A 52-week Open-label (Sponsor-blind), Randomized, Active-controlled, Parallel-group, Multi-center Study to Evaluate the Efficacy and Safety of Daprodustat Compared to Recombinant Human Erythropoietin in Subjects With Anemia Associated With Chronic Kidney Disease Who Are Initiating Dialysis
Phase: PHASE3
Conditions: Anaemia
Sponsor: GlaxoSmithKline

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T h e Gl a x o S mit h Kli n e gr o u p of c o m p a ni e s   
 
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1 
 
TI T L E P A G E  
Di visi o n: W orl d wi de De vel o p me nt 
I nf or m ati o n T y pe: Pr ot oc ol A me n d me nt  
Title:  
A 5 2 -wee k o pe n  la b el (s p o ns or-bli n d), ra n d o miz e d, acti ve-
c o ntr olle d, parallel - gr o u p, m ulti-ce nter st u d y t o e v al uate t he 
efficac y a n d s afet y of d a pr o d ustat c o m pare d t o rec o m bi na nt 
h u ma n er yt hr o p oieti n i n s u bjects wit h a ne mia ass ociate d wit h 
c hr o nic ki d ne y disease w h o are i nitiati n g dial ysis 
S h ort Title:  
A ne mia S t u dies i n C K D: E r yt hr o p oiesis via a N o vel P HI 
D a pr o d ustat-i n Inci de nt D ial ysis ( A S C E N D-I D) 
 
C o m p o u n d N u m ber:  G S K 1 2 7 8 8 6 3 
De vel o p me nt P h ase:   III 
Eff ecti ve D ate:  
0 6- O C T - 2 0 1 7 
 
Pr ot oc ol A me n d me nt N u m ber:  0 1 
A ut h or  (s):
 
 
 
 
 
 
 
 
 
 
 
P P D
C o p yri g ht 2 0 1 7 t he Gla x o S mit h Kli ne gr o u p of c o m pa nies.  All ri g hts reser ve d.  
U na ut h orise d c o p yi n g or use of t his i nf or mati o n is pr o hi bite d. 

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The GlaxoSmithKline group of companies 
 
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Revision Chronology 
GlaxoSmithKline 
Document Number 
Date 
Version 
2015N234534_00 
2016-OCT-18 
Original 
2015N234534_01 
2017-OCT-06  
Amendment No. 1 
Amendment 1 applies to all countries 
• Updated the time period of planning to start dialysis from the day of screening to 6 
weeks to be consistent with the extended screening period, when appropriate 
• Removed number of screening subjects required and stated only an approximate 
number of randomized subjects required in the study 
• Modified peritoneal dialysis (PD) inclusion criteria to allow participants on ≥4 
times/week PD including an incremental schedule 
• Removed France country specific requirement for Informed Consent process from 
inclusion criteria  
• Broadened exclusion to include participation in an interventional study with an 
investigational agent or device 
• Removed option to have Early Treatment Discontinuation visit supersede the 
scheduled study visit 
• Added a provision that in unexpected circumstances where the supply to the site is 
interrupted, then local standard of care for anemia management during this time 
period may be considered 
• Added direction regarding randomized treatment and study continuation for 
subjects who will be away from the research site for an extended period of time 
• Added new darbepoetin alfa dose strengths (not available in all countries) 
• Clarified timeframe for iron management criteria 
• Clarified timing of designated study visits for subjects who have not yet initiated 
dialysis and for subjects on dialysis 
• Shortened visit window for the Week 2 and 4 visits 
• Modified Time and Events Table 6 ‘Schedule of Assessments. Main changes 
include addition of Informed Consent activity; footnotes to allow for more time for 
ECG before randomization visit, more clarity around randomized treatment 
dispensing and compliance; removed capture of rescue medications from 
unscheduled visit (rescue evaluation is triggered at scheduled visits); added 
healthcare resource data collection, added footnote to clarify biomarkers storage 
requirements and added Argentina only pregnancy requirement 
• Added direction to CEC Site Manual for full scope of reporting requirements 
• Clarified timing of weight, blood pressure and heart rate in relation to laboratory 
assessments and dialysis 
• Clarified PK sampling in relation to subjects on dose hold 
• Updated PRO section to add healthcare resource utilization data being collected for 
completeness 
• Changed time point for blinded data cut need for psychometric validation of the 
Chronic Kidney Disease Questionnaire 

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• Revised statistical section to change from two-sided testing at the 5% level to one-
sided testing at the 2.5% level; for secondary endpoints, to change significance 
levels to p-values and to correct the time point for various Patient Reported 
Outcomes 
• Updated wording around exploratory endpoints in Appendix 2 
• Updated Darbepoetin alfa dose steps table in Appendix 3 to remove partial doses 
and clarify booster dosing to be consistent with Interactive Response Technology 
(IRT) system 
• Provision for possible adjustment to the Dose Adjustment Algorithm triggers for 
Hgb values 7.5 g/dL to <9.5 g//dL based on review of blinded instream Hgb data 
• Edited Risk Assessment information in Appendix 4 to align with version 8 of the 
Investigator’s Brochure 
• Updated FSH level to confirm menopause in Appendix 5, Female Eligibility 
Criteria 
• Removed Appendix 11- France country specific requirement 
• Other changes include minor edits, corrections of typos and administrative changes 
throughout. 
 
 
 

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S P O N S O R SI G N A T O R Y 
 
 
 
 
 
Ale xa n der R C o bitz, M. D., P h. D.                 Date 
E xec uti ve Direct or Cli nical De vel o p me nt 
Meta b olic Pat h wa ys & Car di o vasc ular U nit
Gla x o S mit h Kli ne
P P D
O ct o b er 6, 2 0 1 7
P P D

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MEDICAL MONITOR/SPONSOR INFORMATION PAGE 
Medical Monitor/SAE Contact Information:  
As this is a multinational study medical monitor/SAE contact information will be 
provided as a separate document. 
 
Sponsor Legal Registered Address:  
GlaxoSmithKline Research & Development Limited 
980 Great West Road 
Brentford 
Middlesex, TW8 9GS 
UK 
PPD is the contract research organization for this study. 
In some countries, the clinical trial Sponsor may be the local GlaxoSmithKline Affiliate 
Company (or designee). If applicable, the details of the alternative Sponsor and contact 
person in the territory will be provided to the relevant regulatory authority as part of the 
clinical trial application.    
Regulatory Agency Identifying Number(s):   
IND Number:  101,291  
EudraCT:  2016-000507-86     

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INVESTIGATOR PROTOCOL AGREEMENT PAGE 
For protocol 201410  
I confirm agreement to conduct the study in compliance with the protocol, as amended by 
this protocol amendment. 
I acknowledge that I am responsible for overall study conduct. I agree to personally 
conduct or supervise the described study. 
I agree to ensure that all associates, colleagues and employees assisting in the conduct of 
the study are informed about their obligations. Mechanisms are in place to ensure that site 
staff receives the appropriate information throughout the study.  
Investigator Name: 
 
Investigator Address: 
 
 
Investigator Phone Number: 
 
 
 
Investigator Signature 
Date 
 

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TABLE OF CONTENTS 
PAGE 
1. 
PROTOCOL SYNOPSIS ........................................................................................ 11 
2. 
INTRODUCTION .................................................................................................... 12 
2.1. 
Brief Background ........................................................................................ 12 
2.2. 
Study Rationale .......................................................................................... 12 
3. 
OBJECTIVE(S) AND ENDPOINT(S) ...................................................................... 13 
4. 
STUDY DESIGN .................................................................................................... 13 
4.1. 
Overall Design ............................................................................................ 13 
4.2. 
Type and Number of Subjects ..................................................................... 14 
4.3. 
Design Rationale ........................................................................................ 15 
4.4. 
Dose Justification ........................................................................................ 15 
4.4.1. 
Daprodustat ................................................................................. 15 
4.4.2. 
Randomized Treatment Dose Adjustment Scheme ...................... 16 
4.5. 
Benefit:Risk Assessment ............................................................................ 16 
4.5.1. 
Risk Assessment ......................................................................... 16 
4.5.2. 
Benefit Assessment ..................................................................... 16 
4.5.3. 
Overall Benefit:Risk Conclusion ................................................... 16 
5. 
SELECTION OF STUDY POPULATION AND WITHDRAWAL CRITERIA ............. 17 
5.1. 
Inclusion Criteria ......................................................................................... 17 
5.2. 
Exclusion Criteria ........................................................................................ 17 
5.3. 
Screening Failures ...................................................................................... 19 
5.4. 
Subject Retention ....................................................................................... 20 
5.5. 
Permanent Discontinuation of Randomized Treatment ............................... 20 
5.5.1. 
Procedures for Subject Follow-up ................................................ 20 
5.6. 
Withdrawal from Study ................................................................................ 21 
5.6.1. 
Withdrawal of Consent for Contact............................................... 21 
5.6.2. 
Subjects Deemed Lost to Follow-up ............................................. 22 
5.7. 
Subject and Study Completion .................................................................... 22 
6. 
RANDOMIZED TREATMENT................................................................................. 23 
6.1. 
Investigational Product and Other Randomized Treatment ......................... 23 
6.2. 
Randomized Treatment Starting Dose, Dose Steps, and Dose 
Adjustments ................................................................................................ 24 
6.2.1. 
Daprodustat Dosing Information .................................................. 24 
6.2.2. 
rhEPO Dosing Information ........................................................... 24 
6.2.3. 
Daprodustat and rhEPO Dose Adjustment Algorithm ................... 25 
6.3. 
Blinding ....................................................................................................... 25 
6.4. 
Packaging and Product Labeling ................................................................ 25 
6.5. 
Preparation/Handling/Storage/Accountability .............................................. 25 
6.6. 
Compliance with Randomized Treatment Administration ............................ 26 
6.6.1. 
Randomized Treatment Extended Interruption ............................. 26 
6.7. 
Treatment of Randomized Treatment Overdose ......................................... 27 
6.8. 
Treatment after the End of the Study .......................................................... 27 
6.9. 
Concomitant Medications ............................................................................ 27 
6.9.1. 
Permitted Medications ................................................................. 27 

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6.9.2. 
Prohibited Medications ................................................................. 27 
6.10. 
Iron Management Criteria ........................................................................... 28 
6.11. 
Anemia Rescue Therapy ............................................................................ 28 
6.12. 
Subjects Changing Dialysis Modality .......................................................... 29 
7. 
STUDY ASSESSMENTS AND PROCEDURES ..................................................... 29 
7.1. 
Time and Events Tables and Procedures for Subject Follow-up ................. 31 
7.2. 
Screening and Critical Baseline Assessments ............................................ 34 
7.3. 
Efficacy ....................................................................................................... 35 
7.4. 
Safety ......................................................................................................... 35 
7.4.1. 
Events Referred to the Clinical Event Committee (CEC) .............. 35 
7.4.2. 
Other CV Events .......................................................................... 36 
7.4.3. 
Adverse Events (AE) and Serious Adverse Events (SAEs) .......... 36 
7.4.3.1. 
Time period and Frequency for collecting AE 
and SAE information ................................................... 36 
7.4.3.2. 
Method of Detecting AEs and SAEs ........................... 37 
7.4.3.3. 
Follow-up of AEs and SAEs ........................................ 37 
7.4.3.4. 
Regulatory Reporting Requirements for SAEs ............ 37 
7.4.4. 
Adverse Events of Special Interest .............................................. 37 
7.4.5. 
Possible Suicidality Related Adverse Events ............................... 38 
7.4.6. 
Pregnancy ................................................................................... 38 
7.4.7. 
Height and Weight ....................................................................... 38 
7.4.8. 
Blood Pressure and Heart Rate ................................................... 39 
7.4.9. 
Electrocardiogram (ECG) ............................................................. 39 
7.4.10. 
Ultrasound ................................................................................... 39 
7.4.11. 
Clinical Laboratory Assessments ................................................. 40 
7.4.12. 
Liver Chemistry Stopping Criteria ................................................ 41 
7.4.12.1. 
Randomized Treatment Restart .................................. 43 
7.5. 
Pharmacokinetics (PK) ............................................................................... 43 
7.6. 
Genetics ..................................................................................................... 44 
7.7. 
Patient Reported Outcomes ........................................................................ 44 
7.7.1. 
Chronic Kidney Disease - Anemia Questionnaire (CKD-
AQ) .............................................................................................. 44 
7.7.2. 
Patient Global Impression of Severity (PGI-S) and Patient 
Global Impression of Change (PGI-C) ......................................... 45 
7.7.3. 
Health Related Quality of Life (SF-36) ......................................... 45 
7.7.4. 
Health Status (EQ-5D-5L & EQ-VAS) .......................................... 45 
7.7.5. 
Psychometric Analyses of the CKD Anemia Symptoms 
Questionnaire (CKD-AQ) ............................................................. 45 
7.8. 
Storage Biomarkers .................................................................................... 46 
8. 
DATA MANAGEMENT ........................................................................................... 46 
9. 
STATISTICAL CONSIDERATIONS AND DATA ANALYSES ................................. 46 
9.1. 
Primary Hypotheses ................................................................................... 46 
9.2. 
Sample Size Considerations ....................................................................... 47 
9.2.1. 
Sample Size Assumptions ........................................................... 47 
9.2.2. 
Sample Size Sensitivity ................................................................ 47 
9.2.3. 
Sample Size Re-estimation or Adjustment ................................... 48 
9.3. 
Data Analysis Considerations ..................................................................... 48 
9.3.1. 
Analysis Populations .................................................................... 48 
9.4. 
Key Elements of Analysis Plan ................................................................... 48 

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9.4.1. 
Primary Analyses ......................................................................... 48 
9.4.2. 
Secondary Analyses .................................................................... 49 
9.4.2.1. 
Principal Secondary Efficacy Analyses ....................... 49 
9.4.2.2. 
Safety Analyses .......................................................... 49 
9.4.3. 
Multiplicity Strategy ...................................................................... 49 
9.4.4. 
Covariates and Subgroups of Interest .......................................... 50 
9.4.4.1. 
Exploratory Cardiovascular Safety Analysis ............... 50 
9.4.5. 
Interim Analysis ........................................................................... 50 
9.4.6. 
Pharmacokinetic/Pharmacodynamic Analyses ............................. 51 
9.4.7. 
Analysis of Patient Reported Outcomes Measures ...................... 52 
10. STUDY GOVERNANCE CONSIDERATIONS ........................................................ 52 
10.1. 
Posting of Information on Publicly Available Clinical Trial Registers ............ 52 
10.2. 
Regulatory and Ethical Considerations, Including the Informed 
Consent Process ........................................................................................ 52 
10.3. 
Quality Control (Study Monitoring) .............................................................. 53 
10.4. 
Quality Assurance ....................................................................................... 53 
10.5. 
Study and Site Closure ............................................................................... 54 
10.6. 
Records Retention ...................................................................................... 54 
10.7. 
Provision of Study Results to Investigators, Posting of Information 
on Publically Available Clinical Trials Registers and Publication ................. 55 
10.8. 
Review Committees .................................................................................... 55 
10.8.1. 
Independent Data Monitoring Committee ..................................... 55 
10.8.2. 
Clinical Endpoint Committee ........................................................ 55 
10.8.3. 
Steering Committees ................................................................... 56 
10.8.4. 
National Leader Committee ......................................................... 56 
11. REFERENCES ....................................................................................................... 57 
12. APPENDICES ........................................................................................................ 58 
12.1. 
Appendix 1:  Abbreviations and Trademarks ............................................... 58 
12.2. 
Appendix 2:  Secondary, Exploratory, Patient Reported Outcomes, 
and Pharmacokinetics/Pharmacodynamics Objectives/ Endpoints ............. 61 
12.3. 
Appendix 3:  Randomized Treatment Dose Steps and Dose 
Adjustment Scheme .................................................................................... 65 
12.3.1. 
Darbepoetin Alfa Dose Steps ....................................................... 65 
12.3.2. 
Randomized Treatment Dose Adjustment Scheme ...................... 66 
12.4. 
Appendix 4: Benefit:Risk Assessment ......................................................... 67 
12.5. 
Appendix 5:  Female Eligibility Criteria ........................................................ 76 
12.6. 
Appendix 6:  Liver Chemistry Stopping Criteria ........................................... 78 
12.6.1. 
Liver Safety Required Actions and Follow up Assessments ......... 78 
12.6.2. 
Liver Safety Drug Restart Guidelines ........................................... 80 
12.7. 
Appendix 7:  Study Specific Equipment ...................................................... 83 
12.8. 
Appendix 8: Definition of and Procedures for Recording, Evaluating, 
Follow-Up and Reporting of Adverse Events ............................................... 84 
12.8.1. 
Definition of Adverse Events ........................................................ 84 
12.8.2. 
Definition of Serious Adverse Events ........................................... 85 
12.8.3. 
Recording of AEs and SAEs ........................................................ 86 
12.8.4. 
Evaluating AEs and SAEs ............................................................ 87 
12.8.5. 
Reporting of SAEs to PPD ........................................................... 88 
12.9. 
Appendix 9:  Collection of Pregnancy Information ....................................... 89 
12.10. Appendix 10: Genetic Research ................................................................. 90 

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12.11. Appendix 11 – Protocol Changes ................................................................ 93 
12.11.1. Changes Resulting from Protocol Amendment 1 .......................... 93 
 

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1. 
PROTOCOL SYNOPSIS 
This Phase 3 study will evaluate the efficacy and safety of daprodustat (GSK1278863) 
compared to recombinant human erythropoietin (rhEPO) in the treatment of anemia 
associated with chronic kidney disease (CKD) in subjects who are planning to start or 
who have recently started dialysis.  This study will also provide information on 
daprodustat dosing initiation and titration in subjects initiating dialysis. 
Primary Objective/Primary Efficacy Endpoint 
The primary objective of the study is to compare daprodustat to rhEPO for hemoglobin 
(Hgb) efficacy (non-inferiority). 
The primary efficacy endpoint will be the mean change in Hgb between baseline and the 
evaluation period (EP, mean over Weeks 28-52).  
Overall Design 
• This is a randomized, open-label (sponsor blind), active-controlled, parallel-group, 
multi-center study in subjects with anemia associated with CKD who are not 
regularly using erythropoiesis-stimulating agents (ESAs) and who are initiating 
dialysis.   
• This study will comprise three study periods: a screening period (2 weeks*), a 52-
week active treatment period, and a follow-up period (4-6 weeks). 
* Screening period can be extended by an additional 4 weeks for ultrasound 
examination, IV iron supplementation and/or vitamin B12 treatment as needed.   
• Subjects will be stratified by dialysis type (hemodialysis [HD], or peritoneal 
dialysis [PD]) and by whether their dialysis start is planned or unplanned (urgent).      
• Following stratification, subjects will be randomized 1:1 to receive daprodustat or 
rhEPO (darbepoetin alfa); all randomized treatments (Section 6.1) will be supplied 
by GSK. 
• Although prior regular ESA use is prohibited, limited ESA use is allowed around 
the time of dialysis initiation only.   
• To ensure consistency of treatment across the study there are protocol-mandated 
algorithms for dose adjustments of daprodustat and rhEPO, iron management, and 
rescue. 
Type and Number of Subjects 
• The study will enroll the following types of subjects with anemia associated with 
CKD: Planned initiation of dialysis:  Subjects who are planning to start chronic 
dialysis (HD or PD) within the next 6 weeks (from the day of screening).   

