Clinical trial NCT03029208
Conditions: Anaemia
Keywords: Daprodustat, recombinant human erythropoietin, darbepoetin, anemia, chronic kidney disease, dialysis, ESRD
Sponsor: GlaxoSmithKline
Start date: 2017-05-11; Completion date: 2020-09-24
Enrollment: 312 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this multi-center study is to evaluate the efficacy and safety of daprodustat in subjects with anemia associated with CKD.

Detailed description:

Arms: arm 1: Subjects will receive oral daprodustat once daily. arm 2: Subjects will receive darbepoetin alfa subcutaneously or intravenously.
Interventions: intervention 1: Daprodustat intervention 2: Darbepoetin alfa intervention 3: Iron therapy
Intervention descriptions: intervention 1: 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. intervention 2: Darbepoetin alfa will be supplied as prefilled syringes (PFS) for SC/IV injection available in strengths: 20, 30, 40, 60, 80, 100 and 150 mcg. intervention 3: Iron therapy will be administered if ferritin is \<=100 ng/mL and/or TSAT is \<=20%.

Protocol documents:
Prot_000.pdf: 
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C O N FI D E N TI A L  
 
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, 
and accidental trauma (e.g. sprained ankle) which may interfere or prevent everyday 


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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 
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. 
 
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 
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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 
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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 
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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 
binding capacity (TIBC) across all visits to end of 


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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 
– Week 52, Day 1 – Week 52, > Week 28- end of 


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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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Potential Risk of Clinical Significance 
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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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Mitigation Strategy 
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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Potential Risk of Clinical Significance 
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Mitigation Strategy 
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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Mitigation Strategy 
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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Potential Risk of Clinical Significance 
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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
 

SAP_001.pdf: 
 
CONFIDENTIAL 
 
The GlaxoSmithKline group of companies 
 
201410 
1 
 
Division 
: Worldwide Development 
Information Type 
: Reporting and Analysis Plan (RAP) 
 
Title 
: Reporting and Analysis Plan for 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. 
Compound Number  : GSK1278863 
Effective Date  
: Refer to Document Date 
 
Description : 
• 
The purpose of this RAP is to describe the planned analyses and output to be 
included in the Clinical Study Report for Protocol GSK Document Number 
2015N234534_01. 
 
RAP Author(s):  
(Method: E-mail) 
Author 
Date 
Lead 
 
Statistician 
(Specialty Biostatistics) 
20-Nov-2020 
Co-Authors 
 
Director Clinical Statistics  
(Specialty Biostatistics) 
20-Nov-2020 
 
Statistics Leader 
(Specialty Biostatistics) 
20-Nov-2020 
 
Principal Statistician 
(Specialty Biostatistics) 
20-Nov-2020 
 
Director Clinical Pharmacology Modelling and Simulation  
(Clinical Pharmacology and Experimental Medicine) 
20-Nov-2020 
 
Copyright 2020 the GlaxoSmithKline group of companies. All rights reserved.  
Unauthorised copying or use of this information is prohibited. 
201410 | Statistical Analysis Plan   20 Nov 2020 | TMF-5934871 | 2.0
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CONFIDENTIAL 
 
The GlaxoSmithKline group of companies 
 
201410 
2 
 
RAP Team Reviews:  
RAP Team Review Confirmations  
(Method: E-mail) 
Reviewer 
Date 
 
Sr. Director 
Clinical Development Lead 
(Clinical Sciences Respiratory and Specialty) 
20-Nov-2020 
 
Principal Programmer/Analyst 
(Specialty Biostatistics) 
20-Nov-2020 
 
Clinical Statistics and Clinical Programming Line Approvals: 
Clinical Statistics & Clinical Programming Line Approvals  
(Method: Pharma TMF eSignature) 
Approver 
Date 
Approval 
Method 
 
Statistics Director  
(Specialty Clinical Statistics) 
Refer to 
Document Date 
E-signature, 
eTMF 
 
Programming Leader 
(Specialty Clinical Programming) 
Refer to 
Document Date 
E-signature, 
eTMF 
 
 
201410 | Statistical Analysis Plan   20 Nov 2020 | TMF-5934871 | 2.0
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CONFIDENTIAL 
 
 
 
201410 
 
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TABLE OF CONTENTS 
PAGE 
1. 
REPORTING & ANALYSIS PLAN SYNOPSIS ......................................................... 7 
2. 
SUMMARY OF KEY PROTOCOL INFORMATION .................................................. 9 
2.1. 
Changes to the Protocol Defined Statistical Analysis Plan ............................ 9 
2.2. 
Study Objective(s) and Endpoint(s)............................................................. 10 
2.3. 
Study Design .............................................................................................. 14 
2.4. 
Statistical Hypotheses................................................................................. 14 
2.4.1. 
Hgb Efficacy Primary Hypothesis ................................................. 14 
3. 
PLANNED ANALYSES .......................................................................................... 15 
3.1. 
Interim Analyses ......................................................................................... 15 
3.2. 
Final Analyses ............................................................................................ 15 
4. 
ANALYSIS POPULATIONS ................................................................................... 16 
4.1. 
Protocol Deviations and Study Population Exclusions ................................ 17 
5. 
CONSIDERATIONS FOR DATA ANALYSES AND DATA HANDLING 
CONVENTIONS ..................................................................................................... 17 
6. 
STUDY POPULATION ANALYSES ....................................................................... 18 
6.1. 
Overview of Planned Analyses ................................................................... 18 
6.2. 
Display Details ............................................................................................ 19 
6.2.1. 
Populations Analyzed .................................................................. 19 
6.2.2. 
Subject Disposition ...................................................................... 19 
6.2.3. 
Protocol Deviations ...................................................................... 21 
6.2.4. 
Demographic & Baseline Characteristics ..................................... 21 
6.2.5. 
Prior and Concomitant Medications ............................................. 22 
6.2.6. 
Exposure and Randomized Treatment Compliance ..................... 22 
6.2.7. 
COVID-19 Impacted Visits ........................................................... 23 
7. 
PRIMARY STATISTICAL ANALYSES .................................................................... 24 
7.1. 
Primary Hgb Efficacy Analysis .................................................................... 24 
7.1.1. 
Overview of Planned Primary Hgb Efficacy and Supportive 
Analyses ...................................................................................... 24 
7.1.2. 
Planned Primary Hgb Efficacy Statistical Analyses ...................... 24 
7.1.2.1. 
Endpoint / Variables ................................................... 25 
7.1.2.2. 
Summary Measure ..................................................... 25 
7.1.2.3. 
Population of Interest .................................................. 25 
7.1.2.4. 
Strategy for Intercurrent (Post-Randomization) 
Events ........................................................................ 25 
7.1.2.5. 
Statistical Analyses/Methods ...................................... 26 
8. 
OTHER STATISTICAL ANALYSES ....................................................................... 30 
8.1. 
Efficacy Analyses ........................................................................................ 30 
8.1.1. 
Principal Secondary Efficacy Analyses ........................................ 30 
8.1.1.1. 
Overview of Planned Principal Secondary 
Efficacy Analyses ....................................................... 30 
8.1.1.2. 
Planned Principal Secondary Efficacy 
Statistical Analyses..................................................... 31 
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8.1.2. 
Additional Secondary Efficacy Analyses ...................................... 32 
8.1.2.1. 
Overview of Planned Additional Secondary 
Efficacy Analyses ....................................................... 32 
8.1.2.2. 
Planned Additional Secondary Efficacy 
Statistical Analyses..................................................... 34 
8.1.3. 
Exploratory Efficacy Analyses ...................................................... 36 
8.1.3.1. 
Overview of Planned Exploratory Efficacy 
Analyses ..................................................................... 36 
8.1.3.2. 
Planned Exploratory Efficacy Display Details .............. 38 
8.2. 
Safety Analyses .......................................................................................... 42 
8.2.1. 
Secondary Safety Analyses ......................................................... 42 
8.2.1.1. 
Overview of Planned Secondary Safety 
Analyses ..................................................................... 42 
8.2.1.2. 
Planned Secondary Safety Statistical Analyses .......... 42 
8.2.2. 
Exploratory Safety Analyses ........................................................ 44 
8.2.2.1. 
Overview of Planned Exploratory Safety 
Analyses ..................................................................... 44 
8.2.2.2. 
Planned Exploratory Safety Display Details ................ 46 
8.2.2.3. 
Overview of Exploratory Cardiovascular Safety 
Analysis ...................................................................... 47 
8.2.2.4. 
Planned Exploratory Cardiovascular Safety 
Analysis Details .......................................................... 48 
8.2.3. 
Adverse Event Safety Analyses ................................................... 50 
8.2.3.1. 
Overview of Planned Adverse Event Analyses ........... 50 
8.2.3.2. 
Planned Adverse Event Safety Statistical 
Analyses ..................................................................... 51 
8.2.4. 
Clinical Laboratory Safety Analyses ............................................. 55 
8.2.4.1. 
Overview of Planned Clinical Laboratory Safety 
Analyses ..................................................................... 56 
8.2.4.2. 
Planned Clinical Laboratory Safety Display 
Details ........................................................................ 57 
8.2.5. 
Vital Signs Analyses .................................................................... 58 
8.2.5.1. 
Overview of Planned Vital Signs Analyses ................. 59 
8.2.5.2. 
Planned Vital Signs Display Details ............................ 59 
8.2.6. 
Electrocardiograms ...................................................................... 60 
8.2.7. 
Pregnancies ................................................................................. 60 
8.2.8. 
Other Safety Analyses ................................................................. 60 
8.3. 
Pharmacokinetic Analyses .......................................................................... 60 
8.3.1. 
Overview of Planned Pharmacokinetic Analyses ......................... 60 
8.3.2. 
Drug Concentration Measures ..................................................... 61 
8.3.3. 
Pharmacokinetic Parameters ....................................................... 61 
8.3.3.1. 
Deriving Pharmacokinetic Parameters ........................ 61 
8.4. 
Pharmacokinetic / Pharmacodynamic Analyses .......................................... 63 
8.5. 
Patient Reported Outcomes Analyses ........................................................ 65 
8.5.1. 
Overview of Planned Patient Reported Outcomes 
Analyses ...................................................................................... 66 
8.5.2. 
Planned Patient Reported Outcomes Statistical Analyses ........... 67 
8.5.2.1. 
HRQoL and Utility Score ............................................ 67 
8.5.2.2. 
Symptom Severity & Change ...................................... 68 
8.6. 
Biomarker Analyses .................................................................................... 69 
8.7. 
Pharmacogenetics Analyses ....................................................................... 69 
9. 
REFERENCES ....................................................................................................... 70 
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10. APPENDICES ........................................................................................................ 71 
10.1. 
Appendix 1: Protocol Deviation Management and Definitions for Per 
Protocol Population ..................................................................................... 72 
10.1.1. 
Exclusions from Per Protocol Population ..................................... 72 
10.2. 
Appendix 2: Time & Events ......................................................................... 73 
10.2.1. 
Protocol Defined Time & Events .................................................. 73 
10.2.1.1. Time and Events Table for Subjects on 
Randomized Treatment .............................................. 73 
10.2.1.2. Time and Events Table for Subjects that 
Permanently Discontinue Randomized 
Treatment ................................................................... 76 
10.3. 
Appendix 3: Assessment Windows ............................................................. 77 
10.3.1. 
Assessment Windows .................................................................. 77 
10.4. 
Appendix 4: Treatment States and Phases ................................................. 78 
10.4.1. 
Treatment Phases ....................................................................... 78 
10.4.1.1. Treatment States for Hgb, Iron Parameters, IV 
Iron Dose Endpoints, Iron Use Summaries, 
Transfusion and PRO Data ......................................... 78 
10.4.1.2. Treatment States for CV Endpoint Data ...................... 78 
10.4.1.3. Treatment States for BP, Lipid Parameters, 
Clinical Chemistry, Hematology, Other 
Laboratory Tests, Hepatobiliary (Liver) and 
Vital Signs Data .......................................................... 78 
10.4.1.4. Treatment States for AE Data ..................................... 78 
10.4.1.5. Treatment States for Concomitant Medications 
(Other Than IV Iron Dose Endpoints and Iron 
Use Summaries) ......................................................... 80 
10.5. 
Appendix 5: Data Display Standards & Handling Conventions .................... 82 
10.5.1. 
Study Treatment & Sub-group Display Descriptors ...................... 82 
10.5.2. 
Baseline Definition & Derivations ................................................. 82 
10.5.2.1. Baseline Definitions .................................................... 82 
10.5.2.2. Derivations and Handling of Missing Baseline 
Data ........................................................................... 83 
10.5.3. 
Reporting Process & Standards ................................................... 85 
10.6. 
Appendix 6: Derived and Transformed Data ............................................... 88 
10.6.1. 
General ........................................................................................ 88 
10.6.2. 
Study Population .......................................................................... 91 
10.6.2.1. Subject Disposition ..................................................... 91 
10.6.2.2. Demographic & Baseline Characteristics .................... 91 
10.6.2.3. Randomized Treatment Discontinuation and 
Study Withdrawal ....................................................... 96 
10.6.2.4. Prior and Concomitant Medications ............................ 96 
10.6.2.4 
Exposure and Compliance .......................................... 97 
10.6.3. 
Efficacy ........................................................................................ 99 
10.6.3.1. Hemoglobin Endpoints ............................................... 99 
10.6.3.2. Iron Endpoints .......................................................... 101 
10.6.3.3. Time to Rescue ........................................................ 108 
10.6.3.4. RBC and Whole Blood Transfusion Endpoints .......... 109 
10.6.3.5. Dose Adjustment Scheme Endpoints ....................... 113 
10.6.4. 
Safety ........................................................................................ 115 
10.6.4.1. CV Safety Endpoints ................................................ 115 
10.6.4.2. Blood Pressure Endpoints ........................................ 120 
10.6.4.3. Adverse Events ........................................................ 122 
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10.6.4.4. Laboratory Parameters ............................................. 127 
10.6.4.5. Vital Signs ................................................................ 129 
10.6.4.6. COVID-19 ................................................................. 129 
10.6.5. 
Patient Reported Outcomes ....................................................... 130 
10.7. 
Appendix 7: Premature Withdrawals & Handling of Missing Data ............. 133 
10.7.1. 
Premature Withdrawals .............................................................. 133 
10.7.2. 
Handling of Missing Data ........................................................... 133 
10.7.2.1. Handling of Missing and Partial Dates ...................... 133 
10.8. 
Appendix 8: Values of Potential Clinical Importance ................................. 136 
10.8.1. 
Laboratory Values ...................................................................... 136 
10.8.2. 
Vital Signs .................................................................................. 137 
10.9. 
Appendix 9: Multicenter Studies ................................................................ 138 
10.9.1. 
Methods for Handling Centres ................................................... 138 
10.10. Appendix 10: Examination of Covariates, Subgroups & Other Strata ........ 139 
10.10.1. Handling of Covariates, Subgroups & Other Strata .................... 139 
10.10.2. Randomization Stratification ...................................................... 146 
10.11. Appendix 11: Multiple Comparisons & Multiplicity ..................................... 147 
10.11.1. Handling of Multiple of Comparisons & Multiplicity ..................... 147 
10.11.1.1. Interim Analyses ....................................................... 147 
10.11.1.2. Final Analyses .......................................................... 147 
10.11.1.3. Subgroup Analyses .................................................. 147 
10.12. Appendix 12: Model Checking and Diagnostics for Statistical 
Analyses ................................................................................................... 148 
10.12.1. Statistical Analysis Assumptions ................................................ 148 
10.13. Appendix 13: Abbreviations & Trade Marks .............................................. 149 
10.13.1. Abbreviations ............................................................................. 149 
10.13.2. Trademarks ............................................................................... 151 
 
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1. 
REPORTING & ANALYSIS PLAN SYNOPSIS 
Overview 
Key Elements of the RAP 
Purpose 
• 
This RAP describes the planned analyses and outputs required for the final 
Clinical Study Report (CSR) for study 201410 
Protocol 
• 
This RAP is based on the first protocol amendment [(Dated: 06OCT2017) of 
study 201410 (GSK Document Number. 2015N234534_01)]. 
Primary 
Objective 
• 
To compare daprodustat to darbepoetin alfa for hemoglobin (Hgb) efficacy 
(non-inferiority) 
Primary 
Endpoint 
• 
The mean change in Hgb between baseline and the evaluation period (EP, 
mean over Weeks 28-52) 
Study 
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). 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. 
• 
The treatment period consists of (1) the stabilization period, defined as the 
period from Day 1 to Week 28 during which randomized treatment will be 
dose titrated to achieve the appropriate Hgb target and (2) 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. 
• 
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. 
• 
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 darbepoetin alfa (darbepoetin alfa); all randomized treatments 
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 darbepoetin 
alfa, iron management, and anemia rescue therapy. 
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Overview 
Key Elements of the RAP 
Planned 
Analyses 
• 
All planned analyses will be performed after study unblinding. 
• 
No formal interim analyses are planned in this study. 
• 
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.  
Key 
Analysis 
Populations 
• 
The primary population for Hgb efficacy analyses will be the All Randomized 
Intent-To-Treat (ITT) Population. Subjects will be analysed according to the 
treatment to which they were randomized.  
Hypothesis 
• 
The primary Hgb efficacy objective will assess the estimand defined as the 
effect of daprodustat treatment relative to darbepoetin alfa on the change in 
Hgb from baseline to the average of all values in the EP, regardless of 
adherence to treatment including interruptions and discontinuations, the use 
of non-randomized ESA medication for any reason including rescue therapy, 
or the use of blood transfusions in subjects with anemia secondary to CKD 
who are initiating dialysis and assuming subjects do not die before the end of 
the EP. The analysis will test whether daprodustat is non-inferior to 
darbepetin alfa according to the following statistical hypotheses: 
• Null: The difference in mean change in Hgb between baseline and 
EP, between treatment arms (daprodustat-darbepoetin alfa), is less 
than or equal to -0.75 g/dL. 
• Alternative: The difference in mean change in Hgb between baseline 
and EP, between treatment arms (daprodustat-darbepoetin alfa), is 
greater than -0.75 g/dL. 
Primary 
Analyses 
• 
For the Hgb efficacy analyses, an analysis of covariance (ANCOVA) model 
including prognostic randomization stratification factors (dialysis type and 
dialysis start), baseline Hgb, and treatment will be performed to obtain a 
point estimate and the two-sided 95% confidence interval (CI) for the 
treatment difference (daprodustat-darbepoetin alfa) and generate the p-value 
for the non-inferiority test. Non-inferiority will be established if the lower limit 
of the two-sided 95% CI for the treatment difference is greater than -0.75 
g/dL. 
Key 
Secondary 
Analyses 
Principal Secondary Endpoint (adjusted for multiplicity, tested for superiority) 
• Average monthly IV iron dose (mg)/subject from baseline to Week 52 
Safety 
Endpoints 
• Incidence and severity of adverse events (AEs) and serious adverse events 
(SAEs) including those AEs of special interest (AESI) 
• Reasons for discontinuation of randomized treatment 
• Absolute values and changes from baseline in laboratory parameters, blood 
pressure (BP) and heart rate (HR) 
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2. 
SUMMARY OF KEY PROTOCOL INFORMATION 
2.1. 
Changes to the Protocol Defined Statistical Analysis Plan 
In the original RAP, an additional time period of ‘Day 1 -<End of Treatment’ was added 
to the exploratory endpoint of evaluating the dose adjustment schemes, which was not 
part of the first protocol amendment (dated:06OCT2017). Since Week 52 is the end of 
treatment period, ‘Day 1 -<End of Treatment’ has been replaced by ‘Day 1 -<Week 52.’ 
See details in Section 2.2. 
Further changes from the originally planned statistical analysis are outlined in Table 1.  
Table 1 
Changes to Protocol Defined Analysis Plan 
Protocol 
Reporting & Analysis Plan 
Statistical Analysis Plan 
Statistical Analysis Plan 
Rationale for Changes 
• 
None 
• 
New displays related to 
COVID-19 pandemic have 
been added 
• 
Assessing the impact of 
the COVID-19 pandemic 
• 
 Only include randomized 
subjects who have both 
baseline and at least one Hgb 
assessment during the EP in 
the primary Hgb analysis 
• 
All randomized subjects 
will be included in the 
primary Hgb analysis by 
imputing missing post-
baseline Hgb data using 
pre-specified multiple 
imputation approach 
• 
Addressing the feedback 
from FDA 
• 
None 
• 
Worsening of 
Hypertension has been 
added to the list of AESI is 
included in the summary 
and analysis of AESI 
• 
Worsening of 
Hypertension has been 
added to the list of AESI 
based on Safety Review 
Team update on AESI 
• 
None 
• 
Number of RBC whole 
blood and transfusion 
event is included in the 
exploratory efficacy 
analysis of RBC and 
Whole Blood Transfusions 
• 
Number of RBC whole 
blood and transfusion 
event has been defined 
and included in the 
exploratory endpoints 
• 
None 
• 
Time to first RBC and 
whole blood transfusion is 
included in the exploratory 
efficacy analysis of RBC 
and Whole Blood 
Transfusions 
• 
Time to first RBC and 
whole blood transfusion 
has been included in the 
exploratory endpoints 
• 
PK exploratory endpoints 
described as dose normalized 
• 
PK exploratory endpoints 
described as dose 
extrapolated 
• 
Terminology clarification 
following discussion with 
regulatory agencies.  
PK exploratory endpoints include: 
• 
Scatter plots of daprodustat PK 
parameters (Ctau and Cmax) 
dose normalized to 1 mg vs. 
PK exploratory endpoints 
modified as follows: 
• 
Endpoints removed: 
Scatter plots of 
daprodustat PK 
• 
Removed as these 
endpoints do not provide 
additional information for 
efficacy explorations than 
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Protocol 
Reporting & Analysis Plan 
Statistical Analysis Plan 
Statistical Analysis Plan 
Rationale for Changes 
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. 
• 
Boxplots of daprodustat PK 
parameters (Ctau and Cmax) 
dose normalized to 1 mg by 
subjects with or without MACE 
or combined safety endpoint 
parameters (Ctau and Cmax) 
dose normalized to 1 mg 
vs. percent time in range 
during EP. 
• 
Scatter plots of average 
daprodustat dose during 
EP while in target Hgb 
range  vs. percent time in 
range during EP. 
• 
Scatter plots of 
daprodustat PK 
parameters (Ctau and Cmax) 
dose normalized to 
average dose during EP 
while in target Hgb range  
vs. percent time in range 
during EP. 
• 
Endpoints removed: 
Scatter plots of 
daprodustat PK 
parameters (Ctau and Cmax) 
dose normalized to 1 mg 
vs. change from baseline 
of Hgb during EP. 
• 
Endpoints removed: 
Boxplots of daprodustat 
PK parameters (Ctau and 
Cmax) dose normalized to 
1 mg by subjects with or 
without MACE or 
combined safety endpoint 
what will be available from 
remaining endpoints. 
 
