date of study treatment also occurs in the same year; 
in this case the study treatment stop date will be used as 
the stop date. 
o Latest of (start date and latest worsening date) is partial or non-
missing and is after treatment stop date:  
➢ If only the day is missing, the last day of the month will be 
used unless the study conclusion date also occurs in the 
same month; in this case, the study conclusion date will be 
used as the stop date. 
➢ If the day and month are missing, then '31' will be used for 
the day and 'Dec' will be used for the month, unless the 
study conclusion date also occurs in the same year; in this 
case, the study conclusion date will be used as the stop 
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Element 
Reporting Detail 
date. 
• Completely missing start, worsening or end dates will remain missing, with no 
imputation applied. Consequently, time to onset and duration of such events will 
be missing. 
CV Safety 
Endpoint 
Events 
Discussed in Section 10.6.4 
 
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10.8. 
Appendix 8: Values of Potential Clinical Importance 
10.8.1. 
Laboratory Values 
Clinical Chemistry 
Laboratory Parameter 
Units 
Clinical Concern Range 
Low Flag 
High Flag 
Albumin  
g/L 
< 30 g/L 
> 55 g/L 
Aspartate Aminotransferase 
IU/L 
 
 3x ULRR 
Alanine Aminotransferase 
IU/L 
 
 3x ULRR 
Bilirubin (total) 
mol/L 
 
 2x ULRR 
Calcium (albumin corrected) 
mmol/L 
< 1.87 mmol/L 
> 2.56 mmol/L 
Phosphate 
mmol/L 
< 0.81 mmol/L 
> 1.77 mmol/L 
Potassium (serum) 
mmol/L 
> 0.5 mmol/L below 
LLRR 
> 1.0 mmol/L above 
ULRR 
 
Hematology 
Laboratory Parameter 
 
Units 
Clinical Concern Range 
Low Flag 
High Flag 
Platelet Count  
GI/L 
< 80 GI/L 
> 500 GI/L 
Leukocytes (white blood cell count) 
GI/L 
< LLRR 
> 5x ULRR 
Neutrophils 
GI/L 
< 0.5x LLRR 
 
Lymphocytes 
GI/L 
< 0.5x LLRR 
 
 
Iron Parameters 
Laboratory Parameter 
Units 
Clinical Concern Range 
Low Flag 
High Flag 
Ferritin 
ng/mL 
< 100 ng/mL 
> 800 ng/mL 
TSAT 
% 
<15% 
> 40% 
 
Other PCI Values 
Laboratory Parameter 
Units 
Clinical Concern Range 
Low Flag 
High Flag 
iPTH 
ng/L 
 
> 9x ULRR 
10.8.2. 
Vital Signs 
Vital Sign Parameter 
(Absolute) 
Units 
Clinical Concern Range 
Lower 
Upper 
Systolic Blood Pressure 
mmHg 
 85 mmHg 
 180 mmHg 
Diastolic Blood Pressure 
mmHg 
 45 mmHg 
 110 mmHg 
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Vital Sign Parameter 
(Absolute) 
Units 
Clinical Concern Range 
Lower 
Upper 
Heart Rate 
bpm 
 40 bpm 
 110 bpm 
Notes: 
• 
At visits where BP and HR are assessed in triplicate, the average of the 3 values will be used to assess 
PCI criteria. 
• 
For subjects who undergo in-clinic dialysis, the post-dialysis BP and HR values will be used to assess 
PCI criteria, unless otherwise specified. 
 