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•  U n pla n ne d ( ur ge nt) i nitiati o n of dial ysis:  F or S u bj ects w h o ha ve starte d c hr o nic 
dial ysis i n a n ur ge nt ma n ner, mea ni n g t he y starte d H D wit h a te m p ora r y vasc ular 
access wit h n o pre vi o us pla n ni n g f or c hr o nic di al ysis or ha v e starte d P D wit h rece nt 
( < 2 wee ks) P D cat heter i nserti o n a n d/ or w h o ha v e n ot bee n see n b y a ki d ne y 
s pecialist ( ne p hr ol o gist) or ot her s peci alist wit h e x pertise i n dial ysis care wit hin 
pre vi o us 4 m o nt hs pri or t o scree ni n g. 
T his st u d y will ra n d o mize a p pr o xi matel y 3 0 0 s u bj ects, or 1 5 0 s u bjects per treat me nt 
gr o u p.    
Pri m ar y Effi c a c y A n al y si s  
T he pri mar y H g b efficac y a n al ysis will assess w h et her da pr o d ustat is n o n -i nferi or t o 
r h E P O f or ch a n ge fr o m baseli ne. T he a nal ysis will be base d o n t he mea n c h a n ge i n H g b 
bet wee n b aseli ne a n d t he efficac y E P ( defi ne d as Wee ks 2 8 t o 5 2) usi n g a n o n- i nferi orit y 
mar gi n of - 0. 7 5 g/ d L (t w o-si de d 9 5 % CI). A n a nal ysis of t he I T T P o p ulati o n, c o m prisi n g 
all s ubjects wit h at least o ne H g b meas ure me nt ( o n or off -treat me nt) d uri n g t he E P a n d a n 
a nal ysis of c o varia nce ( A N C O V A) m o del will be use d. T he m o del will i ncl u de 
ra n d o mizati o n stratificati o n fact ors, a n d fact ors f or baseli ne H g b a n d treat me nt.     
2.  
I N T R O D U C TI ON 
2. 1.   
Bri ef B a c k gr o u n d 
Da pr o d ustat ( G S K 1 2 7 8 8 6 3) is a n oral h y p o xia- i n d uci ble fact or- pr ol yl h y dr o x ylas e 
i n hi bit or ( HI F-P HI) c urre ntl y bei n g i n vesti gate d as a treat me nt f or a ne mia ass ociate d 
wit h C K D i n b ot h s u bjects o n dial ysis a n d n ot o n dial ysis.  Safet y a n d effi cac y ha v e bee n 
i n vesti gate d i n cli nical trials u p t o 2 4 wee ks’ d urati o n.  B ot h pre-cli nical a n d cli nical data 
s h o w t hat da pr o d ustat sti m ulates e n d o ge n o us er yt hr o p oieti n ( E P O) pr o d ucti o n a n d 
i ncreas e d er yt hr o p oi esis, res ulti n g i n ele v ati o n of H g b c o nce ntrati o ns.  T hese i ncreases i n 
H g b are ac hie v e d wit h pea k plas ma E P O le vels s u bsta ntiall y l o wer t h a n t h ose o bser ve d 
wit h I V r h E P O.  Data fr o m c o m plete d cli nical a n d precli nical st u dies are pr o vi de d i n t he 
c urre nt d a pr o d ustat I n vesti gat or Br oc h ure (I B) a n d I B s u p ple me nt(s) (if a p plica ble).  
2. 2.   
St u d y R ati o n al e 
Base d o n its mec h a nis m of acti o n t o sti m ulate er yt hr o p oiesis via i n hi biti o n of HI F - pr ol yl 
h y dr o x yl ase e nz y m es,
 
A P hase 2 B cli nical trial ( P HI 1 3 3 6 3 3) i n dial ysis s u bjects w it h a ne mia ass ociate d wit h 
C K D de m o nstrate d t hat da pr o d ustat ca n m ai ntai n H g b u p t o 2 4 w ee ks wit h mi ni mal 
effects o n plas ma E P O c o nce ntrati o n.  Da pr o d ustat treat me nt f or u p t o 2 4 wee ks 
de m o nstrate d a n a d vers e e ve nt ( A E) pr ofile c o nsiste nt wit h t he patie nt p o p ulati o n.    
C CI
T his P hase 3 st u d y will e val uate t he safet y a n d efficac y of d a pr o d ustat c o m pare d t o 
r h E P O f or treat me nt of a ne mia ass ociate d wit h C K D i n s u bjects w h o are starti n g dial ysis 
C CI - T hi s s e cti o n c o nt ai n e d Cli ni c al O ut c o m e A s s e s s m e nt d at a c oll e cti o n q u e sti o n n air e s or i n di c e s, w hi c h ar e pr ot e ct e d 
b y t hir d p art y c o p yri g ht l a w s a n d t h er ef or e h a v e b e e n e x cl u d e d.

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or who have recently started dialysis.  Data from this trial are intended to support the use 
of daprodustat for the treatment of anemia in subjects initiating chronic dialysis.   
3. 
OBJECTIVE(S) AND ENDPOINT(S) 
Objectives 
Endpoints 
Primary 
To compare daprodustat to rhEPO for Hgb efficacy 
(non-inferiority)  
Mean change in Hgb between baseline and evaluation 
period (EP, mean over Weeks 28-52) 
Principal Secondary (tested for superiority, adjusted for multiplicity) 
To compare daprodustat to rhEPO on the use of 
intravenous (IV) iron  
1. Average monthly IV iron dose (mg)/subject from baseline 
to Week 52  
Safety 
To compare the safety and tolerability of daprodustat to 
rhEPO 
• Incidence and severity of AEs and SAEs including those 
AEs of special interest 
• Reasons for discontinuation of randomized treatment 
• Absolute values and changes from baseline in laboratory 
parameters, blood pressure, and heart rate 
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 study in subjects with anemia associated with CKD who are not 
regularly using routine erythropoiesis-stimulating agent (ESA) users and who are 
initiating dialysis.    
• The study will comprise three study periods: a screening period (2 weeks*), a 52-
week active treatment period, and a follow-up period (4-6 weeks) (Figure 1).  
Weeks 28-52 are defined as the efficacy evaluation period (EP) for the primary 
efficacy comparison.  
* Screening period can be extended by an additional 4 weeks for ultrasound 
examination, IV iron supplementation and/or vitamin B12 treatment as needed.   
 
• A central randomization approach will be used to protect the trial from potential for 
selection bias due to the open-label design.  All subjects will be treated to achieve 
and maintain an Hgb within a range of 10-11 g/dL. 
• Limited ESA use is allowed around the time of dialysis initiation only (see Section 
5.2 for definition of “limited use”). 
• The treatment period consists of: 

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o 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. 
o The evaluation period (EP), defined as the period from the end of the 
stabilization period (Week 28) to Week 52 (titrations may also occur 
during this treatment period), to assess safety and efficacy.  
• Subjects will be stratified by dialysis type (hemodialysis [HD] or peritoneal dialysis 
[PD]) and by whether their dialysis start is planned or unplanned (urgent).  
• Following stratification, subjects will be randomized 1:1 to receive daprodustat or 
rhEPO (darbepoetin alfa); all randomized treatments (Section 6.1) will be supplied 
by GSK.      
• To ensure consistency of treatment across the study there are protocol-mandated 
algorithms for dose adjustments of daprodustat and rhEPO (Section 6.2), iron 
management (Section 6.10) and anemia rescue therapy (Section 6.11) 
• 
An overview of the study design is provided in Figure 1.  
Figure 1 
Study Schematic 
 
4.2. 
Type and Number of Subjects 
The study will enroll the following types of subjects with anemia associated with CKD: 
• Planned: Subjects who are planning to start dialysis (HD or PD) within the next 6 
weeks (from the day of screening). 
• Unplanned (urgent):  For Subjects who have started chronic dialysis in an urgent 
manner, meaning they started HD with a temporary vascular access with no 
previous planning for chronic dialysis or have started PD with recent (< 2 weeks) 
PD catheter insertion and/or who have not been seen by a kidney specialist 
(nephrologist) or other specialist with expertise in dialysis care within previous 4 
months prior to screening.   

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This study will randomize approximately 300 subjects, or 150 subjects per treatment 
group.  The study will be conducted globally. 
4.3. 
Design Rationale 
This study includes a screening period where iron supplementation is permitted, so that 
subjects who are not iron replete can meet iron status entry criteria prior to 
randomization.   
The study will include subjects who are planning to start dialysis imminently, have 
already recently started dialysis in a planned manner, and those who start dialysis 
urgently. This broad range of subjects will provide data on the effects of daprodustat in 
subjects starting dialysis as well as data on whether there are differences between planned 
and unplanned (urgent) starts. 
Although subjects will be rhEPO non-users, because it is routine medical practice to 
begin treatment with rhEPO around the time of dialysis initiation if subjects have anemia 
(Hgb <11 g/dL), the protocol will allow limited rhEPO use during the four weeks before 
or after starting dialysis (Section 5.2).   
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 
opportunity for subjects to be titrated to their optimal dose of randomized treatment prior 
to the efficacy EP (Weeks 28 to 52).  Some subjects may still need dose titration during 
the EP.  
The selection of the rhEPO control (darbepoetin alfa) is based on feasibility and clinical 
practice in the majority of participating countries.  
The study is open-label (sponsor blind) because it would be complex to double- blind due 
to the differing number of dose steps and different modes of administration (oral vs. 
injection) between randomized treatments   
4.4. 
Dose Justification 
Starting doses, dose steps, and elements of the dose adjustment scheme are provided in 
Section 6.2 and Appendix 3. 
4.4.1. 
Daprodustat 
Daprodustat starting doses are assigned based on Hgb at study entry, and were selected 
such that the target Hgb concentration would be reached after approximately one red 
blood cell lifespan of treatment (up to 90 days, pharmacodynamic steady-state).  
However, due to the between-subject variability in Hgb response to a given dose of 
daprodustat and the relatively narrow Hgb target range, individual dose adjustments of 
daprodustat are expected during the first few months of treatment.  If an individual dose 
adjustment is made, subjects will increase or decrease the daprodustat dose through a 
series of dose steps, one dose step at a time.  The highest dose of daprodustat in the dose 
adjustment scheme is 24 mg once daily. 

2 0 1 5 N 2 3 4 5 3 4 _ 0 1  
C O N FI D E N TI A L  
 
 
 
2 0 1 4 1 0  
 
 
 
 
1 6  
 
T he da pr o d ustat starti n g d oses a n d d ose ste ps w ere selecte d f or t his st u d y b ase d o n 
e x p os ure-res p o nse l o n git u di nal m o deli n g of H g b data c ollecte d acr oss t he P hase 2 
pr o gra m. C o variat e a nal yses el uci date d t hat b aseli ne H g b, b o d y - w ei g ht, a n d pri or E S A 
d ose (if a p plica bl e) w ere t he m ost rele va nt c o v ariates of H g b res p o ns e t o da pr o d ustat.    
4. 4. 2.  
R a n d o mi z e d Tr e at m e nt D o s e A dj u st m e nt S c h e m e  
A ra n d o mize d treat me nt d ose a dj ust me nt al g orit h m was desi g n e d t o mi ni mize 
u n necessar y d ose a dj ust me nts b y all o wi n g f or visit- t o-visit varia bilit y, a n d it is i nf or me d 
b y t he c ha n ge i n H g b fr o m t he pre vi o us visit w he n e val uati n g t he nee d f or a d ose 
a dj ust me nt ( Secti o n  6. 2. 3 ).    
4. 5.  
B e n efit: Ri s k A s s e s s m e nt  
S u m maries of fi n di n gs fr o m b ot h cli nical a n d n o n-cli nical st u dies c o n d ucte d wit h 
da pr o d ustat ca n b e f o u n d i n t he da pr o d ustat I n vesti gat or’s Br oc h ure (I B) a n d I B 
s u p ple me nt(s) (if a p plica ble). 
4. 5. 1.  
Ri s k A s s e s s m e nt  
T he p ote ntial ris ks of cli nical si g nifica nce, i ncl u di n g a d v erse e ve nts of s pecial i nterest 
(see Secti o n 7. 4. 4  f or det ails), a n d t he miti gati o n strate gies f or t his pr ot oc ol ta ki n g i nt o 
acc o u nt t he r es ults of c o m plete d cli nical a n d n o n cli nical st u dies wit h da pr o d ustat are 
o utli ne d i n  A p pe n di x 4  ( Secti o n 1 2. 4 ). I n a d diti o n t o t he miti gati o n strate gies o utli ne d, a n 
I n d e pe n de nt Data M o nit ori n g C o m mittee (I D M C) will m o nit or accr ui n g s afet y data f or 
t his trial ( Secti o n 1 0. 8. 1 ).  
4. 5. 2.  
B e n efit A s s e s s m e nt  
I n cli nical trials of u p t o 2 4 wee ks i n d urati o n, i n s u bjects wit h a ne mia ass ociate d wit h 
C K D, da pr o d ustat has bee n s h o w n t o treat H g b t o tar get ra n ge.  Da pr o d ustat ma y prese nt 
se veral i m p orta nt a d v a nt a ges o ver r h E P O a n d its a nal o gs.  It is a n oral me dicati o n a n d 
d oes n ot re q uire c ol d- c h ai n st ora ge as d oes r h E P O, t h us i ncreasi n g eas e of use f or 
patie nts a n d healt h care pr o vi ders.  After a d mi nistrati o n of da pr o d ustat, data s u g gest t hat 
t he i ncreas es i n H g b ar e ac hie ve d wit h E P O e x p os ure l o wer t ha n t h ose o bs er ve d wit h 
r h E P O.  Treat me nt of a n e mia of C K D wit h r h E P O is ass ociate d wit h i ncrease d C V ris k 
w hic h is p ost ulate d t o be relate d t o t he ass o ciate d s u pra- p h ysi ol o gical i ncreases i n E P O 
e x p os ure wit h r h E P O [Szczec h , 2 0 0 8];
 
4. 5. 3.  
O v er all B e n efit: Ri s k C o n cl u si o n  
C CI - T hi s s e cti o n c o nt ai n e d Cli ni c al O ut c o m e A s s e s s m e nt d at a c oll e cti o n q u e sti o n n air e s or i n di c e s, w hi c h ar e 
pr ot e ct e d b y t hir d p art y c o p yri g ht l a w s a n d t h er ef or e h a v e b e e n e x cl u d e d.
Da pr o d ustat de m o nstrat es a p ositi ve be nefit vs. ris k base d o n t he e vi de n ce as f oll o ws.  I n 
cli nical trials u p t o 2 4 wee ks i n d urati o n, da pr o d ustat treats H g b t o tar get ra n ge, a n d t here 
are n o a d v erse e ve nts t hat ha ve bee n i d e ntifie d as relate d t o treat me nt wit h da pr o d ustat.  
C CI

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This protocol employs precautions to mitigate known and potential risks to enrolled 
subjects (See Appendix 4, Section 12.4, for details).  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 about warnings, precautions, contraindications, AEs, and other 
pertinent information is provided in the daprodustat IB, IB supplement(s) (if applicable), 
the product label for 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 and randomization (Day 1) unless otherwise specified.    
1. 
Age (confirm at screening): 18 to 99 years of age inclusive. 
2. 
Dialysis: Planning to start chronic dialysis within the next 6 weeks (from the date of 
the screening visit) OR have started and received dialysis (as specified below) for 
end-stage renal disease for a maximum of ≤90 days immediately prior to 
randomization and is not expected to stop dialysis during the duration of the trial:  
• HD ≥2X/week  
• PD: ≥4 times/week including incremental schedule; subjects on continuous 
ambulatory peritoneal dialysis (CAPD) and automated peritoneal dialysis 
(APD) are eligible.  
3. 
Hemoglobin concentration as measured by HemoCue (range inclusive): 8-10.5 
g/dL (5-6.5 mmol/L) at screening and 8-11.0 g/dL (5-6.8 mmol/L) at 
randomization. 
4. 
Informed consent (at screening): capable of giving signed informed consent 
which includes compliance with the requirements and restrictions listed in the 
consent form and in this protocol. 
5.2. 
Exclusion Criteria 
A subject will not be eligible for participation in this study if any of the following criteria 
apply at screening or at randomization (Day 1), unless otherwise specified.  

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CKD-related criteria 
1. 
Kidney transplant: Planned living-related or living-unrelated kidney transplant 
during the study. 
Anemia related criteria 
2. 
Ferritin:  ≤100 ng/mL (≤100 µg/L) at screening or after IV iron supplementation. 
3. 
TSAT:  ≤20% at screening or after IV iron supplementation.  
4. 
Vitamin B12:  Below the lower limit of the reference range at screening or after 
vitamin B12 supplementation. 
5. 
Folate:  <2.0 ng/mL (<4.5 nmol/ L) at screening.  
6. 
Aplasias: History of bone marrow aplasia or pure red cell aplasia (PRCA). 
7. 
Other causes of anemia: Untreated pernicious anemia, thalassemia major, sickle 
cell disease, or myelodysplastic syndrome. 
8. 
Gastrointestinal (GI) bleeding: Evidence of actively bleeding gastric, duodenal, or 
esophageal ulcer disease OR clinically significant GI bleeding ≤10 weeks prior to 
screening through to randomization (Day 1). 
 Erythropoiesis treatment criteria  
9. 
Use of any ESA treatment within 8 weeks prior to screening except for limited use 
as part of dialysis initiation.    
Limited use is defined as no more than 6 weeks of short acting ESA (rhEPO or 
biosimilars; maximum of 20000 U total) or long acting ESA (darbepoetin alfa 
[maximum of 100 µg total] or methoxy polyethylene glycol-epoetin beta 
[maximum of 125 µg total]) received before or after starting dialysis. 
Cardiovascular disease-related criteria 
10. Myocardial infarction or acute coronary syndrome:  ≤10 weeks prior to 
screening through to randomization (Day 1). 
11. Stroke or transient ischemic attack:  ≤10 weeks prior to screening through to 
randomization (Day 1). 
12. Heart failure: Chronic Class IV heart failure, as defined by the New York Heart 
Association (NYHA) functional classification system. 
13. Current uncontrolled hypertension:  Current uncontrolled hypertension as 
determined by the Investigator that would contraindicate the use of rhEPO. 
14. QTcB (Day 1): QTcB >500 msec, or QTcB >530 msec in subjects with bundle 
branch block.  There is no QTc exclusion for subjects with a predominantly 
ventricular paced rhythm. 
 
Other disease-related criteria 
15. Liver disease (any one of the following):  
• Alanine transaminase (ALT) >2x upper limit of normal (ULN) (screening 
only) 
• Bilirubin >1.5xULN (screening only) 
NOTE: Isolated bilirubin >1.5xULN is acceptable if bilirubin is fractionated 
and direct bilirubin <35% 

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• Current unstable liver or biliary disease per investigator assessment, generally 
defined by the presence of ascites, encephalopathy, coagulopathy, 
hypoalbuminaemia, esophageal or gastric varices, persistent jaundice, or 
cirrhosis 
NOTE: Stable chronic liver disease (including asymptomatic gallstones, 
chronic hepatitis B or C, or Gilbert’s syndrome) are acceptable if subject 
otherwise meets entry criteria. 
 
16. 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 (i.e. Bosniak Category II F, III or IV) > 3cm.  The only exception is 
localized squamous cell or basal cell carcinoma of the skin that has been 
definitively treated ≥10 weeks prior to screening. 
Concomitant medications and other study treatment-related criteria 
17. Severe allergic reactions: History of severe allergic or anaphylactic reactions or 
hypersensitivity to excipients in the investigational product (refer to daprodustat 
IB) or to darbepoetin alfa (refer to product labelling). 
18. Drugs and supplements (randomization only): Use of strong CYP2C8 inhibitors 
(e.g., gemfibrozil) or strong CYP2C8 inducers (e.g., rifampin/rifampicin). 
19. 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).  
20. Prior treatment with daprodustat:  Any prior treatment with daprodustat for 
treatment duration of > 30 days. 
General health-related criteria 
21. Females ONLY: Subject is pregnant [as confirmed by a positive serum human 
chorionic gonadotropin (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 in the List of Highly Effective 
Methods for Avoiding Pregnancy listed in Appendix 5. 
22.  Other Conditions:  Any other condition, clinical or laboratory abnormality, or 
examination finding that the investigator considers would put the subject at 
unacceptable risk, which may affect study compliance (e.g., intolerance to rhEPO) 
or prevent understanding of the aims or investigational procedures or possible 
consequences of the study.   
5.3. 
Screening Failures 
Screen failures are defined as subjects who consent to participate in the clinical trial but 
are not subsequently randomized.  In this study, subjects can become a screen failure at 
any time from the screening visit to the Day 1 visit prior to randomization.  
Documentation of a minimum set of information on screen failure subjects must be 
collected from subjects that fail screening, including demography, screen failure details, 
eligibility criteria, and serious adverse events (Section 7.4.3.4). 

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Subjects that fail screening are eligible to be rescreened once 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.  
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 
• Reaching criterion to receive rescue (Section 6.11) 
• 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 dermal 
squamous cell or basal cell carcinoma 
• Need for more than 14 days use of a prohibited medication (Section 6.9.2) 
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 re-approached 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 in-clinic study visits 

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through to Follow-up according to the study visit schedule, unless consent is actively 
withdrawn.  Complete details are provided in Table 7 in Section 7.1. 
• Early Treatment Discontinuation visit:  This visit should occur within 2 weeks of 
the last dose of randomized treatment.   
• Remaining in-clinic visits*: 
o Day 1 through Week 52:  Study visits every 12 weeks ± 2 weeks post 
Early Treatment Discontinuation visit. 
o Follow-up: Study visit 4 weeks after Week 52. 
*Phone visit acceptable in exceptional circumstances. 
• In all cases, reasons for Early Treatment Discontinuation and the date of last dose 
will be recorded.   
• 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 
Every effort should be made to keep subjects in the study.  For subjects that choose to 
withdraw consent or are lost to follow up, the reason for not completing the study will be 
recorded in the subject’s eCRF. 
If a subject withdraws from the study, he/she may request destruction of any clinical 
samples taken, and the investigator must document this in the site study records. 
5.6.1. 
Withdrawal of Consent for Contact 
Specific wording is included in the informed consent form which permits subjects to 
discontinue randomized treatment and study procedures, but states an expectation that 
follow up information will always be required. Subject 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 
withdraws consent from the study, the Investigator will review the following contact 
options with the subject:  
• In-clinic and phone visits 
• Follow-up via medical records review and/or other treating physician 
• Follow-up via family member or other third party contact 

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If all of these options are refused, then no further study visits or study-related telephone 
contact 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 study outcomes or 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 eCRF and 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 
Treatment visit with the following exception: subjects who die while on study are also 
considered as having completed the study.   