2.2. 
Study Objective(s) and Endpoint(s) 
Objectives 
Endpoints 
Primary Objectives 
Primary Endpoints 
• 
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 Objectives 
Principal Secondary Endpoints (tested for superiority, 
adjusted for multiplicity) 
• 
To compare daprodustat to 
rhEPO on the use of intravenous 
(IV) iron 
• 
Average monthly IV iron dose (mg)/subject from baseline 
to Week 52 
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 
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Objectives 
Endpoints 
• 
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 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 >1 g/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 
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Objectives 
Endpoints 
• 
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, Week 52 
• 
Number (%) of subjects 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 - < Week 52 
• 
Number of dose adjustments during the following periods: 
o Day 1 - < Week 28 
o Week 28 - < Week 52 
o Day 1 - < Week 52 
• 
Time dose held for Hgb ≥12 g/dL 
• 
To further compare daprodustat 
to rhEPO on BP and BP 
medication changes 
• 
Observed and change from baseline in SBP, DBP and 
MAP by visit 
• 
Number of BP medications per subject by visit 
• 
Change from baseline in the number of BP medications per 
subject by visit 
• 
N (%) of subjects who had no change, an increase or a 
decrease in the dosage or number of BP medications from 
baseline by visit 
• 
To compare daprodustat to 
rhEPO on 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 Wk 8, 12, 28, & 52) in PGI-S 
• 
N (%) of subjects 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. 
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Objectives 
Endpoints 
• 
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. 
Safety Objective  
Safety Endpoints 
• 
To compare the safety and 
tolerability of daprodustat to 
rhEPO 
• 
Incidence and severity of AEs and SAEs including those 
special interest 
• 
Reasons for discontinuation of randomized treatment 
• 
Absolute values and changes from baseline in laboratory 
parameters, BP and heart rate (HR) 
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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2.3. 
Study Design 
Overview of Study Design and Key Features 
 
* Screening period may be extended by an additional 4 weeks for ultrasound examination, IV iron supplementation 
and/or vitamin B12 treatment as needed. 
Design 
Features 
• 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. 
Dosing and 
Randomized 
Treatment 
Assignment 
• A central randomization approach will be used to protect against potential 
selection bias due to the open-label design. The randomization schedule will 
be generated by PPD, and PPD’s IRT system will be used for treatment 
allocation. 
• Subjects will be stratified by dialysis type (hemodialysis [HD], or peritoneal 
dialysis [PD]) 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). 
• Please refer to the protocol for starting doses, dose steps, and elements of 
the dose adjustment scheme. 
Interim 
Analysis 
• An 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. No formal interim analyses are planned in this 
study 
 
2.4. 
Statistical Hypotheses 
2.4.1. 
Hgb Efficacy Primary Hypothesis 
The primary Hgb efficacy objective will assess the estimand defined as the effect of 
daprodustat treatment relative to darbepoetin alfa on the change in Hgb from baseline to 
the average of all values in the EP, regardless of adherence to treatment including 
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interruptions and discontinuations, the use of non-randomized ESA medication for any 
reason including rescue therapy, or the use of blood transfusions, in subjects with anemia 
secondary to CKD who are initiating dialysis and assuming subjects do not die before the 
end of the EP. The analysis will test whether daprodustat is non-inferior to darbepoetin 
alfa according to the following statistical hypotheses:  
• 
Null: The difference in mean change in Hgb between baseline and EP, between 
treatment arms (daprodustat -darbepoetin alfa), is less than or equal to -0.75 g/dL. 
• 
Alternative: The difference in mean change in Hgb between baseline and EP, 
between treatment arms (daprodustat -darbepoetin alfa), is greater than -0.75 g/dL  
The non-inferiority margin is pre-defined as -0.75 g/dL; determined based upon a 
combination of clinical judgment, statistical reasoning and regulatory guidance for 
designing non-inferiority trials.  
Statistical significance of non-inferiority will be assessed at the one-sided 2.5% level. An 
ANCOVA model including randomization stratification factors (dialysis type and 
whether dialysis start is planned or unplanned), baseline Hgb and treatment will be used 
to obtain a point estimate and two-sided 95% CI for the treatment difference (daprodustat 
-darbepoetin alfa) and generate the 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. 
 
3. 
PLANNED ANALYSES 
3.1. 
Interim Analyses 
The IDMC will periodically receive unblinded safety reports containing, at a minimum, 
clinical endpoints (whether adjudicated or pending adjudication) and SAEs, from an 
independent Statistical Data Analysis Center (SDAC) while the study is ongoing. The 
IDMC may recommend stopping the study for safety at any time. Further details will be 
specified in the IDMC charter and RAP. 
There are no prospectively defined interim analyses planned to stop the study early for 
Hgb efficacy or futility.  
3.2. 
Final Analyses 
The final planned primary analyses will be performed after the completion of the 
following sequential steps: 
1. All subjects have completed the study as defined in the protocol and final study 
clinic visits have occurred. 
2. All required database cleaning activities have been completed and final database 
release and database freeze has been declared by PPD Data Management. 
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3. All criteria for unblinding the randomization codes have been met.  
4. Randomization codes have been distributed according to GSK and PPD procedures 
 
4. 
ANALYSIS POPULATIONS 
Inclusion in any analysis population is contingent on a subject signing informed consent. 
Population 
Definition / Criteria 
Analyses Evaluated 
Screened 
• All screened subjects.  
• Study Population 
• Safety 
Intent-To-Treat 
(ITT) 
• All randomized subjects. 
• Subjects will be analyzed according to the 
treatment to which they were randomized. 
• Study Population 
• Efficacy 
• Safety 
Enrolled 
• All randomized subjects. 
• Subjects will be analyzed according to the 
treatment to which they were randomized. 
• Use of the enrolled population is required for 
some displays; for this study, the enrolled and 
ITT populations will be identical. 
• Study Population 
Per-Protocol (PP) • All ITT subjects without PP population 
exclusions. 
• Exclusions from the PP population are defined 
in Section 4.1 (Protocol Deviations and Study 
Population Exclusions) and Section 10.1 
(Protocol Deviation Management and 
Definition for Per-Protocol Population). 
• Subjects will be analyzed according to the 
treatment received.1 
• Efficacy 
 
Safety 
• All randomized subjects who receive at least 
one dose of randomized treatment. 
• Subjects will be analyzed according to the 
treatment received.1 
• Safety 
 
Pharmacokinetic 
(PK) 
• Subjects for whom a PK sample was obtained 
and analyzed 
• PK 
[1]: only subjects receiving incorrect randomized treatment for the duration of 
their study participation will be analysed according to the treatment received. 
Otherwise, subjects will be analyzed according to the treatment to which they were 
randomized. 
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4.1. 
Protocol Deviations and Study Population Exclusions 
• 
Significant protocol deviations will be summarized and listed. 
• 
Exclusions from the study populations will also be summarized and listed. Please 
refer to Appendix 1: Protocol Deviation Management and Definitions for Per 
Protocol Population for further details of Per-Protocol population exclusions. 
• 
Protocol deviations and study population exclusions will be tracked by the study 
team throughout the conduct of the study in accordance with PPD’s Deviation 
Management Plan and Study Deviation Rules Document. 
o Data will be reviewed prior to unblinding the database to ensure all significant 
deviationsare captured and categorised on the protocol deviations dataset.  
o This dataset will be the basis for the summaries and listings of protocol 
deviations. 
• 
A separate summary and listing of all inclusion/exclusion criteria deviations will also 
be provided. This summary will be based on data as recorded on the 
inclusion/exclusion page of the electronic case report form (eCRF). 
 
5. 
CONSIDERATIONS FOR DATA ANALYSES AND DATA 
HANDLING CONVENTIONS 
Table 2 provides an overview of appendices within the RAP for outlining general 
considerations for data analyses and data handling conventions.  
Table 2 
Overview of Appendices 
Section 
Component 
10.1 
Appendix 1: Protocol Deviation Management and Definitions for Per Protocol 
Population 
10.2 
Appendix 2: Time & Events 
10.3 
Appendix 3: Assessment Windows 
10.4 
Appendix 4: Treatment States and Phases 
10.5 
Appendix 5: Data Display Standards & Handling Conventions 
10.6 
Appendix 6: Derived and Transformed Data 
10.7 
Appendix 7: Premature Withdrawals & Handling of Missing Data 
10.8 
Appendix 8: Values of Potential Clinical Importance 
10.9 
Appendix 9: Multicenter Studies 
10.10 
Appendix 10: Examination of Covariates, Subgroups & Other Strata 
10.11 
Appendix 11: Multiple Comparisons & Multiplicity 
10.12 
Appendix 12: Model Checking and Diagnostics for Statistical Analyses 
10.13 
Appendix 13: Abbreviations & Trade Marks 
 
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6. 
STUDY POPULATION ANALYSES 
6.1. 
Overview of Planned Analyses 
The study population analyses will be mostly based on ITT population. Summaries will 
include a total column, unless otherwise specified. Table 3 provides an overview of the 
planned study population analyses. 
Table 3 
Overview of Planned Study Population Analyses 
Parameter 
Analysis 
Population 
Data Displays Generated 
Table 
Figure 
Listing 
Populations Analyzed 
 
 
 
 
Study Populations 
Screened 
Y 
 
 
Screening Status and Reasons for Screen Failure 
Screened 
Y 
 
Y 
Screening Attempts 
Screened 
Y 
 
 
Exclusions from Study Population 
ITT 
Y 
 
Y 
Subject Disposition 
Subject Status and Reasons for Study Withdrawal 
ITT 
Y 
Y 
Y 
Subjects Who Were Rescreened 
Screened 
 
 
Y 
Treatment Status and Reasons for Discontinuation 
of Randomized Treatment 
ITT 
Y 
Y 
Y 
Number of Subjects by Region, Country and Site 
ID 
Enrolled 
Y 
 
 
Type of Subject Contact at Wk52 
ITT 
Y 
 
 
Subject Survival Status 
ITT 
Y 
 
 
Planned and Actual Treatments 
ITT 
 
 
Y 
Protocol Deviations 
 
 
 
 
Significant Protocol Deviations 
ITT 
Y 
 
Y 
Subjects with Inclusion/Exclusion Criteria 
Deviations 
ITT 
Y 
 
Y 
Demographic & Baseline Characteristics 
 
 
 
 
Demographic & Baseline Characteristics 
ITT & Safety 
Y 
 
Y 
Demographic & Baseline Characteristics by 
Baseline Dialysis Type 
ITT 
Y 
 
 
Demographic & Baseline Characteristics by 
Baseline Dialysis Start Manner 
ITT 
Y 
 
 
Age Ranges 
Enrolled 
Y 
 
 
Race and Racial Combinations 
ITT 
Y 
 
Y 
Smoking History 
ITT 
Y 
 
 
Medical Conditions 
ITT 
Y 
 
 
Dialysis Modality and Frequency 
ITT 
Y 
 
 
Dialysis Modality Changes 
ITT 
Y 
 
 
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Parameter 
Analysis 
Population 
Data Displays Generated 
Table 
Figure 
Listing 
Prior and Concomitant Medications 
 
 
 
 
Pre-Treatment Medications 
ITT 
Y 
 
 
On-Treatment Medications 
ITT 
Y 
 
Y 
Post-Treatment Medications 
ITT 
Y 
 
 
Non-randomized ESA Use During Treatment 
Period 
Safety 
Y 
 
Y 
Treatment Compliance 
 
 
 
 
Extent of Exposure to Randomized Treatment 
Safety 
Y 
 
Y 
Randomized Treatment Compliance Categories 
Safety 
Y 
 
 
Randomized Treatment Compliance 
Safety 
Y 
 
 
IRT and eCRF Dose and Frequency Discrepancies 
Safety 
Y 
 
 
 
NOTES : 
• 
Y = Yes display generated. 
6.2. 
Display Details 
6.2.1. 
Populations Analyzed 
The number of subjects in the Screened, Safety, ITT, Enrolled, PP, and PK populations 
will be summarized by treatment group and overall. 
The number and percentage of subjects by screening status (enrolled/randomized, screen 
failed) and associated reasons for screen failure will be summarized for the screened 
population. 
A summary of all screening attempts and associated reasons for screen failure will be 
provided for the screened population. This summary will count each screening attempt 
individually, regardless of whether or not there was a subsequent re-screen. 
A listing of screen failure records will be provided for all subjects who failed screening, 
including site ID, unique subject ID, date of screen failure, and reason(s) for screen 
failure. 
The number and percentage of subjects excluded from the Safety and PP populations will 
be summarized by reason, treatment group and overall in individual displays for each 
study population.  
A listing of subjects excluded from the Safety and PP populations will be provided. The 
listing will include the treatment arm, site ID, unique subject ID, date of deviation, study 
day of deviation, category, coded term, criteria which lead to exclusion, and the 
populations from which the subject was excluded. 
6.2.2. 
Subject Disposition 
The summary of subject status and reasons for study withdrawal will include: 
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• the number and percentage of subjects who completed the study, the number and 
percentage of subjects withdrawing early from the study and the associated 
reasons/subreasons for withdrawal summarized by treatment group and overall. 
For subjects with an adverse event leading to withdrawal of consent, the outcome 
(fatal, non-fatal) of the adverse event will be summarized. 
This summary will be repeated by relationship to COVID-19 pandemic. 
A listing of reasons for study withdrawal will be provided for all subjects who were 
withdrawn from the study. This listing will include treatment, site ID, unique subject ID, 
date of withdrawal, study day of withdrawal, primary reason for withdrawal, and 
subreason for withdrawal. 
A listing of screening status will be provided for all subjects who were rescreened for the 
study. The listing will include unique subject ID, subject ID, screening status, date of 
screen failure, and reason for screen failure.  
The summary of treatment status and reasons for discontinuation of randomized 
treatment will include: 
• the overall number and percentage of subjects who never received randomized 
treatment, the overall number and percentage of subjects who prematurely 
discontinued randomized treatment during the study, including the breakdown of 
the number and percentage of subjects who died while taking randomized 
treatment and those that did not die while taking randomized treatment, and a 
summary of the reasons and subreasons for randomized treatment discontinuation 
overall and separately for subjects who died while taking randomized treatment 
and for subjects who did not die while taking randomized treatment, and the 
overall number and percentage of subjects who did not prematurely discontinue 
randomized treatment during the study summarized by treatment group and 
overall. 
This summary will be repeated by relationship to COVID-19 pandemic. 
A listing of the randomized treatment discontinuation record will be provided for all 
subjects who prematurely discontinued randomized treatment. This listing will include 
treatment, site ID, unique subject ID, date of last dose, study day of discontinuation, 
primary reason for discontinuation, and subreasons for discontinuation.  
A Kaplan-Meier plot of time to early withdrawal from the study will be produced by 
treatment group. 
Two Kaplan-Meier plots of time to permanent randomized treatment discontinuation by 
treatment group will be produced. For both of the plots, the risk set will include all 
subjects who started taking randomized treatment. The first plot will consider an event as 
subjects who discontinued randomized treatment and the second plot will consider an 
event as subjects who discontinued randomized treatment and did not die while on 
treatment. If a subject discontinued treatment due to death, that subject will not count 
towards the event, and will be censored instead. 
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The number and percentage of subjects by region, country, and site ID will be 
summarized by treatment group and overall for the enrolled population. 
The type of subject contact at Week 52 visit will be provided by treatment group and 
overall. 
A summary of the subject survival status by study completion status will be provided by 
treatment group and overall. 
A listing of planned and actual treatments will be provided. This listing will include 
region, country, site ID, investigator name, subject number, randomization number, 
randomization date, randomized treatment, and actual treatment flag. 
6.2.3. 
Protocol Deviations 
The number and percentage of subjects who had significant protocol deviations (defined 
in PPD’s Study Deviation Rules Document) will be summarized by category and by 
treatment group and overall. It will be repeated by relationship to COVID-19 pandemic.  
A listing of significant protocol deviations will be produced. The listing will include 
treatment, site ID, unique subject ID, date of deviation, study day of deviation, protocol 
deviation category, protocol deviation coded term, and protocol deviation description. 
The number and percentage of subjects who had inclusion/exclusion criteria deviations 
will be summarized by inclusion/exclusion type, criteria description and by treatment 
group and overall. 
A listing of subjects with inclusion/exclusion criteria deviations will be provided. The 
listing will include treatment, site ID, unique subject ID, inclusion/exclusion type, and 
criteria description. 
6.2.4. 
Demographic & Baseline Characteristics 
The number and percentage of subjects or summary statistics will be provided by 
treatment group and overall for the demographic and baseline characteristics listed in 
Section 10.10. This table will be repeated by baseline dialysis type (HD/PD) and baseline 
dialysis start manner. 
A listing of demographic characteristics will be produced. This listing will include 
treatment, site ID, unique subject ID, year of birth, age, sex, and ethnicity and may 
include additional demographic characteristics. 
The number and percentage of subjects in the following age ranges: Adult (18-64 years), 
 65 – 84 years, and  85 years will be provided by treatment group and overall. 
A summary of race and racial combinations will be provided by treatment group and 
overall. 
A listing of race will be provided. This listing will include treatment, site ID, unique 
subject ID, race, and race detail. 
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A summary of smoking history will be provided by treatment group and overall. 
A summary of medical conditions will be provided by treatment group and overall. 
A summary of dialysis modality and frequency at randomization, Week 28 and Week 52 
will be provided by treatment group and overall. This summary will include the number 
and percentage of subjects who have temporarily or permanently stopped dialysis at these 
time points, as well as summary statistics for total residual urine volume for subjects on 
hemodialysis and peritoneal dialysis separately. 
The number and percentage of subjects with dialysis modality changes at any point in the 
study will be provided by treatment group and overall. 
6.2.5. 
Prior and Concomitant Medications 
The number and percentage of subjects reporting the use of each concomitant medication 
will be summarized by treatment group and overall, anatomical therapeutic chemical 
(ATC) Level 1, 2, 3, and Ingredient. Summaries of pre-treatment, on-treatment, and post-
treatment medication will be provided separately. See Section 10.4.1.5 for a summary of 
treatment states for concomitant medications. 
A listing of on-treatment concomitant medication records will be provided with details of 
the on-treatment concomitant medication use. 
The number and percentage of subjects with any non-randomized ESA use in addition to 
randomized treatment during the treatment period (see Section 10.6.2) will be provided 
by treatment group and overall. Similarly, the number and percentage of subjects with 
any non-randomized ESA used instead of randomized treatment during the treatment 
period (see Section 10.6.2) will be provided by treatment group and overall. Additionally, 
the duration of the non-randomized ESA use during the treatment period will be 
summarized using mean, standard deviation, minimum, P25, median, P75, and maximum 
by treatment group and overall, as well as by the number and percentage of subjects in 
the following duration categories: < 5 days,  5 days - < 14 days,  14 days - < 28 days,  
28 days. 
A listing of subjects who have non-randomized ESA use will be provided with details of 
the ESA use. 
6.2.6. 
Exposure and Randomized Treatment Compliance 
Months of exposure (see Section 10.6.2) will be summarized using mean, standard 
deviation, minimum, P25, median, P75, and maximum by treatment group and overall. 
Additionally, the number and percentage of subjects in each 6-monthly exposure category 
( 6 months, >6 -  12 months, > 12 -  18 months, etc.) will be provided by treatment 
group and overall.  
A listing of exposure data will be provided. This listing will include treatment, site ID, 
unique subject ID, dose start date, dose stop date, duration of time on dose, dose, dose 
units, dose form, route of administration, and dosing frequency. 
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The number and percentage of subjects in each randomized treatment compliance 
category (see Section 10.6.2) during the study will be summarized by treatment group for 
the following time periods: Day 1 - < Week 28, Week 28 - < Week 52, and Day 1 - < 
Week 52 (Overall Compliance). 
The percentage of time that subjects spend in each of the three compliance categories, 
i.e., under compliant, compliant and over compliant) will be summarized by treatment 
group for the following time periods: Day 1 - < Week 28, Week 28 - < Week 52, and Day 
1 - < Week 52 (Overall Compliance). 
The number and percentage of subjects with no dose discrepancy, and at least one dose 
discrepancy and the number of discrepancies between the IRT-assigned dose and the dose 
recorded in the eCRF will be summarized by treatment group for the following time 
periods: Day 1 - < Week 28, Week 28 - < Week 52, and Day 1 - < Week 52 (Overall 
Compliance). For subjects with at least one dose discrepancy, the number and percentage 
of subjects with 1, 2-3, 4-5 and ≥6 discrepancies will be summarized by treatment group 
for the same time periods.  
A visit schedule will be produced that will be utilized in merging eCRF data with IRT 
data. This Visit schedule will generally be based on the actual visits and dates found in 
the IRT. Supplemental information (to account for items such as skipped visits, 
unscheduled visits, and kit replacements) will be provided by means of a protocol-
defined visit schedule, whereby scheduled visit dates and visit windowing will be based 
on the intervals from randomization to each scheduled visit, as specified in the protocol. 
6.2.7. 
COVID-19 Impacted Visits 
A summary of the number and percentage of subjects with any visit impacted by COVID-
19 pandemic and each visit impacted by COVID-19 pandemic may be produced. The 
summary would include the impact and the reason for impact overall (any visit) and at 
each impacted visit. 
A summary of the number and percentage of subjects with any treatment interruption 
while on treatment due to COVID-19 pandemic overall and by visit may be produced. 
The summary would include the summary on the total duration of interruption per subject 
at a certain visit, since the last visit (e.g. 1-7 days, 8-14 days, etc.). Only the visits that 
had subjects who had treatment interruption, or whose randomized treatment was not able 
to be dispensed at the visit, would be presented in this table. 
A listing of all subjects with visits and assessments impacted by the pandemic will be 
produced.  
A figure of COVID-19 pandemic visit impacts may be produced. The figure would be a 
stacked bar chart for each impacted visit. The stack bar would be color coded by impact. 
 