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10.9. 
Appendix 9: Multicenter Studies 
10.9.1. 
Methods for Handling Centres 
• 
In this multicentre global study, enrolment will be presented by investigative site, 
country, and the regions. 
Region 
Countries2 
Region 1: Asia Pacific 
India, Malaysia1, Republic of Korea1, Singapore1, Taiwan1 
Region 2: Eastern Europe/South 
Africa 
Bulgaria, Turkey, Czech Republic, Estonia, Hungary, Poland, 
Romania, Russian Federation, Ukraine, South Africa1 
Region 3: Western 
Europe/Canada/ANZ 
Australia1, Austria, Belgium, Canada1, Denmark1, France, 
Germany, Greece, Italy, Netherlands1, New Zealand1, Norway1, 
Portugal, Spain1, Sweden1, United Kingdom1 
Region 4: Latin America 
Argentina, Brazil1, Mexico 
Region 5: USA 
USA1 
NOTES: 
[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. 
For any summaries which include information related to a subject’s center or 
investigator, the most recent center and investigator at the time that the database is final 
will be used. 
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10.10. 
Appendix 10: Examination of Covariates, Subgroups & 
Other Strata 
10.10.1. 
Handling of Covariates, Subgroups & Other Strata 
• 
The following is a non-exhaustive list of covariates that may be used in summaries 
of demographics, descriptive summaries and statistical analyses.  
• 
Additional covariates of clinical interest may also be considered.  
• 
If the percentage of subjects is small within a particular subgroup, then the subgroup 
categories may be refined prior to unblinding the trial.   
• 
If the category cannot be refined further, then descriptive rather than statistical 
comparisons may be performed for the particular subgroup. If there are less than 25 
subjects in one of the subgroup categories, any subgroup statistical comparison 
should be interpreted with caution.  
• 
A pre-specified strategy for prioritizing subgroups/covariates is defined below (as 
recommended in the 2015 draft Committee for Medicinal Products for Human Use 
(CHMP) guidance on the investigation of subgroups in confirmatory clinical trials) 
• 
The co-primary and principal secondary endpoints will be evaluated for the 
subgroups below. Although subgroup analyses are aimed to assess for consistency 
with the overall results, they may have low power, especially if the subgroup is small 
or has a low number of events. Statistical models (Cox Proportional Hazards or 
ANCOVA) will be adjusted for the covariates used in the original analysis, 
subgroup, treatment and treatment by subgroup interaction. For the prognostic 
randomization stratification factors (region and dialysis type), the actual status of the 
factor derived from the eCRF will be used (see Section 10.10.2). Note that for the 
cardiovascular risk score covariate, the above model will not include a term for 
dialysis type as this analysis is restricted to HD patients only. For the subgroup 
Regions combined (USA vs. non-USA), the randomization stratification factor 
Region (with 5 levels, Regions 1- 5) will not be included in the statistical model. 
• 
For subgroup analyses of time-to-event endpoints, point estimates and confidence 
intervals for the rate per 100 person-years will be reported for each treatment group 
within a subgroup, as well as the point estimate and two-sided 95% CI for the 
difference in rates between treatments within a subgroup. For within-group rates, the 
two-sided 95% CI will be obtained using an exact Poisson method. For difference in 
rates between treatments, the two-sided 95% CI will be constructed with a Normal 
approximation using Wald’s method [Liu, 2006]. 
• For Hgb and selected PRO endpoints using MMRM model in the original analysis, 
the statistical model for the corresponding subgroup analyses will have the following 
factors: dialysis type, region, baseline value, baseline value by time, and subgroup by 
treatment by time interaction terms. The model will be run without main effects 
(treatment, visit, and subgroup) and two-way interaction terms (subgroup by time, 
treatment by time, and subgroup by treatment) for computational ease since in SAS, 
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the main effects and two-way interaction terms are included within the three-way 
interaction term, thus giving equivalent result. For the selected Hgb, BP, and PRO 
endpoints using MMRM in the original model that contain only main effects and two-
way interaction terms, both the main effects and the two-way interaction terms will be 
included in the model statement. If any of the above MMRM models encounter 
convergence issues, then the following steps will be performed in this sequence: 
• Step 1: Use Fisher scoring method 
• Scoring=0 will be used as the first option, which is equivalent to no 
scoring, and if the model fails to converge, the scoring will be updated 
to scoring=1 
• The scoring will be updated each time the model fails to converge until 
a maximum of scoring=4 is reached. At this point, if the model fails to 
converge, Step 2 will be utilized. 
• Step 2: If the model fails to converge, instead of unstructured, TOEPH 
variance-covariance matrix will be used in conjunction with Step 1 
• Step 3: If the model fails to converge, denominator degrees of freedom will be 
changed from Kenward-Roger to Residual in conjunction with Steps 1 and 2.  
Please note that if any of the models still fail to converge after Step 3, model-adjusted 
analyses will not be performed. The associated descriptive statistics will be displayed.  
If the original model fails to converge, but it converges after one of the three steps, 
the output will display the changes made to the original model in a footnote.  
• 
When a subgroup category assesses the same or a similar parameter (e.g., country is 
similar to region) as one of the prognostic stratification variables, the randomization 
stratification variable will be removed from the model. 
• 
Point estimates and two-sided 95% CIs will be estimated within subgroups, the 
subgroup by treatment interaction two-sided p-value will be calculated and subgroup 
results will be graphically presented (e.g. Forest Plots). Directional consistency in 
subgroup treatment effects and a non-significant interaction p-value (two-sided 10% 
level) would support that the overall treatment effect is broadly applicable to the full 
study population. Subgroup analyses will not be adjusted for multiplicity. 
• 
In addition, a nominal one-sided non-inferiority p-value using a non-inferiority 
margin of -0.75 g/dL and a nominal one-sided superiority p-value will be 
generated for the difference between treatment groups for each level of the 
hyporesponder subgroup analyses of the co-primary Hgb endpoint.
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Category 
Covariates and / or Subgroups 
Summary of 
Demographics & 
Baseline 
Characteristics 
Note: Include 
'Missing' 
categories, if 
applicable. 
Subgroup Analysis for 
Co-primary MACE & 
Principal Secondary 
Safety Endpoints 
Note: Do not include 
'Missing' categories. 
Subgroup Analysis for 
Co-primary Hgb & 
Principal Secondary 
Efficacy Endpoints 
Note: Do not include 
'Missing' categories. 
Key Covariates/Subgroups of Regulatory/Clinical Interest or Potential Biological Plausibility for Different Subgroup Effects 
Age (years) 
Summary statistics of continuous 
values 
Yes 
No 
No 
Age at randomization 
(Grouping 1) 
< 65 years, 65-<75 years, ≥75 years 
Yes 
Yes 
Yes 
Age at randomization 
(Grouping 2) 
18 years, 19 - 64 years, ≥ 65 years 
Yes 
No 
No 
Age at randomization 
(Grouping 3) 
18-64 years, 65 - 84 years, ≥ 85 years 
No (included in 
stand-alone age 
ranges table) 
No 
No 
Gender 
Female, Male 
Yes 
Yes 
Yes 
Ethnicity 
Hispanic or Latino, Not Hispanic or 
Latino 
Yes 
Yes 
Yes 
High level race 
American Indian or Alaskan Native  
Asian 
Black or African American 
Native Hawaiian or Other Pacific 
Islander 
White 
Mixed Race 
Yes 
Yes 
Yes 
Race detail 
American Indian or Alaskan Native 
Yes 
No 
No 
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Category 
Covariates and / or Subgroups 
Summary of 
Demographics & 
Baseline 
Characteristics 
Note: Include 
'Missing' 
categories, if 
applicable. 
Subgroup Analysis for 
Co-primary MACE & 
Principal Secondary 
Safety Endpoints 
Note: Do not include 
'Missing' categories. 
Subgroup Analysis for 
Co-primary Hgb & 
Principal Secondary 
Efficacy Endpoints 
Note: Do not include 
'Missing' categories. 
Asian – Central/South Asian Heritage 
Asian – East Asian Heritage 
Asian – Japanese Heritage 
Asian – South East Asian Heritage 
Black or African American 
Native Hawaiian or Other Pacific 
Islander 
White – Arabic/North African Heritage 
White – White/Caucasian/European 
Heritage 
Mixed Asian Race 
Mixed White Race 
Mixed Race 
Region 
See Region categories defined in 
Section 10.9.1 
Yes 
Yes 
Yes 
Regions combined 
USA, Non-USA 
Yes 
Yes 
Yes 
Country 
See Countries listed in Section 10.9.1 
Yes 
No 
No 
Dialysis type at randomization1 
HD, PD, Missing (repeat using HD - 
conventional, HDF/HF, PD, Missing) 
Yes 
Yes (HD/PD only) 
Yes (HD/PD only) 
Prior ESA type at 
randomization 
Darbepoetin alfa only, Epoetin only, 
Methoxy PEG-epoetin beta only, 
Yes 
No 
No 
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Category 
Covariates and / or Subgroups 
Summary of 
Demographics & 
Baseline 
Characteristics 
Note: Include 
'Missing' 
categories, if 
applicable. 
Subgroup Analysis for 
Co-primary MACE & 
Principal Secondary 
Safety Endpoints 
Note: Do not include 
'Missing' categories. 
Subgroup Analysis for 
Co-primary Hgb & 
Principal Secondary 
Efficacy Endpoints 
Note: Do not include 
'Missing' categories. 
Multiple, Missing 
Standardized prior ESA dose 
(U/week)2 
Summary statistics of continuous 
values 
Yes 
No 
No 
Standardized prior ESA dose 
group2 
< 7,000 U/week, ≥7,000 U/week, 
Missing 
Yes 
Yes 
Yes 
Baseline erythropoietin 
resistance index (ERI) 
(U/kg/wk/g/L) 
Summary statistics of continuous 
values 
Yes 
No 
No 
Baseline ERI quartiles 
Overall ITT Population Quartile 1: <xx 
U/kg/wk/g/L 
Overall ITT Population Quartile 2: xx - 
<xx U/kg/wk/g/L 
Overall ITT Population Quartile 3: xx - 
<xx U/kg/wk/g/L 
Overall ITT Population Quartile 4: ≥ xx 
U/kg/wk/g/L 
Missing 
Yes 
No 
No 
rhEPO hyporesponder2 
No, Yes, Missing 
Yes 
Yes 
Yes 
Standardized Prior ESA Dose 
(U/week) for rhEPO 
Hyporesponders 
Summary statistics of continuous 
values 
Yes 
No 
No 
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Category 
Covariates and / or Subgroups 
Summary of 
Demographics & 
Baseline 
Characteristics 
Note: Include 
'Missing' 
categories, if 
applicable. 
Subgroup Analysis for 
Co-primary MACE & 
Principal Secondary 
Safety Endpoints 
Note: Do not include 
'Missing' categories. 
Subgroup Analysis for 
Co-primary Hgb & 
Principal Secondary 
Efficacy Endpoints 
Note: Do not include 
'Missing' categories. 
Standardized Prior ESA Dose 
(U/week) for rhEPO Non-
hyporesponders 
Summary statistics of continuous 
values 
Yes 
No 
No 
Alternate definition of rhEPO 
hyporesponder Definition 22 
No, Yes, Missing 
Yes 
No 
No 
Alternate definition of rhEPO 
hyporesponder Definition 32 
No, Yes, Missing 
Yes 
No 
No 
Baseline Hgb (g/dL) 
Continuous covariate for Hgb co-
primary analysis; summary statistics of 
continuous values 
Yes 
No 
No 
Baseline Hgb group 
< 9 g/dL, 9- <10 g/dL, 10-11 g/dL, > 11 
g/dL, Missing 
Yes 
Yes 
Yes 
Baseline post-dialysis body 
mass index (kg/m2) 
Summary statistics of continuous 
values 
Yes 
No 
No 
Baseline post-dialysis body 
mass index group 
<30 kg/m2, ≥30 kg/m2, Missing 
Yes 
Yes 
Yes 
Baseline post-dialysis weight 
(kg) 
Summary statistics of continuous 
values  
Yes 
No 
No 
Baseline post-dialysis weight 
group 
<75 kg, ≥75 kg, Missing 
Yes 
No 
No 
Baseline post-dialysis weight 
Overall ITT Population Quartile 1: < xx 
Yes 
Yes 
Yes 
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Category 
Covariates and / or Subgroups 
Summary of 
Demographics & 
Baseline 
Characteristics 
Note: Include 
'Missing' 
categories, if 
applicable. 
Subgroup Analysis for 
Co-primary MACE & 
Principal Secondary 
Safety Endpoints 
Note: Do not include 
'Missing' categories. 
Subgroup Analysis for 
Co-primary Hgb & 
Principal Secondary 
Efficacy Endpoints 
Note: Do not include 
'Missing' categories. 
quartiles 
kg 
Overall ITT Population Quartile 2: xx 
kg - < xx kg 
Overall ITT Population Quartile 3: xx 
kg - < xx kg 
Overall ITT Population Quartile 4: ≥xx 
kg 
Missing 
Baseline hsCRP (mg/L) 
Summary statistics of continuous 
values 
Yes 
No 
No 
Baseline hsCRP group 
3 mg/L, >3 mg/L, Missing 
Yes 
No 
No 
Baseline hsCRP quartiles 
Overall ITT Population Quartile 1: < xx 
mg/L 
Overall ITT Population Quartile 2: xx 
mg/L - < xx mg/L 
Overall ITT Population Quartile 3: xx 
mg/L - < xx mg/L 
Overall ITT Population Quartile 4: ≥ xx 
mg/L 
Missing 
Yes 
Yes 
Yes 
Standardized prior ESA dose 
(U/week) for baseline hsCRP 
Summary statistics of continuous 
values 
Yes 
No 
No 
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Category 
Covariates and / or Subgroups 
Summary of 
Demographics & 
Baseline 
Characteristics 
Note: Include 
'Missing' 
categories, if 
applicable. 
Subgroup Analysis for 
Co-primary MACE & 
Principal Secondary 
Safety Endpoints 
Note: Do not include 
'Missing' categories. 
Subgroup Analysis for 
Co-primary Hgb & 
Principal Secondary 
Efficacy Endpoints 
Note: Do not include 
'Missing' categories. 
Overall ITT Population Quartile 
1: < xx mg/L 
Standardized prior ESA dose 
(U/week) for baseline hsCRP 
Overall ITT Population Quartile 
2: xx -< xx mg/L 
Summary statistics of continuous 
values 
Yes 
No 
No 
Standardized prior ESA dose 
(U/week) for baseline hsCRP 
Overall ITT Population Quartile 
3:xx - < xx mg/L 
Summary statistics of continuous 
values 
Yes 
No 
No 
Standardized prior ESA dose 
(U/week) for baseline hsCRP 
Overall ITT Population Quartile 
4: >= xx mg/L 
Summary statistics of continuous 
values 
Yes 
No 
No 
Dosing algorithm at 
randomization 
Original algorithm, Updated algorithm 
Yes 
No 
Yes (Hgb only) 
Other Exploratory Covariates/Subgroups where Biological Plausibility for Heterogeneous Effects Are Not Known or Anticipated 
CV risk score for HD subjects 
Low risk (Overall ITT Population Tertile 
1: < xx),  
Medium risk (Overall ITT Population 
Tertile 2: xx - < xx),  
High risk (Overall ITT Population 
Yes 
Yes 
No 
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Category 
Covariates and / or Subgroups 
Summary of 
Demographics & 
Baseline 
Characteristics 
Note: Include 
'Missing' 
categories, if 
applicable. 
Subgroup Analysis for 
Co-primary MACE & 
Principal Secondary 
Safety Endpoints 
Note: Do not include 
'Missing' categories. 
Subgroup Analysis for 
Co-primary Hgb & 
Principal Secondary 
Efficacy Endpoints 
Note: Do not include 
'Missing' categories. 
Tertile 3: ≥ xx) 
(Note: only defined for HD subjects 
See Section 10.6.2 for details.) 
Dialysis vintage at screening 
0 - <2 years, 2-<5 years, ≥5 years, 
Missing 
Yes 
Yes 
Yes 
History of diabetes 
No, Yes, Missing 
Yes 
Yes 
Yes 
History of stroke 
No, Yes, Missing 
Yes 
Yes 
Yes 
History of MI 
No, Yes, Missing 
Yes 
Yes 
Yes 
History of cancer 
No, Yes, Missing 
Yes 
Yes 
Yes 
History of heart failure 
No, Yes, Missing 
Yes 
Yes 
Yes 
History of thromboembolic 
events 
No, Yes, Missing 
Yes 
Yes 
Yes 
Hospitalization within 6 months 
prior to screening 
No, Yes, Missing 
Yes 
Yes 
Yes 
Transfusion within 6 months 
prior to screening 
No, Yes, Missing 
Yes 
Yes 
Yes 
Baseline iron use 
No iron use 
IV iron use only 
Oral iron use only 
Other iron use only 
IV and oral iron use only 
Yes 
No 
No 
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Category 
Covariates and / or Subgroups 
Summary of 
Demographics & 
Baseline 
Characteristics 
Note: Include 
'Missing' 
categories, if 
applicable. 
Subgroup Analysis for 
Co-primary MACE & 
Principal Secondary 
Safety Endpoints 
Note: Do not include 
'Missing' categories. 
Subgroup Analysis for 
Co-primary Hgb & 
Principal Secondary 
Efficacy Endpoints 
Note: Do not include 
'Missing' categories. 
IV and other iron use only 
Oral and other iron use only 
IV, oral and other iron use 
Standardized baseline IV iron 
dose (mg/month) 
Continuous covariate for monthly IV 
iron dose analysis, summary statistics 
of continuous values 
Yes 
No 
No 
Standardized baseline IV iron 
dose (mg/month) for subjects 
using IV iron at baseline 
Continuous covariate for monthly IV 
iron dose analysis, summary statistics 
of continuous values 
Yes 
No 
No 
Baseline post-dialysis SBP 
(mmHg) 
Continuous covariate for change from 
baseline in SBP analysis, summary 
statistics of continuous values 
Yes 
No 
No 
Baseline post-dialysis DBP 
(mmHg) 
Continuous covariate for change from 
baseline in DBP analysis, summary 
statistics of continuous values 
Yes 
No 
No 
Baseline post-dialysis MAP 
(mmHg) 
Continuous covariate for change from 
baseline in MAP analysis, summary 
statistics of continuous values 
Yes 
No 
No 
Dialysis access type used at 
randomization 
Arteriovenous fistula 
Arteriovenous graft 
Central venous catheter – tunneled 
Central venous catheter – non-
Yes 
No 
No 
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Category 
Covariates and / or Subgroups 
Summary of 
Demographics & 
Baseline 
Characteristics 
Note: Include 
'Missing' 
categories, if 
applicable. 
Subgroup Analysis for 
Co-primary MACE & 
Principal Secondary 
Safety Endpoints 
Note: Do not include 
'Missing' categories. 
Subgroup Analysis for 
Co-primary Hgb & 
Principal Secondary 
Efficacy Endpoints 
Note: Do not include 
'Missing' categories. 
tunneled 
Peritoneal catheter 
Other 
Missing 
ACEI/ARB use at 
randomization 
No, Yes 
Yes 
Yes 
Yes 
Phosphate binder use at 
randomization 
Iron-based phosphate binders 
Calcium-based phosphate binders 
Non-calcium and non-iron based 
phosphate binders 
No phosphate binder use 
Yes 
No 
No 
Vitamin D use at randomization 
No, Yes 
Yes 
No 
No 
Baseline Kt/V urea for HD 
subjects 
Summary statistics of continuous 
values 
Yes 
No 
No 
Baseline Kt/V urea for PD 
subjects 
Summary statistics of continuous 
values 
Yes 
No 
No 
Baseline URR for HD subjects 
(%) 
Summary statistics of continuous 
values 
Yes 
No 
No 
History of cardiovascular 
disease 
No, Yes 
Yes 
Yes 
No 
Beta blockers use at 
No, Yes 
Yes 
No 
No 
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Category 
Covariates and / or Subgroups 
Summary of 
Demographics & 
Baseline 
Characteristics 
Note: Include 
'Missing' 
categories, if 
applicable. 
Subgroup Analysis for 
Co-primary MACE & 
Principal Secondary 
Safety Endpoints 
Note: Do not include 
'Missing' categories. 
Subgroup Analysis for 
Co-primary Hgb & 
Principal Secondary 
Efficacy Endpoints 
Note: Do not include 
'Missing' categories. 
randomization 
SGLT2i use at randomization 
No, Yes 
Yes 
No 
No 
Statin use at randomization 
No, Yes 
Yes 
No 
No 
Aspirin use at randomization 
No, Yes 
Yes 
No 
No 
Vitamin K antagonist use at 
randomization 
No, Yes 
Yes 
No 
No 
Insulin use at randomization 
No, Yes 
Yes 
No 
No 
Calcimimetics use at 
randomization 
No, Yes 
Yes 
No 
No 
Diabetic medication use at 
randomization 
No, Yes 
Yes 
No 
No 
Baseline estimated dry weight 
(kg) 
Summary statistics of continuous 
values 
Yes 
No 
No 
NOTES: 
1: Subjects who change dialysis modalities during the study will be counted in the subgroup corresponding to their dialysis modality at randomization. 
2: Prior ESA dose standardization and ESA hyporesponsiveness are defined in Section 10.6.2. Supportive definitions of hyporesponders will be included 
in the summary of demographics and baseline characteristics, but will not be used in subgroup analyses. 
 