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6. 
RANDOMIZED TREATMENT 
6.1. 
Investigational Product and Other Randomized Treatment 
The term ‘randomized treatment’ is used throughout the protocol to describe any product 
(i.e., daprodustat or darbepoetin alfa during the treatment period) received by the subject 
as per the protocol design. Randomized treatment will be provided by GSK. 
During the treatment period, iron therapy (supplied locally) will be administered as per 
the iron management criteria (Section 6.10).   
Daprodustat will be supplied as film coated tablets for oral administration containing 1, 2, 
4, 6, 8, or 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).    
Table 1 
Description of Daprodustat Tablets 
Tablet size 
Dose 
Description 
7.0 mm 
 
daprodustat 1 mg, 2 mg, 4 mg,  
7.0 mm round, compound radius, white film 
coated tablets 
9.0 mm 
daprodustat 6 mg, 8 mg, 10 mg,  
9.0 mm round, compound radius, white film 
coated tablets 
Subjects will take daprodustat tablet(s) daily with water, and these tablets can be taken 
without regard to food.     
GSK will supply rhEPO (darbepoetin alfa) for the control group as prefilled syringes 
(PFS) for SC/IV injection.  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. 
Darbepoetin alfa doses from 20 µg to 400 µg will be administered using the strengths in 
Table 2.  See also Appendix 3, Section 12.3.1 for darbepoetin alfa dose steps and dosing 
frequency. Additional details to deliver the total dose are also captured in the SRM. 
Table 2 
Description of Darbepoetin Alfa PFS 
PFS Strengths 
PFS Volume  
20 µg* 
0.5 mL 
30 µg*  
0.3 mL 
40 µg 
0.4 mL 
60 µg 
0.3 mL 
80 µg* 
0.4 mL 
100 µg 
0.5 mL 
150 µg 
0.3 mL 
* Not available in all countries.   

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6.2. 
Randomized Treatment Starting Dose, Dose Steps, and 
Dose Adjustments 
6.2.1. 
Daprodustat Dosing Information 
Daprodustat Starting Dose 
The starting dose of daprodustat will be assigned based on the HemoCue Hgb 
concentration at randomization (Day 1) (Table 3). 
Table 3 
Daprodustat Starting Dose (All Subjects) 
HemoCue Hgb (g/dL) at 
Randomization (Day 1)  
Daprodustat starting dose 
(mg, once daily) 
≥8 to <9 
4 
≥9 to ≤10 
2 
>10 
1 
 
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 (see 
Appendix 3, Section 12.3.2 for details).  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.  
 
6.2.2. 
rhEPO Dosing Information 
Darbepoetin alfa Starting Dose 
For subjects starting HD or PD, the SC/IV darbepoetin alfa dose will be 0.75-1.0 µg/kg 
rounded to the nearest available dose.  Detailed information is provided in Table 4. 
Table 4 
Darbepoetin Alfa Starting Dose 
Weight  
Darbepoetin Alfa Starting Dose  
<60 kg 
40 µg every 4 weeks 
≥ 60 kg to <90 kg 
60 µg every 4 weeks 
≥90 kg to < 120 kg 
40 µg every 2 weeks 
≥ 120 kg 
60 µg every 2 weeks 
 

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Darbepoetin alfa Dose Steps 
Dose adjustments will be made programmatically by the Interactive Response 
Technology (IRT) system.  
Dose-steps and frequency of administration of darbepoetin alfa are pre-defined in this 
study (Appendix 3, Section 12.3.1).  The SC or IV darbepoetin alfa dose adjustment 
increases and decreases are generally within 20% and 33% range, with a few increases of 
50% based on available dose strengths.   
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 as per the randomized treatment (daprodustat and 
darbepoetin alfa) dose adjustment algorithm in Appendix 3. 
 
6.2.3. 
Daprodustat and rhEPO Dose Adjustment Algorithm 
Dose adjustments will be made programmatically by the IRT system to maintain Hgb 
concentrations within the range of 10-11 g/dL based on the Hgb value measured every 2 
to 4 weeks by the HemoCue value disclosed to the IRT system by the investigator.  
The protocol-specified randomized treatment (daprodustat or rhEPO) dose adjustment 
algorithm is provided in Appendix 3, Section 12.3.2.   
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 3 based on the review of aggregate blinded instream Hgb data. 
6.3. 
Blinding 
This is an open-label study; however, the sponsor is blinded to randomized assignment.  
A detailed Blinding Plan will describe the procedures that will be implemented in order 
to minimize the extent to which this blind may be compromised. 
6.4. 
Packaging and Product 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.   Randomized treatment will have the dose 
strength on the label.  
6.5. 
Preparation/Handling/Storage/Accountability 
No special preparation of randomized treatment is required. 
Only subjects enrolled in the study may receive randomized treatment and only 
authorized site staff may supply randomized treatment.  All randomized treatments must 
be stored in a secure environmentally controlled and monitored (manual or automated) 

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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 randomized treatment accountability, reconciliation, and record 
maintenance (i.e. receipt, reconciliation and final disposition records).   
Further guidance and information for final disposition of unused randomized treatment 
are provided in the SRM.  
Under normal conditions of handling and administration, randomized treatment is 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. 
6.6. 
Compliance with Randomized Treatment Administration 
Randomized subjects who administer randomized treatment (daprodustat or rhEPO) 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. 
Subjects randomized to rhEPO, who have randomized treatment administered in the 
clinic, will have the details of each administered rhEPO dose maintained and reconciled 
with randomized treatment and compliance records.  Randomized treatment start and stop 
dates and dosing details, including dates for randomized treatment interruptions and/or 
dose increases/reductions, will be recorded in the eCRF. 
6.6.1. 
Randomized Treatment Extended Interruption 
Every effort must be made to continue randomized treatment and to complete study 
visits, where able; however, sites should contact their PPD study team member if a 
subject cannot return to the research site on a temporary basis for any one of the 
following situations: 
• Subjects who are hospitalized for any duration.  
• Subjects who cannot return to the site for a period >5 weeks. 
In exceptional circumstances, 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.   

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6.7. 
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 so dialysis is not an effective method 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 cardiovascular (CV) events, increased heart rate and hematologic 
abnormalities. 
Consult the approved product label for information on overdose for rhEPOs. 
6.8. 
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. 
6.9. 
Concomitant Medications 
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 and termination) will be 
recorded for certain medications at each visit (i.e., iron and anti-hypertensive 
medications). 
6.9.1. 
Permitted Medications 
Unless specified as a prohibited medication in Section 6.9.2, 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 (i.e., clopidogrel, 
teriflunomide, deferasirox) should be performed with caution.   
6.9.2. 
Prohibited Medications 
Use of any of the following prescription drugs from screening 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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Except for study randomized treatment, no other investigational agents or devices are 
permitted from study entry through completion of the study. 
6.10. 
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 10.8.3) will monitor blinded subject iron data in an 
ongoing fashion to ensure compliance. 
6.11. 
Anemia 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 5.   
This rescue algorithm does not apply to subjects with a low Hgb as a result of an acute or 
sub-acute 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 5 
Rescue Algorithm for Anemia Management 
Evaluate Subject for Rescue if:   
HemoCue Hgb remains <9 g/dL (at a scheduled visit, Week 4 onwards) despite three1 consecutive dose 
increases above the starting dose or post-rescue2 (where HemoCue Hgb<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 Hgb 4 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, 
- HemoCue Hgb remains <9 g/dL despite initial intervention based on the average of 
two HemoCue Hgb values3  
OR 
- More than two units of PRBC were needed for transfusion (and was not related to 
acute bleeding). 
1. 
Two consecutive dose increases if starting/post-rescue dose is daprodustat 12 mg or darbepoetin alfa 200 µg 
over 4 weeks; one dose increase if starting/post-rescue dose is daprodustat 16 mg or darbepoetin alfa 300 µg 
over 4 weeks; and no prior dose increase if starting/post-rescue dose is daprodustat 24 mg or darbepoetin alfa 
400 µg over 4 weeks (top dose). 
2. 
For subjects who previously are evaluated for rescue and who are able to continue in the trial, “post-rescue” 
dose is the dose of randomized treatment that a subject is receiving at the study visit after initial intervention. 
3. 
Repeat HemoCue Hgb at the same study visit to confirm Hgb (using the same sample); take average of 2 
values. 
6.12. 
Subjects Changing Dialysis Modality 
Subjects changing dialysis modality should not be withdrawn from the study, but should 
continue on the same randomized treatment (daprodustat or darbepoetin alfa).  
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. 
Time and Events Tables are provided for subjects receiving randomized treatment (Table 
6) and for subjects who permanently discontinue randomized treatment (Table 7).   
Because Hgb levels become more variable with increased time between dialysis sessions, 

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the designated study visit should occur during the dialysis session with the shortest 
interval from the previous session. 
Designated study visits for subjects in the screening period or study treatment period who 
have not yet initiated dialysis can occur on any day of the week. 
Designated study visits for subjects on dialysis should be scheduled as follows from the 
screening assessment to the end of the study: 
• For subjects on 3X/week HD: The designated study visit must not occur on the 
first dialysis session of the week. For example, if on a Monday-Wednesday-
Friday schedule, the study visit should be on Wednesday or Friday. 
• For subjects on 2X/week HD: The visit should occur during the session that is 
closest to the previous HD 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).  
• For subjects on PD: study visits can occur on any day of the week. 
Details regarding study-specific equipment are provided in Appendix 7. 
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 6 
onwards is ±1 week.  However, to ensure continuity of randomized treatment, study visits 
should be no more than 5 weeks apart.  In exceptional circumstances, minor changes to 
visit structure may be permitted after consultation with the PPD/GSK Medical Monitor. 
Study assessments should preferably be done at dialysis centers, however, in some 
circumstances 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 Tables and Procedures for Subject Follow-up 
Table 6 
TIME AND EVENTS TABLE FOR SUBJECTS ON RANDOMIZED TREATMENT 
Protocol activity (visits ±1 week, 
except Weeks 2 and 4 which are ±3 
days) 
 
Screening  
Week -21 
Randomization 
(Day 1) 
Weeks 2, 6 
Full study visit 
Weeks 4, 16, 28, 40 
Abbreviated  
study visit 
Weeks 8, 12, 20, 24, 
32, 36, 44, 48 
Week 52 
Unscheduled 
Follow-up  
 Weeks 56-58 
Written informed consent19 
X 
 
 
 
 
 
 
 
IRT system  
X 
X 
X 
X 
X 
 
X 
X 
Entry criteria 
X 
X 
 
 
 
 
 
 
History: medical, hospitalization, 
transfusion; demography, height  
X 
 
 
 
 
 
 
Weight and estimated dry (target) 
weight 
X 
X 
X 
X 
X 
X 
X 
X 
SBP/DBP2, HR2  
X 
X2 (triplicate) 
X 
X 
X 
X2 (triplicate) 
X 
X 
ECG3 
X 
X 
 
 
 
 
 
 
Ultrasound of kidneys and adrenal 
glands 
X4 
 
 
 
 
 
 
 
Randomized treatment dispensing16 
 
X 
 
X 
X 
 
X5.6 
 
Randomized treatment compliance16 
 
X 
X 
X 
X 
X7 
 
Iron therapy, transfusions 
 (record in eCRF, if applicable) 
 
X 
X 
X 
X 
X 
 
X 
Rescue medication  
(record in eCRF, if applicable) 
 
X 
X 
X 
X 
 
X 
Females only: estradiol & FSH (if required) 
X 
 
 
 
 
 
 
 
Serum pregnancy test8 (FRP only) 
X 
X 
 
X 
X17 
X 
X 
X 
HemoCue Hgb 
X 
X 
X 
X 
X 
X 
X 
 
Hematology9 
X 
X 
 
X 
Hgb only 
X 
X 
X 
Clinical chemistry9 
X 
X 
 
X 
 
X 
X 
X 
Ferritin, serum iron, UIBC 
X1 
X 
 
X 
 
X 
 
X 
Vitamin B121, folate 
X 
 
 
 
 
 
 
Hepcidin 
 
X 
 
X 
 
X 
 
X 

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Protocol activity (visits ±1 week, 
except Weeks 2 and 4 which are ±3 
days) 
 
Screening  
Week -21 
Randomization 
(Day 1) 
Weeks 2, 6 
Full study visit 
Weeks 4, 16, 28, 40 
Abbreviated  
study visit 
Weeks 8, 12, 20, 24, 
32, 36, 44, 48 
Week 52 
Unscheduled 
Follow-up  
 Weeks 56-58 
 iPTH 
 
X 
 
X 
 
X 
 
X 
Storage biomarkers18  
 
X 
 
Wk 28 
 
X 
 
 
Kt/Vurea for dialysis adequacy10 
 
 
X 
 
X 
 
 
Lipids (non-fasting), direct LDL 
 
X 
 
 
 
X 
 
 
PK Sampling11 
 
 
Weeks 4, 8, 1211 
 
 
 
Genetics sample12 
 
X 
 
 
 
 
 
 
 hsCRP 
 
X 
 
Week 28 only 
 
X 
 
 
EQ-5D-5L & VAS13, SF-3613 
 
X 
 
Weeks 8,12, 28 only 
X 
 
 
CKD Anemia Symptoms Questionnaire 
(CKD-AQ)13,14, PGI-S13 
X 
X 
 
Weeks 8,12, 28 only 
X 
 
 
PGI-C13 
 
 
Weeks 8,12, 28 only 
X 
 
 
Healthcare resource utilization (subject 
reported) 
X 
X 
X 
Weeks 4,8,12,16, 20, 24, 28 only 
X 
 
X 
Hospitalization / kidney transplant 
(record in eCRF, if applicable) 
 
 
X 
X 
 
X 
 
X 
Non-serious AEs, SAEs, AEs of 
Special Interest, clinical events 
X15 
X 
X 
X 
X 
X 
X 
X 
Review concomitant medications  
X 
X 
X 
X 
X 
X 
X 
X 
 

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Abbreviations:  FRP, females of reproductive potential; FSH, follicle stimulating hormone; UIBC, unsaturated iron binding capacity; iPTH, intact parathyroid hormone; hsCRP, high-
sensitivity C-reactive Protein; PGI-S, Patient Global Impression of Severity; PGI-C, Patient Global Impression of Change.  
1. 
The screening period may be extended by an additional 4 weeks for subjects who require IV iron supplementation and/or vitamin B12 as outlined in Section 5.2.  Ferritin, TSAT, 
and/or vitamin B12 must be re-assessed, where appropriate, following iron and/or B12 supplementation prior to randomization to meet entry criteria. 
2. 
A single measurement each of SBP, DBP and HR will be taken, except at Day 1 and Week 52 where the measurements will be take in triplicate.  Measurements will be taken 
post-dialysis for subjects receiving in-center dialysis.  See Section 7.4.8 . 
3. 
ECG assessment must be recorded pre-dialysis for dialysis subjects. ECG may be performed as early as at screening Week -2 and prior to randomization (Day1).   
4. 
Ultrasound of the kidneys and adrenal glands must be performed prior to randomization.  The screening period may be extended up to 4 weeks if needed.  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. 
5. 
Additional visits to check Hgb and dispense randomized treatment are required under the circumstances described in Appendix 3.  Hematology and chemistry samples are not 
required.  For any unscheduled visit, compliance checking will be required when a dose of randomized treatment is changed. 
6. 
Required only if dose is changed or randomized treatment is dispensed. 
7. 
If dose does not change, then randomized treatment is returned to subject. 
8. 
If a subject becomes post-menopausal (as defined in Appendix 5) during the study pregnancy tests are no longer required. 
9. 
Testing panel in Table 8.  Please note, creatinine and eGFR will only be tested and calculated at screening and randomization 
10. 
 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. 
11. 
PK sampling will be collected from all subjects randomized to the daprodustat arm at 1 of these 3 visits, Details in Section 7.5. 
12. 
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. 
13. 
Subjects who are unable to or require assistance to read must not complete the questionnaires. 
14. 
To be completed if available (e.g., translations may be not available in time in all countries).  
15. 
Only SAEs assessed as related to study participation or a GSK product are collected during screening period 
16. 
In circumstances where the new dose of randomized treatment cannot be dispensed on the day of the study visit, the new dose of randomized treatment can be dispensed at 
next HD treatment. For visits after Day 1, prior randomized treatment should be continued unless on dose hold, Hgb ≥12 g/dL. Compliance is deferred until randomized 
treatment is returned 
17. 
For Argentina, ONLY:  pregnancy testing will be performed every 4 weeks for FRP as required by local law 
18. 
Biomarker samples will be stored for future analyses for all subjects, except if not permitted by IRB/EC or refused by subject. 
19. 
Informed consent will be obtained prior to any study procedures. 
 
 
 

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Table 7 
TIME AND EVENTS TABLE FOR SUBJECTS THAT PERMANENTLY 
DISCONTINUE RANDOMIZED TREATMENT 
Protocol Activity 
Dialysis: In-clinic assessments 
done pre-dialysis. 
Early Treatment 
Discontinuation Visit 
(within 2 weeks of the 
last dose of 
randomized 
treatment) 
Day 1 – Week 52  
(every 12 weeks ± 2 
weeks) 
Unscheduled 
Follow-up  
(4 weeks post-
study termination ± 
1 week) 
IRT SYSTEM  
X 
 
 
 
SBP/DBP1, HR1  
X (triplicate) 
X 
X 
X 
Iron therapy, transfusions2 
X 
 
 
 
Serum pregnancy test (FRP only) 
X 
 
 
 
HemoCue Hgb 
X 
X 
X 
 
Hematology 
Hgb only 
X 
 
X 
Clinical chemistry  
X 
 
 
 
Ferritin, serum iron, UIBC, 
hepcidin, lipids 
X 
 
 
 
Hospitalization2 / kidney 
transplant2 
X 
X 
X 
X 
Non-serious AEs, AEs of Special 
Interest, SAEs, clinical events  
X 
X 
X 
X 
Review concomitant medications 
X 
X 
X 
X 
Healthcare resource utilization 
(subject reporting) 
X 
 
 
 
CKD Anemia Symptoms 
Questionnaire (CKD-AQ) 
questionnaire, PGI-S, PGI-C3 
X 
 
 
 
SF-363, EQ-5D-5L3 
X 
 
 
 
1. 
See Section 7.4.8 for details. 
2. 
Record in eCRF, if applicable 
3. 
Subjects who are unable to or require assistance to read must not complete the questionnaires. 
 
 
7.2. 
Screening and Critical Baseline Assessments 
Before any study-specific procedure is performed, valid informed consent must be 
obtained. 
Demography and medical history will be assessed at the initial screening visit. 
Randomization requires an Hgb level within the specified range (Section 5.1) and levels 
of serum ferritin or TSAT as outlined in Section 5.2.    
Full details of screening and baseline (Day 1) assessments are provided in the Time and 
Events Table (Table 6).  

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7.3. 
Efficacy 
Planned time points for all Hgb efficacy assessments are listed in the Time and Events 
Table (Table 6).   
GSK will supply a point-of-care Hgb analyzer (i.e., HemoCue) to each site for rapid 
measurement of Hgb. 
Blood samples (not fingersticks) for measurement of Hgb via HemoCue, and also by the 
central laboratory will be collected as specified in the Time and Events Table (Table 6).  
7.4. 
Safety 
Safety endpoints will include monitoring of deaths, AEs, SAEs, other CV events, AEs of 
special interest, AEs leading to discontinuation of randomized treatment, and laboratory 
parameters, blood pressure and heart rate (HR). 
Planned time points for all safety assessments are listed in the Time and Events Table 
(Table 6).  Unscheduled visits will occur as medically necessary.  Detailed procedures for 
obtaining each assessment are provided in the SRM. 
7.4.1. 
Events Referred to the Clinical Event Committee (CEC) 
Investigators should refer any event suspected to be one of the events below to the CEC. 
The CEC will review and adjudicate the following clinical events. See CEC Site Manual 
for full scope of reporting requirements. 
• All-cause mortality (CV and non-CV mortality) 
• Non-fatal myocardial infarction (MI) 
• Non-fatal stroke 
• Hospitalization for heart failure  
• Thromboembolic events (vascular access thrombosis, symptomatic deep vein 
thrombosis, symptomatic pulmonary embolism) 
Events referred to the CEC will be subjected to blinded adjudication using pre-specified 
diagnostic criteria.  
When the investigator-reported event and the CEC assessment of the event differ, the 
CEC’s decision will be considered final. The detailed descriptions of the endpoint 
definitions used for adjudication are contained within the CEC Charter (available on 
request). 
Source documentation required to support the adjudication of the events is described in 
the CEC Site Manual. 