 
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7. 
PRIMARY STATISTICAL ANALYSES 
7.1. 
Primary Hgb Efficacy Analysis 
7.1.1. 
Overview of Planned Primary Hgb Efficacy and Supportive 
Analyses 
Table 4 provides an overview of the planned primary Hgb efficacy and supportive 
analyses. 
Table 4 
Overview of Planned Primary Hgb Efficacy and Supportive Analyses 
Endpoint 
Analysis 
Population 
Absolute 
Change from Baseline 
Summary Individual 
Stats Analysis 
Summary Individual 
T 
F 
F 
L 
T 
F 
L 
T 
F 
F 
L 
Mean Change in Hgb between Baseline and EP 
Primary 
Analysis 
ITT 
[all available observed 
and imputed (on and 
off treatment) Hgb 
values] 
Y 
Y 
 
 
Y 
Y 
 
Y 
Y 
 
Y 
Supportive 
While On-
Treatment 
Analysis 
ITT 
[evaluable Hgb values 
only] 
Y 
Y 
 
 
Y 
Y 
 
Y 
Y 
 
 
Supportive 
Analysis PP 
PP 
[ evaluable Hgb values 
only] 
Y 
Y 
 
 
Y 
Y 
 
Y 
Y 
 
 
Sensitivity & 
Supportive 
Tipping Point 
Analyses1 
ITT 
 
 
 
 
Y 
Y 
 
 
 
 
 
Supportive 
Analyses 
Alternative 
EP1 
ITT 
Y 
 
 
 
Y 
Y 
 
Y 
 
 
 
By Subgroup1 
ITT 
 
 
 
 
Y 
Y 
 
Y 
 
 
 
NOTES : 
• 
T = Table, F = Figure, L = Listing, Y = Yes display generated. 
• 
Stats Analysis = Represents TFL related to any formal statistical analyses (i.e. modelling) conducted. 
• 
Summary = Represents TFL related to any summaries (i.e. descriptive statistics) of the observed raw data. 
• 
Individual = Represents FL related to any displays of individual subject observed raw data. 
[1] Analysis will be performed using all available observed and imputed (on and off-treatment) Hgb values and 
separately using evaluable Hgb values only (see Section 10.6.3). Subgroup is defined in Section 10.10. 
 
7.1.2. 
Planned Primary Hgb Efficacy Statistical Analyses 
The primary efficacy estimand is the effect of daprodustat relative to darbepoetin alfa on 
the change in Hgb from baseline to the average of all values in the EP, regardless of 
adherence to treatment including interruptions and discontinuations, the use of non-
randomized ESA medication for any reason including rescue therapy, or the use of blood 
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transfusions, in subjects with anemia secondary to CKD who are initiating dialysis and 
assuming subjects do not die before the end of the EP. 
7.1.2.1. 
Endpoint / Variables 
Mean change in Hgb between baseline and over the evaluation period (EP, mean over 
Week 28 and 52).  
7.1.2.2. 
Summary Measure 
Model-adjusted mean treatment difference (LS mean difference) in Hgb change between 
baseline and over the evaluation period.  
7.1.2.3. 
Population of Interest  
The target population is defined by the study’s inclusion and exclusion criteria.   
The analysis population included in the primary efficacy analyses will be based on the 
ITT population, unless otherwise specified. 
7.1.2.4. 
Strategy for Intercurrent (Post-Randomization) Events 
The following are the intercurrent events for the primary efficacy analyses: 
• Death prior to the end of the EP (i.e. before Week 52 visit) 
• Randomized treatment interruption or discontinuation prior to the end of the EP  
• Use of non-randomized ESA medications for any reason including rescue prior to 
the end of the EP 
• Receipt of blood transfusions prior to the end of the EP 
Except for the intercurrent event of deaths prior to the end of the EP, a treatment policy 
strategy will be used in which all Hgb data recorded during the EP (Weeks 28-52) will be 
included in the primary efficacy analysis, regardless of discontinuation or interruption of 
study medication due to any reasons, and regardless of receipt of non-randomized ESA 
medications for any reason including rescue, or blood transfusions. For deaths, a 
hypothetical strategy will be used as described in Section 7.1.2.5 
The following are causes of missing Hgb data affecting the primary efficacy endpoint 
that are not due to intercurrent events: 
• Study withdrawal prior to the end of the EP 
• Permanent switching from clinic visits to remote visits prior to the end of EP 
• Intermittent missing Hgb values at one or more visits with the EP 
Missing data will be imputed as described in Section 7.1.2.5 
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7.1.2.5. 
Statistical Analyses/Methods 
Primary Hgb Efficacy Statistical Analyses 
Endpoint(s) 
• Mean change in Hgb between baseline and EP 
Model Specification 
• Hgb during the EP will be defined as the mean of all available post-randomization Hgb 
values (on and off-treatment) during the EP (Week 28-52). 
• The ANCOVA model used to quantify the difference in mean Hgb change will adjust for the 
following baseline values: 
o Treatment 
o Baseline Hgb (see Section 10.5.2) 
o Dialysis type (as randomized, see Section 0) 
o Dialysis start manner (whether dialysis start is planned or unplanned; as 
randomized)  
Multiple Imputation Analysis 
• Multiple imputation analysis will be performed using all available Hgb values (on and off-
treatment) and conducted under a set of assumptions about missing Hgb values (see 
Section 10.6.3). 
o Intermittent missing post-baseline scheduled Hgb data in both arms through Week 
52 will be imputed using PROC MI procedure with NIMPUTE = 200 and MCMC 
IMPUTE = monotone to generate 200 datasets with only monotone missing 
patterns. Burn in iterations (NBITER) and maximum iteration (MAXITER) will both 
be set to 500. The seed for reproducibility is set to 201410. The imputations will be 
done by randomized treatment, dialysis type, and dialysis starting manner.  
o For each of the monotone missing dataset (out of the 200 imputed as indicated 
above), the missing scheduled Hgb values through Week 52 will be imputed based 
on the MAR assumption and will be performed using PROC MI by treatment, 
dialysis type, and dialysis start manner. The monotone regression will have baseline 
Hgb, prior scheduled (possibly imputed) Hgb values, and may include dialysis type 
and dialysis start manner, as covariates (see Model Checking & Diagnostics, 
below). The seed for reproducibility is set to 201410.  
o The low and high cutoffs at Hgb values of 6 g/dL and 15 g/dL will be applied to all 
imputed Hgb values. 
o EP Hgb values will be computed and compared across treatment groups using the 
co-primary ANCOVA model described above. Rubin’s rules [Rubin, 1987] will be 
used to combine results of the imputed datasets using SAS PROC MIANALYZE 
procedure. As a result, a single estimated treatment difference and its standard 
error will be produced, with which a 95% CI will be calculated. 
Model Checking & Diagnostics 
• Refer to Appendix 12: Model Checking and Diagnostics for Statistical Analyses. 
Model Results Presentation 
• All available observed Hgb values (on and off-treatment) will be summarized using mean, 
standard deviation, minimum, P25, median, P75 and maximum at each visit by treatment 
group. In addition to scheduled visits, the baseline value and mean EP and mean Alt EP 
values will be included (see Section 10.6.3). 
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Primary Hgb Efficacy Statistical Analyses 
o This summary of Hgb will also be repeated for visits up to and including Week 
52, using the data used for the primary Hgb analysis (i.e., including imputed 
values (see Section 10.6.3)). 
• All available observed Hgb change from baseline values (on and off-treatment) will also be 
summarized using mean, standard deviation, minimum, P25, median, P75, and maximum at 
each post-baseline visit, including mean EP and mean Alt EP values (see Section 10.6.3). 
o This summary of Hgb will also be repeated for visits up to and including Week 
52, using the data used for the primary Hgb analysis (i.e., including imputed 
values (see Section 10.6.3)). 
• The number and percentage of subjects with imputed data in the primary Hgb analysis will 
be provided by treatment group. The number and percentage of subjects by reason for data 
imputation will be provided. Reasons include: intermittent missing Hgb values, death before 
Week 28, death during Week 28 – 52, investigator site closed before Week 28, investigator 
site closed during Weeks 28-52, lost to follow-up before Week 28, lost to follow-up during 
Week 28 – 52, consent withdrawn before Week 28, consent withdrawn during Week 28 – 
52, and other monotone missing Hgb values. Subjects will be further classified as either 
having observed all 7 scheduled EP Hgb values, having observed a partial schedule of EP 
Hgb values, having observed no scheduled EP Hgb values with at least one unscheduled 
EP Hgb value, or having observed no EP Hgb values, scheduled or unscheduled. For 
subjects with partial scheduled EP Hgb values, both the pattern of imputed data 
(intermittent, monotone) and the amount of imputed data (1 – 6 scheduled Hgb values 
missing) will be summarized. For subjects with partial scheduled EP Hgb values and a 
monotone imputed data pattern, the reason for the monotone imputed scheduled EP Hgb 
values will be provided. Reasons include: death during Week 28-52, investigator site closed 
during Weeks 28-52, lost to follow-up during Week 28 – 52, consent withdrawn during Week 
28 – 52, and other monotone imputed Hgb values. And for summaries of the amount of 
missing scheduled EP Hgb values, the presence or absence of additional unscheduled EP 
Hgb values will be summarized. 
• The least square (LS) mean estimates and standard errors by treatment group, LS mean 
difference, two-sided 95% CI and one-sided non-inferiority p-value for the difference in the 
primary Hgb endpoint between the daprodustat and darbepoetin alfa arms from the 
ANCOVA model will be presented. The number of subjects contributing to the analysis and 
the associated mean and standard deviation of the baseline and EP Hgb values will also be 
displayed with the results of the ANCOVA model. 
• The LS mean difference, and associated two-sided 95% CI will be displayed on a forest plot 
together with supportive analysis results (excluding the Tipping Point Analysis).  
• All available Hgb values (on and off-treatment, observed and imputed (see Section 10.6.3)) 
will be displayed graphically for each scheduled study visit using a line plot. The line plot of 
mean values  95% CIs by time will include horizontal reference lines to depict the Hgb 
analysis range (10-11.5 g/dL), vertical reference lines to identify the EP (weeks 28-52), and 
the number of subjects by treatment group contributing to each mean value. 
• All available Hgb change from baseline values (on and off-treatment, observed and imputed 
(see Section 10.6.3)) will be displayed graphically for each scheduled study visit using a line 
plot. The line plot of mean values  95% CIs by time will include vertical reference lines to 
identify the EP (Weeks 28-52), and the number of subjects by treatment group contributing 
to each mean value. 
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Primary Hgb Efficacy Statistical Analyses 
• A listing of all hemoglobin values will be provided, including treatment, most recent dose, 
site ID, unique subject ID, visit, assessment date, select demographic information and 
central laboratory and HemoCue Hgb values. 
Model Results Interpretation 
• Non-inferiority will be achieved if the lower limit of the two-sided 95% CI of the treatment 
difference is greater than the pre-specified non-inferiority margin of -0.75 g/dL. 
 
Sensitivity Statistical Analyses 
Tipping Point (Multiple Imputation) Analysis 
• Tipping point analysis will be performed using all available Hgb values (on and off-treatment) 
as a sensitivity for the primary estimand. 
• Tipping point sensitivity analyses will be conducted under a range of missing data 
assumptions to determine how extreme assumptions need to be for non-inferiority 
conclusions to change. Assumptions about missing Hgb values on the daprodustat and 
darbepoetin alfa arms will vary independently, and will include scenarios where subjects with 
missing data on daprodustat have worse outcomes than subjects with missing data on 
darbepoetin alfa. 
• Intermittent missing scheduled Hgb data in both arms through Week 52 will be 
imputed using PROC MI procedure with NIMPUTE = 200 and MCMC IMPUTE 
= monotone to generate 200 datasets with only monotone missing patterns. 
Burn in iterations (NBITER) and maximum iteration (MAXITER) will both be set 
to 500. The seed for reproducibility is set to 201410. The imputations will be 
done by randomized treatment, dialysis start manner, and dialysis type. 
• For each of the monotone missing dataset (out of the 200 imputed as indicated 
above), the missing scheduled Hgb values in both arms through Week 52 will 
be imputed based on the MAR assumption and will be performed using PROC 
MI by treatment, dialysis start manner, and dialysis type. The monotone 
regression will include baseline Hgb, prior scheduled (possibly imputed) Hgb 
values, and may have dialysis start manner, and dialysis type as covariates 
(see Model Checking & Diagnostics, below). The seed for reproducibility is set 
to 201410.  
o For each treatment arm separately, the imputed monotone missing Hgb values 
will vary from the MAR scenario by a multiple of delta, where delta represents a 
change in Hgb over a 4-week interval. No delta adjustments will be done for 
intermittent missing values. Beginning with the first missed visit (which could 
occur before Week 28), for every 4-week interval, the imputed Hgb value would 
shift an additional delta. For example, the first missed visit will use delta, the 
second missed visit will use 2*delta, etc. The deltas explored for each treatment 
arm will range from -4 g/dL to 4 g/dL per 4-week interval with a 0.1 g/dL 
increment respectively. Delta scenarios which are known ahead of time to not 
possibly represent the tipping point may not be explored. 
• The low and high cutoffs at Hgb values of 6 g/dL and 15 g/dL will be applied to 
all imputed Hgb values. 
• EP Hgb values will be computed for each pair of deltas and compared across 
treatment groups using the co-primary ANCOVA model described above 
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Sensitivity Statistical Analyses 
(including unscheduled visit). Rubin’s rules [Rubin, 1987] will be used to 
combine results of the imputed datasets using SAS PROC MIANALYZE 
procedure. As a result, for each pair of delta values, a single estimated 
treatment difference and its standard error will be produced, with which a 95% 
CI will be calculated. 
Model Checking & Diagnostics 
• Refer to Appendix 12: Model Checking and Diagnostics for Statistical Analyses. 
Model Results Presentation 
• The delta pairs, their corresponding model-adjusted mean Hgb change from baseline to EP 
in the two treatment arms, the model-adjusted treatment difference, and two-sided 95% CI 
will be presented. The non-inferiority conclusion will be drawn if the lower confidence limit of 
the two-sided 95% CI is greater than -0.75, which will also be presented in the tables.  
• Graphics depicting treatment difference and non-inferiority surfaces will be produced using 
an enhanced tipping point approach [Liublinska, 2014]. A colored heat map that illustrates 
the gradual change of treatment difference will be produced. Colored borders will be used to 
highlight the delta combinations that result in rejecting the null hypothesis (i.e., non-inferiority 
established). 
 
Supportive Statistical Analyses 
While On-Treatment Evaluable Hgb Analysis 
• This estimand utilizes the same endpoint, summary measure and target population as the 
co-primary Hgb estimand. For the intercurrent events of death, randomized treatment 
discontinuation, use of non-randomized ESA medication for any reason including rescue, 
and blood transfusions, a ‘while on-treatment’ strategy will be used. 
• This estimand reflects the effect of daprodustat treatment relative to darbepoetin alfa, while 
on-treatment and without the use of non-randomized ESA medication or blood transfusions. 
• For this analysis, the primary Hgb analyses and summaries described above will be 
performed using evaluable Hgb values (see Section 10.6.3.  
• No data will be imputed in this analysis, so a summary of missing data will be provided 
• The LS mean treatment difference, and associated 95% CI from this analysis will be 
included on a forest plot with the primary Hgb analysis results. 
• The number and percentage of subjects meeting each evaluable Hgb (see Section 10.6.3) 
exclusion criterion will be summarized by scheduled visit. 
• A tipping point analysis similar to the one described above will be performed as a sensitivity 
analysis for this estimand using evaluable Hgb values only. 
PP Population Analysis 
• The while on-treatment evaluable Hgb analysis and summaries described above (with the 
exception of the missing data summary) will also be performed using the PP population and 
evaluable Hgb values (see Section 10.6.3). 
• The LS mean treatment difference, and associated two-sided 95% CI from this analysis will 
be included on a forest plot with the primary Hgb analysis results. 
Alternative EP (Week 28-36) Analysis 
• The following analyses will be repeated using an alternative EP from Week 28-36: 
o The primary analysis and summaries (using on- and off-treatment, observed 
and imputed Hgb values (see Section 10.6.3)) 
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Supportive Statistical Analyses 
o Supportive analysis and summaries of the alternative estimand that uses 
evaluable Hgb values and a while on-treatment strategy for handling 
intercurrent events will be repeated using an alternative EP from Week 28-36. 
• Summaries of imputed/missing Hgb values will not be repeated. 
• The LS mean treatment difference, and associated two-sided 95% CI from these analyses 
will be included on a forest plot with the primary Hgb analysis results. 
COVID Supportive Analyses 
• The adjusted treatment difference in mean change in Hgb from baseline to the EP and the 
corresponding 95% CI will be estimated using the same ANCOVA model specified in the co-
primary Hgb analysis. Then they will be presented quarterly in a scatter plot, starting at 
around a year after the first subject was randomized, and ending after the last subject last 
visit. At each time point, all available observed post-randomization Hgb values (on and off 
treatment) up to that time will be used to fit the ANCOVA model as in the Hgb efficacy co-
primary analysis(See Section 7.1.2). A vertical reference line will be used to represent the 
date the pandemic measures begin in the majority of the countries. 
Subgroup Analysis 
• Subgroup analysis will be performed using all available observed and imputed Hgb values 
(on and off-treatment). Rubin’s rules [Rubin, 1987] will be used to combine results of the 
imputed datasets using SAS PROC MIANALYZE procedure.  
• Subgroup analysis will also be performed separately using evaluable Hgb values only (see 
Section 10.6.3). 
• Subgroup analysis details are discussed in Section 10.10.1. 
 
8. 
OTHER STATISTICAL ANALYSES 
8.1. 
Efficacy Analyses 
8.1.1. 
Principal Secondary Efficacy Analyses 
8.1.1.1. 
Overview of Planned Principal Secondary Efficacy Analyses 
Table 5 provides an overview of the planned principal secondary efficacy analyses. 
Table 5 
Overview of Planned Principal Secondary Efficacy Analyses 
Endpoint 
Analysis 
Population 
Absolute 
Stats Analysis 
Summary 
Individual 
T 
F 
L 
T 
F 
F 
L 
Iron Use 
Average monthly IV iron dose 
(mg)/Subject from baseline to Week 52 
ITT 
Y 
 
 
Y 
Y 
 
Y 
Supportive analysis: Average monthly 
IV iron dose (mg)/subject to Week 52 
using on and off-treatment IV iron 
records 
ITT 
Y 
 
 
Y 
Y 
 
 
By subgroup1 
ITT 
Y 
Y 
 
 
 
 
 
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NOTES : 
• 
T = Table, F = Figure, L = Listing, Y = Yes display generated. 
• 
Stats Analysis = Represents TFL related to any formal statistical analyses (i.e. modelling) conducted. 
• 
Summary = Represents TFL related to any summaries (i.e. descriptive statistics) of the observed raw data. 
• 
Individual = Represents FL related to any displays of individual subject observed raw data. 
[1] Subgroup is defined in Section 10.1.1 
 
8.1.1.2. 
Planned Principal Secondary Efficacy Statistical Analyses 
Principal Secondary Efficacy Statistical Analyses: Average Monthly IV Iron Dose 
Endpoint(s) 
• 
Average monthly IV iron dose (mg)/subject from baseline to Week 52 
Model Specification 
• Average monthly IV iron dose (mg)/subject from baseline to Week 52 will be determined by 
calculating the total IV iron dose per subject from Day 1 to the earliest of ((Week 52 visit 
date, first blood (RBC or whole blood) transfusion date, and treatment stop date + 1 day) 
which corresponds to the time while the subject was on randomized treatment and before 
receiving a blood transfusion. This total IV iron dose will be divided by (the number of days 
from Day 1 to the earliest of (Week 52 visit date, first blood transfusion date (RBC or whole 
blood), and treatment stop date +1) /30.4375 days). See Section 10.4 for the definition of 
on-treatment IV iron. 
• An ANCOVA model will be used to compare the difference in average monthly IV iron dose 
per subject between arms, adjusting for:  
o Treatment 
o Baseline monthly IV iron dose (see Section 10.5.2) 
o Dialysis type (as randomized, see Section 0) 
o Dialysis start manner (whether dialysis start is planned or unplanned; as 
randomized, see Section 0). 
Model Results Presentation 
• The number and percentage of subjects with baseline IV iron use, on-treatment EP IV iron 
use, and on-treatment IV iron use to Week 52 will be summarized by treatment. 
• Average monthly IV iron dose at baseline, while on treatment during the EP, and while on 
treatment to Week 52 will be summarized by treatment group using mean, standard 
deviation, minimum, P25, median, P75, and maximum. 
• The least square (LS) mean estimates and standard errors by treatment group, LS mean 
difference, two-sided 95% CI and one-sided superiority p-value for the difference in average 
monthly IV iron dose/subject to Week 52 between the daprodustat and darbepoetin alfa 
arms from the ANCOVA model will be presented. The number of subjects contributing to the 
analysis and the associated mean and standard deviation of the baseline and Week 52 
values will also be displayed with the results of the ANCOVA model. 
• A listing of average monthly IV iron dose will be provided including treatment, site ID, unique 
subject ID, time period, and average monthly IV iron dose to Week 52. 
Model Results Interpretation 
• See Section 10.11.1. 
 