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10.10.2. 
Randomization Stratification 
Randomization is stratified by dialysis type (HD or PD), region and by participation in an 
ABPM sub-study to ensure balance across treatment groups for both the overall parent 
study and within the ABPM sub-study. The prognostic stratification factors (i.e., dialysis 
type and region) will be taken into account within the analysis models. Stratification by 
ABPM sub-study participation was implemented for logistical reasons, and will not be 
taken into account within analysis models. 
Baseline dialysis type strata will be identified by two data sources: 
• 
PPD’s IRT dataset 
• 
eCRF  
The proposed approach is to use the IRT strata in the adjusted analysis models in order to 
provide a randomization-based test statistic in accordance with the principle of ‘analyze 
as randomized’. In summaries of subgroups however, the actual status of the factor for 
stratification derived from the eCRF form will be used. Additionally, subjects who 
change dialysis modality during the study will remain in the dialysis modality strata that 
was assigned at randomization. 
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10.11. 
Appendix 11: Multiple Comparisons & Multiplicity 
10.11.1. 
Handling of Multiple Comparisons & Multiplicity 
10.11.1.1. Interim Analyses 
The interim analysis will only result in stopping the study for harm or futility. There are 
no prospectively defined plans to stop any of the ASCEND trials early for benefit. As 
such, no multiplicity adjustments are required since the type I error rate will not be 
increased. Further details including stopping guidelines for harm and futility are included 
in the IDMC charter. 
10.11.1.2. Final Analyses 
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 principal secondary analyses.  
Figure 1 illustrates the structure of the statistical testing plan. First, the co-primary 
endpoints will be evaluated for at least non-inferiority by comparing each two-sided 95% 
CI to the appropriate non-inferiority margin. Then, the principal secondary analyses will 
be performed and superiority will be tested for the individual analyses. Conditional on 
both co-primary endpoints achieving non-inferiority (i.e., passing the gatekeeper), the 
family of principal secondary analyses 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. 
 