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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 categories 
of events: 
• Arrhythmias   
• Pulmonary hypertension* 
• Valvulopathy 
• Revascularization  
(* Pulmonary hypertension is also an AE of special interest for the current study, see 
Section 7.4.4 for details.) 
7.4.3. 
Adverse Events (AE) and Serious Adverse Events (SAEs) 
The definitions of an AE and SAE can be found in Appendix 8. 
The investigator or their designees are responsible for detecting, documenting and 
reporting events that meet the definition of an AE or SAE.   
7.4.3.1. 
Time period and Frequency for collecting AE and SAE information 
• 
Any SAE 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 from the time subject consents to participate in the study up to and 
including any follow-up contact.  
• 
AEs will be collected from the start of randomized treatment until the Follow-up 
visit, at the timepoints specified in the Time and Events Table (Table 6). 
• 
Medical occurrences that begin prior to the start of randomized treatment but after 
obtaining informed consent will be recorded on the Medical History/Current Medical 
Conditions section of the eCRF. 
• 
All SAEs will be recorded and reported to PPD within 24 hours, as indicated in 
Appendix 8. 
• 
Investigators are not obligated to actively seek AEs or SAEs in former study 
subjects. However, if the investigator learns of any SAE, including a death, at any 
time after a subject has been discharged from the study, and he/she considers the 
event reasonably related to the randomized treatment or study participation, the 
investigator must promptly notify PPD. 
NOTE: The method of recording, evaluating and assessing causality of AEs and SAEs 
plus procedures for completing and transmitting SAE reports to PPD are provided in 
Appendix 8. 

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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 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 5.6.2).   Further information on follow-up procedures is given in 
Appendix 8. 
7.4.3.4. 
Regulatory Reporting Requirements for SAEs 
Prompt notification by the investigator to PPD of SAEs related to 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 event that may represent the AEs of special interest listed below (using preferred 
terms): 
• Thrombosis and/or tissue ischemia secondary to excessive erythropoiesis  

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• Death, myocardial infarction, stroke, heart failure, , thromboembolic events, 
thrombosis of vascular access 
• 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  
The results of any investigation should be recorded on the AE page and in the relevant 
AE of special interest page of the subjects’ eCRFs. 
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). 
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 after the start of dosing and 
until 7 days after the last dose. 
• 
If a pregnancy is reported, the investigator should inform PPD within 2 weeks of 
learning of the pregnancy and should follow the procedures outlined in Appendix 9.  
7.4.7. 
Height and Weight 
Height and weight will be measured as specified in the Time and Events Table (Table 6).  
Weight will be measured in clinic with the subject wearing indoor daytime clothing with 
no shoes.  For HD subjects, this will be measured pre and post dialysis when possible, or 
at study visits between dialysis sessions.  For PD subjects these assessments will be done 
at study visits, as per standard of care.  
Estimated dry (target) weight will be calculated at each study visit as specified in the 
Time and Events Table (Table 6). 

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7.4.8. 
Blood Pressure and Heart Rate 
Measurement of systolic blood pressure (SBP), diastolic blood pressure (DBP) and heart 
rate (HR) will be taken at the time points specified in the Time and Events Table (Table 
6). 
• One measurement each of SBP, DBP and HR will be taken, except at Day 1, 
Week 52, and the Early Treatment Discontinuation visit (if applicable), when 
SBP, DBP and HR will be measured in triplicate. 
• For HD subjects, measurements will be taken pre-and post dialysis with the 
subject in a semi-supine or seated position in the dialysis chair after at least a 5-
minute rest period.  
• 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. 
7.4.9. 
Electrocardiogram (ECG) 
ECG measurements will be taken at the time points specified in Table 6 and must be 
recorded pre-dialysis.  Full 12-lead ECGs will be recorded with the subject in a supine 
position. Heart rate, PR interval, QRS duration, and QT (uncorrected) interval will be 
measured. QTcB will be calculated (machine-read or manually). 
For the Day 1 ECG, two additional ECGs are required if the initial ECG indicates 
prolonged QTc using the automated or manually calculated QTcB value.  The average 
QTcB value of all three ECGs will be used to determine eligibility (Section 5.2 for 
detail).  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, HR (in-center HD only) 
and before collection of blood samples for laboratory testing. 
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 subjects 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 (Section 5.2), provided the size and cyst category has been 

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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 8, must be conducted in 
accordance with the Laboratory Manual, and Protocol Time and Events Schedule (Table 
6).  Laboratory assessments will be done pre-dialysis for HD subjects 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 subject’s source notes.   
Refer to the SRM for appropriate processing and handling of samples.   
All study-required laboratory assessments will be performed by a central laboratory with 
the exception of HemoCue Hgb which will be performed at the clinical site.  The results 
of each HemoCue Hgb must be entered into the subject’s eCRF. 

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Table 8 
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 
ALT  
AST 
 Bilirubin  
(total and direct/indirect) 
Potassium (serum) 
Urea (serum)   
Albumin (serum) 
 
Calcium (total and 
albumin-adjusted) 
Inorganic phosphate  
Creatinine (eGFR CKD-
EPI)4,5 
Iron parameters 
Serum iron 
Ferritin 
UIBC 
 
Hepcidin 
TSAT (calculated) 
TIBC (calculated)  
Lipid parameters 
Total cholesterol 
LDL-C (direct) 
HDL-C 
Other  
laboratory tests 
Serum hCG pregnancy 
test2 
Follicle stimulating 
hormone3 
Estradiol3 
 
HemoCue Hgb 
hsCRP 
iPTH 
 
Stored sample (blood) 
Vitamin B12 
Folate 
Abbreviations:  WBC, white blood cells; MCV, mean corpuscular volume; MCH, mean corpuscular hemoglobin; MCHC, 
mean corpuscular hemoglobin concentration; RDW, red blood cell distribution width, AST, aspartate transaminase; 
ALT, alanine transaminase; LDL-C, low density lipoprotein-C; HDL-c high density lipoprotein-C; UIBC,  unsaturated 
iron binding capacity; TIBC, Total iron binding capacity;  TSAT, Transferrin saturation; hsCRP, high-sensitivity C-
reactive protein; iPTH; intact parathyroid hormone; hCG, human chorionic gonadotropin; CKD-EPI, Chronic Kidney 
Disease Epidemiology Collaboration 
1. Details of Liver Chemistry Stopping Criteria and Required Actions and Follow-Up Assessments after liver stopping 
or monitoring event are given in Appendix 6. 
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. Detail on the regional specific calculation will be summarized in the SPM. 
5. Creatinine and eGFR will only be tested and calculated at screening and randomization 
All laboratory tests with values that are considered clinically significantly abnormal 
during participation in the study or within 7 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 
etiology should be identified and 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 FDA 
premarketing clinical liver safety guidance). 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM174090.pdf 

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Phase 3 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 6. 
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*
 

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Liver Safety Required Actions and Follow up Assessments Section can be found in 
Appendix 6.  
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 
The full liver safety drug restart guideline is provided in Appendix 6. 
7.5. 
Pharmacokinetics (PK) 
PK sampling will be performed in all in-center HD subjects randomized to the 
daprodustat arm. 
Blood samples will be collected at the Week 4, Week 8 or Week 12 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 relative to dosing of randomized treatment: 
• Predose, 0.5, 1, 2, and 3 h 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 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 parent daprodustat 

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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.   
7.6. 
Genetics 
Information regarding genetic research is included in Appendix 10.   Samples for genetic 
analysis will be taken at the time points specified in the Time and Events Table (Table 6). 
7.7. 
Patient Reported Outcomes 
The patient-reported effect of daprodustat and rhEPO on symptoms, health-related 
quality of life (HR-QoL), and health status (e.g. utility) will be assessed.  Symptoms will 
be assessed using a symptoms questionnaire which is specific to anemia of CKD (CKD-
AQ).  Overall symptom severity will be assessed using the patient global impression of 
severity (PGI-S) and overall symptom change using the patient global impression of 
change (PGI-C). Quality of life will be measured via SF-36, and health status via the EQ-
5D-5L and EQ-5D-VAS. In addition, healthcare resource utilization will be assessed 
including out-patient visits. 
All questionnaires used in this study have been translated and culturally adapted 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.  Details on patient reported outcomes are provided in the study 
reference manual. 
The CKD-AQ, PGI-S, PGI-C, HR-QoL, and Health Status questionnaires should be 
completed by subjects at a clinic visit, in the order specified: PGI-S, PGI-C, CKD-AQ, 
SF-36, EQ-5D 5L, and EQ-VAS.  Subjects who are unable to or require assistance to read 
must not complete the questionnaires. If there are other exceptional circumstances 
whereby the Patient Reported Outcomes assessments cannot be conducted, the 
completion of these assessments will be discussed with the Sponsor on a case-by-case 
basis. 
7.7.1. 
Chronic Kidney Disease - Anemia Questionnaire (CKD-AQ) 
A novel symptom questionnaire – CKD-AQ has been developed to collect concepts of 
interest for the anemia of CKD population over the past 24 hours.  Unlike the Functional 
Assessment of Cancer Therapy – Anemia (FACT-AN) and Functional Assessment of 
Chronic Illness Therapy – Fatigue (FACIT-Fatigue) which have not demonstrated content 
validity specific for the anemia of CKD population, the novel CKD-AQ instrument was 
developed to verify and ensure that concepts specific for anemia of CKD were captured 
and measured. It will measure both the frequency and/or severity in anemia of CKD 
concepts such as weakness, energy, tiredness, shortness of breath, exertion, chest pain, 
memory, concentration, standing, sleep and distress over the past seven days.  

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7.7.2. 
Patient Global Impression of Severity (PGI-S) and Patient Global 
Impression of Change (PGI-C) 
The Patient Global Impression of Severity (PGI-S) is a 1-item questionnaire designed to 
assess patient’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 Patient Global Impression of Change (PGI-C) is a 1-item questionnaire designed to 
assess a subject’s impression of symptom change of their anemia of CKD.  It is measured 
on a 7-point Likert- type response scale (very much improved, moderately improved, 
minimally improved, no change, minimally worse, moderately worse, or very much 
worse) since they first started the study.  
7.7.3. 
Health Related Quality of Life (SF-36) 
The SF-36 acute version is a general health status questionnaire designed to elucidate the 
subject’s perception of their health on several domains, including physical functioning, 
role physical, bodily pain, vitality, social functioning, role emotional, mental health, and 
general health.  The questionnaire contains 36 questions within these domains that ask the 
subject to recall how they felt during the past seven days. 
7.7.4. 
Health Status (EQ-5D-5L & EQ-VAS) 
EQ-5D-5L consists of two concepts – the EQ-5D-5L descriptive system and the EQ-
VAS. The EQ-5D-5L is a self-reported descriptive system of health-related quality of life 
states consisting of five dimensions (mobility, self-care, usual activities, pain/discomfort, 
anxiety/depression) each of which can take one of five responses. The responses record 
five levels of severity (no problems/slight problems/moderate problems/severe 
problems/extreme problems) within a particular EQ-5D dimension. Self-reported health 
status captured by EQ-5D-5L relates to the subject’s situation at the time of completion.  
The EQ VAS records the respondent’s self-rated health on a vertical, visual analogue 
scale where the endpoints are labeled ‘the best health you can imagine’ and ‘the worst 
health you can imagine’.  This information is used as a quantitative measure of health 
outcome as judged by individual subjects. 
7.7.5. 
Psychometric Analyses of the CKD Anemia Symptoms 
Questionnaire (CKD-AQ) 
In order establish and evaluate the measurement properties of the CKD-AQ, an interim 
cut of blinded observations of the first 50 subjects who completed the week 28 visit will 
be taken.  In order to establish content validity, the data cut will require a comparison to 
the following variables: PGI-C, PGI-S, Hgb, SF-36, demographic & baseline clinical 
characteristics.  All data will be abstracted from screening until week 28.    
The interim data cut will be used to conduct confirmatory factor analysis in order to 
establish a scoring algorithm for potential instrument domains and to evaluate the 
reliability, validity and responsiveness of the instrument without regard to treatment 
group.   A full description of the data cut, variables of interest and analyses to establish 

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the scoring and evaluate the measurement properties of the CKD-AQ will be specified a 
priori within the psychometric analysis plan.  
7.8. 
Storage Biomarkers 
Blood (serum and plasma) samples will be collected as outlined in the Time and Events 
Table (Table 6) for potential future analysis of CV risk and iron metabolism. 
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. 
• Adverse events and concomitant medications terms will be coded using MedDRA 
(Medical Dictionary for Regulatory Activities) and an internal validated medication 
dictionary, GSKDrug, 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 
9.1. 
Primary Hypotheses 
The primary Hgb efficacy objective will assess the estimand defined as the comparative 
treatment effect in mean Hgb change between baseline and EP (i.e., Weeks 28 to 52 
inclusive) in all randomized 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. 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; selected to be consistent across 
all clinical trials in the daprodustat Phase 3 clinical development program in subjects with 
anemia of chronic kidney disease, and determined based upon a combination of clinical 
judgment, statistical reasoning and regulatory guidance for designing non-inferiority 
trials.   

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Statistical significance of non-inferiority will be assessed at the one-sided 2.5% level. An 
analysis of covariance (ANCOVA) model including randomization stratification factors, 
baseline hemoglobin 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. 
9.2. 
Sample Size Considerations 
9.2.1. 
Sample Size Assumptions 
The size of this study has been determined to be sufficient to meet the ICH E1 guideline 
for subject exposure, number and duration and to provide at least 90% power to test the 
primary non-inferiority hypothesis with a two-sided 95% CI.  
Approximately 300 subjects are planned to be randomized (150 per arm) to receive 
daprodustat or rhEPO, to provide at least 100 subjects exposed to daprodustat for one 
year.  Subjects will be treated to achieve and maintain Hgb between 10 and 11 g/dL. The 
expected difference in mean Hgb change from baseline and the EP, between arms, is 0 
g/dL and the anticipated between subject standard deviation (SD) is 1.5 g/dL, based on 
historical rhEPO trials and daprodustat clinical trial experience to date.  With a pre-
specified non-inferiority margin of -0.75 g/dL, a two-sample T-test and assuming that up 
to approximately 30% of subjects will permanently stop randomized treatment before 
Week 28 (start of EP), 300 randomized subjects will provide >90% power to test the 
primary hypothesis.  
With 300 randomized subjects, it is anticipated that the difference in mean Hgb change 
from baseline between arms will be estimated with a precision of 0.408 g/dL (half width 
of the two-sided 95% CI) and the largest (most negative) difference between arms that 
would meet the statistical criterion for non-inferiority would be -0.342 g/dL. 
9.2.2. 
Sample Size Sensitivity 
The following table illustrates the impact on power for the primary efficacy analysis 
based on alternative assumptions for the between subject SD and the percentage of non-
evaluable subjects. 
Between 
subject Hgb 
SD (g/dL) 
% non-evaluable 
(number of subjects per arm) 
20% 
25% 
30% 
35% 
40% 
(n=120) 
(n=113) 
(n=105) 
(n=98) 
(n=90) 
1 
>99% 
>99% 
>99% 
>99% 
>99% 
1.25 
>99% 
>99% 
>99% 
99% 
98% 
1.5 
97% 
96% 
95% 
94% 
92% 
1.75 
91% 
89% 
87% 
85% 
82% 
2 
82% 
80% 
77% 
74% 
71% 

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9.2.3. 
Sample Size Re-estimation or Adjustment 
No sample size re-estimation is planned for this study. 
9.3. 
Data Analysis Considerations 
9.3.1. 
Analysis Populations 
The primary population for Hgb efficacy analyses will be the All Randomized (ITT) 
Population. Subjects will be analyzed according to the treatment to which they were 
randomized. In order to assess the sensitivity of the primary efficacy analysis, an analysis 
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.   
For analyses of time to event endpoints such as all-cause mortality, Major Adverse 
Cardiovascular Events (MACE) and hospitalizations, the All Randomized (ITT) 
Population will also be used. Subjects will be analyzed according to the treatment to 
which they were randomized. 
The primary population for safety (Safety Population) will consist of 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. 
9.4. 
Key Elements of Analysis Plan 
9.4.1. 
Primary Analyses 
Mean change in Hgb between baseline and EP (Weeks 28-52): The primary efficacy 
estimand is to compare the effect of treatment for the evaluation of mean change from 
baseline in Hgb during a 24-week evaluation period (Weeks 28 to 52 inclusive) in all ITT 
subjects with at least one Hgb during the EP.   The analysis will use an analysis of 
covariance (ANCOVA) model.  For each subject, the baseline Hgb will be the value 
obtained on Day 1, prior to taking randomized treatment, and Hgb during EP will be 
determined by calculating the mean of all available Hgb values between Weeks 28 to 52 
inclusive regardless of adherence to randomized treatment.  The ANCOVA model will 
include randomization stratification factors, baseline hemoglobin, and treatment.  It will 
provide a point estimate and two-sided 95% CI for the treatment effect, together with the 
one-sided non-inferiority test p-value.  Non-inferiority will be established if the lower 
limit of the two-sided 95% CI is greater than the margin of -0.75 g/dL.  There will be no 
imputation for missing data but imputation will be explored via sensitivity analyses  
Sensitivity and Supplementary Analyses: Sensitivity analyses for the primary estimand 
will include a multiple imputation-based “tipping point” analysis where assumptions are 
adjusted until non-inferiority is lost by imputing data for subjects who did not fully 
complete the EP. A further supplementary analysis will evaluate efficacy in those 
subjects who adhere to randomized treatment, defined as ITT subjects with at least one 

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on-treatment Hgb during the EP (this approach corresponds to evaluating an efficacy 
estimand). A similar “tipping point” analysis as that described above for the primary 
analysis will be performed for this “on-drug” analysis. In addition, a supplementary per-
protocol analysis will estimate the treatment effect in subjects who strongly adhere to the 
protocol, and sensitivity analyses to explore a shorter EP (Weeks 28 to 36) will be 
performed for the primary effectiveness estimand and “on-drug” efficacy estimand. Full 
details of all sensitivity and supplementary analyses will be provided in the RAP.     
9.4.2. 
Secondary Analyses 
9.4.2.1. 
Principal Secondary Efficacy Analyses 
Conditional on the primary endpoint achieving non-inferiority at the one-sided 2.5% 
level, statistical testing will progress to the principal secondary endpoint with a focus on 
superiority using a one-sided 2.5% significance level.      
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 while on treatment 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 randomization stratification factors.  
Additional secondary/exploratory endpoints are listed in Appendix 2.  All analyses of 
secondary endpoints are of exploratory nature, summary statistical and nominal one-sided 
-p values will be used to describe the results and for any treatment comparisons. 
9.4.2.2. 
Safety Analyses 
Safety data, including all AEs (i.e., non-serious, serious and AEs of special interest), 
laboratory data, vital signs, concomitant medications and meeting protocol defined 
stopping criteria (e.g., liver chemistry) will be descriptively summarized by treatment 
arm.  Reasons for stopping randomized treatment and for early study withdrawal will also 
be summarized by treatment group and time to stopping treatment or study will be 
presented graphically and assessed.  Full details of all safety data reporting will be 
described in the RAP.  
9.4.3. 
Multiplicity Strategy 
The primary endpoint will be tested first for non-inferiority, using the lower limit of the 
2-sided 95% confidence interval. Conditional on achieving statistical significance (i.e. 
passing the primary gate by establishing non-inferiority) the single principal secondary 
endpoint will be tested for superiority using a one-sided 2.5% significance level. This 
two-step hierarchical strategy will preserve the study-wise Type I error rate at a one-sided 
2.5% level.   
The additional secondary/exploratory endpoints as listed in Appendix 2, if tested, will not 
be adjusted for multiplicity. A nominal one-sided 2.5% significance level will be applied 
per test. 