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Supportive Statistical Analyses 
Average monthly IV iron dose (mg)/subject to Week 52 using on and off treatment IV iron 
records, regardless of transfusion 
• The summaries and analysis described above for the principal secondary average monthly 
IV iron dose/subject to Week 52 will be repeated using all available IV iron records during 
the Day 1 – Week 52 visits, regardless of whether or not a subject was on treatment or 
transfusion 
• The average monthly IV iron dose (mg)/subject to Week 52 for this analysis will be 
determined by calculating the total IV iron dose per subject from Day 1 to the earliest of 
(Week 52 visit date, study completion/withdrawal date)and dividing by (earliest of the (Week 
52 visit date, study completion/withdrawal date) – Randomization date + 1 day)/30.4375 
days. 
Subgroup Analysis 
• Subgroup analysis details are discussed in Section 10.10.1. 
8.1.2. 
Additional Secondary Efficacy Analyses 
8.1.2.1. 
Overview of Planned Additional Secondary Efficacy Analyses 
Table 6 provides an overview of the planned additional secondary efficacy analyses 
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Table 6 
Overview of Planned Additional Secondary Efficacy Analyses 
Endpoint 
Analysis 
Population 
Absolute 
Change from Baseline 
Stats Analysis 
Summary 
Individual 
Stats Analysis 
Summary 
Individual 
T 
F 
L 
T 
F 
F 
L 
T 
F 
L 
T 
F 
F 
L 
Hgb Variability 
Hgb change from baseline 
to Week 521, 2 
ITT 
 
 
 
 
 
 
 
Y 
Y 
 
Y 
 
 
 
Hgb change from baseline 
to Week 52 by 
subgroup1,2,3 
ITT 
 
 
 
 
 
 
 
Y 
Y 
 
 
 
 
 
Hgb responders2 
ITT 
Y 
 
 
Y 
 
 
 
 
 
 
 
 
 
 
Hgb responders by 
subgroup2,3 
ITT 
Y 
Y 
 
 
 
 
 
 
 
 
 
 
 
 
% of time Hgb in analysis 
range2 
ITT 
Y 
 
 
Y 
 
 
 
 
 
 
 
 
 
 
% of time Hgb in analysis 
range by subgroup2,3 
ITT 
Y 
Y 
 
 
 
 
 
 
 
 
 
 
 
 
Time to Rescue 
Time to stopping 
randomized treatment due 
to meeting rescue criteria 
ITT 
Y 
Y 
 
Y 
 
 
 
 
 
 
 
 
 
 
NOTES : 
• 
T = Table, F = Figure, L = Listing, Y = Yes display generated. 
• 
Stats Analysis = Represents TFL related to any formal statistical analyses (i.e. modelling) conducted. 
• 
Summary = Represents TFL related to any summaries (i.e. descriptive statistics) of the observed raw data. 
• 
Individual = Represents FL related to any displays of individual subject observed raw data. 
[1] Analysis will be performed using all available observed and imputed (on and off-treatment) Hgb values. 
[2] Analysis will be performed using evaluable Hgb values only (see Section 10.6.3). 
[3] Subgroup analysis will be only using stratification factors (dialysis type and dialysis start manner). 
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8.1.2.2. 
Planned Additional Secondary Efficacy Statistical Analyses 
Hgb Variability 
Additional Secondary Efficacy Statistical Analyses: Hgb Variability 
Endpoint(s) 
• Hgb change from baseline to Week 52 
• N (%) responders, defined as mean Hgb within the Hgb analysis range 10-11.5 g/dL during 
EP 
• % time Hgb in analysis range (10-11.5 g/dL) during the evaluation period (EP, Week 28 to 
52) (non-inferiority analysis that will use a margin of 15 percentage points less time in range)  
Model Specification 
• For the secondary analysis of Hgb change from baseline to Week 52, a mixed model 
repeated measures (MMRM) approach will be used with an unstructured covariance matrix 
to compare the difference in means between arms. The model will be fitted to Hgb data 
collected after baseline up to Week 52, excluding values collected during the stabilization 
period (Randomization date + 1 day to <Week 28). The model will include factors for 
treatment, time, prognostic randomization stratification factors (as randomized, see Section 
0), baseline Hgb and the baseline Hgb by time and treatment by time interaction terms. 
Analyses will be done with the MIXED procedure in SAS, using the Kenward-Roger option to 
estimate denominator degrees of freedom and standard errors. This analysis will be 
performed using all available Hgb values (on and off-treatment) and separately using 
evaluable Hgb values only (see Section 10.6.3). In the analysis using all available Hgb 
values, subjects who withdraw from the study before Week 52 are considered to be missing 
at random and in the analysis using evaluable Hgb values, subjects who permanently 
discontinue randomized treatment before Week 52 are assumed to be missing at random.  
• For the Hgb responder analysis, mean Hgb during the EP will be defined as in the while on-
treatment supportive analysis (Section 10.6.3). Responders will be subjects with a mean 
Hgb during the EP that falls within the Hgb analysis range of 10-11.5 g/dL. A Cochran-
Mantel-Haenszel (CMH) chi-squared test, adjusting for treatment and the prognostic 
randomization stratification factors (as randomized, see Section 0), will be used to compare 
the number and % of responders between the treatment groups. 
• For the analysis of % time in range, the method by Rosendaal [Rosendaal, 1993] will be 
used to calculate the percentage of time (days) a subject’s Hgb is below, within and above 
the Hgb analysis range of 10 to 11.5 g/dL during the EP (Weeks 28-52) (See Section 
10.6.3). A van Elteren test (stratified Wilcoxon rank sum test) will be used to compare the 
percentage of time in range between treatment arms, adjusting for treatment and the 
prognostic randomization stratification factors (see Section 0). This analysis will be 
performed using evaluable Hgb values only. Hodges-Lehmann estimate of the treatment 
difference will be used to assess non-inferiority in % time in range.  
Model Results Presentation 
• For the MMRM analysis of change from baseline in Hgb, an LSMEANS statement will 
provide adjusted treatment group means and standard errors and a point estimate and two-
sided 95% confidence interval for the adjusted mean treatment difference (daprodustat - 
darbepoetin alfa) at Week 52. The one-sided non-inferiority p-value for this test will be 
calculated. 
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Additional Secondary Efficacy Statistical Analyses: Hgb Variability 
• For the responder analysis, the number and percentage of subjects with mean EP Hgb 
above, within and below the Hgb analysis range will be summarized by treatment group. 
• For the responder analysis, the number and % of responders by treatment group, difference 
in response rate (daprodustat – darbepoetin alfa) and two-sided 95% CI using Wald method 
will be provided along with the one-sided CMH p-value for the treatment group comparison. 
If the CMH adjusted treatment difference is positive, then the one-sided p-value is p/2, and if 
the CMH adjusted treatment difference is negative, then the one-sided p-value is 1-p/2, 
where p is the two-sided p-value from the CMH test. 
• The % time Hgb is above, in and below the Hgb analysis range (10-11.5 g/dL) during the EP 
will be summarized using mean, standard deviation, minimum, P25, median, P75, and 
maximum by treatment group. 
• The percent time in range for each treatment group, the stratified Mann-Whitney estimate of 
the treatment difference (daprodustat - darbepoetin alfa) and associated two-sided 95% CI 
[Kawaguchi, 2011] will be presented in addition to the one-sided superiority p-value from the 
van Elteren test. Hodges-Lehmann estimate of the treatment difference (daprodustat-
darbepoetin alfa) and associated two-sided 95% CI will be presented. 
Model Results Interpretation 
• For the MMRM analysis of change from baseline in Hgb, the NI margin used in the primary 
analysis of Hgb (-0.75 g/dL) will be used for reference in this comparison, thus generating 
support for non-inferiority if the lower bound of the two-sided 95% CI is above -0.75 g/dL. 
• For the responder analysis, the one-sided CMH p-value will be compared to 0.025 to assess 
nominal significance. 
• For the percent time in range analysis, a NI margin of -15% will be used as a reference in 
this comparison, thus generating support for non-inferiority if the lower limit of the two-sided 
95% CI of Hodges-Lehmann estimate is above -0.15. If non-inferiority is established, 
nominal superiority will be achieved if the one-sided p-value from the van Elteren test is < 
0.025. 
 
Supportive Statistical Analyses 
Subgroup Analysis 
• Subgroup analyses will be performed for all Hgb variability endpoints, using the stratification 
factor subgroups only (described in Section 0 ). 
Time to Rescue 
Additional Secondary Efficacy Statistical Analyses: Time to Rescue 
Endpoint(s) 
• Time to stopping randomized treatment due to meeting rescue criteria 
Model Specification 
• The Cox Proportional Hazards model will adjust for the following baseline categorical values: 
o Treatment 
o Dialysis type (as randomized, see Section 0) 
o Dialysis start manner (whether dialysis start is planned or unplanned; as 
randomized, see Section 0) 
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Additional Secondary Efficacy Statistical Analyses: Time to Rescue 
• Confidence intervals for the rate per 100 person-years will also be reported. For within-group 
rates, the 95% CI will be obtained using an exact Poisson method. For difference in rates 
between treatments, the two-sided 95% CI will be constructed with a Normal approximation 
using Wald’s method [Liu, 2006]. 
• Analysis will include only those efficacy endpoints occurring within the time period for 
treatment discontinuation. Calculation of time-to-event or censoring is described in further 
detail in Section 10.6.3. 
• Time to stopping study medication due to meeting rescue criteria is defined as the time from 
Randomization until the date on which a subject permanently stops study medication due to 
meeting criteria for rescue. 
Model Results Presentation 
• Summaries will include (see Section 10.6.3):  
o the number and percentage of subjects meeting evaluation criteria for rescue 
and the number of occurrences (events),  
o the number and percentage of subjects unable to be evaluated for rescue, and  
o the number and percentage of subjects meeting rescue. 
• The hazard ratio, two-sided 95% CI, and one-sided p-value for the statistical superiority test 
will be presented for the comparison of daprodustat vs. darbepoetin alfa using the Cox 
Proportional Hazards model. The number and percentage of subjects with the event of 
stopping treatment due to meeting rescue criteria and the number censored at the end of the 
study, the incidence rate per 100 person-years, and associated two-sided 95% CI will be 
displayed with the results of the Cox proportional hazards regression model. 
Model Results Interpretation 
• One-sided p-values will be compared to 0.025 to assess nominal significance. 
 
8.1.3. 
Exploratory Efficacy Analyses 
8.1.3.1. 
Overview of Planned Exploratory Efficacy Analyses 
Table 7 provides an overview of the planned exploratory efficacy analyses. 
Table 7 
Overview of Planned Exploratory Efficacy Analyses 
Endpoint 
Analysis 
Population 
Absolute 
Change from Baseline 
Summary 
Individual 
Summary 
Individual 
T 
F 
F 
L 
T 
F 
F 
L 
Hgb Variability 
Hgb observed (including imputed) 
and change from baseline (CFB) 
cross all visits to end of treatment 
ITT 
Included with Hgb primary and supportive analyses 
(Section 7.1) 
% of time Hgb is above, within 
and below Hgb analysis range 
(10-11.5 g/dL) during EP  
ITT 
Included with Hgb secondary analyses (Section 
8.1.2) 
Number (%) of subjects with 
mean Hgb above, within and 
below Hgb analysis range during 
EP and at the end of treatment 
ITT 
Included with Hgb secondary analyses (Section 
8.1.2) 
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Endpoint 
Analysis 
Population 
Absolute 
Change from Baseline 
Summary 
Individual 
Summary 
Individual 
T 
F 
F 
L 
T 
F 
F 
L 
Number (%) of subjects with Hgb 
< 7.5 g/dL during EP1 
ITT 
Y 
 
 
 
 
 
 
 
Number of times Hgb < 7.5 g/dL 
during EP1 
ITT 
Y 
 
 
 
 
 
 
 
Number (%) of subjects with a 
>1g/dL increase in Hgb over 2 
weeks (assessed at Week 2 and 
Week 4) or a >2 g/dL increase in 
Hgb within any 4 week period 
from Week 4 to Week 521 
ITT 
Y 
 
 
 
 
 
 
 
Number (%) of subjects with a 
>1g/dL decrease in Hgb over 2 
weeks (assessed at Week 2, 
Week4, Week6, and Week 8) or a 
>2 g/dL decrease in Hgb within 
any 4 week period from Week 4 
to Week 521 
ITT 
Y 
 
 
 
 
 
 
 
N(%) of subjects with a Hgb value 
 12 g/dL during the EP1 
ITT 
Y 
 
 
 
 
 
 
 
Number of times Hgb  12 g/dL 
during the EP1 
ITT 
Y 
 
 
 
 
 
 
 
% of time Hgb  12 g/dL during 
the EP1 
ITT 
Y 
 
 
 
 
 
 
 
Iron Parameters 
Hepcidin, ferritin, TSAT, total iron, 
TIBC observed and CFB cross all 
visits to end of treatment 
ITT 
Y 
Y 
 
 
Y 
Y 
 
 
Average quarterly IV iron 
dose/subject 
ITT 
Y 
Y 
 
 
 
 
 
 
Average quarterly TSAT 
ITT 
Y 
Y 
 
 
 
 
 
 
Average quarterly ferritin 
ITT 
Y 
Y 
 
 
 
 
 
 
Subjects who met iron 
management criteria 
ITT 
Y 
 
 
 
 
 
 
 
RBC and Whole Blood Transfusions 
Number (%) of subjects receiving 
at least one RBC or whole blood 
transfusion by Week 52  
ITT 
Y 
 
 
 
 
 
 
 
Number of RBC and whole blood 
transfusion events per 100 patient 
years 
ITT 
Y 
 
 
 
 
 
 
 
Number of RBC and whole blood 
transfusions per 100 patient years 
ITT 
Y 
 
 
 
 
 
 
 
Number of RBC and whole blood 
units per 100 patient years 
ITT 
Y 
 
 
 
 
 
 
 
Time to first RBC or whole blood 
transfusion 
ITT 
Y 
Y 
 
 
 
 
 
 
Dose Adjustment Scheme Evaluation 
Assigned dose by visit 
ITT 
Y 
Y 
 
 
 
 
 
 
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Endpoint 
Analysis 
Population 
Absolute 
Change from Baseline 
Summary 
Individual 
Summary 
Individual 
T 
F 
F 
L 
T 
F 
F 
L 
Most recent dose by visit 
ITT 
 
Y 
 
 
 
 
 
Y 
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 - < the end of treatment 
ITT 
Y 
 
 
 
 
 
 
 
Number of dose adjustments 
during the following periods: Day 
1 - <Week 28, Week 28 -< Week 
52, Day 1 -< the end of treatment 
ITT 
Y 
 
 
 
 
 
 
 
Time dose held for Hgb  12 g/dL 
ITT 
Y 
 
 
 
 
 
 
 
NOTES : 
• 
T = Table, F = Figure, L = Listing, Y = Yes display generated. 
• 
Summary = Represents TFL related to any summaries (i.e. descriptive statistics) of the observed raw data. 
• 
Individual = Represents FL related to any displays of individual subject observed raw data. 
[1] Summaries will be presented using evaluable Hgb values only (see Section 10.6.3). 
 
8.1.3.2. 
Planned Exploratory Efficacy Display Details 
Hgb Variability 
The number and percentage of subjects with a Hgb value < 7.5g/dL and the number of 
times a Hgb value < 7.5 g/dL occurs during the EP will be summarized by treatment 
group using central laboratory Hgb values and separately using HemoCue Hgb values. 
This summary will be presented using evaluable Hgb values only (see Section 10.6.3). 
The central laboratory summary will be considered the primary summary of this data. 
The number and percentage of subjects with a >1 g/dL increase in Hgb over 2 weeks 
(assessed at Week 2, and Week 4) or a >2 g/dL increase in Hgb within any 4-week period 
from Week 4 to Week 52 will be summarized by visit and overall at Week 52 by 
treatment group using HemoCue Hgb values. This summary will be presented using 
evaluable Hgb values only (see Section 10.6.3).  
The number and percentage of subjects with a >2 g/dL increase in Hgb within any 4-
week period from Week 4 to Week 52 will be summarized by visit and overall at Week 
52 by treatment group using central laboratory Hgb values. This summary will be 
presented using evaluable Hgb values only (see Section 10.6.3). The central laboratory 
summary will be considered the primary summary of this data. 
The number and percentage of subjects with a >1 g/dL decrease in Hgb over 2 weeks 
(assessed at Week 2, and Week 4) or a >2 g/dL increase in Hgb within any 4-week period 
from Week 4 to Week 52 will be summarized by visit and overall at Week 52 by 
treatment group using HemoCue Hgb values. This summary will be presented using 
evaluable Hgb values only (see Section 10.6.3).  
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The number and percentage of subjects with a >2 g/dL decrease in Hgb within any 4-
week period from Week 4 to Week 52 will be summarized by visit and overall at Week 
52 by treatment group using central laboratory Hgb values. This summary will be 
presented using evaluable Hgb values only (see Section 10.6.3). The central laboratory 
summary will be considered the primary summary of this data. 
The number and percentage of subjects with a Hgb value  12 g/dL and the number of 
times a Hgb value  12 g/dL occurs during the EP will be summarized by treatment 
group using central laboratory Hgb values and separately using HemoCue Hgb values. 
This summary will be presented using evaluable Hgb values only (see Section 10.6.3). 
The central laboratory summary will be considered the primary summary of this data. 
The percentage of time Hgb is  12 g/dL and the percentage of time Hgb is  12 g/dL for 
subjects with at least one Hgb  12 g/dL during the EP will be calculated using the 
Rosendaal method as described in Section 8.1.2. The percentage of time Hgb is  12 g/dL 
during the EP will be summarized using mean, standard deviation, minimum, P25, 
median, P75, and maximum by treatment group. This summary will be presented using 
evaluable Hgb values only (see Section 10.6.3). 
Iron Parameters 
Hepcidin, ferritin, and total iron on-treatment values will be log-transformed (see Section 
10.5.2) and summarized using geometric mean, coefficient of variation, minimum, P25, 
median, P75, and maximum for each scheduled visit by treatment group. Graphical 
summaries will be provided. 
TSAT and TIBC on-treatment values will be summarized using mean, standard deviation, 
minimum, P25, median, P75, and maximum for each scheduled visit by treatment group. 
Graphical summaries will be provided. 
Percent change from baseline in log-transformed (see Section 10.5.2) hepcidin, ferritin, 
and total iron on-treatment values will be summarized using geometric mean, 95% 
confidence interval, minimum, P25, median, P75, and maximum for each scheduled visit 
by treatment group. Graphical summaries will be provided. 
Change from baseline in TSAT and TIBC on-treatment values will be summarized using 
mean, standard deviation, minimum, P25, median, P75, and maximum for each scheduled 
visit by treatment group. Graphical summaries will be provided. 
Average quarterly IV iron dose/subject while on treatment will be summarized by 
presenting average monthly IV iron dose by quarter (see Section 10.6.3). Summaries will 
include mean, standard deviation, minimum, P25, median, P75, and maximum by 
treatment group. Graphical summaries will be provided. 
Average quarterly TSAT while on treatment will be summarized by presenting average 
TSAT values for the quarters used to generate IV iron dose by quarter (see Section 
10.6.3). Summaries will include mean, standard deviation, minimum, P25, median, P75, 
and maximum by treatment group. Graphical summaries will be provided. 
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Average quarterly ferritin while on treatment will be summarized by presenting average 
ferritin values by quarter (see Section 10.6.3). Summaries will include geometric mean, 
coefficient of variation, minimum, P25, median, P75, and maximum by treatment group. 
Graphical summaries will be provided. 
The number and percentage of subjects that met the iron management criteria during the 
study while on treatment will be summarized by treatment group for each 3-month period 
of the study and across the entire study. There are two types of iron management 
thresholds: the first type requires that iron therapy be administered if subjects have 
ferritin and/or TSAT values that are too low; the second type requires that all iron 
(excluding multivitamins) must be stopped if ferritin and/or TSAT values are too high. It 
is also possible for a subject to meet starting and stopping criteria on the same day with a 
low ferritin and a high TSAT. These subjects will also be summarized (see Section 
10.6.3). Assessment of meeting iron management thresholds will be made based on 
central laboratory data values at the scheduled visits for ferritin and TSAT assessments, 
according to the schedule outlined in the Time and Events table (see Section 10.2.1). 
Further, the subjects who met the threshold requiring iron administration to start or stop 
will while on IV iron be grouped by the action taken with iron therapy in the 8 weeks 
following the date the threshold was met (i.e., starting or increasing iron therapy, 
maintaining existing iron therapy, receiving no iron therapy, stopping or decreasing iron 
therapy with no increase see Section 10.6.3) according to concomitant medication records 
for IV iron. 
RBC and Whole Blood Transfusions 
Summary and analysis tables will use the ITT population. 
The total number of on-treatment RBC and whole blood transfusion events, transfusions 
and units for each subject will be derived as described in Section 10.6.3.4. 
The number of on-treatment RBC and whole blood transfusion events per subject, the 
number of subjects with at least one RBC and whole blood transfusion event, and total 
number of RBC and whole blood transfusion events will be summarized.  
The number of on-treatment RBC and whole blood transfusions events per 100 patient 
years will be summarized by treatment group. 
The number of on-treatment RBC and whole blood transfusions per 100 patient years will 
be summarized by treatment group.  
The number of on-treatment RBC and whole blood units per 100 patient years will be 
summarized by treatment group.  
The reason for transfusion events will be summarised. 
The above summaries will be produced for the Evaluation Period and  Week 52. 
An analysis of time to first RBC or whole blood transfusion will be performed as 
described in Section 10.6.3.4., including a Kaplan-Meier plot. 
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Dose Adjustment Scheme 
See Section 10.6.3 for additional details of dose adjustment scheme endpoints. 
The assigned dose by visit will be summarized using mean, standard deviation, 
minimum, P25, median, P75, and maximum by treatment group.  
The assigned dose by visit will also be summarized by treatment group using the number 
and percentage of subjects assigned to each dose level. Stacked bar graphs displaying 
assigned dose at all scheduled visits starting with Day 1 will be provided by treatment 
group.  
The median assigned dose by treatment and visit will be displayed graphically for each 
scheduled study visit using a line plot. The line plot of median assigned dose along with 
the first and the third quartiles by time will include vertical reference lines to identify the 
EP as well as the number of subjects by treatment group contributing to each median 
value. 
The following summaries of dose adjustments will be produced twice – the first time 
counting all dose adjustments, including adjustments related to periods of dose holds (i.e., 
IRT assignment of a 0-dose), the second time excluding dose adjustments related to 
periods of dose hold. 
The number and percentage of subjects with 0, 1, 2, …, 10, or >10 dose adjustments will 
be summarized by treatment group. Summaries will be presented for the following 
categories of time: Day 1 – < Week 28, Week 28 – <Week 52, and Day 1 – < Week 52. 
The number of dose adjustments per subject will be summarized using mean, standard 
deviation, minimum, P25, median, P75, and maximum by treatment group. Summaries 
will be presented for the following categories of time: Day 1 – < Week 28, Week 28 – 
<Week 52, and Day 1 – < Week 52. 
The time (in days) that study treatment was withheld for Hgb values  12 g/dL per 
subject will be summarized for all subjects and for subjects who had a dose hold using 
mean, standard deviation, minimum, P25, median, P75, and maximum by treatment 
group. Summaries will be presented for the following categories of time: Day 1 – < Week 
28, Week 28 – <Week 52, and Day 1 – < Week 52. 
Summary tables for the dose adjustment scheme endpoints will also be repeated for the 
following subgroups (see Section 10.10.1 for subgroup definitions): 
• Dialysis type at randomization 
• Dialysis start manner 
• Baseline weight quartiles 
The median most recent dose by treatment and visit will be displayed graphically for each 
scheduled study visit using a line plot. The line plot of median most recent dose along 
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with the first and the third quartiles by time will include vertical reference lines to 
identify the EP as well as the number of subjects by treatment group contributing to each 
median value. This plot will be overlaid on a graph of corresponding mean Hgb values by 
visit 
8.2. 
Safety Analyses 
8.2.1. 
Secondary Safety Analyses 
8.2.1.1. 
Overview of Planned Secondary Safety Analyses 
Table 8 provides an overview of the planned secondary safety analyses. 
Table 8 
Overview of Planned Secondary Safety Analyses 
Endpoint 
Analysis 
Population 
Absolute 
Change from Baseline 
Stats 
Analysis 
Summary Individual 
Stats 
Analysis 
Summary Individual 
T F L 
T 
F 
F 
L 
T F L 
T 
F 
F 
L 
Blood Pressure 
SBP, DBP and 
MAP changes 
from Baseline1,2 
ITT 
 
 
 
Y 
Y 
 
 
Y 
 
 
Y 
Y 
 
 
Number of BP 
exacerbation 
events per 100 
patient years2 
ITT 
Y 
 
 
Y 
 
 
 
 
 
 
 
 
 
 
Subjects 
experiencing at 
least one BP 
exacerbation 
event during 
study2 
ITT 
Y 
 
 
Y 
 
 
 