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Figure 1 
Multiplicity controlled statistical testing plan  
 
Details of the Holm-Bonferroni procedure for testing secondary endpoints: 
The procedure starts with conducting the statistical analyses for each of the principal 
secondary analyses and ranking the resulting one-sided p-values from most significant 
(i.e. the lowest p-value) to the least significant. The Holm-Bonferroni formula is 
calculated for each rank using a target alpha. The formula for the Holm-Bonferroni 
method is: 
 
Where:  
• 
the 
is the overall alpha level (one-sided 2.5% significance) 
• 
is the total number of tests 
The most significant p-value is compared to the rank-associated alpha derived from the 
Holm-Bonferroni method. If a positive statistically significant treatment effect is 
observed, then the testing continues to the next ranked test. If the endpoint fails to 
achieve statistical significance when compared to the Holm-Bonferroni rank-associated 
alpha, the testing stops and all subsequent endpoints are declared to have failed to 
achieve statistical significance. This algorithm is described in detail in Figure 2 for the 
four principal secondary analyses defined for the trial.  
 
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Figure 2 
The Holm-Bonferroni Procedure for Multiplicity Control 
 
 
10.11.1.3. Subgroup Analyses 
Subgroup analyses will not be adjusted for multiplicity. 
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10.12. 
Appendix 12: Model Checking and Diagnostics for 
Statistical Analyses 
10.12.1. 
Statistical Analysis Assumptions 
Endpoint(s) • Hgb Change from Baseline to the EP 
Analysis 
• ANCOVA 
• Distributional assumptions underlying the model used for analysis will be examined by 
obtaining a normal probability plot of the residuals and a plot of the residuals versus the fitted 
values (i.e. checking the normality assumption and constant variance assumption of the model 
respectively) to gain confidence that the model assumptions are reasonable. 
• If there are any departures from the distributional assumptions, alternative models will be 
explored using appropriate transformed data. 
• Models will be examined for treatment interactions with baseline Hgb and stratification factors 
Analysis 
• Multiple Imputation/Tipping Point Analysis 
 
• Intermittent missing data imputation: 
o If there are error and or warning messages related to the by 
statement (e.g. not enough observations to fit regression models), 
try to impute by randomized treatment and baseline dialysis type, 
then by randomized treatment only until no error/warning 
messages. 
o If convergence issue still occurs, the convergence precision may be 
set to 1E-3.  
• Monotone missing data imputation: 
o When imputing for each of the monotone missing dataset (out of 
the 200), if there are error and or warning messages related to the 
by statement and/or regression model (e.g. not enough 
observations with the Monotone statement), try 1) impute by 
randomized treatment and baseline dialysis type, with baseline Hgb 
and region as covariates, 2) impute by randomized treatment, with 
baseline Hgb, baseline dialysis type, and region as covariates, 3) 
impute by randomized treatment, with baseline Hgb, and baseline 
dialysis type as covariates, 4) impute by randomized treatment with 
baseline Hgb as a covariate, until no error/warning messages. 
Endpoint(s) • Time to first event endpoints: MACE and MACE or thromboembolic events or 
hospitalization for HF 
Analysis 
• Cox proportional hazards 
• To inform on the validity of the adjusted Cox proportional hazards model, the proportional 
hazards assumption will be assessed by plotting the logarithm of the negative logarithm of the 
estimated survivor function against the logarithm of time, for each treatment group, region and 
dialysis type. If the hazards are proportional, the lines should be approximately parallel. 
• Should there be evidence of a violation of the proportional hazards assumption, the following 
methods may be considered: 
o Use of a stratified Cox proportional hazards model (including prognostic factors in a 
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STRATA statement in PROC PHREG, rather than in the MODEL statement) 
Endpoint(s) • Time to first event endpoints with death as a competing risk 
Analysis 
• Cox proportional hazards 
• If there is a notable difference between one or both of all-cause mortality and non-CV mortality, 
and one or more of the secondary CV endpoints that do not include death as a component, 
then additional analysis methods to address competing risks may be pursued such as: 
o Fine & Gray’s Subdistribution Hazards (Fine, 1999) 
o Use of cumulative incidence functions instead of KM curves 
 
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10.13. 
Appendix 13: Pharmacokinetic Sub-study Analysis Plan 
10.13.1. 
Overview of Planned Pharmacokinetic Analyses 
The pharmacokinetic (PK) analyses will be based on the “Pharmacokinetic” population, 
unless otherwise specified. The Pharmacokinetic population is defined as subjects for 
whom additional PK eligibility was confirmed and have at least one non-missing PK 
sample measurement. 
Table 16 provides an overview of the planned analyses.  
Table 16 
Overview of Planned Pharmacokinetic Analyses for GSK1278863, 
and/or GSK2391220 (M2), GSK2506104 (M3) and GSK2531401 (M13) 
Parameter 
Untransformed 
Log-Transformed 
Stats 
Analysis 
Summary Individual 
Stats Analysis 
Summary Individual 
T 
F 
L 
T 
F 
F 
L 
T 
F 
L 
T 
F 
F 
L 
GSK1278863, GSK2391220 (M2), GSK2506104 (M3) and GSK2531401 (M13) 
GSK1278863 and 
Metabolites Plasma 
Pharmacokinetic 
Concentration Time 
Data (ng/ml) by 
Treatment 
 
 
 
Y 
Y1 
Y 
Y 
 
 
 
 
Y1 
Y 
 
GSK1278863 and 
Metabolites Plasma 
Pharmacokinetic 
Parameter2 Data 
 
 
 
Y 
 
 
Y 
 
 
 
Y 
 
 
 
GSK1278863 
GSK1278863 Dose 
Parameter Data 
 
 
 
Y 
 
 
Y 
 
 
 
 
 
 
 
GSK1278863 Special 
Parameter3 Data 
 
 
 
Y 
 
 
Y 
 
 
 
Y 
 
 
 