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9.4.4. 
Covariates and Subgroups of Interest 
The primary and principal secondary endpoint will be evaluated for a set of pre-specified 
subgroups to support the proposed indication.  Subgroup analyses are aimed to assess for 
consistency with the overall result, they may have low power if the subgroup is small. 
Statistical models will be adjusted for the covariates used in the original analysis, 
baseline, 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  
US, EU, RoW (repeat using US, Non-US) 
Dialysis type  
HD, PD (repeat using HD, HDF/HF, PD) 
Dialysis status 
Planned, unplanned (urgent) start 
Baseline Hgb  
<9, 9 to <10, 10 to 11, >11 g/dL 
BMI  
<30, ≥30  
Weight  
< 75kg, ≥75kg  
Baseline hsCRP 
≤3 mg/L, >3 mg/L 
Additional exploratory subgroups may be defined in the RAP. 
 
9.4.4.1. 
Exploratory Cardiovascular Safety Analysis 
This study is not designed or sufficiently powered for formal statistical analyses to assess 
cardiovascular safety. With fewer than 80 first MACE (defined as all-cause mortality, 
non-fatal MI, or non-fatal stroke) expected to occur during the trial, incidence rates and 
two-sided 95% CIs will be computed for the following mortality and CV composite or 
component endpoints: 1) MACE; 2) MACE or a thromboembolic event (vascular access 
thrombosis, a symptomatic deep vein thrombosis or a symptomatic pulmonary 
embolism); 3) MACE or hospitalization for heart failure; 4) all cause mortality; 5) CV 
mortality; 6) MI (fatal and non-fatal); 7) stroke (fatal and non-fatal); 8) CV mortality or 
non-fatal MI; 9) all cause hospitalization. 
9.4.5. 
Interim Analysis 
The IDMC will periodically receive unblinded safety reports containing clinical 
endpoints (whether adjudicated or pending adjudication) and SAEs, from an independent 
Statistical Data Analysis Center (SDAC) while Phase 3 studies with daprodustat are 
ongoing. The IDMC may recommend stopping this study for safety at any time.  

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There is no formal intent to evaluate interim data from this study for the purposes of 
stopping early for Hgb efficacy or futility.   
Further details will be specified in the IDMC charter and RAP.  
9.4.6. 
Pharmacokinetic/Pharmacodynamic Analyses 
The ‘PK Population' is defined as subjects for whom a PK sample was obtained and 
analyzed.  This will be the population used for all the PK displays. 
The following plasma PK parameters will be determined for daprodustat and metabolites: 
Ctau (pre-dose) and Cmax. 
Plasma daprodustat and metabolites concentration data will be listed and summarized by 
planned collection time and daprodustat dose administered at PK visit.  PK parameter 
data will be listed and summarized by daprodustat dose administered at PK visit, and 
dose-normalized (per mg) PK parameter data will be summarized. 
All PK data will be stored in the Archives, GlaxoSmithKline Pharmaceuticals, R&D. 
The following exploratory graphics will be created.  Based on these, and the efficacy and 
safety results from other Phase 3 studies, post-hoc exploratory exposure-response/safety 
modelling may be conducted, including exploratory graphics with metabolites.  Further 
details will be provided in the RAP. 
• 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. 
• Boxplots of daprodustat PK parameters dose normalized to 1 mg by subjects with or 
without MACE or a combined safety endpoint of MACE + thromboembolic event + 
hospitalization for heart failure  

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• Boxplots of daprodustat PK parameters 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 
 
9.4.7. 
Analysis of Patient Reported Outcomes Measures 
Analysis to compare the patient reported effects of daprodustat and rhEPO on symptoms, 
severity, HR-QoL, and health status, as discussed in Section 7.7, will be described in the 
RAP.  In order to establish and evaluate the measurement properties of the CKD-QA, an 
interim cut of blinded observations of at least 50 subjects who completed the Week 28 
visit will be taken.  The data cut will require the following variables through Week 28: 
PGI-C, PGI-S, Hgb, SF-36, demographic and baseline clinical characteristics.   
The interim data cut will be used to conduct confirmatory factor analysis in order to 
establish a scoring algorithm for potential instrument domains and to evaluate the 
reliability, validity and responsiveness of the instrument without regard to treatment 
group.  A full description of the data cut, variables of interest and analyses to establish 
the scoring and to evaluate the measurement properties of the CKD-QA will be specified 
a priori within a separate psychometric analysis plan. 
10. 
STUDY GOVERNANCE CONSIDERATIONS 
10.1. 
Posting of Information on Publicly Available Clinical Trial 
Registers 
Study information from this protocol will be posted on publicly available clinical trial 
registers before enrollment of subjects begins. 
10.2. 
Regulatory and Ethical Considerations, Including the 
Informed Consent Process 
Prior to initiation of a site, GSK will obtain favourable 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 or approval of the study protocol and 
amendments as applicable 
• Obtaining signed informed consent for each subject prior to participation in the 
study 

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• Investigator reporting requirements (e.g. reporting of AEs/SAEs/protocol deviations 
to IRB/IEC) 
• GSK will provide full details of the above procedures, either verbally, in writing, or 
both. 
• 
The IEC/IRB, and where applicable the regulatory authority, approve the clinical 
protocol and all optional assessments, including genetic research.   
• Optional assessments (including those in a separate protocol and/or under separate 
informed consent) and the clinical protocol should be concurrently submitted for 
approval unless regulation requires separate submission.   
• Approval of the optional assessments may occur after approval is granted for the 
clinical protocol where required by regulatory authorities.  In this situation, written 
approval of the clinical protocol should state that approval of optional assessments 
is being deferred and the study, with the exception of the optional assessments, can 
be initiated. 
10.3. 
Quality Control (Study Monitoring) 
• In accordance with applicable regulations including GCP, and GSK procedures, 
PPD monitors will contact the site prior to the start of the study to review with the 
site staff the protocol, study requirements, and their responsibilities to satisfy 
regulatory, ethical, and GSK requirements.   
• When reviewing data collection procedures, the discussion will also include 
identification, agreement and documentation of data items for which the eCRF will 
serve as the source document. 
PPD will monitor the study and site activity to verify that the: 
• Data are authentic, accurate, and complete. 
• Safety and rights of subjects are being protected. 
• Study is conducted in accordance with the currently approved protocol and any 
other study agreements, GCP, and all applicable regulatory requirements. 
The investigator and the head of the medical institution (where applicable) agrees to 
allow the monitor direct access to all relevant documents 
10.4. 
Quality Assurance 
• To ensure compliance with GCP and all applicable regulatory requirements, PPD 
may conduct a quality assurance assessment and/or audit of the site records, and the 
regulatory agencies may conduct a regulatory inspection at any time during or after 
completion of the study.  
• 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. 

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10.5. 
Study and Site Closure 
• Upon completion or premature discontinuation of the study, the PPD monitor will 
conduct site closure activities with the investigator or site staff, as appropriate, in 
accordance with applicable regulations including GCP, and PPD Standard 
Operating Procedures. 
• GSK reserves the right to temporarily suspend or prematurely discontinue this study 
at any time for reasons including, but not limited to, safety or ethical issues or 
severe non-compliance. For multicenter studies, this can occur at one or more or at 
all sites.   
• If GSK determine such action is needed, PPD will discuss the reasons for taking 
such action with the investigator or the head of the medical institution (where 
applicable).  When feasible, PPD will provide advance notification to the 
investigator or the head of the medical institution, where applicable, of the 
impending action. 
• If the study is suspended or prematurely discontinued for safety reasons, PPD will 
promptly inform all investigators, heads of the medical institutions (where 
applicable) and/or institution(s) conducting the study. GSK or PPD will also 
promptly inform the relevant regulatory authorities of the suspension or premature 
discontinuation of the study and the reason(s) for the action.   
• If required by applicable regulations, the investigator or the head of the medical 
institution (where applicable) must inform the IRB/IEC promptly and provide the 
reason for the suspension or premature discontinuation. 
10.6. 
Records Retention 
• Following closure of the study, the investigator or the head of the medical 
institution (where applicable) must maintain all site study records (except for those 
required by local regulations to be maintained elsewhere), in a safe and secure 
location.   
• The records must be maintained to allow easy and timely retrieval, when needed 
(e.g., for a GSK audit or regulatory inspection) and must be available for review in 
conjunction with assessment of the facility, supporting systems, and relevant site 
staff.   
• Where permitted by local laws/regulations or institutional policy, some or all of 
these records can be maintained in a format other than hard copy (e.g., microfiche, 
scanned, electronic); however, caution needs to be exercised before such action is 
taken.   
• The investigator must ensure that all reproductions are legible and are a true and 
accurate copy of the original and meet accessibility and retrieval standards, 
including re-generating a hard copy, if required.  Furthermore, the investigator must 
ensure there is an acceptable back-up of these reproductions and that an acceptable 
quality control process exists for making these reproductions. 

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• PPD will inform the investigator of the time period for retaining these records to 
comply with all applicable regulatory requirements.  The minimum retention time 
will meet the strictest standard applicable to that site for the study, as dictated by 
any institutional requirements or local laws or regulations, PPD 
standards/procedures, and/or institutional requirements.   
• The investigator must notify PPD of any changes in the archival arrangements, 
including, but not limited to, archival at an off-site facility or transfer of ownership 
of the records in the event the investigator is no longer associated with the site. 
10.7. 
Provision of Study Results to Investigators, Posting of 
Information on Publically Available Clinical Trials Registers 
and Publication 
Where required by applicable regulatory requirements, an investigator signatory will be 
identified for the approval of the clinical study report.  The investigator will be provided 
reasonable access to statistical tables, figures, and relevant reports and will have the 
opportunity to review the complete study results at a GSK site or other mutually 
agreeable location. 
GSK or PPD will also provide the investigator with the full summary of the study results.  
The investigator is encouraged to share the summary results with the study subjects, as 
appropriate. 
10.8. 
Review Committees 
In addition to GSK, medical governance will also be provided by the following 
independent committees: 
10.8.1. 
Independent Data Monitoring Committee 
An IDMC unblinded to treatment allocation 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 analysis 
plan for IDMC review is described in the charter which is available upon request.  
10.8.2. 
Clinical Endpoint Committee 
An external independent CEC blinded to treatment allocation will adjudicate all clinical 
events reported during this study that are referred for adjudication, including major 
adverse cardiovascular events (MACE; composite of all-cause mortality [CV and non-CV 
mortality], non-fatal MI and non-fatal stroke) and additional components for a broader 
definition of MACE including thromboembolic events (vascular access thrombosis, 
symptomatic deep vein thrombosis, symptomatic pulmonary embolism), and 
hospitalization for heart failure (Section 7.4.1).   

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10.8.3. 
Steering Committees 
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. Additional information about the committee is 
included in the Executive Steering Committee charter, which is available upon request. 
The broader Steering Committee in collaboration with the Executive Steering Committee 
is responsible for the scientific content and integrity of all aspects of study conduct 
including participation in the study sub-committees and providing advice to the National 
Leader Committee if needed.   
10.8.4. 
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 
Brodie, M. J.; Mintzer, S.; Pack, A. M.; Gidal, B. E.; Vecht, C. J.; Schmidt, D. Enzyme 
induction with antiepileptic drugs: Cause for concern? Epilepsia 2013, 54(1):11–27. 
Eckardt KU, Gillespie IA, Kronenberg F, Richards S, Stenvinkel P, Floege J, ARO 
Steering Committee, et al.  High cardiovascular event rates occur within the first weeks 
of starting hemodialysis.  Kidney Int.  2015;8(5):1117-25 
GlaxoSmithKline Document Number RM2008/00267/07, Version 7 to GSK1278863 
Investigator's Brochure, 14-OCT-2015. 
Haase VH.  Mechanisms of Hypoxia Responses in Renal Tissue.  JASN, 2013; 24: 537-
541. 
Hommel, G.  A stagewise ejective multiple test procedure based on a modified bonferroni 
test.  Biometrika.  1988;75:383-386. 
Kurella Tamura M1, Covinsky KE, Chertow GM, Yaffe K, Landefeld CS, McCulloch 
CE.  Functional status of elderly adults before and after initiation of dialysis.  N Engl J 
Med.  2009;361(16):1539-47. 
Ohnhaus, E. E.; Breckenridge, A. M.; Park, B. K. Urinary Excretion of 6b-
Hydroxycortisol and the Time Course Measurement of Enzyme Induction in Man. 
European Journal of Clinical Pharmacology 1989, 36:39-46. 
Pfeffer MA, Burdmann EA, Chen C, Cooper ME, de Zeeuw D, Eckardt K, Solomon SD, 
Toto R for the TREAT Investigators, et al.  A Trial of Darbepoetin Alfa in Type 2 
Diabetes and Chronic Kidney Disease.  N Engl J Med.  2009;361: 2019-2032.   
Rosansky SJ1, Eggers P, Jackson K, Glassock R, Clark WF.  Early start of hemodialysis 
may be harmful.  Arch Intern Med.  2011;171(5):396-403. 
Rosendaal FR, Cannegieter SC, Van der Meer, FJM, Briet, E. A Method to Determine the 
Optimal Intensity of Oral Anticoagulant Therapy. Thrombosis and Haemostasis 1993; 69 
(3): 236 – 239. 
Szczech, L. A.; Barnhart, H. X.; Inrig, J. K.; Reddan, D. N.; Sapp, S.; Califf, R. M.; Patel, 
U. D.; Singh, A. K. Secondary analysis of the CHOIR trial epoetin-alpha dose and 
achieved Hgb outcomes. Kidney Int. 2008; 74:791-8.  

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12. 
APPENDICES 
12.1. 
Appendix 1:  Abbreviations and Trademarks 
Abbreviations 
AE 
Adverse event 
AESI 
Adverse event of Special Interest 
ALT 
Alanine transaminase 
ANOVA 
Analysis of variance  
ANCOVA 
Analysis of covariance 
APD 
Automated peritoneal dialysis 
AST 
Aspartate transaminase 
AUC 
Area under curve 
BCRP 
Breast cancer resistant protein 
BP 
Blood pressure 
CAPD 
Continuous ambulatory peritoneal dialysis 
CEC 
Clinical Event Committee 
CI 
Confidence interval  
CKD 
Chronic kidney disease 
CKD-AQ 
Chronic kidney disease anemia symptoms questionnaire  
CKD-EPI 
Chronic kidney disease epidemiology collaboration 
Cmax 
Maximum plasma concentration 
CONSORT 
Consolidated Standards of Reporting Trials 
CPK 
Creatine phosphokinase  
CRA 
Clinical Research Assistant  
CT 
Computed tomography 
CTR 
Clinical Trials Register 
CV 
Cardiovascular 
DBP 
Diastolic blood pressure 
DGF 
Delayed graft function 
DILI 
Drug induced liver injury  
dL 
Deciliter 
ECG 
Electrocardiogram 
ECHO 
Echocardiography 
eCRF 
Electronic Case Report Form 
eGFR 
Estimated glomerular filtration rate 
EP 
Evaluation period 
EPO 
Erythropoietin 
EQ-5D-5L 
Dimension 5 Level Health Utility Index 
ESA 
Erythropoiesis-stimulating agent 
FDA 
Food and Drug Administration 
FRP 
Females of reproductive potential  
FSH 
Follicle stimulating hormone 
g 
Grams 
GCP 
Good Clinical Practice 

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GI 
Gastrointestinal 
GSK 
GlaxoSmithKline 
hCG 
Human chorionic gonadotropin 
HD 
Hemodialysis  
HDF 
Hemodiafiltration  
HDL-c 
High density lipoprotein-C 
HF 
Hemofiltration 
Hgb 
Hemoglobin 
HIF 
Hypoxia-inducible factor 
HR 
Heart rate 
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 
IU  
International Units 
IV 
Intravenous 
Kg 
Kilograms 
LDL-C 
Low density lipoprotein-C 
MACE 
Major adverse cardiovascular event 
MCH 
Mean corpuscular hemoglobin 
MCHC 
Mean corpuscular hemoglobin concentration 
MCV 
Mean corpuscular volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
MI 
Myocardial infarction 
MIU 
Milliinternational units 
mL 
milliliter 
mmHg 
Millimeter of mercury 
MRI 
Magnetic resonance imaging 
MSDS 
Material Safety Data Sheet 
ND 
Non-dialysis  
NYHA 
New York Heart Association 
PAH 
Pulmonary artery hypertension 
PASP 
Pulmonary artery systolic pressure 
PCM 
Progressive cardiomyopathy 
PGI-C 
Patient Global Impression of Change 
PGI-S 
Patient Global Impression of Severity 
PD 
Peritoneal dialysis  
PFS 
Prefilled syringes 
pg 
Picogram 
PHD 
Prolyl hydroxylase domain enzymes 

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PHI 
Prolyl hydroxylase inhibitor 
PP 
Per-protocol  
PPD 
Pharmaceutical Product Development, LLC 
PRBC 
Packed red blood cells 
PRCA 
Pure red cell aplasia  
PRVP 
Peak right ventricular pressure 
RAP 
Reporting and Analysis Plan 
RSM-L 
Remote Site Monitor-Lead 
PSRAE 
Possible Suicidality Related Adverse Events 
QD 
Once daily 
QoL 
Quality of life 
RAP 
Reporting and Analysis Plan 
RBC 
Red blood cell 
RDW 
Red blood cell distribution width 
rhEPO 
Recombinant human erythropoietin  
RoW 
Rest of world 
SAE 
Serious adverse event 
SBP 
Systolic blood pressure 
SC 
Subcutaneous 
SD 
Standard deviation  
SDAC 
Statistical Data Analysis Center  
SRM  
Study Reference Manual  
TIW 
Three times weekly 
TSAT 
Transferrin saturation 
UIBC 
Unsaturated iron binding capacity 
ULN 
Upper limit of normal 
US 
United States 
VEGF 
Vascular endothelial growth factor 
WBC 
White blood cell 
 
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, Exploratory, Patient Reported 
Outcomes, and Pharmacokinetics/Pharmacodynamics 
Objectives/ Endpoints 
Objectives 
Endpoints 
• 
Secondary Objectives 
• 
Secondary Endpoints (tested for superiority1, 
no multiplicity adjustment) 
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 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 the EP 
(Weeks 28 to 52) 
• % time Hgb in analysis range 10-11.5 g/d during the 
EP (non-inferiority analysis that will use a margin of 
15% less time in range)1 
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 (PCS, MCS 
and 8 health domains) between baseline and Weeks 
8, 12, 28, 52, of particular interest are the changes 
from baseline in the vitality and physical functioning 
domains at Weeks 28 and 52 
• Change from baseline in Health Utility (EQ-5D-5L) 
score at Week 52 
• Change from baseline in EQVAS at Week 52 
To compare daprodustat to rhEPO on the symptom 
severity and change 
• Change from Baseline at Wk 52 by domain and 
overall symptom score on the CKD-AQ  
• Change from Baseline at Wk 8,12, 28, 52 in PGI-S 
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 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 analysis 
range (10-11.5 g/dL) during EP  
• Number (%) of subjects with mean Hgb above, within 

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Objectives 
Endpoints 
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 
• Number of times Hgb < 7.5 g/dL during the EP 
• Number (%) 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 
• 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  
• Number of times Hgb ≥ 12 g/dL during the EP 
• % of time Hgb ≥ 12 g/dL during the EP 
To compare daprodustat to rhEPO on measures of 
iron parameters  
• Observed and change from baseline in hepcidin, 
ferritin, transferrin saturation, total iron, total iron 
binding capacity (TIBC) across all visits to end of 
treatment 
• Average quarterly TSAT 
• Average quarterly ferritin 
• Average quarterly IV iron dose/subject 
• N (%) of subject who met iron management criteria 
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 transfusion by Week 52  
• Number of RBC and whole blood transfusions per 100 
patient years  
• Number of RBC and whole blood units per 100 patient 
years 
To evaluate the dose adjustment schemes 
• 
Assigned dose by visit and at Day 1, Week 28, 
Week 52 
• 
Most recent dose prior to Week 28 and Week 52 
• 
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 
• 
Number of dose adjustments during the following 
periods: 
o Day 1 - <Week 28 
o Week 28 - <Week 52 
• Time dose held for Hgb ≥12 g/dL 
To further compare daprodustat to rhEPO on BP 
• Observed and change from baseline in SBP, DBP 

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Objectives 
Endpoints 
and BP medication changes     
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 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 further compare daprodustat to rhEPO on the 
symptom severity and change  
• Change from Baseline at Wk 8,12, 28, & 52, by item  
on  the CKD-AQ  
• Shift tables (Baseline to 8, 12, 28, & 52) in PGI-S 
• N(%) of patients within each PGI-C symptom 
change level at Wk 8, 12, 28, 52. 
To  further compare daprodustat to darbepoetin 
alfa on HRQoL and Utility score 
• Change from baseline in Health Utility (EQ-5D-5L) 
score at Weeks 8,12, &28  
• Change from baseline in EQ VAS at Weeks 8, 12, & 
28 
To 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. 
To evaluate graphical relationships between 
daprodustat exposure and MACE and the 
composite endpoint of MACE+thromboembolic 
event+ hospitalization for heart failure 
• Boxplots of daprodustat PK parameters (Ctau and 
Cmax) dose normalized to 1 mg by subjects with or 
without MACE or combined safety endpoint. 
• Boxplots of daprodustat PK parameters (Ctau and 
Cmax) dose normalized to dose at time of MACE or 
combined safety endpoint (or end of treatment if no 
endpoint) by subjects with or without MACE or 
combined safety endpoint. 
 