 
 
 
 
 
 
 
NOTES : 
• 
T = Table, F = Figure, L = Listing, Y = Yes display generated. 
• 
Stats Analysis = Represents TFL related to any formal statistical analyses (i.e. modelling) conducted. 
• 
Summary = Represents TFL related to any summaries (i.e. descriptive statistics) of the observed raw data. 
• 
Individual = Represents FL related to any displays of individual subject observed raw data. 
[1] Analysis will be performed using all available (on and off treatment) BP values. 
[2] Analysis will be performed using on-treatment BP values only. 
8.2.1.2. 
Planned Secondary Safety Statistical Analyses 
Secondary Safety Statistical Analyses: Blood Pressure 
Endpoint(s) 
• Change from baseline in SBP, DBP and MAP at Week 52 and at end of treatment 
• Number of BP exacerbation events per 100 patient years  
• N (%) of subjects with at least one BP exacerbation event during study 
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Secondary Safety Statistical Analyses: Blood Pressure 
Model Specification 
• The difference in change from baseline in BP (SBP, DBP, and MAP) at Week 52 will be 
analyzed with a mixed model repeated measures (MMRM) approach with an unstructured 
covariance matrix to compare the difference in means between arms. The models will be 
fitted to scheduled BP data collected after baseline up to Week 52. Models will be run two 
times: 
o On-treatment BP values only, excluding values collected during the stabilization 
period (Randomization date + 1 day to <Week 28). 
o On-treatment BP values only, including values collected during the stabilization 
period. 
The models will include factors for treatment, time, prognostic randomization stratification 
factors (see Section 0), baseline BP parameter and the baseline BP parameter by time and 
treatment by time interaction terms. Analyses will be done with the MIXED procedure in 
SAS, using the Kenward-Roger option to estimate denominator degrees of freedom and 
standard errors. For analyses using on- and off-treatment values, subjects who withdraw 
from the study before Week 52 are considered to be missing at random and in the analysis 
using on-treatment values only, subjects who permanently discontinue randomized 
treatment before Week 52 are assumed to be missing at random. 
• The difference in change from baseline in BP (SBP, DBP, and MAP) at the derived end of 
treatment (see Section 10.6.4) will be analyzed with an ANCOVA model including terms for 
treatment, prognostic randomization stratification factors (see Section 0) and the 
corresponding baseline BP parameter. This analysis will be performed using on-treatment 
BP values only. 
• The number of on-treatment BP exacerbation events per 100 patient years will be calculated 
(see Section 10.6.4). Confidence intervals for the rate per 100 patient years will also be 
reported. For within group rates and the ratio of model estimated exacerbation rates,, the 
point estimates, two-sided 95% confidence intervals, and one-sided p-value for the 
treatment group comparison  will be obtained using a negative binomial model with 
treatment and the prognostic randomization strata as covariates and the logarithm of time 
on-treatment as an offset variable. 
Model Results Presentation 
• BP parameter values (SBP, DBP, and MAP) will be summarized using mean, standard 
deviation, minimum, P25, median, P75, and maximum at each visit by treatment group. In 
addition to scheduled visits, the derived baseline value and end of treatment values will be 
summarized (see Section 10.6.4). Summaries of on-treatment BP values only and on- and 
off-treatment BP values together will be produced. A summary of on-treatment BP values by 
baseline dialysis type will be produced. On-treatment BP parameter values will be plotted by 
visit using a line plot. 
• BP parameter change from baseline values (SBP, DBP, and MAP) will be summarized using 
mean, standard deviation, minimum, P25, median, P75, and maximum at each post-
baseline visit by treatment group. In addition to scheduled visits, the derivedend of treatment 
values will be summarized (see Section 10.6.4). Summaries of on-treatment BP values only 
and on- and off-treatment BP values together will be produced. A summary of change from 
baseline in on-treatment BP parameter values by baseline dialysis type will be produced. 
On-treatment BP parameter change from baseline values will be plotted by visit using a line 
plot. 
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Secondary Safety Statistical Analyses: Blood Pressure 
• For the MMRM analyses of change from baseline in BP parameters to Week 52, an 
LSMEANS statement will provide adjusted treatment group means and standard errors and 
a point estimate and two-sided 95% confidence interval for the adjusted mean treatment 
difference (daprodustat - darbepoetin alfa) and a one-sided superiority p-value for this test. 
• For the ANCOVA analyses of change from baseline in BP parameters to the derived end of 
treatment, the adjusted mean estimates and standard errors by treatment group, adjusted 
mean difference, two-sided 95% CI and one-sided superiority p-value for the difference in 
BP parameter between the daprodustat and darbepoetin alfa arms from the ANCOVA model 
will be presented. The number of subjects contributing to the analysis and the associated 
mean and standard deviation of the baseline and end of treatment values will also be 
displayed with the results of the ANCOVA model. 
• The model estimated on-treatment BP exacerbation rates per 100 patient years and 
associated 95% confidence intervals will be provided by treatment group. The ratio of model 
estimated on-treatment BP exacerbation rates and associated two-sided 95% confidence 
interval and one-sided p-value will also be provided for the comparison of daprodustat vs. 
darbepoetin alfa.  
• On-treatment BP exacerbations will be summarized as follows: The number and percent of 
subjects with 0, 1, 2, 3, 4, 5 and >5 on-treatment BP exacerbations will be provided by 
treatment group. Additionally, the number and percent of subjects with on-treatment BP 
exacerbations and number of on-treatment BP exacerbation events will be provided by 
treatment group, in total and by BP exacerbation type (see Section 10.6.4). The total 
treatment exposure in years and overall on-treatment BP exacerbation rate per 100 PY will 
be provided by treatment group. 
o The BP exacerbation summary above will be repeated for the following groups 
and BP values: 
▪ All subjects, on-treatment post-dialysis BP values only 
▪ All subjects, on-treatment pre-dialysis BP values only 
▪ Hemodialysis subjects, all on-treatment BP values 
▪ Hemodialysis subjects, on-treatment post-dialysis BP values only 
▪ Peritoneal dialysis subjects, on-treatment post-dialysis BP values only 
Model Results Interpretation 
• One-sided p-values will be compared to 0.025 to assess nominal significance. 
 
8.2.2. 
Exploratory Safety Analyses 
8.2.2.1. 
Overview of Planned Exploratory Safety Analyses 
Table 9 provides an overview of the planned exploratory safety analyses.
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Table 9 
Overview of Planned Exploratory Safety Analyses 
Endpoint 
Analysis 
Population 
Absolute 
Change from Baseline 
Summary 
Individual 
Summary 
Individual 
T 
F 
F 
L 
T 
F 
F 
L 
BP and BP Medication Changes 
SBP, DBP and MAP by visit 
ITT 
 
Included with BP secondary analyses (Section 8.2.1) 
 
SBP, DBP, and MAP change from baseline to 
last record prior to change in BP medications1 
ITT 
 
 
 
 
Y 
 
 
 
Number of BP medications per subject by visit1 
ITT 
Y 
 
 
 
 
 
 
 
CFB in number of BP medications per subject by 
visit1 
ITT 
 
 
 
 
Y 
 
 
 
Number (%) of subjects who had no change, an 
increase or a decrease in dosage or number of 
BP medications from baseline by visit1 
ITT 
Y 
 
 
 
 
 
 
 
Lipid Parameters 
Lipid parameters by visit (TC, LDL-C, HDL-C) 
ITT 
Y 
Y 
 
 
Y 
 
 
 
NOTES : 
• 
T = Table, F = Figure, L = Listing, Y = Yes display generated. 
• 
Summary = Represents TFL related to any summaries (i.e. descriptive statistics) of the observed raw data. 
• 
Individual = Represents FL related to any displays of individual subject observed raw data. 
[1]: Summary will include on-treatment BP values or BP medications taken while the subject was on treatment only. 
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8.2.2.2. 
Planned Exploratory Safety Display Details 
Blood Pressure 
The last on-treatment BP parameter change from baseline value (SBP, DBP, and MAP) 
recorded prior to the first change in BP medications will be summarized using mean, 
standard deviation, minimum, P25, median, P75, and maximum by treatment group. The 
first change in blood pressure medication occurs at the earliest time a new anti-
hypertensive medication is administered or if the dose or frequency of an existing blood 
pressure medication is changed for any reason (increased, decreased, discontinued, or 
switched to another agent) in any anti-hypertensive medication, except medication 
records with frequencies of “Once only” and “PRN.”  
Number of BP medications per subject while the subject was on treatment will be 
summarized using mean, standard deviation, minimum, P25, median, P75, and maximum 
for each scheduled visit by treatment group. Number of BP medications for each subject 
at baseline is defined as the number of medications taken on the day before randomized 
treatment start date.  For end of treatment, it is defined as the number of medications 
taken on last non-zero dose date + 1 day. The number of BP medications at all other 
nominal visits is defined as the number of medications taken on the day of the visit.  
Medication records with frequencies of “Once only” and “PRN” will be excluded from 
this summary.   
Change from baseline in the number of BP medications per subject while the subject was 
on treatment will be summarized using mean, standard deviation, minimum, P25, median, 
P75, and maximum for each scheduled visit by treatment group.  The number of BP 
medications at baseline, end of treatment and all other nominal visits will be defined as 
described in the previous paragraph. Medication records with frequencies of “Once only” 
and “PRN” will be excluded from this summary.  
Additionally, the number and percentage of subjects who had no change, at least one 
change, an increase, a decrease or a switch in the dosage or number of BP medications 
from baseline while the subject was on treatment will be summarized for each scheduled 
post-baseline visit by treatment group (see Section 10.6.4 for details of classifying BP 
medication changes). Medication records with frequencies of “Once only” and “PRN” 
will be excluded from this summary.   
Cumulative number of changes in on-treatment BP medications from baseline to Week 
52 will be summarized by treatment group. For all records except with frequencies “Once 
only” and “PRN,” the cumulative number of changes will be summarized using mean, 
standard deviation, minimum, P25, median, P75, and maximum. The number of 
percentage of subjects with no change and at least one medication change will be 
displayed excluding “Once only” and “PRN” records.  For subjects with at least one 
change, the number and percentage of subjects for each reason (increase, decrease, and 
switch) will be displayed (see Section 10.6.4 for details of counting BP medication 
cumulative changes) by treatment group. Number and percentage of subjects for each 
reason of BP medication change will be displayed by treatment group. Cumulative 
number of changes in on-treatment BP medication from baseline to Week 52 for “Once 
only” records only will be summarized using mean, standard deviation, minimum, P25, 
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median, P75, and maximum (see Section 10.6.4 for details of counting BP medication 
cumulative changes) by treatment group. 
Number and percentage of subjects with at least one PRN record at baseline and on-
treatment BP medication during the period from randomized treatment start date to Week 
52 will be displayed by treatment group.  
Number and percentage of subjects with any BP medication taken at baseline (the day 
before randomized treatment start date) and any on-treatment BP medication during the 
period from randomized treatment start date to Week 52 will be displayed by treatment 
group.  
Lipid Parameters 
Lipid parameter values for this study include total cholesterol, LDL-C (direct) and HDL-
C. These values are collected according to the schedule outlined in the Time and Events 
table (see Section 10.2.1). Lipid parameter values follow the derivation guidelines for 
laboratory values outlined in Section 10.6.4. The summaries described below will include 
summaries in both SI units and conventional units for each of the lipid parameters and 
will summarize log-transformed values. 
Total cholesterol, LDL-C (direct), and HDL-C on-treatment values will be summarized 
using geometric mean, CV, minimum, P25, median, P75, and maximum for each 
scheduled visit by treatment group.  
Percent change from baseline in log-transformed on-treatment total cholesterol, LDL-C 
(direct), and HDL-C values will be summarized using percent change geometric mean, 
95% confidence interval, minimum, P25, median, P75, and maximum for each scheduled 
visit by treatment group. 
8.2.2.3. 
Overview of Exploratory Cardiovascular Safety Analysis 
Table 10 provides an overview of exploratory cardiovascular safety analyses. 
Table 10 
Overview of Exploratory Cardiovascular Safety Analyses 
Endpoint1 
Analysis 
Population 
Absolute 
Stats Analysis 
Summary 
Individual 
T 
F 
L 
T 
F 
F 
L 
MACE 
ITT 
Y 
 
 
Y 
Y 
 
Y 
MACE or a thromboembolic event 
ITT 
Y 
 
 
Y 
 
 
 
MACE or hospitalization for HF 
ITT 
Y 
 
 
Y 
 
 
 
All-cause mortality 
ITT 
Y 
 
 
Y 
 
 
Y 
CV mortality 
ITT 
Y 
 
 
Y 
 
 
 
MI (fatal and non-fatal) 
ITT 
Y 
 
 
Y 
 
 
 
Stroke (fatal and non-fatal) 
ITT 
Y 
 
 
Y 
 
 
 
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Endpoint1 
Analysis 
Population 
Absolute 
Stats Analysis 
Summary 
Individual 
T 
F 
L 
T 
F 
F 
L 
CV mortality or non-fatal MI 
ITT 
Y 
 
 
Y 
 
 
 
All-cause hospitalization 
ITT 
Y 
 
 
Y 
 
 
 
NOTES : 
• 
T = Table, F = Figure, L = Listing, Y = Yes display generated. 
• 
Stats Analysis = Represents TFL related to any formal statistical analyses (i.e. modelling) conducted. 
• 
Summary = Represents TFL related to any summaries (i.e. descriptive statistics) of the observed raw data. 
• 
Individual = Represents FL related to any displays of individual subject observed raw data. 
 [1] Adjudicated events used where available. 
 
8.2.2.4. 
Planned Exploratory Cardiovascular Safety Analysis Details 
Exploratory CV Safety Analyses 
Endpoint(s)1: 
• MACE (all-cause mortality, non-fatal MI, or non-fatal stroke) 
• MACE or a thromboembolic event 
• MACE or hospitalization for HF 
• All-cause mortality 
• CV mortality  
• MI (fatal and non-fatal) 
• Stoke (fatal and non-fatal) 
• CV mortality or non-fatal MI 
• All-cause hospitalization 
Model Specification 
• For all exploratory CV endpoints, confidence intervals for the rate per 100 person-years will 
be reported. For within-group rates, the 95% CI will be obtained using an exact Poisson 
method. For difference in rates between treatments, the two-sided 95% CI will be 
constructed with a normal approximation using Walds’ method [Liu, 2006]. 
•  
• For MACE endpoint, the calculation of time-to-event or censoring is described in further 
detail in Section 10.6.4.1. 
• First occurrence of adjudicated MACE for a subject is defined as the first adjudicated event, 
determined by the event date, which is indicated as all-cause mortality, non-fatal MI or non-
fatal stroke with further details in Section 10.6.4.1. 
• For those endpoints or components of endpoints intended to go through the adjudication 
process, only the adjudicated results will be used. 
Model Results Presentation 
• A summary of the number and percentage of subjects having first-occurrence MACE will be 
provided by treatment group. The number and percentage of the types of events that make 
up the first occurrence of MACE will also be provided by treatment group. This summary 
table will be repeated for MACE plus thromboembolic events, for MACE plus hospitalization 
for heart failure and for MACE plus thromboembolic events or hospitalization for CHF. 
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Exploratory CV Safety Analyses 
• A summary of all MACE including the number and percentage of subjects and number of 
events (including first and subsequent MACE) by type of event will be provided by treatment 
group. 
• A summary of the number and percentage of subjects having first-occurrence adjudicated 
COVID-19 MACE will be provided by treatment group. The number and percentage of the 
types of events that make up the first occurrence of adjudicated COVID-19 MACE will also 
be provided by treatment group. 
• Summaries of adjudication details of all-cause mortality will include the number and 
percentage of subjects by cause of death. 
• Summaries of adjudication details of MI will include the number and percentage of events by 
outcome of MI (fatal or non-fatal), type of MI, increased cardiac markers (y/n), ST segment 
classification [ST-elevation myocardial infarction (STEMI), non-ST-elevation myocardial 
infarction (NSTEMI), ECG not interpretable, ECG not available], and Q wave classification 
(Q wave MI, Non Q wave MI, ECG not interpretable, ECG not available). 
• Summaries of adjudication details of stroke will include the number and percentage of 
events by outcome of stroke (fatal or non-fatal), type of stroke (ischemic, hemorrhagic, or 
undetermined) and ischemic details (with/without hemorrhagic transformation) and location if 
hemorrhagic (intraparenchymal, intraventricular, subarachnoid, retinal, unknown location). 
• Summaries of adjudication details of heart failure will include the number of events by type: 
hospitalization for heart failure, heart failure requiring urgent ER/ED visit, heart failure 
requiring urgent office/practice visit, and fatal heart failure events identified by cause of 
death only. 
• Summaries of adjudication details of thromboembolic events will include the number and 
percentage of events by type of thromboembolic event (DVT, PE, VAT).  
o Summaries of PEs will include outcome of PE (fatal or non-fatal). 
o Summaries of VATs will include type of VAT (AV fistula, AV graft, central 
venous catheter, other), method of diagnosis (ultrasound/Doppler, AV imaging, 
CVC imaging, other), and treatment (thrombolytic therapy, thrombectomy, 
angioplasty, stent, surgical intervention, not specified). 
• A summary of adjudicated exploratory CV endpoints above (except all-cause hospitalization) 
will be provided to include the number and percentage of subjects and the number of events 
for each endpoint. 
• The model results presentation for the endpoints above (except all –cause hospitalization) 
will be provided to include within-group incidence rates per 100 person-years (along with 
two-sided 95% CI), and difference in rates between treatments (along with two-sided 95% 
CI), For composite endpoints, the number and percentage of the type of first occurrence will 
be provided by treatment group. 
• A summary of all-cause hospitalization will be provided by treatment group including 
summaries of the number of hospitalizations per subject, average length of stay per 
hospitalization and primary diagnosis at discharge by system organ class and lower level 
term. 
• Time from Randomization to first occurrence of adjudicated MACE event or end of trial will 
be evaluated using Kaplan-Meier (KM) methodology and displayed graphically for the 
comparison of daprodustat vs. darbepoetin alfa. 
• • 
Summary of concordance between events referred for adjudication and adjudicated 
endpoint events (Positively Adjudicated or Negatively Adjudicated) will be presented. 
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Exploratory CV Safety Analyses 
• A listing of all MACE events occurring during the study will be provided and will include 
treatment, site ID, unique subject ID, select demographic information, event type, event 
date, and study day. 
• A listing of all all-cause mortality events that occur during the study will be provided. This 
listing will include treatment, site ID, unique subject ID, select demographic information, 
event date, study day, and cause of death. 
[1] Adjudicated events used where available. 
8.2.3. 
Adverse Event Safety Analyses 
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) coding dictionary. For the purpose of AE summaries and analysis, the 
investigator-reported AE details will be used, regardless of the adjudication outcome of 
the event. 
See Section 10.4.1 for AE treatment state definitions. The adverse event safety analyses 
will be based on the Safety population, unless otherwise specified. 
8.2.3.1. 
Overview of Planned Adverse Event Analyses 
Table 11 provides an overview of the planned adverse event safety analyses. 
Table 11 
Overview of Planned Adverse Event Safety Analyses 
Parameter 
Absolute 
Summary 
Individual 
T 
F 
F 
L 
AESIs 
Summary of AESIs 
Y 
Y 
 
 
Adverse Events 
All AEs by System Organ Class (SOC) and Preferred Term 
Y 
 
 
Y 
All AEs by System Organ Class (SOC) and Preferred Term (subjects 
and occurrences) 
Y 
 
 
 
All AEs by SOC and Preferred Term by Subgroups 
Y 
 
 
 
All AEs by Overall Frequency 
Y 
 
 
 
Common AEs by Overall Frequency 
Y 
Y1 
 
 
All AEs by Maximum Intensity 
Y 
 
 
 
All Drug-Related AEs by Maximum Intensity 
Y 
 
 
 
All Drug-Related AEs by SOC and Preferred Term 
Y 
 
 
 
Common Non-Serious AEs by SOC and Preferred Term (subjects and 
occurrences) 
Y 
 
 
 
Subject Numbers for Individual AEs 
 
 
 
Y 
Relationship Between AE SOCs, Preferred Term & Verbatim Text 
 
 
 
Y 
Pregnancy Data 
 
 
 
Y 
Serious and Other Significant Adverse Events 
SAEs by SOC and Preferred Term (subjects and occurrences) 
Y 
 
 
 
SAEs by Maximum Intensity 
Y 
 
 
 
Reasons for Considering as a SAE 
 
 
 
Y 
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Parameter 
Absolute 
Summary 
Individual 
T 
F 
F 
L 
Drug-Related SAEs by SOC and Preferred Term (subjects and 
occurrences) 
Y 
 
 
 
Fatal SAEs by SOC and Preferred Term (subjects and occurrences) 
Y 
 
 
Y 
Non-Fatal SAEs by SOC and Preferred Term (subjects and 
occurrences) 
Y 
 
 
Y 
Drug-Related Fatal SAEs by SOC and Preferred Term (subjects and 
occurrences) 
Y 
 
 
 
AEs Leading to Permanent Discontinuation of Randomized Treatment 
by SOC and Preferred Term 
Y 
 
 
Y 
BP Exacerbation Events 
Y 
 
 
 
BP Exacerbation SAEs 
Y 
 
 
 
Other Significant AEs 
 
 
 
Y 
NOTES : 
• 
T = Table, F = Figure, L = Listing, Y = Yes display generated. 
• 
Summary = Represents TFL related to any summaries (i.e. descriptive statistics) of the observed raw data. 
• 
Individual = Represents FL related to any displays of individual subject observed raw data. 
[1]: Plot of common AEs and relative risk will be generated. 
 