NOTES: 
• 
T = Table, F = Figure, L = Listings, Y = Display generated. 
• 
Stats Analysis = Represents TFL related to any formal statistical analyses (i.e. modelling) conducted. 
• 
Summary = Represents TFL related to any summaries (i.e. descriptive statistics) of the observed raw data. 
• 
Individual = Represents FL related to any displays of individual subject observed raw data.   
1. Mean and median plots will be generated 
2. Cmax, Tmax, Ctau 
3. Ctau/1mg Dose, Ctau/avg Dose EP TIR, Ctau/ avg Dose EP, Ctau/ Dose at MACE, Ctau/Final Dose for subjects 
without MACE, Ctau/ Dose at MACE++, Ctau/ Final Dose for subjects without MACE++, Cmax/1mg Dose, 
Cmax/avg Dose EP TIR, Cmax/avg Dose EP, Cmax/ Dose at MACE, Cmax/ Final Dose for subjects without 
MACE, Cmax/ Dose at MACE++, Cmax/ Final Dose for subjects without MACE++   
10.13.2. 
Drug Concentration Measures 
Refer to Appendix 5: Data Display Standards & Handling Conventions (Section 10.5.3 
Reporting Process & Standards). 
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10.13.3. 
Pharmacokinetic Parameters 
10.13.3.1. Deriving Pharmacokinetic Parameters 
• Refer to Appendix 5: Data Display Standards & Handling Conventions 
(Section 10.5.3 Reporting Process & Standards). 
• The pharmacokinetic parameters of parent GSK1278863, and metabolites 
(GSK2391220 (M2), GSK2506104 (M3), and GSK2531401 (M13)) will be 
calculated by programming methods. 
• All calculations of non-compartmental parameters will be based on actual sampling 
times. 
• Pharmacokinetic parameters described in Table 17 will be determined from the 
plasma concentration-time data, as data permits. 
Table 17 
Derived Pharmacokinetic Parameters for GSK1278863, and/or 
GSK2391220 (M2), GSK2506104 (M3) and GSK2531401 (M13) 
Parameter 
Parameter Description 
GSK1278863, GSK2391220 (M2), GSK2506104 (M3) and GSK2531401 (M13) 
tmax 
Time to reach Cmax, determined directly from the concentration-time data. 
Ctau 
Observed concentration at dosing interval (tau=24 h, predose sample)  
Cmax 
Maximum observed concentration, determined directly from the concentration-time data. 
GSK1278863 
Avg Dose EP 
TIR 
The average daily GSK1278863 dose when the subject is on-treatment and in target Hgb 
range during the evaluation period (EP) Weeks 28-52 (See Section 10.6.3.1). Evaluable 
Hgb values are used to determine time in range. Subjects who permanently stop 
randomized treatment before the beginning of the EP, and subjects who have 0% time in 
range (e.g., subjects who have an evaluable Hgb below or above range for the entire EP) 
will have a missing value for this parameter. 
Avg Dose EP 
The average daily GSK1278863 dose when the subject is on-treatment during the EP. 
Dose at first 
MACE 
The daily GSK1278863 dose at the time of the subject’s first on-treatment adjudicated 
MACE. If the subject does not have an on-treatment adjudicated MACE, this value is 
missing. 
Final Dose for 
Subjects 
without 
MACE 
For subjects without an on-treatment adjudicated MACE, this is the subject’s final 
GSK1278863 dose during the study. 
Dose at first 
MACE++ 
The daily GSK1278863 dose at the time of the subject’s first on-treatment adjudicated 
MACE++ (defined as the first adjudicated MACE, hospitalization for heart failure, or 
thromboembolic event) If the subject does not have an on-treatment adjudicated MACE++, 
this value is missing. 
Final Dose for 
Subjects 
without 
MACE++ 
For subjects without an on-treatment adjudicated MACE++, this is the subject’s final 
GSK1278863 dose during the study. 
Ctau/1mg 
Dose 
Ctau extrapolated to 1mg dose: Observed Ctau divided by dose administered on the PK 
day 
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Parameter 
Parameter Description 
Ctau/Avg 
Dose EP TIR 
Ctau extrapolated to average dose during EP TIR: Ctau/1mg multiplied by the average 
daily GSK1278863 dose when the subject is on-treatment and in target Hgb range during 
Weeks 28-52 (see Section 10.6.3.1). Evaluable Hgb values are used to determine time in 
range. 
Ctau/Avg 
Dose EP 
Ctau extrapolated to average dose during EP: Ctau/1mg multiplied by the average daily 
GSK1278863 dose during the EP. 
Ctau/Dose at 
first MACE 
Ctau extrapolated to dose at first on-treatment adjudicated MACE: Ctau/1mg multiplied by 
the daily GSK1278863 dose at the time of the subject’s first on-treatment adjudicated 
MACE. 
Ctau/Final 
Dose for 
subjects 
without 
MACE 
For subjects without an on-treatment adjudicated MACE, this is the subject’s Ctau/1mg 
multiplied by the subject’s final daily GSK1278863 dose during the study. 
Ctau/Dose at 
first MACE++ 
Ctau extrapolated to dose at first on-treatment adjudicated MACE++: Ctau/1mg multiplied 
by the daily GSK1278863 dose at the time of the subject’s first on-treatment adjudicated 
MACE++. 
Ctau/Final 
Dose for 
subjects 
without 
MACE++ 
For subjects without an on-treatment adjudicated MACE++, this is the subject’s Ctau/1mg 
multiplied by the subject’s final daily GSK1278863 dose during the study. 
Cmax/1mg 
Dose 
Cmax extrapolated to 1mg dose: Observed Cmax divided by dose administered on the PK 
day 
Cmax/Avg 
Dose EP TIR 
Cmax extrapolated to average dose during EP TIR: Cmax/1mg multiplied by the average 
daily GSK1278863 dose when the subject is on-treatment and in target Hgb range during 
Weeks 28-52 (see Section 10.6.3.1). Evaluable Hgb values are used to determine time in 
range. 
Cmax/Avg 
Dose EP 
Cmax extrapolated to average dose during EP: Cmax/1mg multiplied by the average daily 
GSK1278863 dose during the EP. 
Cmax/Dose 
at first MACE 
Cmax extrapolated to dose at MACE: Cmax/1mg multiplied by the daily GSK1278863 dose 
at the time of the subject’s first on-treatment adjudicated MACE. 
Cmax/Final 
Dose for 
subjects 
without 
MACE 
For subjects without an on-treatment adjudicated MACE, this is the subject’s Cmax/1mg 
multiplied by the subject’s final daily GSK1278863 dose during the study. 
Cmax/Dose 
at first 
MACE++ 
Cmax extrapolated to dose at MACE++: Cmax/1mg multiplied by the daily GSK1278863 
dose at the time of the subject’s first on-treatment adjudicated MACE++. 
Cmax/Final 
Dose for 
subjects 
without 
MACE++ 
For subjects without an on-treatment adjudicated MACE++, this is the subject’s Cmax/1mg 
multiplied by the subject’s final daily GSK1278863 dose during the study. 
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10.13.4. 
Pharmacokinetic / Pharmacodynamic Analyses 
• 
The primary goal of this analysis is to characterize the 
pharmacokinetic/pharmacodynamic relationship of parent GSK1278863 and efficacy 
and safety endpoints in the “Pharmacokinetic” population from this study. 
o The influence of subject demographics and baseline characteristics, including 
disease activity in this population may be investigated. 
• A summary of the planned population pharmacokinetic/pharmacodynamic analyses 
are outlined below: 
o Relationships between drug exposure and selected efficacy, MACE and MACE 
++ events will be explored and characterized as data permit. The exposure will be 
estimated on the sparse PK collected in a sub-set of the study population.  The 
data may be dose- extrapolated to the dose administered during the PK collection 
period.  Any changes to the proposed analyses would be described in the CSR. 
Table 18 
Overview of Planned Pharmacokinetic / Pharmacodynamic Analyses 
for GSK1278863 
Parameter 
Untransformed 
Log-Transformed 
Stats 
Analysis 
Summary Individual 
Stats Analysis 
Summary Individual 
T 
F 
L 
T 
F 
F 
L 
T 
F 
L 
T 
F 
F 
L 
GSK1278863 
Scatter plot of % Time 
Evaluable Hgb in Range 
during EP vs. Avg Dose 
EP TIR 
 
 
 
 
 
Y 
 
 
 
 
 
 
 
 
Scatter plot of Evaluable 
Hgb Change from 
Baseline during EP vs. 
Avg Dose EP 
 
 
 
 
 
Y 
 
 
 
 
 
 
 
 
Scatter plot of % Time 
Evaluable Hgb in Range 
during EP vs. Ctau/Avg 
Dose EP TIR 
 
 
 
 
 
Y 
 
 
 
 
 
 
 
 
Scatter plot of 
Evaluable Hgb Change 
from Baseline during 
EP vs. Ctau/Avg Dose 
EP 
 
 
 
 
 
Y 
 
 
 
 
 
 
 
 
Boxplot of Ctau/Dose at 
on-treatment MACE or 
MACE++ by subjects with 
or without on-treatment 
MACE or MACE++ 
 
 
 
 
 
Y 
 
 
 
 
 
 
 
 
Scatter plot of % Time 
Evaluable Hgb in Range 
during EP vs. Cmax/Avg 
 
 
 
 
 
Y 
 
 
 
 
 
 
 