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• 
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 100-110 g/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 primary 
analysis. % time in range is tested first for non-inferiority, then for superiority. 
 

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12.3. 
Appendix 3:  Randomized Treatment Dose Steps and Dose 
Adjustment Scheme 
12.3.1. 
Darbepoetin Alfa Dose Steps  
 
Total 4-weekly Dose (µg) 
PFS Dose and Frequency (PD/HD) 
20 µg 
20 µg Q4 weeks 
30 µg 
30 µg Q4 weeks 
40 µg* 
40 µg every 4 weeks 
60 µg* 
60 µg every 4 weeks 
80 µg* 
40 µg every 2 weeks 
120 µg* 
60 µg every 2 weeks 
160 µg 
80 µg every 2 weeks  
200 µg 
100 µg every 2 weeks 
300 µg 
150 µg every 2 weeks 
400 µg 
100 µg once a week   
* Subjects starting on these doses at the Randomization (Day1) who have >1 g/dL Hgb decrease 
or Hgb < 7.5 g/dL at Week 2 or Week 6 from the last visit will receive a “booster” dose of 20 µg in 
addition to their previous dose.       
 
 
 

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12.3.2. 
Randomized Treatment Dose Adjustment Scheme 
HemoCue Hgb at 
current study visit1 
(g/dL) 
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 change  
Increase to the next higher dose 
step    
7.5 to <9.5 
Increasing  
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 scheduled study visits (every 4 weeks through Week 52).   
2. 
This rule also applies to any mandated visit or an 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 Weeks 2, 4, 6, and 8 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. 
 
 

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12.4. 
Appendix 4: Benefit: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. 
Phase 2 dose-ranging studies, and associated statistical and exposure 
response modelling has informed Phase 3 dose rationale, starting doses, 
dose levels, and dose adjustment scheme to optimize Hgb management. 
Following review of clinical data received to date, this has not been identified 
as a safety concern for daprodustat. 
 
• Specific eligibility criteria related to requirements 
for entry Hgb are detailed in Section 5.1 
• Hgb will be closely monitored throughout the 
dosing period as outlined in the Time and Events 
Table (Table 6) 
• Specific guidance for dose adjustment, dose 
interruption, or discontinuation of daprodustat 
based on achieved Hgb (including rate of change) 
is provided in Section 6.2 and Section 6.11 
• Unblinded monitoring of safety data by an IDMC in-
stream throughout the study.  
 
Death, MI, stroke, heart failure, 
thromboembolic events, thrombosis of 
vascular access at Hgb levels which are within 
the normal range (i.e. not polycythemic 
conditions) 
Marketed rhEPO and its analogs have been associated with an increased risk 
for death and serious cardiovascular events when used in patients with 
anemia of CKD. 
In non-clinical studies 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. 
• 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 (Table 6) 
• Unblinded monitoring of safety data by an IDMC in-
stream throughout the study   
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 
• Suspected GI bleeding or significant symptoms 
consistent with erosions or ulcers should be 
investigated diagnostically (i.e. endoscopic 
examination) as clinically warranted. 
• Unblinded monitoring of safety data by an IDMC in-
stream throughout the study.  

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Potential Risk of Clinical Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
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. 
Cancer-related mortality and tumor 
progression and recurrence 
In clinical trials, use of rhEPO and its analogs in patients with cancer has been 
associated with increased risk of cancer related morbidity and mortality. 
Administration of 60mg/kg daprodustat to mice caused minimal increases in 
circulating VEGF while significant EPO increases were observed. 
There were no test article-related neoplastic findings in 2-year rat (oral 
daprodustat) or mouse (daprodustat + subcutaneous injection of the 3 major 
human metabolites; M2, M3 and M13) carcinogenicity studies. 
In clinical studies conducted to date, administration of daprodustat has been 
associated with: 
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 
• 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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Potential Risk of Clinical Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
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.  

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Potential Risk of Clinical Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
Pulmonary artery hypertension (PAH) 
A role for HIF-regulated pathways in the pathophysiology of PAH has been 
suggested based on well-established effects of acute and chronic hypoxia in 
man on the pulmonary vasculature (vasoconstriction), and by findings in 
patients with naturally occurring mutations that result in decreased HIF 
degradation [Smith, 2006; Formenti, 2011]. 
There have been no histopathologic findings suggestive of PAH in pre-clinical 
safety studies with daprodustat up to 13-weeks duration in dogs, up to 2-years 
in rats and mice, and up to 39-weeks in monkeys. 
Acute hypoxic challenge (rats):  Daprodustat produced increases in peak right 
ventricular pressure (PRVP) during acute hypoxia that were slightly higher 
than the vehicle control group. However, these hypoxia-induced PRVP 
changes were within the range of PRVP changes noted among un-treated 
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 had 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 Total: 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 drug; 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 
• Unblinded monitoring of safety data by an IDMC in-
stream throughout the study  

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Potential Risk of Clinical Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
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 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 with 
daprodustat. 
Following review of clinical data received to date, this has not been identified 
as a safety concern for daprodustat. 
• Unblinded monitoring of safety data by an IDMC in-
stream throughout the study. 
Proliferative retinopathy, macular edema, 
choroidal neovascularization 
Increases in local (ocular) VEGF production with retinal neovascularization 
and macular edema observed in diabetic retinopathy and to choroidal 
leakage, edema and neovascularization seen in age-related macular 
degeneration [Campochiaro, 2006]. 
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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Potential Risk of Clinical Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
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 with daprodustat 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 30mg administered 
three times weekly. In studies up to 24 weeks duration at doses up to 25mg, 
changes in VEGF plasma concentrations were variable but similar relative to 
control. 
Ophthalmologic assessments performed in phase 2b studies (24 weeks 
treatment duration) did not identify any clinically meaningful changes in 
proliferative retinopathy, macular edema, or choroidal neovascularization for 
daprodustat. 
Following review of clinical data received to date, this has not been identified 
as a safety concern for daprodustat. 

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Potential Risk of Clinical Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
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 were 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. 
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. 
• Co-administration of daprodustat with strong 
CYP2C8 inhibitors (e.g., gemfibrozil) and inducers 
(e.g., rifampin/rifampicin) is not permitted as 
outlined in Section 6.9.2.  
• 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 6.9.1. 
• Specific guidance on the management of potential 
drug-drug interactions and concomitant 
medications is provided in Section 6.9.. 
• Hgb will be closely monitored throughout the 
dosing period as outlined in the Time and Events 
Table (Table 6) 
•Specific guidance for dose adjustment, dose 
interruption, or discontinuation of daprodustat 
based on achieved Hgb is provided in Section 
6.2.1 and Appendix 3. 
•Unblinded monitoring of safety data by an IDMC in-
stream throughout the study. 

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Potential Risk of Clinical Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
Daprodustat is an inhibitor of CYP2C8:  A clinical drug interaction study 
between 25mg and 100mg daprodustat with a CYP2C8 substrate 
(pioglitazone) showed that there is no PK interaction at these doses of 
daprodustat. 
Daprodustat is a substrate of BCRP: Population PK analysis from Phase 2 
studies suggested that while BCRP inhibitors were a covariate for daprodustat 
CL/F (8.6% lower clearance) the predicted change in exposure was not 
considered to be of clinical relevance.  
Daprodustat is an inhibitor of OATP1B1/1B3: A clinical drug interaction study 
between 25mg and 100mg daprodustat with an OATP1B1/1B3 substrate 
(rosuvastatin) showed that there is no PK interaction at these doses of 
daprodustat 
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, thromboembolic events, thrombosis of vascular access, and for 
Increased 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, Risk of death, MI, stroke, thromboembolic 
events, thrombosis of vascular access, and for 
Increased 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:   
Campochiaro PA.  Ocular versus extraocular neovascularization: mirror images or vague 
resemblances.  Invest Ophthalmol Vis Sci. 2006;47(2):462-74. 
Formenti F, Beer PA, Croft QP, Dorrington KL, Gale DP, Robbins PA, et al.  
Cardiopulmonary function in two human disorders of the hypoxia-inducible factor (HIF) 
pathway: von Hippel-Lindau disease and HIF-2alpha gain-of-function mutation.  FASEB 
J. 2011;25(6):2001-11.  
Muz B, Khan MN, Kiriakidis S, Paleolog EM.  Hypoxia. The role of hypoxia and HIF-
dependent signalling events in rheumatoid arthritis.  Arthritis Res Ther. 2009;11(1):201. 
Smith TG, Brooks JT, Balanos GM, Lappin TR, Layton DM, Robbins PA. et al. 
Mutation of von Hippel-Lindau tumour suppressor and human cardiopulmonary 
physiology.  PLoS Med. 2006 Jul;3(7):e290. 
Westra J, Molema G, Kallenberg CG.  Hypoxia-inducible factor-1 as regulator of 
angiogenesis in rheumatoid arthritis - therapeutic implications.  Curr Med Chem.  
2010;17(3):254-63. 
 

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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 below in the 
Modified List of Highly Effective Methods for Avoiding Pregnancy in FRP from 
30 days prior to the first dose of randomized treatment and until completion 
of the Follow-up visit (4-6 weeks after the end of randomized treatment); 
those who permanently discontinue randomized treatment prior to the end of the 
study should continue contraceptive methods following the Early Treatment 
Discontinuation Visit until the final pregnancy test assessment at a subsequent 
study visit (at least 4 weeks after the end of randomized treatment) as described in 
the Time and Events Table (Section 7.1). 
 
1. Contraceptive subdermal implant. 
2. Intrauterine device or intrauterine system. 
3. Combined estrogen and progestogen oral contraceptive [Trussell, 2011] 
4. Injectable progestogen [Trussell, 2011] 
5. Contraceptive vaginal ring [Trussell, 2011] 
6. Percutaneous contraceptive patches [Trussell, 2011] 
7. Male partner sterilization prior to the female subject's entry into the study, and 
this male is the sole partner for that subject [Trussell, 2011]. The documentation 
on male sterility can come from the site personnel’s: review of subject’s medical 
records, medical examination and/or semen analysis, or medical history interview 
provided by her or her partner. 
These allowed methods of contraception are only effective when used consistently, 
correctly and in accordance with the product label.  The investigator is responsible for 
ensuring that subjects understand how to properly use these methods of contraception. 
The list does not apply to FRP with same sex partners or for subjects who are and will 
continue to be abstinent from penile-vaginal intercourse on a long term and persistent 
basis, when this is their preferred and usual lifestyle.  Periodic abstinence (e.g. calendar, 
ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable 
methods of contraception. 
• 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;  
2. Postmenopausal defined as 12 months of spontaneous amenorrhea. In 
questionable cases, a blood sample with simultaneous FSH and estradiol 

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consistent with menopause is confirmatory (FSH ≥23MIU/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:  Liver Chemistry Stopping Criteria 
12.6.1. 
Liver Safety Required Actions and Follow up Assessments 
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 CRF 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 (Section 12.6.2)  
• If restart not allowed or not granted, 
permanently discontinue randomized 
treatment and may continue subject in the 
• 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 pharmacokinetic (PK) 
analysis, obtained within 24 hr 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 

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study for any protocol specified follow up 
assessments  
 
 
 
MONITORING: 
For bilirubin or INR criteria:  
• Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin) and perform 
liver event follow up assessments within 24 
hrs 
• Monitor 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 hrs  
• Monitor subjects weekly until liver 
chemistries resolve, stabilize or return to 
within baseline 
hypersensitivity, on the AE report form 
• Record use of concomitant medications on 
the concomitant medications report form 
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]). NOTE: 
not required in China  
• Liver imaging (ultrasound, magnetic 
resonance, or computerised tomography) 
and /or liver biopsy to evaluate liver 
disease; complete Liver Imaging and/or 
Liver Biopsy CRF forms. 
1. Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin fractionation is not 
immediately available, discontinue 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, 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 CRF. 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 GSK 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.  
 
12.6.2. 
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 in writing (as described below), 
• Ethics and/or IRB approval is obtained, if required, and 

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• Separate consent for treatment restart is signed by the subject 
If GSK Medical Governance approval to restart subject with randomized treatment is not 
granted, then subject must permanently discontinue randomized treatment and may 
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 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. 

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• PPD Medical Monitor, and the Ethics Committee or Institutional Review Board as 
required, must be informed of the subject’s outcome following randomized 
treatment restart.  
• PPD to be notified of any AEs, as per Section 7.4 and Appendix 8. 
References: 
Andrade RJ, Robles M, Lucena MI.  Rechallenge in drug-induced liver injury: the 
attractive hazard.  Expert Opin Drug Saf. 2009;8:709-714. 
Hunt, CM.  Mitochondrial and immunoallergic injury increase risk of positive drug 
rechallenge after drug-induced liver injury: A systematic review.  Hepatol. 
2010;52:2216-2222. 
Papay JI, Clines D, Rafi R, Yuen N, Britt SD, Walsh JS, Hunt CM.  Drug-induced liver 
injury following positive drug rechallenge.  Regul Tox Pharm. 2009;54:84-90.  
  

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12.7. 
Appendix 7:  Study Specific Equipment 
Study specific equipment required: 
• Refrigerator 
• Freezer (-20oC or lower)   
• Centrifuge 
• Point-of-care HemoCue Hgb analyzer - to be provided as part of the study 
 

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12.8. 
Appendix 8: Definition of and Procedures for Recording, 
Evaluating, Follow-Up and Reporting of Adverse Events 
12.8.1. 
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, vital signs 
measurements), including those that worsen from baseline, and felt to be clinically 
significant in the medical and scientific judgement 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 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 
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 fulfil the definition 
of an AE or SAE. 
 
Events NOT meeting definition of an AE include: 
• Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the subject’s condition. 
• The disease/disorder being studied or expected progression, signs, or symptoms of 
the disease/disorder being studied, unless more severe than expected for the 
subject’s condition. 

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• Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that 
leads to the procedure is an AE. 
• Situations where an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital). 
• Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) 
present or detected at the start of the study that do not worsen. 
 
12.8.2. 
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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life functions but do not constitute a substantial disruption 
e. 
Is a congenital anomaly/birth defect 
f. 
Other situations: 
• Medical or scientific judgment should be exercised in deciding whether reporting is 
appropriate in other situations, such as important medical events that may not be 
immediately life-threatening or result in death or hospitalization but may jeopardize 
the subject or may require medical or surgical intervention to prevent one of the 
other outcomes listed in the above definition.  These should also be considered 
serious. 
• Examples of such events are invasive or malignant cancers, intensive treatment in 
an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug 
dependency or drug abuse 
g. Is associated with liver injury and impaired liver function defined as: 
• ALT ≥ 3xULN and total bilirubin* ≥ 2xULN (>35% direct), or 
• ALT ≥ 3xULN and INR** > 1.5. 
* Serum bilirubin fractionation should be performed if testing is available.  If 
fractionation is unavailable and ALT ≥ 3xULN and total bilirubin ≥ 2xULN, then the 
event is still to be reported as an SAE. 
** INR testing not required per protocol and the threshold value does not apply to 
subjects receiving anticoagulants.  If INR measurement is obtained, the value is to be 
recorded on the SAE form. 
12.8.3. 
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 CRF 
• It is not acceptable for the investigator to send photocopies of the subject’s medical 
records to PPD in lieu of completion of the PPD/GSK, AE/SAE CRF 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, 
symptoms, and/or other clinical information.  In such cases, the diagnosis will be 

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documented as the AE/SAE and not the individual signs/symptoms. 
• Subject-completed Patient Reported Outcomes questionnaires and the collection of 
AE data are independent components of the study. 
 
12.8.4. 
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 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 
randomized treatment will be considered and investigated. 
• The investigator will also consult the Investigator Brochure (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 prior to the initial transmission of the SAE data to PPD. 

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• 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. 
• If a subject dies during participation in the study or during a recognized follow-up 
period, the investigator will provide GSK with a copy of any post-mortem findings, 
including histopathology. 
• New or updated information will be recorded in the originally completed CRF. 
• The investigator will submit any updated SAE data to GSK within the designated 
reporting time frames. 
 
12.8.5. 
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 will be provided in a separate document. 

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12.9. 
Appendix 9:  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 
2 weeks of learning of a subject's pregnancy. 
• 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 
reasonably related to the randomized treatment by the investigator, will be reported 
to PPD as described in Section 12.8.5.  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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12.10. 
 Appendix 10: 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 enrolled in the study can participate in genetic research.  Any subject 
who has received an allogeneic bone marrow transplant must be excluded from the 
genetic research. 

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

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

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12.11. 
Appendix 11 – Protocol Changes 
12.11.1. 
Changes Resulting from Protocol Amendment 1  
This is an amendment to the original protocol dated 18
-Oct-2016 
This amendment applies to all countries.
 
12.11.1.1. Summary of Changes 
• Updated the time period of planning to start dialysis from the day of screening to 6 
weeks to be consistent with the extended screening period, when appropriate 
• Removed number of screening subjects required and stated only an approximate 
number of randomized subjects required in the study 
• Modified peritoneal dialysis (PD) inclusion criteria to allow participants on ≥4 
times/week PD including an incremental schedule 
• Removed France country specific requirement for Informed Consent process from 
inclusion criteria  
• Broadened exclusion to include participation in an interventional study with an 
investigational agent or device 
• Removed option to have Early Treatment Discontinuation visit supersede the 
scheduled study visit 
• Added a provision that in unexpected circumstances where the supply to the site is 
interrupted, then local standard of care for anemia management during this time 
period may be considered 
• Added direction regarding randomized treatment and study continuation for subjects 
who will be away from the research site for an extended period of time 
• Added new darbepoetin alfa dose strengths (not available in all countries) 
• Clarified timeframe for iron management criteria 
• Clarified timing of designated study visits for subjects who have not yet initiated 
dialysis and for subjects on dialysis 
• Shortened visit window for the Week 2 and 4 visits 
• Modified Time and Events Table 6 ‘Schedule of Assessments. Main changes include 
addition of Informed Consent activity; footnotes to allow for more time for ECG 
before randomization visit, more clarity around randomized treatment dispensing and 
compliance; removed capture of rescue medications from unscheduled visit (rescue 
evaluation is triggered at scheduled visits); added healthcare resource data collection, 
added footnote to clarify biomarkers storage requirements and added Argentina only 
pregnancy requirement 
• Added direction to CEC Site Manual for full scope of reporting requirements 
• Clarified timing of weight, blood pressure and heart rate in relation to laboratory 
assessments and dialysis 
• Clarified PK sampling in relation to subjects on dose hold 
• Updated PRO section to add healthcare resource utilization data being collected for 
completeness 
• Changed time point for blinded data cut need for psychometric validation of the 
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• Revised statistical section to change from two-sided testing at the 5% level to one-
sided testing at the 2.5% level; for secondary endpoints, to change significance levels 
to p-values and to correct the time point for various Patient Reported Outcomes 
• Updated wording around exploratory endpoints in Appendix 2 
• Updated Darbepoetin alfa dose steps table in Appendix 3 to remove partial doses and 
clarify booster dosing to be consistent with Interactive Response Technology (IRT) 
system 
• Provision for possible adjustment to the Dose Adjustment Algorithm triggers for Hgb 
values 7.5 g/dL to <9.5 g//dL based on review of blinded instream Hgb data 
• Edited Risk Assessment information in Appendix 4 to align with version 8 of the 
Investigator’s Brochure 
• Updated FSH level to confirm menopause in Appendix 5, Female Eligibility Criteria 
• Removed Appendix 11- France country specific requirement 
• Other changes include minor edits, corrections of typos and administrative changes 
throughout. 
 
12.11.1.2. List of Specific Changes 
Section 1. Protocol Synopsis, type and Number of Subjects, updated time period of start of 
chronic dialysis (HD or PD) to within the 6 weeks from the day of screening to be consistent with 
extended screening period.   
Revised Text: 
The study will enroll the following types of subjects with anemia associated with 
CKD: Planned initiation of dialysis:  Subjects who are planning to start chronic 
dialysis (HD or PD) within the next 2-4 weeks 6 weeks (from the day of screening).   
Section 1. Protocol Synopsis, type and number of subjects, changed the number of subjects that 
need to be screened.  
Revised Text: 
Approximately 600  subjects are expected to be screened in order to randomize 
approximately 300 subjects, or 150 subjects per treatment group
 
This study will randomize approximately 300 subjects, or 150 subjects per 
treatment group 
Section 4.2 Type and Number of Subjects, updated the time period of planning to start dialysis 
from the day of screening to be consistent with the extended screening period, when 
appropraite. 
Revised Text: 
• 
Planned: Subjects who are planning to start dialysis (HD o
r PD) within the next 2
-4 6 
weeks (from the day of screening).
 