8.2.3.2. 
Planned Adverse Event Safety Statistical Analyses 
AESIs Analyses 
Adverse events of special interest are described in Section 10.6.4.  
Summaries of AESIs will include the number, percentage and rate per 100 person-years 
of subjects having at least one occurrence, the number of events, the number of subjects 
by number of occurrence, the characteristics of the AE (serious, drug-related, etc.), 
outcome, maximum intensity, time to first onset/worsening, and action taken summarized 
by treatment group. For each count, a subject will be summarized as follows: 
• Serious/drug-related/severe/fatal: If any specific AE falls in the respective 
category, the subject will be counted in that category. 
• Outcome: The subject will be counted within a category if there is at least one 
specific AE in that category. 
• Maximum intensity: The specific AE with the maximum intensity will be counted 
for this purpose. For example, a subject will be counted in the ‘severe’ category if 
there is at least one specific AE with severe intensity. A subject will be counted in 
the ‘moderate’ category if there is at least one specific AE with moderate intensity 
and there is no specific AE with severe intensity. 
• Time to first onset/worsening (days): The earliest of onset dates for the specific 
AE – treatment start + 1 
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If the AE onset date/AE worsening and/or resolution date is missing or incomplete in the 
database for any occurrence of the specific AE, time to first onset /worsening will be left 
missing for the subject. These summaries of special interest AEs will be provided for 
those AEs classified as treatment emergent. 
Cumulative incidence function (CIF) plots may be produced for each AESI summarizing 
the time to first occurrence of the AESI by treatment group, with the exception of the 
composite endpoint AESI (death, myocardial infarction, stroke, heart failure, 
thromboembolic events, thrombosis of vascular access). This endpoint will use a Kaplan-
Meier plot. If there are less than 20 subjects total for both the daprodustat and 
darbepoetin alfa arm, then these plots will not be created. Competing risks for the AESI 
cumulative incidence plots include: 
AE of Special Interest (Event of interest) 
Competing Risk Events 
Thrombosis and/or tissue ischemia secondary 
to excessive erythropoiesis 
Death due to any cause prior to the AESI 
Cardiomyopathy 
Death due to any cause prior to the AESI 
Pulmonary artery hypertension 
Death due to any cause prior to the AESI 
Cancer-related mortality and tumor 
progression and recurrence 
All other non-cancer-related death prior to the 
AESI (use death date as the competing risk 
date) 
Esophageal and gastric erosions 
Death due to any cause prior to the AESI 
Proliferative retinopathy, macular edema, 
choroidal neovascularization 
Death due to any cause prior to the AESI 
Exacerbation of rheumatoid arthritis 
Death due to any cause prior to the AESI 
Worsening of hypertension 
Death due to any cause prior to the AESI 
 
Dot plots displaying the incidence of the event will be provided for AESIs by AESI term 
and treatment group. The incidence rate in each treatment group and corresponding two-
sided 95% confidence interval for the relative risk of the daprodustat group compared to 
the darbepoetin alfa group will be provided. 
Adverse Events 
The number and percentage of subjects reporting at least one AE will be provided for 
each treatment group. These events will be summarized by treatment group, primary 
system organ class, and preferred term. Pre-treatment and treatment emergent AEs will 
be summarized separately. 
The number and percentage of subjects and the number of occurrences of all treatment 
emergent AEs will be summarized by primary system organ class, and preferred term. 
Summaries of all treatment emergent AEs will be produced for the age group, gender, 
race group, baseline dialysis type, baseline dialysis start manner, and weight quartile 
subgroups. Summaries of treatment emergent AEs by subgroup will be produced twice: 
by system organ class and preferred term and separately by overall frequency. 
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A listing of AE records for all subjects who reported AEs will be produced. 
Summaries of all treatment emergent AEs will be provided by maximum intensity. For 
AEs reported more than once by a subject, the most severe intensity will be included in 
summaries where applicable. The max intensity will be presented as “Unknown” if 
Missing and/or N/A are the only available severity values. Analysis will be repeated for 
all drug-related treatment emergent AEs. 
The number and percentage of subjects reporting the most common treatment emergent 
AEs (those occurring in  5% of subjects in any treatment group) will be summarized by 
preferred term and treatment group.  
Additionally, the most common treatment emergent AEs will be summarized graphically 
by preferred term and treatment group. The incidence rate in each treatment group and 
corresponding two-sided 95% confidence interval for the relative risk of the daprodustat 
group compared to the darbepoetin alfa group will be provided. Displays will be sorted 
by magnitude of risk, from largest to smallest. 
The number and percentage of subjects reporting treatment emergent AEs assessed by the 
investigator to be related to the study drug will be summarized by treatment group, 
primary system organ class, and preferred term, and separately by overall frequency 
The number and percentage of subjects and the number of occurrences of common non-
serious treatment emergent adverse events (those occurring in  5% of subjects in any 
treatment group) will be summarized by primary system organ class, preferred term, and 
treatment group, and separately by overall frequency. 
A listing of which subjects reported specific adverse events will be produced. 
The hierarchical relationship between MedDRA SOCs, PTs and verbatim text will be 
listed for all adverse events. 
A listing of subjects who became pregnant while participating in the study will be 
provided. 
Serious and Other Significant Adverse Events 
The number and percentage of subjects and the number of occurrences of treatment 
emergent SAEs will be provided for each treatment group. These events will be 
summarized by treatment group, primary system organ class, and preferred term. 
Treatment emergent SAE preferred terms will also be summarized by treatment group 
and overall frequency. 
Summaries of treatment emergent SAEs will be provided by maximum intensity. 
A listing of reasons for considering as a SAE will be produced for all treatment emergent 
SAEs. 
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The number and percentage of subjects and the number of occurrences of treatment 
emergent drug-related SAEs, fatal SAEs, non-fatal SAEs, and drug-related fatal SAEs 
will be summarized by treatment group: by primary system organ class and preferred 
term and separately by overall frequency. 
A listing of treatment emergent fatal SAE records and a listing of treatment emergent 
non-fatal SAE records will be provided. 
The number and percentage of subjects reporting treatment emergent AEs leading to 
discontinuation of randomized treatment will be summarized by treatment group, primary 
system organ class, and preferred term. 
A listing of treatment emergent AEs leading to discontinuation of randomized treatment 
will be provided. 
BP events and BP-related SAEs are defined in Section 10.6.4. 
The number and percentage of subjects with at least one on-treatment BP event will be 
provided for each treatment group. In addition, this summary will include the number and 
percentage of subjects with at least one on-treatment BP event that is considered 
clinically significant and the number and percentage of subjects with at least one on-
treatment BP event that is considered to be symptomatic. 
The number and percentage of subjects reporting at least one treatment emergent BP-
related SAE will be provided for each treatment group. In addition, the number of on-
treatment BP-related SAEs will be summarized by treatment group, primary system 
organ class, and preferred term. 
A listing of other significant adverse events will be produced. Other significant adverse 
events are events that are not reported as fatal or serious but represent ICH-defined 
‘Other significant adverse events’ (i.e., marked haematological and other laboratory 
abnormalities and any adverse events that led to an intervention, including withdrawal of 
drug treatment, dose reduction, or significant additional concomitant therapy). For this 
study, other significant AEs will be defined as non-fatal non-serious AEs resulting in an 
action taken with study treatment of either ‘dose interrupted/delayed’ or ‘dose reduced’. 
Other CV Events 
GSK has identified other CV events of interest for all clinical studies. In this study, 
investigators will be required to fill out the specific CV event page of the eCRF for the 
following CV AEs and SAEs or any event that may potentially be one of the categories 
listed: 
• Arrhythmias 
• Pulmonary hypertension 
• Valvulopathy 
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• Revascularization 
Electronically generated patient profiles for subjects reporting these events will not be 
prospectively created. 
8.2.4. 
Clinical Laboratory Safety Analyses 
Clinical chemistry, hematology and other laboratory tests are assessed in this study 
according to the schedule outlined in the Time and Events table (see Section 10.2.1). The 
following tests will be summarized in clinical laboratory displays: 
Clinical 
Chemistry 
Alanine aminotransferase 
(ALT) 
Aspartate 
aminotransferase (AST) 
Bilirubin (total and 
direct/indirect) 
Potassium (serum) 
Blood urea nitrogen 
(BUN) 
Albumin 
Calcium (albumin 
corrected) 
Phosphate 
Creatinine (and eGFR CKD-
EPI) 
 
Hematology 
Platelet count 
RBC indices: 
Leukocyte (white blood cell) 
count with Differential 
Erythrocyte (red blood 
cell) count 
Mean corpuscular 
volume (MCV) 
Neutrophils (absolute and 
segmented) 
Reticulocyte count 
Mean corpuscular 
hemoglobin (MCH) 
Lymphocytes 
Hematocrit 
Mean corpuscular 
hemoglobin 
concentration (MCHC) 
Monocytes 
 
Erythrocytes (red cell) 
distribution width (RDW) 
Eosinophils 
 
 
Basophils 
 
Other 
Laboratory 
Tests 
 
Intact parathyroid 
hormone (iPTH) 
High-sensitivity C-
reactive protein (hsCRP) Vitamin B12 
Vitamin B9 
 
 
 
Summaries of central laboratory Hgb values, HemoCue Hgb values, iron parameter 
values (serum iron, ferritin, hepcidin, TIBC, TSAT), and lipid parameter values (total 
cholesterol, direct LDL-C, HDL-C) are included in earlier efficacy and safety sections 
and will not be included with clinical laboratory displays. However, these parameters 
may be included in PCI summaries. 
The clinical chemistry tests performed in this study include ALT, AST and bilirubin. In 
addition to being summarized with the clinical chemistry values, these laboratory values 
will be included in some of the Hepatobiliary (liver) displays. 
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In addition to the visits listed for the laboratory assessments in the Time and Events table 
(see Section 10.2.1), any of these assessments can be performed at an unscheduled/retest 
visit or at the follow-up visit at the discretion of the investigator. See Section 10.5.3 for 
handling of unscheduled values. The laboratory’s normal range values will be provided 
by the central laboratory and potential clinical importance thresholds are defined in 
Section 10.8.1. 
All of the tabular summaries described below will include summaries in SI units; 
conventional units will also be provided for the following laboratory tests: MCHC, 
albumin corrected calcium, creatinine, eGFR, phosphate, albumin, BUN, total 
cholesterol, LDL-C, HDL-C, and Vitamin B9. Conversions from SI units to conventional 
units are included in Section 10.6.4. Hemoglobin summaries will only use conventional 
mg/dL units. Summaries of reticulocytes will be provided for the total count and percent 
of total erythrocytes and summaries of neutrophils, lymphocytes, monocytes, eosinophils, 
and basophils will be provided for total counts and differentials (percent of total 
leukocytes). 
The clinical laboratory safety analyses will be based on the Safety population, unless 
otherwise specified. 
8.2.4.1. 
Overview of Planned Clinical Laboratory Safety Analyses 
Table 12 provides an overview of the planned clinical laboratory safety analyses. 
Table 12 
Overview of Planned Clinical Laboratory Safety Analyses 
Parameter 
Absolute 
Change from Baseline 
Summary 
Individual 
Summary 
Individual 
T 
F 
F 
L 
T 
F 
F 
L 
Clinical Chemistry 
Chemistry Values by Visit 
Y 
 
 
 
Y 
 
 
 
Worst Case Chemistry Results by PCI 
Criteria Post-Baseline Relative to Baseline 
Y 
 
 
 
 
 
 
 
Hematology 
Hematology Values by Visit 
Y 
 
 
 
Y 
 
 
 
Worst Case Hematology Results by PCI 
Criteria Post-Baseline Relative to Baseline 
Y 
 
 
 
 
 
 
 
Other Laboratory Tests 
Other Laboratory Values by Visit 
Y 
 
 
 
Y 
 
 
 
Worst Case Other Laboratory Results by PCI 
Criteria Post-Baseline Relative to Baseline 
Y 
 
 
 
 
 
 
 
Hepatobiliary (Liver) 
Liver Monitoring/Stopping Event Reporting 
Y 
 
 
 
 
 
 
 
Hepatobiliary Laboratory Abnormalities 
Y 
 
 
 
 
 
 
 
Medical Conditions for Subjects with Liver 
Stopping Events 
 
 
 
Y 
 
 
 
 
Substance Use for Subjects with Liver 
Stopping Events 
 
 
 
Y 
 
 
 
 
Scatter Plot of Maximum vs. Baseline for ALT 
 
Y 
 
 
 
 
 
 
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Parameter 
Absolute 
Change from Baseline 
Summary 
Individual 
Summary 
Individual 
T 
F 
F 
L 
T 
F 
F 
L 
Scatter Plot of Maximum ALT vs. Maximum 
Total Bilirubin 
 
Y 
 
 
 
 
 
 
All Laboratory 
All Laboratory Data for Subjects with Any 
Value of PCI 
 
 
 
Y 
 
 
 
 
All Laboratory Data 
 
 
 
Y 
 
 
 
 
Iron 
Worst Case Iron Results by PCI Criteria 
Post-Baseline Relative to Baseline 
 
 
 
Y 
 
 
 
 
 
 
 
 
 
 
 
 
 
NOTES : 
• 
T = Table, F = Figure, L = Listing, Y = Yes display generated. 
• 
Summary = Represents TFL related to any summaries (i.e. descriptive statistics) of the observed raw data. 
• 
Individual = Represents FL related to any displays of individual subject observed raw data. 
8.2.4.2. 
Planned Clinical Laboratory Safety Display Details 
Clinical Chemistry 
Continuous on-treatment values (see Section 10.4.1) will be summarized using mean, 
standard deviation, minimum, P25, median, P75, and maximum for each scheduled visit 
and for baseline and end of treatment (see Section 10.6.4) by treatment group.  
Continuous on-treatment change from baseline values will be summarized using mean, 
standard deviation, minimum, P25, median, P75, and maximum for each scheduled visit 
and for end of treatment (see Section 10.6.4) by treatment group.  
The number and percentage of subjects with on-treatment worst case laboratory results 
relative to PCI criteria (see Section 10.8.1) which are post-baseline relative to baseline 
will be summarized by laboratory test, category and treatment group. See Section 10.6.4 
for additional information on worst case values and PCI categories. 
Hematology 
The displays presented for clinical chemistry laboratory values will also be presented for 
the hematology laboratory tests listed in Section 8.2.4. 
Other Laboratory Tests 
The displays presented for clinical chemistry laboratory values will also be presented for 
the other laboratory tests listed in Section 8.2.4.. 
On-treatment hsCRP values will be log-transformed (see Section 10.5.2) and summarized 
using geometric mean, coefficient of variation, minimum, P25, median, P75, and 
maximum for each scheduled visit by treatment group. 
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Percent change from baseline in log-transformed (see Section 10.5.2) on-treatment 
hsCRP values will be summarized using geometric mean, 95% confidence interval, 
minimum, P25, median, P75, and maximum for each scheduled visit by treatment group. 
Hepatobiliary (Liver) 
Please refer to the protocol for details of liver chemistry stopping criteria. 
Liver monitoring/stopping events will be summarized by treatment group. 
Hepatobiliary laboratory abnormalities will be summarized by treatment group. 
Medical conditions for subjects with liver stopping events and substance use for subjects 
with liver stopping events will be listed. 
A scatter plot of maximum on-treatment ALT values versus baseline ALT values will be 
produced. 
A scatter plot of maximum on-treatment total bilirubin (xULN) versus maximum on-
treatment ALT (xULN) values will be produced. 
All Laboratory 
A listing of all laboratory data for subjects with on-treatment laboratory values outside of 
PCI criteria will be provided. 
A listing of all laboratory data will be provided. 
Iron parameters 
The number and percentage of subjects with on-treatment or post-treatment worst case 
laboratory results relative to PCI criteria (see Section 10.8.1) which are post-baseline 
relative to baseline will be summarized by laboratory test, category and treatment group. 
See Section 10.6.4 for additional information on worst case values and PCI categories. 
8.2.5. 
Vital Signs Analyses 
Vital signs are assessed in this study according to the schedule outlined in the Time and 
Events table (see Section 10.2.1) and include the following assessments: 
• Height 
• HR 
• Weight 
• Estimated Dry Weight 
Summaries and analyses of BP values are described in earlier safety sections and will not 
be included with vital signs summaries. However, BP values will be included in PCI 
summaries. 
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The vital signs analyses will be based on the Safety population, unless otherwise 
specified. 
8.2.5.1. 
Overview of Planned Vital Signs Analyses 
Table 13 provides an overview of the planned vital signs analyses. 
Table 13 
Overview of Planned Vital Signs Analyses 
Parameter 
Absolute 
Change from Baseline 
Summary 
Individual 
Summary 
Individual 
T 
F 
F 
L 
T 
F 
F 
L 
Vital Signs 
Vital Signs by Visit 
Y 
 
 
 
Y 
 
 
 
Summary of Worst Case Vital 
Signs Results by PCI Criteria 
Y 
 
 
 
 
 
 
 
All Vital Signs for Subjects with 
Any Value of Potential Clinical 
Importance 
 
 
 
Y 
 
 
 
 
NOTES : 
• 
T = Table, F = Figure, L = Listing, Y = Yes display generated. 
• 
Summary = Represents TFL related to any summaries (i.e. descriptive statistics) of the observed raw 
data. 
• 
Individual = Represents FL related to any displays of individual subject observed raw data. 
8.2.5.2. 
Planned Vital Signs Display Details 
Vital sign values will be summarized using mean, standard deviation, minimum, P25, 
median, P75, and maximum for each scheduled visit and for baseline and end of 
treatment by treatment group.  
Vital sign change from baseline values will be summarized using mean, standard 
deviation, minimum, P25, median, P75, and maximum for each scheduled visit and for 
end of treatment by treatment group.  
The number and percentage of subjects with on-treatment or post- treatment worst case 
vital sign results relative to PCI criteria (see Section 10.8.1) which are post-baseline 
relative to baseline will be summarized by test, category and treatment group. See 
Section 10.6.4 for additional information on worst case values and PCI categories. Pre-
dialysis BP values outside of the PCI range will be summarized separately.  
The difference between on-treatment post-dialysis weight and estimated dry weight will 
be summarized using mean, standard deviation, minimum, P25, median, P75, and 
maximum for each scheduled visit during the evaluation period and for baseline and end 
of treatment by treatment group. A corresponding line plot will be provided to display 
this data graphically. 
A listing of all vital signs data for subjects with on-treatment vital signs values outside of 
PCI criteria will be provided. 
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8.2.6. 
Electrocardiograms 
Electrocardiograms (ECGs) will be read locally and ECG data will not be included in 
summary tables or individual subject listings.  
8.2.7. 
Pregnancies 
A listing of all subjects who became pregnant during the study will be included. 
8.2.8. 
Other Safety Analyses 
Medical Conditions 
A listing of all medical conditions for all subjects will be provided by treatment group. 
Each subject’s corresponding medical condition(s) will be provided using the medical 
history free text.   
COVID-19 Analyses 
The following COVID-19 related displays will be provided. 
A summary of the number and percentage of subjects for the following assessments will 
be produced:  Case Diagnosis, COVID-19 Test performed, and Results of the COVID-
19 test. 
A summary of exposure adjusted incidence rates over time (see Section 10.6.4) will be 
produced by treatment group for any treatment emergent AE, any treatment emergent 
SAE, and any treatment emergent Severe AE, for two periods – pre COVID-19 pandemic 
and during COVID-19 pandemic. The summary will be produced overall, by Country, 
Region, Sex, and by Age at randomization (Grouping 2) (see Section 10.10.1). A 
summary of exposure adjusted incidence rates by treatment group will also be produced 
for Common (>5%) AEs for two periods – pre COVID-19 pandemic and during COVID-
19 pandemic. 
 
8.3. 
Pharmacokinetic Analyses 
8.3.1. 
Overview of Planned Pharmacokinetic Analyses 
The pharmacokinetic (PK) analyses will be based on the “Pharmacokinetic” population, 
unless otherwise specified. 
Table 14 provides an overview of the planned analyses.  
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Table 14 
Overview of Planned Pharmacokinetic Analyses for GSK1278863, 
and/or GSK2391220 (M2), GSK2506104 (M3) and GSK2531401 (M13) 
Parameter 
Untransformed 
Log-Transformed 
Stats 
Analysis 
Summary Individual 
Stats Analysis 
Summary Individual 
T 
F 
L 
T 
F 
F 
L 
T 
F 
L 
T 
F 
F 
L 
GSK1278863, GSK2391220 (M2), GSK2506104 (M3) and GSK2531401 (M13) 
GSK1278863 and 
Metabolites Plasma 
Pharmacokinetic 
Concentration Time 
Data (ng/mL) by 
Treatment 
 
 
 
Y 
Y1 
Y 
Y 
 
 
 
 
Y1 
Y 
 
GSK1278863 and 
Metabolites Plasma 
Pharmacokinetic 
Parameter2 Data 
 
 
 
Y 
 
 
Y 
 
 
 
Y 
 
 
 
GSK1278863 
GSK1278863 Dose 
Parameter Data 
 
 
 
Y 
 
 
Y 
 
 
 
 
 
 
 
GSK1278863 Special 
Parameter3 Data 
 
 
 
Y 
 
 
Y 
 
 
 
Y 
 
 
 