 
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Parameter 
Untransformed 
Log-Transformed 
Stats 
Analysis 
Summary Individual 
Stats Analysis 
Summary Individual 
T 
F 
L 
T 
F 
F 
L 
T 
F 
L 
T 
F 
F 
L 
Dose EP TIR 
Scatter plot of 
Evaluable Hgb Change 
from Baseline during EP 
vs. Cmax/Avg Dose EP 
 
 
 
 
 
Y 
 
 
 
 
 
 
 
 
Boxplot of Cmax/Dose at 
on-treatment MACE or 
MACE++ by subjects with 
or without on-treatment 
MACE or MACE++ 
 
 
 
 
 
Y 
 
 
 
 
 
 
 
 
NOTES : 
• 
T = Table, F = Figure, L = Listings, Y = Display generated. 
• 
Stats Analysis = Represents TFL related to any formal statistical analyses (i.e. modelling) conducted. 
• 
Summary = Represents TFL related to any summaries (i.e. descriptive statistics) of the observed raw data. 
• 
Individual = Represents FL related to any displays of individual subject observed raw data. 
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10.14. 
Appendix 14: ABPM Sub-study Analysis Plan 
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 blood pressure.  ESA-induced elevation of BP often necessitates initiation of, 
or increases in, anti-hypertensive medications in patients with CKD. While both SBP and 
DBP are 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 ambulatory blood pressure monitoring (ABPM) 
sub-study.   In addition, ABPM is being used to measure BP in this sub-study because 
previous studies have used this BP measurement modality in dialysis subjects to establish 
an association with mortality [Agarwal, 2010]. 
This sub-study is intended to compare daprodustat to rhEPO on BP as assessed by ABPM 
in dialysis-dependent subjects with anemia associated with CKD who switch from ESAs.   
10.14.1. 
Summary of Key Protocol Information 
10.14.1.1. Changes to the Protocol Defined Statistical Analysis Plan 
No statistical analysis will be conducted for this sub-study due to the small number of 
subjects recruited. Instead all data will either be summarized or listed. 
10.14.1.2. ABPM Sub-Study Objectives and Endpoints 
Objectives 
Endpoints 
Summary 
plans 
Primary Objective 
Primary Endpoint 
 
• To compare 
daprodustat to rhEPO 
for effect on SBP 
(superiority) by ABPM 
in subjects receiving 
maintenance 
hemodialysis in the 
ABPM ITT population 
• Change in 24-hour average SBP from 
baseline to end of sub-study [1] between 
treatment groups 
• Summary 
only 
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Objectives 
Endpoints 
Summary 
plans 
Secondary Objectives 
Secondary Endpoints  
 
• To assess the effect of 
daprodustat and 
rhEPO independently 
within treatment 
groups on SBP, DBP 
and mean arterial 
blood pressure (MAP) 
by ABPM in the ABPM 
ITT population 
• 
Change in 24-hour average SBP from 
baseline to end of sub-study [1] within each 
treatment group 
• 
Change in 24-hour average DBP from 
baseline to end of sub-study [1] within each 
treatment group 
• 
Change in 24-hour average MAP from 
baseline to end of sub-study [1] within each 
treatment group 
• 
Summary 
only 
• 
To compare the effect 
of daprodustat to 
rhEPO on DBP and 
MAP by ABPM in the 
ABPM ITT population 
• 
Change in 24-hour average DBP from 
baseline to end of sub-study [1] between 
treatment groups 
• 
Change in 24-hour average MAP from 
baseline to end of sub-study [1] between 
treatment groups 
• 
Summary 
only 
• 
To compare the effect 
of daprodustat to 
rhEPO on BP 
parameters in the 
ABPM Per-Protocol 
population 
• Change in 
o  24-hour average SBP 
o  24-hour average DBP 
o  24-hour average mean arterial pressure 
from baseline to end of sub-study [1] 
between treatment groups 
• Not done 
(i.e., no 
ABPM PP 
summaries) 
• 
To assess the effect 
of daprodustat and 
rhEPO on BP 
parameters in the 
ABPM Per-Protocol 
population 
• Change in: 
o 24-hour average SBP 
o 24-hour average DBP 
o 24-hour average mean arterial pressure 
from Baseline to end of sub-study [1] 
within each treatment group 
• Not done 
(i.e., no 
ABPM PP 
summaries) 
• 
To compare the 
percentage of 
subjects in each 
treatment group 
requiring a change in 
anti-hypertensive in 
the ABPM ITT 
population 
• 
Difference between treatment groups in 
percentage of subjects requiring no change in 
number or dosage of anti-hypertensive 
medications 
• 
Difference between treatment groups in 
percentage of subjects requiring an increase 
in number or dosage of anti-hypertensive 
medications 
• 
Difference between treatment groups in 
percentage of subjects requiring a decrease 
in number or dosage of anti-hypertensive 
medications 
• 
Not done 
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Objectives 
Endpoints 
Summary 
plans 
• 
To characterize the 
dipping pattern of 
sleeping blood 
pressure in each 
treatment group in 
the ABPM ITT and 
ABPM Per-Protocol 
populations 
• 
24-hour blood pressure 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 
is >10% to 20% of mean SBP during 
waking hours the day, 
• extreme dippers when this reduction is 
>20%, 
• non-dippers when the reduction is 0% to 
10%, and reverse dippers when the 
mean sleep SBP is higher than the 
awake SBP [Bakris, 2014] 
• 
Not done 
• 
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-study [1] 
• 
Not done 
• 
To compare the 
percentage of 
subjects that convert 
from dipper status to 
non-dipper status 
between treatment 
groups in the ABPM 
ITT and ABPM Per-
Protocol populations 
• 
Difference between treatment groups in 
percentage of subjects that convert from 
dipper status at baseline to non-dipper status 
at end of sub-study [1] 
• 
Not done 
• 
To compare 
daprodustat to rhEPO 
on heart rate by 
ABPM in the ABPM 
ITT population 
• 
Change in 24-hour average heart rate from 
baseline to end of sub-study [1] as measured 
by ABPM relative to time since administration 
of medication 
• 
Summary 
only 
[1] The end of sub-study is defined as the date recorded in the ABPM sub-study conclusion form. It is 
expected that the majority of the participants will complete this form after the completion of week 16 
ABPM assessment, however, a small number of the participants will complete this form after the 
completion of their week 28 ABPM assessment, since before this protocol amendment, the scheduled 
second ABPM assessment was at week 28 instead of week 16. 
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10.14.1.3. Study Design 
Overview of Study Design and Key Features 
Design 
Features 
• This is a multi-center sub-study of the main protocol focusing on subjects that 
meet the additional inclusion and exclusion criteria outlined in the sub-study 
protocol.  The main study is stratified by participation in this sub-study. 
Dosing and 
Treatment 
Assignment 
• A central randomization approach will be used in the main study to protect 
against potential selection bias due to the open-label design. The 
randomization schedule will be generated by PPD and PPD’s Interactive 
Response Technology (IRT) will be used for treatment allocation. 
• Subjects will be stratified by dialysis type [hemodialysis (HD*) or peritoneal 
dialysis (PD)], by region (see Section 10.9.1) and by participation in this ABPM 
sub-study. Following stratification, subjects will be randomized 1:1 to receive 
open-label oral daprodustat or rhEPO (IV epoetin alfa for HD subjects and SC 
darbepoetin alfa for PD subjects). 
* In addition to HD this group also includes combination methods such as 
hemodiafiltration (HDF) or hemofiltration (HF). 
• This sub-study includes a subset of subjects that are in the HD and ABPM 
participant strata from the main study. 
• Please refer to the protocol for starting doses, dose steps and elements of the 
dose adjustment scheme. 
Interim 
Analysis 
• An IDMC will review safety data periodically from all ongoing clinical trials in 
the daprodustat clinical development program for the treatment of subjects with 
anemia of chronic kidney disease. 
• In addition, a formal interim analysis is planned for the main study. See Section 
3.1 for further details.  Information from this sub-study will be included in the 
IDMC evaluation at the interim. 
10.14.1.4. Statistical Hypothesis 
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 with evaluable ABPM assessments at both baseline and end of sub-study 
(effectiveness estimand).  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.  The primary analysis population will be the ABPM ITT 
population defined in Section 10.14.3, and subjects’ randomized medication will be used 
for this analysis. 
The statistical hypotheses are as follows: 
Null:  The difference between treatment groups (Dapro – rhEPO) in change from 
baseline in 24-hour average SBP at end of sub-study is  0. 
Alternative: The difference between treatment groups (Dapro - rhEPO) in change from 
baseline in 24-hour average SBP at end of sub-study is less than 0. 
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ABPM measurements are only collected once post randomization, and it is expected that 
approximately 20% of subjects will have missing end of sub-study ABPM data.  To 
assess the impact of missing data on the interpretation of the primary analysis, the reason 
for missing data will be assessed.  If the majority (> 70%) of missing data is due to either 
patient unwillingness to repeat the ABPM procedure or due to an un-evaluable reading, 
then the data will be considered to be missing at random and no adjustment will be made 
to the primary analysis.   
If more than 30% of the data is missing for other reasons, then multiple imputation will 
be used for subjects with data missing due to these reasons.  Regardless of randomized 
treatment group, this data will be imputed using the distribution of non-missing rhEPO 
subject data.  There will be no imputation for subjects with data missing due to either 
patient unwillingness to repeat the ABPM procedure or due to an un-evaluable reading.  
This is in keeping with the primary interest in the effectiveness estimand. 
The efficacy estimand is also of interest, so the primary analysis will be repeated with the 
ABPM Per-Protocol population using actual treatment received.  Missing data will not be 
imputed for this analysis. 
The originally-planned statistical hypotheses described above will no longer be tested. 
10.14.2. 
Planned Analyses 
10.14.2.1. Interim Analysis 
ABPM sub-study information will be used by the IDMC in the overall assessment of risk 
throughout the trial.  In particular, there is a planned interim analysis for futility for 
which this data will be included.  As these interim looks will not be used to stop the trial 
for benefit, there will be no adjustment to the significance level, alpha. 
10.14.2.2. Final Analysis 
The final analysis will be performed after the completion of the trial as outlined in the 
main study RAP. 
10.14.3. 
Analysis Populations 
10.14.3.1. Populations 
Population 
Definition / Criteria 
Analyses Evaluated 
ABPM Screened 
• All screened subjects for ABPM sub-study 
• ABPM sub-study 
• Study Pop 
ABPM ITT 
• Subjects in the ‘ITT’ population who signed the 
informed consent for the sub-study and were 
also entered into the ABPM sub-study. 
• Subjects will be analyzed according to the 
treatment to which they were randomized. 
• ABPM sub-study 
• Study Pop 
• Efficacy 
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Population 
Definition / Criteria 
Analyses Evaluated 
ABPM Safety 
• ABPM ITT subjects who receive at least one 
dose of randomized treatment. 
• Subjects will be analyzed according to the 
treatment received.1 
• ABPM sub-study 
• Safety 
[1]: Only subjects receiving incorrect study treatment for the duration of their study participation will 
be analyzed according to the treatment received. Otherwise, subjects will be analyzed according to 
the treatment to which they were randomized. 
10.14.4. 
Considerations for Data Analyses and Data Handling 
Conventions 
The definition of assessment windows, treatment states and phases, data display 
standards and handling conventions, reporting processes and standards, data derivations, 
and handling of partial dates will be the same as the main study RAP except where 
specifically highlighted in this sub-study RAP. 
10.14.4.1. ABPM Evaluation Criteria 
In order to be considered an evaluable assessment, the following criteria need to be met 
for the 24-hour ABPM assessment: 
1) There must be at least 20 awake ABPM readings and 10 sleep ABPM readings 
captured during the 24 hours that the subject wears the ABPM device.   
2) Any ABPM readings collected after the 24 hour period will not be analyzed.  
The subject’s reported times of waking up and going to sleep during this 24-hour period 
will be recorded in the eCRF.   
10.14.4.2. Dipping Status 
For each ABPM measurement, dipping status will be defined based on asleep and awake 
SBP measurements as follows: 
o dippers (normal): the reduction in the average SBP during the sleeping period 
is >10% to 20% of mean SBP during awake hours 
o extreme dippers:  the reduction in the average SBP during sleeping is >20% of 
the mean SBP during awake hours 
o non-dippers: the reduction in the average SBP during sleeping is 0% to 10% 
of the mean SBP during awake hours 
o reverse dippers: when the average SBP during sleeping is greater than the 
mean SBP during awake hours [Bakris, 2014] 
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10.14.4.3. End of Sub-study Values 
o The majority of the participants reach the end of sub-study after the 
completion of Week 16 ABPM assessment. If the ABPM fails the QC criteria 
at week 16, up to two additional attempts may be made and can be considered 
as week 16 ABPM.  
o It is also expected that a small percentage of the participants would have 
Week 28 ABPM assessment instead of Week 16 ABPM assessment due to 
enrollment before the third study protocol amendment (dated 05OCT2017). 
Their Week 28 ABPM and other parameters of interests will be used as the 
end of sub-study value in the analyses unless specified otherwise. If the 
ABPM fails the QC criteria at week 28, up to two additional attempts may be 
made and can be considered as week 28 ABPM.  
10.14.4.4. Data Handling Conversions 
o Timepoint averages: The 24-hour ABPM readings will be sorted by the time 
of the day (not the order in which the ABPM readings were measured). The 
timepoint 0h is associated with data collected in 00:00-00:29, timepoint 0.5h 
is associated with date collected in 00:30-00:59, timepoint 1h is associated 
with data collected in 01:00-01:29, etc. For a specific timepoint, the average 
of all measurements that associate with the specified timepoint will be 
calculated, per subject per visit. 
o 24-hour average: Average of all measurements collected on a subject at a visit 
using all 24-hour ABPM data. 
10.14.5. 
Study Population Analyses 
Study population displays described in this section will be created for the ABPM ITT or 
Safety population where applicable. 
10.14.5.1. Overview of Planned Analyses 
Parameter  
Data Displays Generated  
Table  
Figure  
Listing  
Disposition  
Reasons for Screen Failure for the Sub-study  
Y  
 