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Section 4.2 Type and Number of Subjects, changed the screen failure rate and the number of 
subjects that need to be screened.  
Revised Text: 
Based on an assumed screen failure rate of 50%, approximately 600
 subjects are 
expected to be screened in order to randomize approximately 300 subjects, or 150 
subjects per treatment group.  
This study will randomize approximately 300 subjects, or 150 subjects per 
treatment group.  
Section 4.5.2. Benefit Assessment. Clarified wording around other ESAs. 
Revised Text: 
Daprodustat may present several important advantages over rhEPO and other 
ESAs its analogs.  
Treatment of anemia of CKD with rhEPO is associated with increased CV risk 
which is postulated to be related to the associated supra-physiological increases in 
EPO exposure with rhEPO [Szczech, 2008]; therefore, daprodustat has the 
potential to raise Hgb without the same CV risk associated with rhEPO and its 
analogs.   
Section 5.1. Inclusion Criteria, Inclusion #2: updated updated the time period of planning to start 
dialysis from the day of screening to be consistent with the extended screening period, when 
appropriate. 
Revised Text 
2.Dialysis: Planning to start chronic dialysis within the next 
4 6 weeks (from the date of 
the screening visit) OR have started and received dialysis (as specified below) for end
-
stage renal disease for a maximum of 
≤90 days immediately prior to randomizatio
n and 
is not expected to stop dialysis during the duration of the trial
 
Section 5.1. Inclusion Criteria; inclusion #2: Updated frequency of dialysis descriptions. 
Revised Text: 
Daily PD (Including continuous and automated PD): PD ≥4 times/week including 
incremental schedule; subjects on continuous ambulatory peritoneal dialysis 
(CAPD) and automated peritoneal dialysis (APD) are eligible  
 
Section 5.1. Inclusion Criteria; inclusion #4.  Clarified study visit this is confirmed. 

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Revised Text: 
a. Informed consent (at screening): capable of giving signed informed consent 
which includes compliance with the requirements and restrictions listed in the 
consent form and in this protocol
 
Section 5.1 Inclusion Criteria: Inclusion #5 and Section 12.11.1: Removed country specific 
requirements for France, as the study is not being conducted there.  
Revised Text: 
4. Informed consent: 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 is provided in 
Appendix 11  (see Section 12.11.1, Item 3 for details)
 
5.  Other study eligibility criteria considerations: The countr y-specific requirements for 
France ONLY for the eligibility for inclusion in this study is provided in 
Appendix 11  (see 
Section 12.11.1,Item 1 for details
) 
.  
Section 5.2. Exclusion Criteria; exclusion #1.  Added or living-unrelated to clarify.  
Revised Text: 
1. Kidney transplant: Planned living -related or living-unrelated donor kidney transplant 
within 52 weeks after study start (Day 1).
 
Section 5.2. Exclusion Criteria; exclusion #7. Added Untreated to clarify. 
Revised Text: 
7. Other causes of anemia:  Untreated pernicious anemia, thalassemia major, sickle cell 
disease or myelodysplastic syndrome.  
Section 5.2. Exclusion Criteria; exclusion #14. Clarified QTcB exclusion criteria 
Revised Text: 
14. 
QTcB (Day 1): QTcB >500 msec, or QTcB >530 msec in subjects wi
th bundle 
branch block. There is no QTc exclusion for subjects with a predominantly 
ventricular 
paced rhythm  
Section 5.2. Exclusion Criteria; exclusion #19. Broadened exclusion to include participation in an 
interventional study with an investigational agent or device. 
Revised Text: 

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19. Prior investigational product exposure: Use of an investigational drug (other than 
daprodustat – see next criterion) ≤30 days or within five half
-lives of the investigational 
agent, whichever is longer prior to screening.
 
19. 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. Removed the word ‘chronic’ 
from use of prohibited medication 
Revised Text: 
Need for chronic (more than 14 days) use of a prohibited medication (Section 
6.9.2) 
Section 5.5. Permanent Discontinuation of Randomized Treatment. Added wording regarding re-
starting randomized treatment 
Subjects may be re-approached about restarting randomized treatment in certain 
circumstances if the Sponsor and the investigator agree 
Section 5.5.1. Procedures for Subject Follow-up; deleted second sentence in first bullet to clarify 
Revised Text: 
• 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 5.5.1. Procedures for Subject Follow-up; deleted 2 from 2-4 weeks in the second sub-
bullet as this was an error 
Revised Text: 
• Follow-up: Study visit 2 to 4 weeks after Week 52. 
  
Section 5.7 Subject and Study Completion; included wording in second sentence to 
clarify 
Revised Text: 
• A completed subject is one who has completed all periods of the study through 
the End of Treatment visit with the following exception: subjects who die while 
on study are also considered as having completed the study.  

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Section 6.1. Investigational Product and Other Randomized Treatment. Added the following 
wording to the end of the first paragraph to clarify: 
Revised Text: 
Randomized treatment will be provided by GSK. 
Section 6.1. Investigational Product and Other Randomized Treatment. Added wording under 
Table 1 to provide direction if supply of randomized treatment is interrupted and added wording 
for clarification of darbepoetin alfa doses. 
GSK will supply rhEPO (darbepoetin alfa) for the control group
. Darbepoetin alfa as 
prefilled syringes (PFS) for SC/IV injection. 
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. 
Darbepoetin alfa doses from 20 µg to 400 µg will be administered using the strengths in 
Table 2.  See also Appendix 3, Section 12.3.1 for darbepoetin alfa dose steps and 
dosing frequency. Additional details to deliver the total dose are also captured in the 
SRM. 
Section 6.1. Investigational Product and Other Randomized Treatment. Updated Table 2 to add 
additional dose strengths of darbepoetin alfa 
Revised Text:  
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 6.2.2. rhEPO Dosing Information. Corrected error to remove ‘total weekly’ wording in 
first paragraph. 
Revised Text: 

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For subjects starting HD or PD, the SC/IV darbepoetin alfa total weekly
 dose will be  0.75 
1.0 µg/kg rounded to the nearest available dose.
 
Section 6.2.2. rhEPO Dosing Information, Darbepoetin alfa dose steps: IRT term expanded as 
appears in document for the first time 
Revised Text 
Dose adjustments will be made programmatically by the Interactive Response 
Technology (IRT) system 
Section 6.2.3. Daprodustat and rhEPO Dose Adjustment Algorithm.  Removed the full word 
Interactive Response Technology as previously stated as full phrase and added wording for 
adjustments to the algorithm in this section to allow for adjustments by the Sponsor to the 
dosing algorithm. 
Revised Text: 
Dose adjustments will be made programmatically by 
the Interactive Response 
Technology (IRT) system to maintain Hgb concentrations within the range of 10
-11 g/dL 
based on the Hgb value measured every 2 to 4 weeks by the HemoCue value disclosed 
to the IRT system by the investigator.
 
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 3 based on the review of aggregate blinded instream Hgb data. 
Section 6.6.1. 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. 
Revised Text: 
6.6.1. Randomized Treatment Extended Interruption 
Every effort must be made to continue randomized treatment and to 
complete study visits, where able; however, sites should contact their PPD 
study team member if a subject cannot return to the research site on a 
temporary basis for any one of the following situations: 
• 
Subjects who are hospitalized for any duration.  
• 
Subjects who cannot return to the site for a period >5 weeks. 
In exceptional circumstances, 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 

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Section 6.9.2. Prohibited Medications; new text added for clarification that no other 
investigational agents or devices are permitted during the study. 
Revised Text: 
Except for study randomized treatment, no other investigational agents or 
devices are permitted from study entry through completion of the study. 
 
Section 6.10. Iron Management Criteria; paragraph 1.  Added clarification for when the criteria 
start and stop. 
Revised Text: 
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 6.11. Anemia rescue therapy; paragraph 2. Minor clarification in wording. 
Revised Text: 
This rescue algorithm do es 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 6.11. Anemia recue therapy; added wording in Table 5 to clarify the rescue applies at 
scheduled visits only 
Revised Text: 
HemoCue Hgb remains <9 g/dL (at a scheduled visit
, Week 4 onwards) despite three 1 
consecutive dose increases above the starting dose or post-
rescue2 (where HemoCue 
Hgb<9 g/dL prior to each dose inc
rease) OR HemoCue Hgb is <7.5 g/dL despite a dose 
increase at the prior study visit
 
Section 7. Study Assessments and Procedures; paragraphs leading up to 1st bullet. Clarified valid 
study period for study visits. 
Revised Text: 
Study visit days should be sc
heduled as follows:  
Designated study visits for subjects in the screening period or study treatment period 
who have not yet initiated dialysis can occur on any day of the week. 
Designated study visits for subjects on dialysis should be scheduled as follows from 
the screening assessment to the end of the study: 

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• For subjects on 3X/week HD: The designated study visit must not occur on 
the first dialysis session of the week. 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 visit should occur during the session that is closest 
to the previous HD 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). 
• 
For subjects on PD: study visits can occur on any day of the week. 
Section 7. Study Assessments and Procedures;1st paragraph after bullets.  Inserted new text to 
state the revised visit window for the Week 2 and 4 visits. 
Revised Text: 
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 6 12 onwards is ±1 week. 
 
Section 7.1. Table 6, Time and Events Table for Subjects on Randomized Treatment.  Updated 
visit window text. 
Revised Text: 
Protocol activity (visits ±1 week, 
(Note: all visit timings except 
Weeks 2 and 4 which are 
relative to Day1) ±3 days) 
Screening  
Week -21 
Randomization 
(Day 1) 
Weeks 2, 
6 
Full study visit 
Weeks 4, 16, 
28, 40 
Abbreviated  
study visit 
Weeks 8, 12, 
20, 24, 32, 
36, 44, 48 
Week 
52 
Unscheduled
Follow-
up  
 Weeks 
56-58 
 
Section 7.1. Table 6, Time and Events Table for Subjects on Randomized Treatment. Added 
Informed Consent activity and associated footnote (#19) as these were missing. 
Revised Text: 
Protocol activity (visits ±1 
week, except Weeks 2 and 4 
which are ±3 days) 
Screening 
Week -21 
Randomization 
(Day 1) 
Weeks 2, 
6 
Full study 
visit 
Weeks 4, 
16, 28, 40 
Abbreviated 
study visit 
Weeks 8, 
12, 20, 24, 
32, 36, 44, 
48 
Week 
52 
UnscheduledFollow-
up  
 Weeks 
56-58 
Written informed consent19 
X 
 
 
 
 
 
 
 
 

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Section 7.1. Table 6, Time and Events Table for Subjects on Randomized Treatment.  Updated IRT 
system timing to indicate it is not notified at Week 52. 
Revised Text: 
Protocol activity (visits ±1 
week, except Weeks 2 and 4 
which are ±3 days) 
 
Screening 
Week -21 
Randomization 
(Day 1) 
Weeks 2, 
6 
Full study 
visit 
Weeks 4, 
16, 28, 40 
Abbreviated 
study visit 
Weeks 8, 
12, 20, 24, 
32, 36, 44, 
48 
Week 
52 
UnscheduledFollow-
up  
 Weeks 
56-58 
IRT system  
X 
X 
X 
X 
X 
x 
X 
X 
 
Section 7.1, Table 6, Time and Events Table for Subjects on Randomized Treatment. Added EGG 
to screening visit and updated corresponding footnote to clarify ECG can be done between 
screening and before randomization to treatment. 
Revised Text: 
Protocol activity (visits 
±1 week, except Weeks 
2 and 4 which are ±3 
days) 
 
Screening  
Week -21 
Randomization 
(Day 1) 
Weeks 2, 
6 
Full study 
visit 
Weeks 4, 16, 
28, 40 
Abbreviated 
study visit 
Weeks 8, 12, 
20, 24, 32, 
36, 44, 48 
Week 
52 Unscheduled
Follow-up  
 Weeks 56-58 
ECG3 
X 
X 
 
 
 
 
 
 
3All ECGs assessment must be recorded pre-dialysis for dialysis subjects. ECG may be 
performed as early as at screening Week -2 and prior to randomization (Day1).   
 
Section 7.1, Table 6, Time and Events Table for Subjects on Randomized Treatment. Removed 
randomized treatment dispensing at Week 52 and added Healthcare resource utilization (subject 
reported) for completeness. 
Revised Text: 
Protocol activity (visits ±1 
week, except Weeks 2 and 4 
which are ±3 days) 
 
Screening 
Week -21 
Randomization 
(Day 1) 
Weeks 2, 
6 
Full study 
visit 
Weeks 4, 
16, 28, 40 
Abbreviated
study visit 
Weeks 8, 
12, 20, 24, 
32, 36, 44, 
48 
Week 
52 
Unscheduled Follow-
up  
 Weeks 
56-58 
Randomized treatment 
dispensing 
 
X 
 
X 
X 
X 
X 
 
Healthcare resource 
utilization (subject reported) 
X 
X 
X 
Weeks 4,8,12,16, 20, 24, 
28 only 
X 
 
X 
 

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Section 7.1. Table 6, Time and Events Table for Subjects on Randomized Treatment. Replaced 
“MACE” wording with “Clinical events” in order to more accurately represent all safety data 
being collected.  
Revised Text: 
Non-serious AEs, SAEs, AEs of 
Special Interest, MACE clinical 
events 
X15 
X 
X 
X 
X 
X 
X 
X 
 
Section 7.1. Table 6, Time and Events Table for Subjects on Randomized Treatment. Modified 
footnote 1 to clarify that Ferritin, TSAT and/or vitamin B12 must be re-assessed, where 
appropriate, following iron and/or B12 supplementation prior to randomization to meet entry 
criteria 
Revised Text 
1. 
The screening period may be extended by an additional 4 weeks for subjects 
who require IV iron supplementation and/or vitamin B12 as outlined in Section 5.2. 
HemoCue Hgb, Ferritin, TSAT, and/or vitamin B12 must be re
-assessed, where 
appropriate, following iron and/or B12 supplementation prior to randomization to 
meet entry criteria  
Section 7.1. Table 6, Time and Events Table for Subjects on Randomized Treatment. Added 
footnotes associated with randomized treatment dispensing and compliance (#16); pregnancy 
testing for Argentina only as required by local law (#17), clarity around Biomarker samples 
storage (#18) and Informed Consent requirement before any study procedures (#19) 
Revised Text: 
16. In circumstances where the new dose of randomized treatment cannot be 
dispensed on the day of the study visit, the new dose of randomized treatment can be 
dispensed at next HD treatment. For visits after Day 1, prior randomized treatment 
should be continued unless on dose hold, Hgb ≥12 g/dL. Compliance is deferred until 
randomized treatment is returned 
17. For Argentina ONLY:  pregnancy testing will be performed every 4 weeks for FRP as 
required by local law 
18. Biomarker samples will be stored for future analyses for all subjects, except if not 
permitted by IRB/EC or refused by subject. 
19. Informed consent will be obtained prior to any study procedures. 
 
Section 7.1. Table 7 Time and Events Table for subjects that permanently discontinue randomized 
treatment. Removed Recue Medication, corrected MACE to Clinical events and updated 
footnotes 
Revised Text: 

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Protocol Activity 
Dialysis: In-clinic assessments 
done pre-dialysis. 
Early Treatment 
Discontinuation Visit 
(within 2 weeks of the 
last dose of 
randomized 
treatment) 
Day 1 – Week 52  
(every 12 weeks ± 2 
weeks) 
Unscheduled 
Follow-up  
(4 weeks post-
study termination ± 
1 week) 
IRT SYSTEM call 
X 
X 
X 
X 
SBP/DBP1, HR1  
X (triplicate) 
X 
X 
X 
Iron therapy, transfusions2 
X 
 
 
 
Rescue medication 
 
 
 
 
Serum pregnancy test (FRP only) 
X 
 
 
 
HemoCue Hgb 
X 
X 
X 
 
Hematology 
Hgb only 
X 
 
X 
Clinical chemistry  
X 
 
 
 
Ferritin, serum iron, UIBC, 
hepcidin, lipids 
X 
 
 
 
Hospitalization2 / kidney 
transplant2 
X 
X 
X 
X 
Non-serious AEs, AEs of Special 
Interest, SAEs, MACE, clinical 
events  
X 
X 
X 
X 
Review concomitant medications 
X 
X 
X 
X 
Healthcare resource utilization 
X 
 
 
 
CKD Anemia Symptoms 
Questionnaire (CKD-AQ) 
questionnaire, PGI-S, PGI-C23 2 
X 
 
 
 
SF-362, EQ-5D-5L23 2 
X 
 
 
 
1. See Section 7.4.8 for details. 
2. Record in eCRF, if applicable 
4 3. Subjects who are unable to or require assistance to read must not complete the questionnaires 
3.See details on Rescue in Section 6.11. 
 
Section 7.3. Efficacy, corrected third paragraph 
Revised Text: 
Blood samples (not fingersticks) for measurement of Hgb via HemoCue and also by the 
central laboratory will be collected and
 as specified in the Time and Events Table (Table 
6). and the collection will be recorded in the eCRF 
Section 7.4.1. Events Referred to the Clinical Events Committee; 1st paragraph. Replaced “MACE” 
wording with “Clinical events”.  Added reference to CEC Site Manual for scope of reporting 
requirements 
Revised Text: 
Investigators should refer any event suspected to be one the following MACE
 events 
below to the CEC . The CEC will review and adjudicate the following MACE
 clinical 
events.  See CEC Site Manual for full scope of reporting requirements.   

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Section 7.4.1. Events Referred to the Clinical Events Committee; 3rd paragraph after bullets.  
Added clarity where to find description of source documentation required to support 
adjudication of events.   
Revised Text: 
Source documentation required to support the adjudi
cation of the events is described in 
the SRM CEC Site Manual. 
Section 7.4.4. Adverse Events of Special Interest. Corrected venous thromboembolism to 
thromboembolic events  
Revised Text: 
• 
Death, myocardial infarction, stroke, heart failure, venous thromboembolism 
thromboembolic events, thrombosis of vascular access 
Section 7.4.4. Adverse Events of Special Interest. Added wording to clarify where Adverse Events 
of Special Interest should be recorded. 
Revised Text  
The results of any investigation should be r
ecorded in the relevant sections  on the AE 
page and in the relevant AE of special interest page of the subjects’ eCRFs  
Section 7.4.7. Height and Weight. Added clarity on timing of assessments. 
Revised Text: 
For HD subjects, this will be measured pre-and post dialysis when possible, or at study 
visits between dialysis sessions.  For PD subjects these assessments will be done at 
study visits, as per standard of care. 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.  
Revised Text: 
• 
Measurements For HD subjects M measurements will be taken pre and post dialysis
 
with the subject in a semi
-supine or seated position in the dia
lysis chair after at least a 
5-minute rest period (pre - and post - dialysis). 
• 
For PD subjects, this assessment will be done at study visits, as per standard of care. 
For HD subjects,  SBP, DBP and HR will be performed before collection of blood samples for 
laboratory testing, where applicable. measured pre and post -dialysis. For PD subjects these 
assessments will be done between treatments. Pre
-dialysis measurements will be taken prior to 
blood sample collection  
 

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Section 7.4.9. Electrocardiogram (ECG). Added clarity on reading of ECGs 
 
Revised Text: 
 
For the Day 1 ECG At the Day 1 visit when ECGs are performed
, two additional ECGs are 
required if the initial ECG indicates prolonged QTc using the automated or manually 
calculated QTcB value. The average QTcB value of all three ECGs will be used to 
determine eligibility (Section 5.2, item 14 for detail). 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. 
 
Section 7.4.11. Clinical Laboratory Assessments. Clarified timing of laboratory assessments for 
HD and PD subjects in the first paragraph and made a correction with reference to source notes 
in the third paragraph. 
 
Revised Text: 
All protocol required laboratory assessments, as defined in Table 8, must be conducted 
in accordance with the Laboratory Manual, and Protocol Time and Events Schedule 
(Table 6). Laboratory assessments will be done pre-dialysis for in center  HD subjects, in 
between dialysis sessions and at the study visits and at the study visits for PD subjects, 
as per standard of care. 
If additional non -protocol specified laboratory assessments are perfor
med 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 subject’s
 source notes eCRF. 
 