NOTES : 
• 
T = Table, F = Figure, L = Listings, Y = Display generated. 
• 
Stats Analysis = Represents TFL related to any formal statistical analyses (i.e. modelling) conducted. 
• 
Summary = Represents TFL related to any summaries (i.e. descriptive statistics) of the observed raw data. 
• 
Individual = Represents FL related to any displays of individual subject observed raw data.     
1. 
Mean and median plots will be generated 
2. 
Cmax, Tmax, Ctau 
3. 
Ctau/1mg Dose, Ctau/avg Dose EP TIR, Ctau/avg Dose EP, Ctau/ Dose at MACE, Ctau/ Final Dose for subjects 
without MACE, Ctau/ Dose at MACE++, Ctau/ Final Dose for subjects without MACE++, Cmax/1mg Dose, 
Cmax/avg Dose EP TIR, Cmax/avg Dose EP, Cmax/ Dose at MACE, Cmax/ Final Dose for subjects without MACE, 
Cmax/ Dose at MACE++, Cmax/ Final Dose for subjects without MACE++ 
8.3.2. 
Drug Concentration Measures 
Refer to Appendix 5: Data Display Standards & Handling Conventions (Section 10.5.3 
Reporting Process & Standards). 
8.3.3. 
Pharmacokinetic Parameters 
8.3.3.1. 
Deriving Pharmacokinetic Parameters 
• Refer to Appendix 5: Data Display Standards & Handling Conventions (Section 
10.5.3 Reporting Process & Standards). 
• The pharmacokinetic parameters of parent GSK1278863, and metabolites 
(GSK2391220 (M2), GSK2506104 (M3), and GSK2531401 (M13)) will be 
calculated by programming methods. 
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• All calculations of non-compartmental parameters will be based on actual sampling 
times. 
• Pharmacokinetic parameters described in Table 15 will be determined from the 
plasma concentration-time data, as data permits. 
Table 15 
Derived Pharmacokinetic Parameters for GSK1278863, and/or 
GSK2391220 (M2), GSK2506104 (M3) and GSK2531401 (M13) 
Parameter 
Parameter Description 
GSK1278863, GSK2391220 (M2), GSK2506104 (M3) and GSK2531401 (M13) 
Tmax 
Time to reach Cmax, determined directly from the concentration-time data. 
Ctau 
Observed concentration at dosing interval (tau=24 h, predose sample)  
Cmax 
Maximum observed concentration, determined directly from the concentration-time 
data. 
GSK1278863 
Avg Dose 
during EP TIR 
The average daily GSK1278863 dose when the subject is on-treatment and in target 
Hgb range during the evaluation period (EP) Weeks 28-52 (see Section 10.6.3.1). 
Evaluable Hgb values are used to determine time in range. Subjects who permanently 
stop randomized treatment before the beginning of the EP, and subjects who have 0% 
time in range (e.g., subjects who have an evaluable Hgb below or above range for the 
entire EP) will have a missing value for this parameter. 
Avg Dose EP 
The average daily GSK1278863 dose when the subject is on-treatment during the EP. 
Dose at first 
MACE 
The daily GSK1278863 dose at the time of the subject’s first on-treatment adjudicated 
MACE. If the subject does not have an on-treatment adjudicated MACE, this value is 
missing. 
Final Dose for 
Subjects 
without MACE 
For subjects without an on-treatment adjudicated MACE, this is the subject’s final 
GSK1278863 dose during the study. 
Dose at first 
MACE++ 
The daily GSK1278863 dose at the time of the subject’s first on-treatment adjudicated 
MACE++ (defined as the first adjudicated MACE, hospitalization for heart failure, or 
thromboembolic event) If the subject does not have an on-treatment adjudicated 
MACE++, this value is missing. 
Final Dose for 
Subjects 
without 
MACE++ 
For subjects without an on-treatment adjudicated MACE++, this is the subject’s final 
GSK1278863 dose during the study. 
Ctau/1mg 
Dose 
Ctau extrapolated to 1mg dose: Observed Ctau divided by dose administered on the 
PK day 
Ctau/Avg 
Dose EP TIR 
Ctau extrapolated to average dose during EP TIR: Ctau/1mg multiplied by the average 
daily GSK1278863 dose when the subject is on-treatment and in target Hgb range 
during Weeks 28-52 (see Section 10.6.3.1). Evaluable Hgb values are used to 
determine time in range. 
Ctau/Avg 
Dose EP 
Ctau extrapolated to average dose during EP: Ctau/1mg multiplied by the average daily 
GSK1278863 dose during the EP. 
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Parameter 
Parameter Description 
Ctau/Dose at 
first MACE 
Ctau extrapolated to dose at first on-treatment adjudicated MACE: Ctau/1mg multiplied 
by the daily GSK1278863 dose at the time of the subject’s first on-treatment 
adjudicated MACE. 
Ctau/Final 
Dose for 
subjects 
without MACE 
For subjects without an on-treatment adjudicated MACE, this is the subject’s Ctau/1mg 
multiplied by the subject’s final daily GSK1278863 dose during the study. 
Ctau/Dose at 
first MACE++ 
Ctau extrapolated to dose at first on-treatment adjudicated MACE++: Ctau/1mg 
multiplied by the daily GSK1278863 dose at the time of the subject’s first on-treatment 
adjudicated MACE++. 
Ctau/Final 
Dose for 
subjects 
without 
MACE++ 
For subjects without an on-treatment adjudicated MACE++, this is the subject’s 
Ctau/1mg multiplied by the subject’s final daily GSK1278863 dose during the study. 
Cmax/1mg 
Dose 
Cmax extrapolated to 1mg dose: Observed Cmax divided by dose administered on the 
PK day 
Cmax/Avg 
Dose EP TIR 
Cmax extrapolated to average dose during EP TIR: Cmax/1mg multiplied by the 
average daily GSK1278863 dose when the subject is on-treatment and in target Hgb 
range during Weeks 28-52 (see Section 10.6.3.1). Evaluable Hgb values are used to 
determine time in range. 
Cmax/Avg 
Dose EP 
Cmax extrapolated to average dose during EP: Cmax/1mg multiplied by the average 
daily GSK1278863 dose during the EP. 
Cmax/Dose at 
first MACE 
Cmax extrapolated to dose at MACE: Cmax/1mg multiplied by the daily GSK1278863 
dose at the time of the subject’s first on-treatment adjudicated MACE. 
Cmax/Final 
Dose for 
subjects 
without MACE 
For subjects without an on-treatment adjudicated MACE, this is the subject’s 
Cmax/1mg multiplied by the subject’s final daily GSK1278863 dose during the study. 
Cmax/Dose at 
first MACE++ 
Cmax extrapolated to dose at MACE++: Cmax/1mg multiplied by the daily 
GSK1278863 dose at the time of the subject’s first on-treatment adjudicated MACE++. 
Cmax/Final 
Dose for 
subjects 
without 
MACE++ 
For subjects without an on-treatment adjudicated MACE++, this is the subject’s 
Cmax/1mg multiplied by the subject’s final daily GSK1278863 dose during the study. 
 
8.4. 
Pharmacokinetic / Pharmacodynamic Analyses 
• 
The primary goal of this analysis is to characterize the 
pharmacokinetic/pharmacodynamic relationship of parent GSK1278863 and efficacy 
and safety endpoints in the “Pharmacokinetic” population from this study. 
o The influence of subject demographics and baseline characteristics, including 
disease activity in this population may be investigated. 
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• A summary of the planned population pharmacokinetic/pharmacodynamic analyses 
are outlined below: 
o Relationships between drug exposure and selected efficacy, MACE and MACE 
++ events will be explored and characterized as data permit. The exposure will be 
estimated on the sparse PK collected in a sub-set of the study population. The data 
may be dose- extrapolated to the dose administered during the PK collection 
period. Any changes to the proposed analyses would be described in the CSR. 
Table 16 
Overview of Planned Pharmacokinetic / Pharmacodynamic Analyses 
for GSK1278863 
Parameter 
Untransformed 
Log-Transformed 
Stats 
Analysis 
Summary Individual 
Stats 
Analysis 
Summary Individual 
T 
F 
L 
T 
F 
F 
L 
T 
F 
L 
T 
F 
F 
L 
GSK1278863 
Scatter plot of % Time 
Evaluable Hgb in Range 
during EP vs. Avg Dose 
EP TIR 
 
 
 
 
 
Y 
 
 
 
 
 
 
 
 
Scatter plot of Evaluable 
Hgb Change from 
Baseline during EP vs. 
Avg Dose EP 
 
 
 
 
 
Y 
 
 
 
 
 
 
 
 
Scatter plot of % Time 
Evaluable Hgb in Range 
during EP vs. Ctau/Avg 
Dose EP TIR  
 
 
 
 
 
Y 
 
 
 
 
 
 
 
 
Scatter plot of Evaluable 
Hgb Change from 
Baseline during EP vs. 
Ctau/Avg Dose EP  
 
 
 
 
 
Y 
 
 
 
 
 
 
 
 
Boxplot of Ctau/Dose at 
On-treatment MACE or 
MACE++ by Subjects with 
or without On-treatment 
MACE or MACE++ 
 
 
 
 
 
Y 
 
 
 
 
 
 
 
 
Scatter plot of % Time 
Evaluable Hgb in Range 
during EP vs. Cmax/Avg 
Dose EP TIR 
 
 
 
 
 
Y 
 
 
 
 
 
 
 
 
Scatter plot of Evaluable 
Hgb Change from 
Baseline during EP vs. 
Cmax/Avg Dose EP 
 
 
 
 
 
Y 
 
 
 
 
 
 
 
 
Boxplot of Cmax/Dose at 
On-treatment MACE or 
MACE++ by Subjects with 
or without On-treatment 
MACE or MACE++ 
 
 
 
 
 
Y 
 
 
 
 
 
 
 
 
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NOTES : 
• 
T = Table, F = Figure, L = Listings, Y = Display generated. 
• 
Stats Analysis = Represents TFL related to any formal statistical analyses (i.e. modelling) conducted. 
• 
Summary = Represents TFL related to any summaries (i.e. descriptive statistics) of the observed raw data. 
• 
Individual = Represents FL related to any displays of individual subject observed raw data.     
8.5. 
Patient Reported Outcomes Analyses 
This study includes the following patient reported outcomes (PROs) that are assessed 
according to the schedule in the Time and Events table in Section 10.2.1   
• SF-36 
• EQ-5D-5L & EQ-VAS 
• PGI-S 
• PGI-C 
• CKD-AQ 
Additional details on these questionnaires can be found in Section 10.6.5. All analyses 
will use on-treatment values only unless otherwise specified. 
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8.5.1. 
Overview of Planned Patient Reported Outcomes Analyses 
Table 17 provides an overview of the planned patient reported outcomes analyses. 
Table 17 
Overview of Planned Patient Reported Outcomes Analyses 
Endpoint 
Analysis  
Population 
Absolute 
Change from Baseline 
Stats Analysis 
Summary 
Individual 
Stats Analysis 
Summary 
Individual 
T 
F 
L 
T 
F 
F 
L 
T 
F 
L 
T 
F 
F 
L 
HRQoL and Utility Scores  
SF-36 domain and component scores 
ITT 
 
 
 
Y 
 
 
 
Y 
Y 
 
Y 
 
 
 
EQ-5D-5L & EQ-VAS 
ITT 
 
 
 
Y 
 
 
 
Y 
Y 
 
Y 
 
 
 
Symptom Severity 
PGI-S score 
ITT 
 
 
 
Y 
 
 
 
Y 
Y 
 
Y 
 
 
 
PGI-S categories 
ITT 
 
 
 
 
 
 
 
 
 
 
Y 
 
 
 
PGI-C categories 
ITT 
 
 
 
Y 
 
 
 
 
 
 
 
 
 
 
CKD-AQ domain and single item 
scores 
ITT 
 
 
 
Y 
 
 
 
Y 
Y 
 
Y 
 
 
 
NOTES : 
• 
T = Table, F = Figure, L = Listing, Y = Yes display generated. 
• 
Stats Analysis = Represents TFL related to any formal statistical analyses (i.e. modelling) conducted. 
• 
Summary = Represents TFL related to any summaries (i.e. descriptive statistics) of the observed raw data. 
• 
Individual = Represents FL related to any displays of individual subject observed raw data. 
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8.5.2. 
Planned Patient Reported Outcomes Statistical Analyses 
8.5.2.1. 
HRQoL and Utility Score 
Patient Reported Outcomes Statistical Analyses: HRQoL and Utility Score 
Secondary Endpoints Endpoint(s) 
• Mean change in SF-36 HRQoL scores (PCS, MCS and 8 health domains) between baseline 
and Wk 8, 12, 28 and 52 of particular interest are the changes from baseline in the vitality 
and physical functioning domains at Wk 28 and 52. 
• Change from baseline in Health Utility (EQ-5D-5L) score at Week 52 
• Change from baseline in EQ VAS at Week 52 
Exploratory Endpoint(s) 
• Change from baseline in Health Utility (EQ-5D-5L) score at Weeks 8, 12 and 28.  
• Change from baseline in EQ VAS at Weeks 8, 12 and 28.  
Model Specification 
• Scoring for the SF-36 parameters and EQ-5D parameters is outlined in Section 10.6.5. 
• The mean change from baseline in SF-36 HRQoL scores (PCS, MCS, and 8 health 
domains), EQ-5D-5L score, and EQ-VAS score will be analyzed using an MMRM approach 
with an unstructured covariance matrix to compare the difference in means between arms. 
The models will be fitted to HRQoL data collected after baseline up to Week 52. The model 
will include factors for treatment, time, prognostic randomization stratification factors, 
baseline HRQoL parameter value and the baseline HRQoL parameter by time and treatment 
by time interaction terms. Analyses will be done with the MIXED procedure in SAS, using 
the Kenward-Roger option to estimate denominator degrees of freedom and standard errors. 
Model Results Presentation 
• SF-36 domain scores (PCS, MCS, and 8 health domains) will be summarized using mean, 
standard deviation, minimum, P25, median, P75, and maximum by treatment group at all 
scheduled visits. 
• Change from baseline in SF-36 domain scores (PCS, MCS, and 8 health domains) will be 
summarized using mean, standard deviation, minimum, P25, median, P75, and maximum by 
treatment group at all scheduled visits. 
• Bar graphs displaying mean change from baseline for the Week 8, 12, 28, and 52 visits for 
the SF-36 PCS, MCS, and 8 health domains will be provided by treatment group. 
• EQ-5D-5L responses will be summarized by dimension at all scheduled visits, including the 
derived end of treatment visit. 
• EQ-5D-5L and EQ-VAS scores will be summarized using mean, standard deviation, 
minimum, P25, median, P75, and maximum by treatment group at all scheduled visits, 
including the derived end of treatment visit. 
• Change from baseline in EQ-5D-5L and EQ-VAS scores will be summarized using mean, 
standard deviation, minimum, P25, median, P75, and maximum by treatment group at all 
scheduled visits, including the derived end of treatment visit. 
• Bar graphs displaying mean baseline and Week 52 visit scores for the EQ-5D-5L will be 
provided by treatment group. 
• For the MMRM analyses of change from baseline in HRQoL parameters, an LSMEANS 
statement will provide adjusted treatment group means and standard errors and a point 
estimate and two-sided 95% confidence interval for the adjusted mean treatment difference 
(daprodustat - darbepoetin alfa) and a one-sided superiority p-value for this test at Weeks 8, 
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Patient Reported Outcomes Statistical Analyses: HRQoL and Utility Score 
12, 28, and 52 for the SF-36 component scores and domains, and at Week 52 for the EQ-
5D-5L and EQ VAS.  
Model Results Interpretation 
• One-sided p-values will be compared to 0.025 to assess nominal significance. 
• Clinically meaningful effects for PRO assessments focused on metrics that would be needed 
for a reimbursement agency or health technology assessment agency will be specified in a 
separate supplemental RAP. 
Subgroup Analysis 
• Subgroup analyses will be performed for the change from baseline in the SF-36 PCS, MCS, 
vitality and physical functioning domains at Week 28 and 52 using the age and gender 
subgroups only (described in Section 10.10), in a method similar to that described for the 
subgroup analysis of the secondary Hgb change from baseline analyses. 
8.5.2.2. 
Symptom Severity & Change 
Patient Reported Outcomes Statistical Analyses: Symptom Severity & Change 
Secondary Endpoint(s) 
• Change from Baseline at Wk 52 by domain and single item on the CKD-AQ 
• Change from Baseline at Wk 8,12, 28, 52 in PGI-S 
Exploratory Endpoint(s) 
• Shift tables (Baseline to Weeks 8, 12, 28, and 52) in PGI-S 
• N(%) of subjects within each PGI-C symptom change level at Weeks 8, 12, 28, 52 
Model Specification 
• Scoring for the PGI-S, PGI-C, and CDK-AQ parameters is outlined in Section 10.6.5. 
• The mean change from baseline in PGI-S scores, CKD-AQ domain and single item scores will 
be analyzed using an MMRM approach with an unstructured covariance matrix to compare the 
difference in means between arms. The models will be fitted to data collected after baseline up 
to Week 52. The model will include factors for treatment, time, prognostic randomization 
stratification factors, the corresponding baseline score value (e.g. using baseline PGI-S score 
for PGI-S MMRM analysis) and the baseline score by time and treatment by time interaction 
terms. Analyses will be done with the MIXED procedure in SAS, using the Kenward-Roger 
option to estimate denominator degrees of freedom and standard errors. 
Model Results Presentation 
• PGI-S scores, CKD-AQ domain and single item scores will be summarized using mean, 
standard deviation, minimum, P25, median, P75, and maximum by treatment group at all 
scheduled visits. 
• Change from baseline in PGI-S values, CKD-AQ domain and single item scores will be 
summarized using mean, standard deviation, minimum, P25, median, P75, and maximum by 
treatment group at all scheduled visits. 
• Bar graphs displaying mean baseline and at visit values for the Week 8, 12, 28, and 52 visits 
for the CKD-AQ domain and single item scores will be provided by treatment group. 
• For the MMRM analyses of change from baseline in PGI-S, CKD-AQ domain and single item 
scores, an LSMEANS statement will provide adjusted treatment group means and standard 
errors and a point estimate and two-sided 95% confidence interval for the adjusted mean 
treatment difference (daprodustat - darbepoetin alfa) and a one-sided superiority p-value for 
this test at Weeks 8, 12, 28, and 52. 
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Patient Reported Outcomes Statistical Analyses: Symptom Severity & Change 
• Additionally, shift tables by treatment group will be generated that display the number and 
percentage of subjects in each PGI-S category at baseline and the resulting PGI-S category at 
each scheduled visit. 
• Stacked bar charts will be produced by treatment group that display the percentage of subjects 
with each PGI-S response at baseline and Weeks 8, 12, 28 and 52. 
• The number and percentage of subjects in each PGI-C category at each scheduled visit will be 
summarized. 
Model Results Interpretation 
• One-sided p-values will be compared to 0.025 to assess nominal significance. 
• Clinically meaningful effects for PRO assessments will be specified in a separate 
reimbursement RAP. 
8.6. 
Biomarker Analyses 
Blood samples will be collected as outlined in the Time and Events Table in Section 
10.2.1 for potential future analysis of CV risk, inflammation and iron metabolism. If 
biomarker analysis is pursued, details will be included in a separate RAP. 
8.7. 
Pharmacogenetics Analyses 
Blood samples will be collected as outline in the Time and Events Table in Section 10.2.1 
for potential future pharmacogenetics (PGx) analysis of the response to daprodustat 
(GSK1278863). If PGx analysis is pursued, details will be included in a separate RAP. 
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9. 
REFERENCES 
GlaxoSmithKline Document Number 2015N234534_01, 201410, 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, 06-OCT-2017 
GlaxoSmithKline Document Number 2015N230102_03, 200808, A phase 3 randomized, 
open-label (sponsor-blind), active-controlled, parallel-group, multicenter, event driven 
study in non-dialysis subjects with anemia associated with chronic kidney disease to 
evaluate the safety and efficacy of daprodustat compared to darbepoetin alfa (ASCEND-
ND). 12-OCT-2016 
GlaxoSmithKline Document Number Atlas IS 16443, GSK1278864, Evaluating the 
measurement properties of the chronic kidney disease and anemia questionnaire (CKD-
AQ) in two Phase 3 randomized open-label studies in patients with anemia associated 
with chronic kidney disease. 3-OCT-2018 
Iverson C, Christiansen S, Flanagin A, et al. AMA Manual of Style: A Guide for Authors 
and Editors. 10th ed. New York, NY: Oxford University Press; 2007. 
Kawaguchi A, Koch GG, Wang X. Stratified multivariate Mann-Whitey estimators for 
the comparison of two treatments with randomization based covariance adjustment. 
Statistics in Biopharmaceutical Research. 2011; 3 (2): 217-231. 
Liu GF, Wang J, Liu K, Snavely DB. Confidence intervals for an exposure adjusted 
incidence rate difference with applications to clinical trials. Statistics in Medicine 2006; 
25: 1275-1286. 
Liublinska V, Rubin DB. Sensitivity analysis for a partially missing binary outcome in a 
two-arm randomized clinical trial. Statistics in Medicine 2014; 33(24): 4170-4185. 
Rosendaal FR, Cannegieter SC, Van der Meer, FJM, and Briet, E. A Method to 
Determine the Optimal Intensity of Oral Anticoagulant Therapy. Thrombosis and 
Haemostasis. 1993; 69 (3): 236 – 239. 
Rubin DB. Multiple Imputation for Nonresponse in Surveys.  John Wiley & Sons, 1987. 
 
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10. 
APPENDICES 
Section 
Appendix 
RAP Section 4 : Analysis Populations 
Section 10.1 
Appendix 1: Protocol Deviation Management and Definitions for Per Protocol 
Population 
RAP Section 5 : General Considerations for Data Analyses & Data Handling Conventions 
Section 10.2 
Appendix 2: Time & Events 
Section 10.3 
Appendix 3: Assessment Windows 
Section 10.4 
Appendix 4: Treatment States and Phases 
Section 10.5 
Appendix 5: Data Display Standards & Handling Conventions 
• Study Treatment & Sub-group Display Descriptors 
• Baseline Definitions & Derivations 
• Reporting Process & Standards 
Section 10.6 
Appendix 6: Derived and Transformed Data 
• General 
• Study Population 
• Efficacy 
• Safety 
• Patient Reported Outcome 
Section 10.7 
Appendix 7: Premature Withdrawals & Handling of Missing Data 
• Premature Withdrawals 
• Handling of Missing Data 
Section 10.8 
Appendix 8: Values of Potential Clinical Importance 
• Laboratory Values 
• Vital Signs 
Section 10.9 
Appendix 9: Multicenter Studies 
• Methods for Handling Centres 
Section 10.10 
Appendix 10: Examination of Covariates, Subgroups & Other Strata 
• Handling of Covariates, Subgroups & Other Strata 
• Randomization Stratification 
Section 10.11 
Appendix 11: Multiple Comparisons & Multiplicity 
Section 10.12 
Appendix 12: Model Checking and Diagnostics for Statistical Analyses 
Other RAP Appendices 
Section 10.13 
Appendix 13: Abbreviations & Trade Marks 
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10.1. 
Appendix 1: Protocol Deviation Management and Definitions 
for Per Protocol Population 
10.1.1. 
Exclusions from Per Protocol Population 
Exclusions from the PP population include events that, if they should occur, might: 
• Directly impact the hemoglobin efficacy endpoint; or 
• Lead to permanent discontinuation of study treatment or study withdrawal and 
hence indirectly impact the efficacy endpoint by causing data to be missing. 
The following criteria define the events which, if they occur prior to the end of the EP, 
may lead to exclusion of a subject from the PP population. Exclusions from the PP 
Population will be subject to blinded review by the study team. The study team will also 
review the listing of unique concomitant medication terms to identify the prohibited 
medications. These reviews will occur before database has been unblinded for analysis. 
A subject meeting any of the following criteria will be excluded from the Per Protocol 
population: 
Number 
Exclusion Description 
01 
Baseline HemoCue Hgb value outside of Randomization (Day 1) Hgb entry criteria 
range  
02 
Less than 5 out of 7 scheduled evaluable1 Hgb values2 from the EP 
03 
Non-compliance with randomized treatment (compliance category of under 
compliant or over compliant) during the EP, based on eCRF randomized medication 
exposure and compliance forms 
04 
Inadequate iron status during EP, defined as ferritin  100 ng/mL on two 
consecutive scheduled visits or TSAT  20% on two consecutive scheduled visits 
05 
Subject received prohibited medication3 for more than two weeks during EP 
NOTES: 
1. See Section 10.6.3. 
2. Based on central laboratory Hgb values. If central laboratory Hgb value is missing, a non-missing 
HemoCue Hgb value will be used.  
3. Prohibited medications include strong inhibitors of CYP2C8 (e.g., gemfibrozil) and strong inducers of 
CYP2C8 (e.g., rifampin/rifampicin). 
 
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10.2. 
Appendix 2: Time & Events 
10.2.1. 
Protocol Defined Time & Events 
10.2.1.1. 
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 
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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 
Vitamin B121, folate 
X 
 
 
 
 
 
 
Hepcidin 
 
X 
 
X 
 
X 
 
X 
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 Protocol 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 Protocol 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 (Day 1). 
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 
Protocol Section 7.4.10. 
5. Additional visits to check Hgb and dispense randomized treatment are required under the circumstances described in Protocol 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 Protocol Appendix 5) during the study pregnancy tests are no longer required. 
9. Testing panel in Protocol Table 9. 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 Protocol 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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10.2.1.2. 
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 Protocol 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. 
 