 
Summary of Subject Disposition for the Sub-study  
Y  
 
 
Demographic & Baseline Characteristics  
 
 
 
Demographic and Baseline Characteristics  
Y  
 
 
Treatment Compliance  
 
 
 
Extent of Exposure to Randomized Treatment During the 
Sub-study  
Y  
 
 
NOTES : Y = Yes display generated.  
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10.14.5.2. Display Details 
Disposition 
The number and percentage of subjects completing the sub-study, withdrawing early 
from the sub-study, or discontinuing study treatment during the sub-study, overall and by 
reason, will be summarized by treatment group.   
The number and percentage of subjects who failed screening for the sub-study (e.g. lack 
of eligibility, withdrawal of consent or other reasons such as needing to wear a device) 
and were therefore not entered into the sub-study, overall and by reason, will be 
summarized by treatment group. 
Demographic & Baseline Characteristics 
The number and percentage of subjects or summary statistics will be provided by 
treatment group for the demographic and baseline characteristics described in the main 
RAP. 
Treatment Compliance 
Months on randomized medication during the sub-study will be summarized using mean, 
P25, median, P75, standard deviation, minimum and maximum by treatment group. 
10.14.6. 
Efficacy Analyses 
ABPM summaries will be performed using the ABPM ITT population. All analyses 
performed on ABPM ITT population will use on and off treatment values. 
10.14.6.1. Overview of Efficacy Analyses 
Parameter  
Absolute  
Change from BL  
Analysis 
Summary  
Individual  Analysis  Summary  
Individual  
T  
F  
T  
F  
L  
T  
F 
F  
T  
F  
L  
ABPM  
SBP, DBP, MAP, 
Heart Rate ABPM 
Values – ABPM ITT 
 
 
Y 
Y 
 
 
  
 
 
 
24-hour average 
SBP, DBP, MAP, 
Heart Rate - ABPM 
ITT  
 
 
Y  
 
 
 
  
Y   
 
In-Clinic Visit 
SBP, DBP, Heart 
Rate, Weight and 
Dry Weight from in-  
 
Y 
 
 
 
   
 
 
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Parameter  
Absolute  
Change from BL  
Analysis 
Summary  
Individual  Analysis  Summary  
Individual  
T  
F  
T  
F  
L  
T  
F 
F  
T  
F  
L  
clinic visits 
Anti-hypertensive Medications  
Listing of anti-
hypertensive 
medication use 
 
 
 
 
Y 
 
  
 