Section 7.4.11. Clinical Laboratory Assessments. Table 8; Clarified that Iron parameters TSAT and 
TIBC will be calculated and not actual measurements will be considered 
 
Revised Text: 
 
Iron parameters 
Serum iron 
Ferritin 
UIBC 
 
Hepcidin 
TSAT (calculated) 
TIBC (calculated)  
 
 
Section 7.5 Pharmacokinetics; edited text. Minor change to clarify PK assessment will be 
performed in all subjects on daprodustat and added wording to clarify PK sampling in relation to 
subjects on dose hold. 
 
Revised Text: 
 
PK sampling w ill Only be performed in all  in-center HD subjects randomized to the 
daprodustat arm.  
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.  

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[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 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 7.7. Patient Reported Outcomes. Edited wording to change “procedure” to “reference”  
Revised Text: 
Details on patient reported outcomes are provided in the study reference 
procedure 
manual. 
Section 7.7. Patient Reported Outcomes; new text in 1st paragraph. Clarified healthcare resource 
utilization data to be collected. 
Revised Text: 
In addition, healthcare resource utilization will be assessed including out-patient visits 
Section 7.7. Patient Reported Outcomes; new text in last paragraph. Added process for 
exceptional circumstances when Patient Reported Outcomes cannot be conducted. 
Revised Text 
If there are other exceptional circumstances whereby the Patient Reported Outcomes 
assessments cannot be conducted, the completion of these assessments will be 
discussed with the Sponsor on a case-by-case basis. 
Section 7.7.4. Health Status (EQ-5D-5L & EQ-VAS). Updated endpoint labels for clarification. 
Revised Text: 
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 best imaginable 
health state ’ and ‘ the worst health you can imagine worst imaginable health state ’. This 
information is used as a quantitative measure of health outcome as judged by individual 
subjects. 
 
Section 7.7.5 Psychometric Analysis of the CKD Anemia Symptoms Questionnaire (CKD-AQ), 
updated study visit for interim data cut.  
 
Revised Text: 
 
In order establish and evaluate the measurement properties of the CKD
-AQ, a interim 
cut of blinded observations of the first 50 subjects who completed the week 28 52
 visit 
will be taken. In
 order to establish content validity, the data cut will require a 

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comparison to the following variables: PGI
-C, PGI -S, Hgb, SF -36, demographic & baseline 
clinical characteristics. All data will be abstracted from screening until week 28 
52. 
 
Section 9.1. Primary hypothesis; in the third paragraph. Change from two-sided testing at the 5% 
level to one-sided testing at the 2.5% level and two-sided 95% CI. 
Revised Text: 
Statistical significance of non -inferiority will be assessed at the two
 one-sided 2.5% 
level. An analysis of covariance (ANCOVA) model including randomization stratification 
factors, baseline hemoglobin 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, in the third paragraph. Added two-sided 95% CI.  
Revised Text: 
With 300 randomized subjects, it is anticipated that the difference in mean Hgb change 
from baseline between arms w
ill be estimated with a precision of 0.408 g/dL (half width 
of the two -sided 95% CI)  
Section 9.4.1 Primary analysis; first and second paragraph. Added supplementary analyses 
information.  
Revised Text: 
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. 
Sensitivity and Supplementary Analyses: Sensitivity analyses for the primary estimand 
will include a multiple imputation
-based “tipping point” analysis where assumptions 
are 
adjusted until non- inferiority is lost by imputing data for subjects who did not fully 
complete the EP. A further 
supplementary 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 similar “tipping point” analysis as that described above for the primary 
analysis will be performed for this “on
-drug” analysis. In addition, a 
supplementary per-
protocol sensitivity analysis will estimate the treatment effect in subjects who strongly 
adhere to the protocol, and sensitivity analyses to explore a shorter EP (Weeks 28 to 36) 
will be performed for the primary effectiveness estimand and “on
-drug” efficacy 
estimand. Full details of all sensitivity and 
supplementary analyses will be provided in 
the RAP.    
Section 9.4.2.1. Principal Secondary Efficacy Analyses; first and last paragraph. Added one-sided 
2.5% and Changed significance levels to p-values. 

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Revised Text: 
Conditional on the primary endpoint achieving non
-inferiority at the two one-sided 
2.5% level, statistical testing will progress to the principal secondary endpoint with a 
focus on superiority using a two
 one-sided 2.5% significance leve l. 
 
All analyses of secondary endpoints are of exploratory nature, summary statistical 
and nominal two-one-sided 5% significance levels p-values will be used for any 
treatment comparisons. 
 
Section 9.4.3 Multiplicity Strategy. Added one-sided 2.5% wording in both paragraphs.  
 
Revised Text: 
 
The primary endpoint will be tested first for non
-inferiority, using the lower limit of the 
2-sided 95% confidence interval. Conditional on achieving statistical significance (i.e. 
passing the primary gate by establishing non
-inferiority) the single principal secondary 
endpoint will be tested for superiority using a
 two one-sided 2.5% significance level. 
This two -step hierarchical strategy will preserve the study
-wise Type I error rate at a 
two one-sided 2.5% level.  
The additional secondary/exploratory endpoints as listed in 
Appendix 2, if tested, will 
not be adjusted for multiplicity. A nominal one
-sided 2.5% significance level will be 
applied per test.  
Section 9.4.4. Covariates and Subgroups of Interest; paragraph 2. Revised sentence to more 
complete describe adjustments to statistical model. 
Revised Text: 
Statistical models will be adjusted for the covariates used in the original analysis,
 
baseline, 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 9.4.4.1. Exploratory Cardiovascular Safety Analysis. Added two-sided for 95% CI 
Revised Text: 
With fewer th an 80 first MACE (defined as all-
cause mortality, non -fatal MI, or non -fatal 
stroke) expected to occur during the trial, incidence rates and two
-sided 95% CIs will be 
computed for the following mortality and CV composite or component endpoints: 1) 
MACE; 2)  MACE or a thromboembolic event (vascular access thrombosis, a symptomatic 
deep vein thrombosis or a symptomatic pulmonary embolism); 3) MACE or 
hospitalization for heart failure; 4) all cause mortality; 5) CV mortality; 6) MI (fatal and 

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non-fatal); 7) str oke (fatal and non -fatal); 8) CV mortality or non
-fatal MI; 9) all cause 
hospitalization 
Section 9.4.7 Analysis of Patient Reported Outcomes Measures Paragraph 1. Updated 
study visit for interim data cut.  
Revised Text: 
 
In order to establish and evaluate 
the measurement properties of the CKD
-QA, an 
interim cut of blinded observations of at least 50 subjects who completed the Week 
52 
28 visit will be taken. The data cut will require the following variables through Week 
52 
28: PGI -C, PGI -S, Hgb, SF-36, demo graphic and baseline clinical characteristics. 
 
Section 12.2. Appendix 2:  Exploratory Objectives/ Endpoints; exploratory endpoints. Minor 
updates to blood transfusion objective and iron parameter, blood transfusion, and dose 
adjustment endpoints.  
Revised Text: 
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 analysis 
range (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 EP 
and MP  
• Number of times Hgb < 7.5 g/dL during the EP. 
• Number (%) 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 
• Number (%) 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 
• N (%) of subjects with a Hgb value ≥ 12 g/dL during the 
EP  
• Number of times Hgb ≥ 12 g/dL during the EP 
• % of time Hgb ≥ 12 g/dL during the EP 
To compare daprodustat to rhEPO on measures of  
iron parameters  
• Observed and change from baseline in hepcidin, 
ferritin, transferrin saturation, total iron, total iron 
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treatment 
• Average quarterly TSAT 
• Average quarterly ferritin 
• 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) to EP (defined as average monthly 
IV iron dose (mg) over Weeks 28-52) 
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 transfusion by Week 52  
• Number of RBC and whole blood transfusions per 
100 patient years  
• Number of RBC and whole blood units per 100 
patient years 
To evaluate the dose adjustment schemes 
• 
Assigned dose by visit and at Day 1, Week 28, 
Week 52 
• 
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 during Day 1 - < 
End of Treatment 
• Final (mean and median) dose at Week 28, Week 
52, and at end of treatment  
• Number (%) of subjects with 0, 1, 2 or >2 dose 
adjustments during the following periods: Day 
1 - < Week 28, Week 28 – Week 52, Day 1 – 
Week 52, > Week 28- end of treatment Day 1 – 
the end of treatment. 
• Number of dose adjustments during the 
following periods: Day 1 - < Week 28, Week 28 
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treatment, Day 1 – the end of treatment  
• Time dose held for Hgb ≥12 g/dL 
 
Section 12.3.1. Darbepoetin Alfa Dose Steps. Removed partial dosing as partial doses 
will no longer be available; clarified “every week” frequency to be “once a week” and 
added a * and footnote to clarify which 4-weekly starting doses will have ‘booster’ doses 
where appropriate. 
Revised Text: 
 
Total 4-weekly Dose (µg) 
PFS Dose and Frequency (PD/HD) 
20 µg 
20 µg (0.2 ml of 40 µg) Q4 weeks 
30 µg 
30 µg (0.3 ml of 40 µg) Q4 weeks 
40 µg* 
40 µg every 4 weeks 
60 µg* 
60 µg every 4 weeks 
80 µg* 
40 µg every 2 weeks 
120 µg* 
60 µg every 2 weeks 
160 µg 
80 µg (0.4 ml of 100 µg) every 2 weeks  
200 µg 
100 µg every 2 weeks 
300 µg 
150 µg every 2 weeks 
400 µg 
100 µg every once a week 
* Subjects starting on these doses at the Randomization (Day1) who have >1 g/dL Hgb 
decrease or Hgb < 7.5 g/dL at Week 2 or Week 6 from the last visit will receive a “booster” 
dose of 20 µg in addition to their previous dose.       
 
 
 

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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.
 
Phase 2 dose-ranging studies, and associated statistical and 
exposure response modelling has informed Phase 3 dose 
rationale, starting doses, dose levels, and dose adjustment 
scheme to optimize Hgb management. 
Following review of clinical data received to date, this has not 
been identified as a safety concern for daprodustat.
 
Phase 2 dose -ranging studies, and associated statistical and 
exposure response mod elling has informed Phase 3 dose 
rationale, starting doses, dose levels, 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 (Table 6)  
• 
Specific guidance for dose 
adjustment, dose interruption, or 
discontinuation of daprodustat 
based on achieved Hgb (including 
rate of change) is provided in 
Section 6.2 and Sectio n 6.11 
• 
Unblinded monitoring of safety 
data by an IDMC in
-stream 
throughout the study.  
 
Risk of Death, MI, stroke, heart 
failure, thromboembolic events, 
Marketed rhEPO and its analogs have been associated with an 
increased risk for death and serious cardiovascular events 
• 
Specific eligibility criteria related 
to CV risk are outlined in Section 

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thrombosis of vascular access  at Hgb 
levels which are within the normal 
range (i.e. not polycythemic 
conditions) 
when used in patients with anemia of CKD.
 
In non- clinical studies conducted to date, not observed at 
tolerated doses when hemo globin/hematocrit within normal 
range for species. 
The clinical data received to date are insufficient to conclude or 
refute this risk.  
5.2 
• 
Hgb will be closely monitored 
throughout th e dosing period as 
outlined in the Time and Events 
Table (Table 6)  
• 
Unblinded monitoring of safety 
data by an IDMC in
-stream 
throughout the study  
Esophageal and gastric erosions  
In animal studies, undesirable GI effects including emesis, 
abnormal feces and/or decreased food consumption/body 
weight loss and stomach erosions/ ulcers with hemorrhage 
were observed with daprodustat. 
 
In rodents rats stomach erosions were observed with 
intravenous and oral administration of daprodustat.
 
Stomach erosions/ulcers also reported in  rats with some 
marketed rhEPO and its analogs. 
Gender-averaged systemic exposure (AUC) at the no observed 
adverse effect levels (NOAEL) are 3.3 -
fold (monkeys) and 737 -
fold (rats) above human exposure (25 mg daprodustat).
 
In clinical trials to date with daprodustat, mild
-moderate GI 
signs and symptoms represent the most frequently reported 
• 
Suspected GI bleeding or 
significant symptoms consistent 
with erosions or ulcers should be 
investigated diagnostically (i.e. 
endoscopic examination) as 
clinically warranted.  
• 
Unblinded monitoring of safety 
data by  an IDMC in -stream 
throughout the study.  

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adverse event, however causal association has not been 
established. 
Following review of clinical data received to date, GI erosions 
have not been iden tified as a safety concern for daprodustat.
 
Cancer-related mortality and tumor 
progression and recurrence  
In clinical trials, use of rhEPO 
and its analogs in patients with 
cancer has been associated with increased risk of cancer 
related morbidity and mortality.  
Administration of 60mg/kg daprodustat to mice caused 
minimal increases in circulating VEGF while significant EPO 
increases were observed.  
 
There were no test article-related neoplastic findings in 2
-year 
rat (oral daprodustat) or mouse (daprodustat + 
subcutaneous 
injection of the 3 major human metabolites; M2, M3 and M13) 
carcinogenicity studies.  
 
In clinical studies with daprodustat up to 4 weeks duration, a 
dose-ordered increase in VEGF plasma concentrations, an 
angiogenic factor that has been implic
ated in tumor growth, 
was observed at doses ranging from 10 to 150 mg. In clinical 
studies up to 24 weeks duration at doses up to 25mg, changes 
• 
Specific eligibility criteria related 
to personal history of malignancy 
or subjects with complex kidney 
cyst are outlined in Section 5.2..
 
• 
Stopping criteria for subj ects with 
treatment emergent malignancy 
are outlined in Section 5.5.
 
• 
Unblinded monitoring of safety 
data by an IDMC in
-stream 
throughout the study   

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in VEGF plasma concentrations were variable but similar 
relative to control.  
 
In clinical studies conducted to date, administration of 
daprodustat has been associated with: 
Once daily administration: 
• 
In studies up to 4 weeks duration, a dose-ordered 
increase in VEGF plasma concentrations was observed at 
doses ranging from 10 to 150 mg.  
• 
In studies up to 24 weeks duration at doses up to 25mg, 
changes in VEGF plasma concentration were variable but 
similar relative to control. 
• 
Systemic EPO concentrations within the physiologic 
range. 
Three times weekly administration: 
• 
In studies up to 4 weeks duration at doses of 10 to 30 mg: 
o Dose dependent increases in plasma VEGF and 
EPO concentrations were observed. 
o Pre-dose concentrations of EPO and VEGF were 

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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; Forment i, 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 weeks 2
-years in rats and 
mice, and up to 39
-weeks in monkeys.  
Acute hypoxic challenge (rats):  Daprodustat produced 
increases in peak right ventricular pressure (PRVP) during acute 
hypoxia that were slightly higher than the vehicle control 
group. However, these hypoxia -induced PRVP changes were 
within the range of PRVP changes noted among 
non un -treated 
rats. 
• 
Unblinded monitoring of safety 
data by an IDMC in
-stream 
throughout the study  

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Results from a clinical study of acute hypoxic challenge in 
healthy volunteers demonstrated that short-term (5 days) 
therapy with daprodustat 5mg or 100mg had no clinically 
significant effect on transthoracic echocardiographically 
(ECHO) estimatesd of 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 s PASP in subjects not on dialysis for daprodustat. In 
hemodialysis subjects, mean absolute change from baseline in 
sPASP was similar for both treatment groups; however, there 
was a numeric imbalance (daprodustat Total: 8 [7%]; Control 0) 
in subjects reaching the s
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 sPA SP on safety follow -up ECHOs had 
confounding conditions that could contribute to resolution 
other than discontinuation of study drug; and there was no 
dose relationship for subjects meeting the sP
ASP 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 

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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 mod
el and experimental 
conditions utilized.  
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.  
With lifetime exposure to daprodustat in a 2-year rat oral 
carcinogenicity study, an exacerbation of rat spontaneous, 
progressive cardiomyopathy (PCM)(focal myofiber 
degeneration/necrosis with inflammatory infiltrates) was 
observed at doses of 0.8 mg/kg/day and above, although 
total incidence and severity distribution within any 
daprodustat-group were within historical control ranges.  This 
is consistent with an equivocal threshold for exacerbation of 
spontaneous, progressive cardiomyopathy at 0.8 mg/kg/day 
which is also the threshold dose for observing increased Hct 
values in individual rats. 
Cardiomyopathy has not been associated with naturally 
• 
Unblinded monitoring of safety 
data by an IDMC in
-stream 
throughout the study.  

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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 with 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 edem a 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. 
No ocular abnormalities with daprodustat were seen in non
-
clinical studies of up to 13 weeks duration in mice and dogs, 26 
• 
Suspected p roliferative 
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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weeks in rats, and 39
-weeks in monkeys. 
 
In clinical studies with daprodustat 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 30mg administered three times 
weekly. In studies up to 24 weeks duration at doses up to 
25mg, changes in VEGF plasma concentrations were variable 
but similar relative to control. 
Ophthalmologic assessments performed in phase 2b studies 
(24 weeks treatment duration) did not identify any clinically 
meaningful changes in proliferative retinopathy, macular 
edema, or choroidal neovascularization for daprodustat.
 
Following review of clinical data 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 were seen in non
-clinical studies conducted 
to date for daprodus tat. 
Following review of clinical data received to date, this has not 
• 
Unblinded monitoring of safety 
data by an IDMC in
-stream 
throughout the study.  

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been identified as a safety concern for daprodustat.
 
Drug-drug interactions  
Daprodustat is a substrate of CYP2C8:  Co-administration of 
daprodustat with a strong CYP2C8 inhibitor (gemfibrozil) 
increased the Cmax and AUC of daprodustat, 4- and 19 -fold, 
respectively, while co -administration of a weak inhibitor 
(trimethoprim) increased the Cmax and AUC of daprodu
stat 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. 
daprodustat is an inhibitor of CYP2C8 in vitro, with an IC
50 value 
of 21 µM.  
Population PK analysis from completed Phase 2 studies 
suggests that co -administration of daprodustat with 
clopidogrel (a moderate CYP2C8  inhibitor) leads to a ~ 2
-fold 
increase in AUC, with no clinically
-significant increase in the 
measured Hgb response. 
Co-administration of daprodustat 
with moderate CYP2C8 inhibitors (i.e., clopidogrel, 
teriflunomide, deferasirox) should be performed wit
h caution  
Co-administration of daprodustat with potent BCRP inhibitors 
• 
Co-administration of daprodustat with 
strong CYP2C8 inhibitors (e.g., 
gemfibrozil) and inducers (e.g., 
rifampin/rifampicin) is not permitted 
as outlined in Section 6.9.2
. 
• 
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 6.9.1.
 
• 
Specific guidance on the management 
of potential drug- drug interactions 
and concomitant medications is 
provided in Section 6.9..  
• 
Hgb will be closely mo
nitored 
throughout the dosing period as 
outlined in the Time and Events 

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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 an inhibitor of OATP1B1/1B3 in vitro, with IC
50 
values of 6 µM and 11
 µM, respectively.  A clinical drug 
interaction study between 25mg daprodustat with either a 
CYP2C8 substrate or an OATP1B1/1B3 substrate showed that 
there is no PK interaction at th
is dose of daprodustat.  
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 
Table (Table 6)  
•Specific guidance for dose adjustment, 
dose interruption, or discontinuation of 
daprodustat based on achieved Hgb is 
provided in Section 6.2.1 and Appendix 3.
 
•Unblinded monitoring of safety data by 
an IDMC in -stream throughout the study.  

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systemic exposure will decrease over time which will result in 
a lag period before an effect on Hgb is recognized and is of 
clinical concern. 
Daprodustat is an inhibitor of CYP2C8:  A clinical drug 
interaction study between 25mg and 100mg daprodustat with 
a CYP2C8 substrate (pioglitazone) showed that there is no PK 
interaction at these doses of daprodustat. 
Daprodustat is a substrate of BCRP: Population PK analysis 
from Phase 2 studies suggested that while BCRP inhibitors 
were a covariate for daprodustat CL/F (8.6% lower clearance) 
the predicted change in exposure was not considered to be of 
clinical relevance.  
Daprodustat is an inhibitor of OATP1B1/1B3:
 A clinical drug 
interaction study between 25mg and 100mg daprodustat with 
an OATP1B1/1B3 substrate (rosuvastatin) showed that there is 
no PK interaction at these doses of daprodustat
 
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, thr omboembolic 
events, thrombosis of vascular access, and for Increased 
cancer-related mortality and tumor progression.
 
•See mitigation strategies outlined in 
table for daprodustat for Excessive 
erythropoiesis (p olycythemia) leading to 
thrombosis and/or tissue ischemia,  Risk of 
death, MI, stroke, thromboembolic 

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• 
Uncontrolled hypertension  
• 
Pure red cell aplasia  
events, thrombosis of vascular access, and 
for Increased 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 12.5. 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. 
Rationale for change: 
Revised Text: 
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 12.11, Appendix 11 is totally removed. France is not taking part in this study so this 
Appendix is no longer relevant