 
Efficacy Summary Details 
ABPM 
ABPM parameter values (SBP, DBP, MAP, and Heart Rate) will be summarized at each 
collected time point using mean, median, standard deviation, minimum, P25, P75, and 
maximum at baseline and end of sub-study by treatment group. These parameters will 
also be displayed graphically via a line plot of the means and 95% confidence intervals. 
24-hour average ABPM parameter values (SBP, DBP, MAP, and Heart Rate) will be 
summarized using mean, median, standard deviation, minimum, P25, P75, and maximum 
at baseline and end of sub-study by treatment group. 
ABPM parameter change from baseline values (SBP, DBP, MAP, and Heart Rate) will be 
summarized using mean, median, standard deviation, minimum, P25, P75, and maximum 
at end of sub-study by treatment group. 
A data listing of ABPM data will be produced. 
In Clinic Visit 
The BP measurements (SBP, DBP, Heart Rate) and weight before and after dialysis, and 
estimated dry weight before dialysis from in-clinic visits will be summarized using mean, 
median, standard deviation, minimum, P25, P75, and maximum at each visit by treatment 
group. 
Anti-hypertensive Medications 
The types of anti-hypertensive medications are:  
1) Angiotensin-II Receptor Blockers/ Angiotensin Converting Enzyme Inhibitors 
(ARB/ACE-I) 
2) Calcium Channel Blockers (CCB) 
3) Beta-Adrenergic Receptor Blockers 
4) Alpha-Adrenergic Receptor Blockers 
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5) Centrally Acting Agents (e.g. clonidine, methyldopa)   
6) Direct Vasodilators (e.g. hydralazine) 
A data listing of anti-hypertensive medication use during the ABPM sub-study will be 
produced. 
10.14.7. 
Safety Analyses 
Safety displays described in this section will be created for the ABPM Safety population. 
10.14.7.1. Overview of Planned Adverse Event Analyses 
Parameter  
Data Display To Be Generated  
Summary 
Individual 
T 
F 
L 
Adverse Events (AEs) and Blood Pressure related Events  
All on-treatment Blood Pressure Related Events 
During the ABPM Sub-study [1]   
Y 
 
Y 
Subject Numbers for Individual Blood Pressure 
Related AEs During the Sub-study [2]  
 
 
Y 
Serious and Other Significant Adverse Events and other safety related events 
Treatment Emergent Blood Pressure Related SAEs 
During the Sub-study [2] by Primary System Organ 
Class and Preferred Term  
Y 
 
 
Treatment Emergent AEs Leading to Permanent 
Discontinuation of Study Treatment During the Sub-
study [2] by Primary System Organ Class and 
Preferred Term  
Y 
 
Y 
[1] As identified by the CRF described in Section 10.14.7.  
[2] Include AEs that have a start or worsening date up to and including the earliest of the last non-zero dose 
date +1 day or the final ABPM Visit date + 1 day  
10.14.7.2. AE Summary Details 
Blood Pressure Related AEs/ Events Identification 
Blood pressure AEs will be identified during the study via periodic programmatic sweeps 
of preferred terms entered into the eCRF. AEs identified this way will require an 
additional eCRF page to be filled out that characterizes the event as clinically significant 
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and/or symptomatic. In addition, subjects that experience BP (in clinic) that meet the 
following criteria at any visit will be required to fill out this eCRF: 
• SBP: an increase from baseline of  25 mmHg or SBP  180 mmHg 
• DBP: an increase from baseline of  15 mmHg or DBP  110 mmHg 
The number and percentage of subjects reporting at least one on-treatment BP event in 
this eCRF during the sub-study will be provided for each treatment group. In addition, 
this summary will include the number and percentage of subjects with at least one event 
that is considered clinically significant and the number and percentage of subjects with at 
least one event that is considered to be symptomatic.  
The number and percentage of subjects reporting at least one treatment emergent blood 
pressure related SAE during the sub-study will be provided for each treatment group by 
primary system organ class and preferred term. Treatment emergent blood pressure 
related SAEs are those that have been identified via the eCRF page described above.  
The number and percentage of subjects reporting each treatment emergent AE leading to 
permanent discontinuation of study treatment during the sub-study will be summarized 
by treatment group using primary system organ class and preferred term. 
Data listings of on-treatment blood pressure related events during the ABPM sub-study, 
subject numbers for individual blood pressure related AEs during the ABPM sub-study, 
and treatment emergent AEs leading to permanent discontinuation of randomized 
treatment during the ABPM sub-study will be produced. 
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10.15. 
Appendix 15 – Abbreviations & Trade Marks 
10.15.1. 
Abbreviations 
Abbreviation 
Description 
ABPM 
Ambulatory Blood Pressure Monitoring 
ADaM 
Analysis Data Model 
AE 
Adverse Event 
AESI 
Adverse Event of Special Interest 
ALT 
Alanine Aminotransferase 
ANCOVA 
Analysis of Covariance 
AST 
Aspartate Aminotransferase 
ATC 
Anatomical Therapeutic Chemical 
BP 
Blood Pressure 
CDISC 
Clinical Data Interchange Standards Consortium 
CEC 
Clinical Endpoint Committee 
CFB 
Change from Baseline 
CHMP 
Committee for Medicinal Products for Human Use 
CI 
Confidence Interval 
CKD 
Chronic Kidney Disease 
CMH 
Cochran-Mantel-Haenszel 
CSR 
Clinical Study Report 
CV 
Cardiovascular 
DBP 
Diastolic Blood Pressure 
DGF 
Delayed Graft Function 
DP 
Decimal Places 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Record Form 
EOS 
End of Study 
EP 
Evaluation Period 
ERI 
Erythropoietin Resistance Index 
ESA 
Erythropoiesis Stimulating Agent 
FDA 
Food and Drug Administration 
FDR 
False Discovery Rate 
FSH 
Follicle-stimulating Hormone 
GSK 
GlaxoSmithKline 
HbA1c 
Hemoglobin A1c 
HBPM 
Home Blood Pressure Monitoring 
HD 
Hemodialysis 
HDF 
Hemodiafiltration 
HDL-C 
High Density Lipoprotein Cholesterol 
HF 
Heart Failure 
HF 
Hemofiltration 
Hgb 
Hemoglobin 
HR 
Heart Rate 
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Abbreviation 
Description 
HRQoL 
Health Related Quality of Life 
hsCRP 
High-sensitivity C-reactive Protein 
ICH 
International Conference on Harmonisation 
IDMC 
Independent Data Monitoring Committee  
IDSL 
Integrated Data Standards Library 
IG 
Implementation Guide 
IMMS 
International Modules Management System 
iPTH 
Intact Parathyroid Hormone 
IRT 
Interactive Response Technology 
ITT 
Intent-To-Treat 
IV 
Intravenous 
KM 
Kaplan-Meier 
LDL-C 
Low Density Lipoprotein Cholesterol 
LS 
Least Squares 
MACE 
Major Adverse Cardiovascular Event 
MAP 
Mean Arterial Pressure 
MAR 
Missing at Random 
MCH 
Mean Corpuscular Hemoglobin 
MCHC 
Mean Corpuscular Hemoglobin Concentration 
MCS 
Mental Component Score 
MCV 
Mean Corpuscular Volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
MI 
Myocardial Infarction 
MMRM 
Mixed Model Repeated Measures 
MP 
Maintenance Period 
NI 
Non-inferiority 
PCI 
Potential Clinical Importance  
PCS 
Physical Component Score 
PD 
Pharmacodynamic 
PGx 
Pharmacogenetics 
PhRMA 
Pharmaceutical Research and Manufacturers of America 
PK 
Pharmacokinetic 
PP 
Per-Protocol 
PPD 
Pharmaceutical Product Development 
PRO 
Patient Reported Outcome 
PT 
Preferred Term 
QC 
Quality Control 
RAP 
Reporting & Analysis Plan 
RBC 
Red Blood Cell  
RDW 
Red Cell Distribution Width 
RTF 
Rich Text Format 
SAE 
Serious Adverse Event 
SBP 
Systolic Blood Pressure 
SC 
Subcutaneous 
SDTM 
Study Data Tabulation Model 
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Abbreviation 
Description 
SE 
Standard Error 
SI 
System Independent 
SMQ 
Standard MedDRA Query 
SOC 
System Organ Class 
SPERT 
Safety Planning Evaluation Reporting Team 
TC 
Total Cholesterol 
TFL 
Tables, Figures & Listings  
TIBC 
Total Iron Binding Capacity 
TSAT 
Transferrin Saturation 
UK 
United Kingdom 
US 
United States 
VAS 
Visual Assessment Scale 
WBC 
White Blood Cell 
 
10.15.2. 
Trademarks 
Trademarks of the GlaxoSmithKline 
Group of Companies 
 
Trademarks not owned by the 
GlaxoSmithKline Group of Companies 
NONE 
 
SAS 
 
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