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10.3. 
Appendix 3: Assessment Windows 
10.3.1. 
Assessment Windows 
Data for continuous variables that are not related to time-to-event will be summarized 
according to the scheduled visit time period for which they were recorded in the eCRF. 
Unscheduled assessments will not be slotted to a particular time point, but will remain as 
unscheduled if they are either summarized or listed unless otherwise specified (i.e. Hgb 
endpoints described in Section 10.6.3 and BP endpoints described in Section 10.6.4). 
 
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10.4. 
Appendix 4: Treatment States and Phases 
10.4.1. 
Treatment Phases 
Assessments and events will be classified according to the time of occurrence relative to 
treatment start and stop dates and last non-zero dose date (see Section 10.6.1). 
10.4.1.1. 
Treatment States for Hgb, Iron Parameters, IV Iron Dose Endpoints, 
Iron Use Summaries, Transfusion and PRO Data 
Treatment Phase 
Definition 
Pre-Treatment  
Date ≤ Treatment Start Date 
On-Treatment 
Treatment Start Date < Date ≤ Treatment Stop Date + 1 day 
Post-Treatment 
Date > Treatment Stop Date + 1 day 
Post-Randomization 
Randomization Date < Date 
NOTES:  
If the treatment stop date is missing and the treatment start date is non-missing and Date > Treatment Start Date, then 
the assessment will be considered to be On-Treatment 
10.4.1.2. 
Treatment States for CV Endpoint Data 
Treatment State 
Definition 
Pre-Treatment 
Date < Treatment Start Date 
On-Treatment 
Treatment Start Date  Date ≤ Last Non-Zero Dose Date + 28 days 
Post-Treatment 
Date > Last Non-Zero Dose Date + 28 days 
Post-Randomization 
Randomization Date  Date 
NOTES:  
• 
If the last non-zero dose date is missing and the treatment start date is non-missing and Date ≥ Treatment 
Start Date, then the assessment will be considered to be On-Treatment 
• 
Treatment state definitions use the imputed CV endpoint date 
10.4.1.3. 
Treatment States for BP, Lipid Parameters, Clinical Chemistry, 
Hematology, Other Laboratory Tests, Hepatobiliary (Liver) and Vital 
Signs Data 
Treatment State 
Definition 
Pre-Treatment 
Date ≤ Treatment Start Date 
On-Treatment 
Treatment Start Date < Date ≤ Last Non-Zero Dose Date + 1 day 
Post-Treatment 
Date > Last Non-Zero Dose Date + 1 day 
Post-Randomization 
Randomization Date < Date 
NOTES:  
• 
If the last non-zero dose date is missing and the treatment start date is non-missing and Date > treatment start 
date, then the assessment will be considered to be On-Treatment 
10.4.1.4. 
Treatment States for AE Data 
AEs are to be recorded on the eCRF from the start of randomization treatment until the 
Follow-up visit, at the timepoints specified in the Time and Events table from Section 
10.2.1. Serious AEs assessed as related to study participation or related to a GSK product 
are to be reported on the eCRF from the time a subject consents to participate in the study 
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up to and including any follow-up contact. AE of worsening of an on-going event will be 
counted once in a particular treatment state. 
 
Treatment 
State 
Definition 
Pre-Treatment 
• 
For subjects with a non-missing screen failure date, if AE onset is on or before the 
screen failure date: AE Start Date  Screen Failure Date 
• 
For randomized subjects with a missing treatment start date, all AEs are 
considered pre-treatment 
• 
For randomized subjects with a non-missing treatment start date, if AE onset date 
is before treatment start date: AE Start Date < Treatment Start Date 
Post-
Randomization 
If AE onset date or AE worsening date is on or after the randomization date 
Randomization date  AE Start Date 
Randomization date  AE Worsening Date 
AE worsening during post-randomization will be defined relative to the maximum 
intensity of AE prior to randomization date.  
AE worsening date is the first date in the post-randomization period, when AE 
intensity increased relative to the maximum intensity of the AE prior to randomization 
date. 
Treatment 
emergent 
If AE onset date or AE worsening date is on or after treatment start date & on or 
before the last non-zero dose date plus 1 day.  
Treatment Start Date ≤ AE Start Date ≤ Last Non-Zero Dose Date + 1 day 
Treatment Start Date ≤ AE Worsening Date ≤ Last Non-Zero Dose Date + 1 day 
AE worsening during treatment emergent will be defined relative to the maximum 
intensity of AE prior to randomized treatment start date.  
AE worsening date is the first date in the treatment emergent period, when AE 
intensity increased relative to the maximum intensity of the AE prior to randomized 
treatment start date. 
Follow-up 
If AE onset date or AE worsening date is after the last non-zero dose date plus 1 day. 
AE Start Date > Last Non-Zero Dose Date + 1 day 
AE Worsening Date > Last Non-Zero Dose Date + 1 day 
AE worsening during follow-up will be defined relative to the maximum intensity of AE 
prior to randomized treatment start date.  
AE worsening date is the first date in the follow-up period, when AE intensity 
increased relative to the maximum intensity of the AE prior to randomized treatment 
start date. 
Onset 
/Worsening 
Time Since 1st 
Dose (Days) 
If Treatment Start Date ˃  AE Onset Date: AE Onset Date - Treatment Start Date 
If Treatment Start Date ≤ AE Onset Date: AE Onset Date - Treatment Start Date +1 
If Treatment Start Date ˃  AE Worsening Date: AE Worsening Date - Treatment 
Start Date 
If Treatment Start Date ≤ AE Worsening Date: AE Worsening Date - Treatment Start 
Date +1 
Missing otherwise. 
Onset 
/Worsening 
Time Since Last 
Dose (Days) 
If Last Non-Zero Dose Date AE onset date: AE onset date – last non-zero dose date 
+ 1 
If Last Non-Zero Dose Date > AE onset date: AE onset date – last non-zero dose date 
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Treatment 
State 
Definition 
If Last Non-Zero Dose Date  AE worsening date: AE worsening date – last non-zero 
dose date + 1 
If Last Non-Zero Dose Date > AE worsening date: AE worsening date – last non-zero 
dose date 
Missing otherwise. 
Duration (Days)  AE Resolution Date – AE Onset Date/AE Worsening Date + 1 
Drug-related 
If relationship is marked ‘YES’ on eCRF or if the value is missing. 
NOTES:  
• 
AEs that occur or worsen during interruptions of randomized study treatment will be classified as treatment 
emergent and post-randomization. 
• 
If the last non-zero dose date is missing and the treatment start date is non-missing and the AE onset date or 
AE worsening date is on or after the treatment start date, then the AE will be considered to be treatment 
emergent. 
• 
If AE onset date or AE worsening date is missing and AE resolution date is before the treatment start date, 
then the AE will be classified as Pre-treatment. 
• 
If AE onset date or AE worsening date is missing and AE resolution date is either missing or on or after 
treatment start date, then the AE will be classified as treatment emergent and post-randomization. 
 
10.4.1.5. 
Treatment States for Concomitant Medications (Other Than IV Iron 
Dose Endpoints and Iron Use Summaries) 
Pre-treatment medications are those taken (i.e., started) before the start date of 
randomized treatment. On-treatment medications are those taken (i.e., started or 
continued) at any time between the randomized treatment start date and the last non-zero 
dose date + 1 day, inclusive. Pre-treatment medications that were continued during this 
on-treatment period are also considered to be on-treatment medications. Post-treatment 
medications are those taken (i.e., started or continued) at any time after the last non-zero 
dose date + 1 day. On-treatment medications that were continued during this post-
treatment period are also considered to be post-treatment medications. Post-
randomization medications are those taken (i.e., started or continued) at any time on or 
after the randomization date. 
It will be assumed that the medication has been taken on the date in which it is reported 
as started or stopped.  Also, for any medication starting on the same date as randomized 
treatment, it will be assumed that the medication was taken after the subject started taking 
randomized treatment. 
Illustrations of the pre-treatment, on-treatment, and post-treatment treatment states are 
included below: 
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Pre-
treatment 
On-treatment 
Post-
treatment 
Pre-
treatment 
medicatio
n 
On-
treatment 
medicatio
n 
Post-
treatment 
medicatio
n 
(a) 
x⎯⎯x 
Randomized Treatment Start Date 
 
Last Non-zero Dose Date + 1 Day 
Last Non-zero Dose Date + 2 Days 
 
Y 
N 
N 
(b) 
x⎯⎯ 
⎯⎯x 
 
Y 
Y 
N 
(c) 
x⎯⎯ 
⎯⎯⎯ 
⎯⎯⎯x 
Y 
Y 
Y 
(d) 
 
x⎯⎯x 
 
N 
Y 
N 
(e) 
 
x⎯⎯ 
⎯⎯⎯x 
N 
Y 
Y 
(f) 
 
 
x⎯⎯x 
N 
N 
Y 
(g) 
?⎯⎯ x 
 
 
Y 
N 
N 
(h) 
?⎯⎯⎯ 
⎯⎯x 
 
Y* 
Y 
N 
(i) 
?⎯⎯⎯ 
⎯⎯⎯ 
⎯⎯⎯x 
Y* 
Y* 
Y 
(j) 
x⎯⎯⎯ 
⎯⎯⎯ 
⎯⎯⎯? 
Y 
Y** 
Y** 
(k) 
 
x⎯⎯ 
⎯⎯⎯? 
N 
Y 
Y** 
(l) 
 
 
x⎯⎯? 
N 
N 
Y 
(m) ?⎯⎯⎯ 
 
⎯⎯⎯  
 
⎯⎯⎯? 
Y*** 
Y*** 
Y*** 
(n) 
x⎯⎯⎯ 
x 
 
 
 
 
Y 
Y 
N 
(o) 
?⎯⎯⎯ 
x 
 
 
 
 
Y* 
Y 
N 
(p) 
 
x 
⎯⎯x 
 
 
 
N 
Y 
N 
(q) 
 
x 
⎯⎯⎯ 
x 
 
 
N 
Y 
N 
(r) 
 
 
 
x 
⎯ ⎯⎯⎯x 
N 
Y 
Y 
(s) 
 
 
 
x 
⎯ ⎯⎯⎯? 
N 
Y 
Y** 
(t) 
 
 
 
 
x 
⎯⎯⎯x 
N 
N 
Y 
(u) 
 
 
 
 
x 
⎯⎯⎯? 
N 
N 
Y 
(v) 
 
 
x⎯⎯ 
⎯ 
x 
 
N 
Y 
Y 
x = start/stop date of medication 
? = missing start/stop date of medication 
* If a medication is stopped On-treatment or Post-treatment and no start date is recorded it will be 
assumed that the medication was ongoing from the Pre-treatment phase 
** If a medication is started Pre-treatment or On-treatment and no stop date is recorded then 
usage will be assumed to be ongoing for the remainder of the study 
*** If a medication has no start or stop date it will be assumed that the medication was ongoing 
from the Pre-treatment phase to the Post-treatment phase 
 
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10.5. 
Appendix 5: Data Display Standards & Handling 
Conventions 
10.5.1. 
Study Treatment & Sub-group Display Descriptors 
Treatment Group Descriptions 
IVWRS 
Data Displays for Reporting  
Code 
Description 
Description 
Order [1] 
1 
daprodustat 
Dapro 
1 
2 
darbepoetin alfa 
Darbe 
2 
 
 
Total 
3 
NOTES: 
1. 
Order represents treatments being presented in TFL, as appropriate. 
 
10.5.2. 
Baseline Definition & Derivations 
10.5.2.1. 
Baseline Definitions 
For all endpoints (except as noted) the baseline value will be the latest non-missing pre-
dose assessment on or before the randomization date. This is generally expected to be the 
pre-dose value from the Day 1 visit, although such values may be missing. 
Parameter 
Study Assessments Considered As 
Baseline 
Baseline Used 
in Data Display 
Screening Week -
2 
Day 1 (Pre-Dose) 
Efficacy 
Hgb 
 
X 
Randomization 
Date 
Monthly IV iron1 
 
X 
Randomization 
Date 
Iron parameters 
 
X 
Randomization 
Date 
Safety 
Subjects who have in-clinic 
HD: pre-dialysis BP 
parameters, HR and weight 
 
X 
Randomization 
Date 
Subjects who have in-clinic 
HD: post-dialysis BP 
parameters, HR, weight, and 
dry weight2 
X 
 
Week -
2/Randomization 
Date 
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Parameter 
Study Assessments Considered As 
Baseline 
Baseline Used 
in Data Display 
Screening Week -
2 
Day 1 (Pre-Dose) 
Subjects who do not have in-
clinic HD: BP parameters, 
HR, weight, and dry weight 
 
X 
Randomization 
Date 
Lipid parameters, clinical 
chemistry, hematology, other 
laboratory and hepatobiliary 
(liver) tests 
 
X 
Randomization 
Date 
PRO 
SF-36 domain and 
component scores 
 
X 
Randomization 
Date 
EQ-5D-5L & VAS 
 
X 
Randomization 
Date 
PGI-S 
 
X 
Randomization 
Date 
CKD-AQ 
 
X 
Randomization 
Date 
NOTES : 
• 
Unless otherwise stated, the mean of replicate assessments at any given time point will be used as the value 
for that time point. 
[1]: Baseline monthly IV iron dose will be defined as total IV iron (mg) over the 10 weeks prior to randomization. See 
Section 10.6.3.  
[2]: Post-dialysis baseline values for subjects with in-clinic dialysis will be defined as the latest non-missing pre-dose 
assessment before the randomization date. This will most often be the value recorded at the Week -2 visit. 
10.5.2.2. 
Derivations and Handling of Missing Baseline Data 
Change from Baseline 
Definition 
Reporting Details 
Change from Baseline 
= Post-Baseline Visit Value – Baseline 
NOTES : 
• 
Unless otherwise specified, the baseline definitions specified in Section 10.5.2. Baseline Definitions will be 
used for derivations for endpoints / parameters and indicated on summaries and listings. 
• 
Unless otherwise stated, if baseline data is missing no derivation will be performed and the change from 
baseline value will be set to missing. 
• 
The baseline definition will be footnoted on all change from baseline displays. 
Percent Change from Baseline 
Lipid parameters will be log-transformed and the percent change from baseline will be 
reported. Other endpoints may also be log-transformed if deemed appropriate. 
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To calculate a geometric mean for baseline measurement or at a specified timepoint, the 
following steps are used: 
1. Log-transform the data points 
2. Calculate the mean and standard error (SE) of the log-transformed data 
3. Exponentiate the mean, (if required, the mean – SE, mean + SE) and the endpoints of 
the confidence interval back to the original scale in order to obtain the geometric 
mean, (the geometric mean – SE, the geometric mean + SE) and the confidence 
interval for the geometric mean. 
4. Coefficient of variation will be calculated as  
1
)
exp(
log
−
=
scale
Var
CV
 100% 
 
To calculate a geometric mean for the ratio of a specific timepoint to baseline (expressed 
as a percent change from baseline), the following steps are used: 
1. Log-transform the data at both the baseline and the specified timepoint  
2. For each subject, calculate a change from baseline using the log-transformed data 
3. Calculate the mean and standard error (SE) of change from baseline using the log-
transformed data 
4. Exponentiate the mean, (if required, the mean – SE, the mean + SE), back to the 
original scale and then subtract 1, then multiply everything by 100% in order to 
express the geometric mean, (the geometric mean – SE, the geometric mean + SE) as 
the  percent change from baseline. 
So, geometric mean for percent change from baseline = 
    [Exp(∑ {log(value at specified time point_i) – log(baseline value_i) }/n) – 1] x 100, 
Where i = subject, n= total number of subjects, and ∑ represents the sum over all 
subjects. 
To calculate a 95% CI of the geometric mean for the ratio of a specific timepoint to 
baseline (expressed as a percent change from baseline), the following steps are used: 
1. Log-transform the data at both the baseline and the specified timepoint  
2. For each subject, calculate a change from baseline using the log-transformed data 
3. Calculate the mean and standard error (SE) of change from baseline using the log-
transformed data 
4. Calculate the lower and upper limits of the 95% CI of change from baseline using the 
log-transformed data assuming a normal distribution: Mean -/+ z(1- α/2)*SE (z for 
α=0.05 is obtained through PROBIT function in SAS that is specified as 
PROBIT(0.975)) 
5.  Exponentiate the lower and upper limits of the 95% CI, back to the original scale 
and then subtract 1, then multiply everything by 100% in order to express the 
confidence interval (CI) as the percent change from baseline. 
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To calculate the minimum, median and maximum for the ratio of a specific timepoint to 
baseline (expressed as a percent change from baseline), the following steps are used: 
1. Log-transform the data at both the baseline and the specified timepoint  
2. For each subject, calculate a change from baseline using the log-transformed data 
3. Calculate the minimum (median and maximum) of change from baseline using the 
log transformed data. 
4. Exponentiate the minimum (median and maximum),  back to the original scale and 
then subtract 1, then multiply everything by 100% in order to express the minimum 
(median and maximum) as the  percent change from baseline.  
So, minimum percent change from baseline = 
   [Exp( min{log(value at specified time point_i) – log(baseline value_i) }) – 1 ] x 100, 
Where i = subject. 
Unless otherwise specified, the baseline definitions specified in Section 10.5.2 will be 
used for derivations for endpoints/parameters and indicated on summaries and listings. 
Unless otherwise specified, if baseline data is missing, no derivation will be performed 
and the % change from baseline value will be set to missing. The baseline definition will 
be footnoted on all change from baseline displays. 
10.5.3. 
Reporting Process & Standards 
Reporting Process 
Software 
• The currently supported versions of SAS software, Version 9.4 (or higher) will be used for all 
analyses unless otherwise specified. Additionally, R Version 3.6.2 or higher may be used for 
analysis and the production of graphics. 
Analysis Datasets  
• Analysis datasets will be created according to clinical data interchange standards 
consortium (CDISC) standards study data tabulation model (SDTM) implementation guide 
(IG) Version 3.1.3 with some updates from Version 3.2. Analysis data model (ADaM) IG 
Version 1.1, and GSK ADaM specification template. 
• For creation of ADaM datasets (ADCM/ADAE), the same version of dictionary datasets will 
be implemented for conversion from system independent (SI) to SDTM. 
Generation of RTF Files 
• Rich text format (RTF) files will be generated. 
Reporting Standards 
General 
• The current GSK Integrated Data Standards Library (IDSL) will be applied for reporting, 
unless otherwise stated: 
o 4.03 to 4.23: General Principles 
o 5.01 to 5.08: Principles Related to Data Listings 
o 6.01 to 6.11: Principles Related to Summary Tables 
o 7.01 to 7.13: Principles Related to Graphics  
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Reporting Process 
Formats 
• GSK IDSL Statistical Principles (5.03 & 6.06.3) for decimal places (DP’s) will be adopted for 
reporting of data based on the raw data collected. 
• Numeric data will be reported at the precision collected on the eCRF. 
• The reported precision from non eCRF sources will follow the IDSL statistical principles but 
may be adjusted to a clinically interpretable number of DP’s.  
Planned and Actual Time 
• Reporting for tables, figures and formal statistical analyses : 
• Planned time relative to randomization will be used in figures, summaries, statistical 
analyses and calculation of any derived parameters, unless otherwise stated. 
• All scheduled visits, regardless of deviation from the planned assessment times and/or 
scheduled visit days will be used in tables, figures and formal statistical analyses unless 
otherwise stated. 
• The derived end of treatment value (see Section 10.6.1) will also be included in displays 
of data by visit. 
• Tables presenting data values by visit will also include values from scheduled visits 
occurring on or before the Day 1 visit, despite the description contained in the title (e.g., 
post-randomization, evaluable, or on-treatment). The description in the title refers to the 
post-randomization values that are included in the table. 
• Reporting for Data Listings:  
• Planned and actual time relative to study drug dosing will be shown in listings (Refer to 
IDSL Statistical Principle 5.05.1). 
• Unscheduled or unplanned readings will be presented within the subject’s listings.  
• Visits outside the protocol defined time-windows (i.e. recorded as protocol deviations) 
will be included in listings  
Unscheduled Visits 
• Unscheduled visits will not be included in summary tables, with the following exceptions: 
• If the table includes a row for all post-baseline assessments, unscheduled visits will be 
included in this row. 
• Some Hgb endpoints will include unscheduled Hgb values (See Section 10.6.3) 
• Some BP endpoints will include unscheduled BP values (see Section 10.6.4) 
• Unscheduled visits will not be included in figures, with similar exceptions: 
• If the figure includes a data value for all post-baseline assessments, unscheduled visits 
will be included in this value. 
• Some Hgb endpoints will include unscheduled Hgb values (See Section 10.6.3) 
• Some BP endpoints will include unscheduled BP values (see Section 10.6.4) 
• All unscheduled visits will be included in listings. 
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Reporting Process 
Descriptive Summary Statistics 
Continuous Data 
Refer to IDSL Statistical Principle 6.06.1 
Categorical Data 
N, n, frequency, % 
Graphical Displays 
• Refer to IDSL Statistical Principals 7.01 to 7.13. 
Adjusted Means 
• SAS option OBSMARGINS will be used to generate all adjusted mean values, e.g. 
LSMEANS statement in relevant SAS procedures will include the OBSMARGINS option (or 
OM as an abbreviation), to weight least square means coefficients of the categorical 
variables in the model to be proportional to those found in the input dataset.  
 
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10.6. 
Appendix 6: Derived and Transformed Data 
10.6.1. 
General 
Multiple Measurements at One Time Point 
• Mean of the measurements (except patient-reported outcome data) will be calculated and 
used in any derivation of summary statistics but if listed, all data will be presented. 
o Triplicate BP and HR measurements are expected at certain time points (See 
Section 10.2.1) 
o If there are multiple responses recorded by a subject for a PRO questionnaire at the 
same visit, the first complete response will be used 
• Subjects having both High and Low values for Normal Ranges at any post-baseline visits for 
safety parameters will be counted in both the High and Low categories of “Any visit post-
baseline” row of related summary tables. This will also be applicable to relevant Potential 
Clinical Importance summary tables. 
Randomization Date 
• Date subject was randomized 
Treatment Start Date 
• First randomized treatment start date 
Last Non-Zero Dose Date 
• Date of last actual dose of randomized study treatment from IP Discontinuation eCRF form.  
o The dose steps used by the dosing algorithm described in the protocol include a 
dose hold or a zero dose. If subjects are assigned by the algorithm to a zero dose, 
they do not receive randomized treatment for that period. Hence, it would be 
possible for a subject to complete the study, while still following the dosing 
algorithm, but not actually be taking any actual randomized treatment. The last non-
zero dose date, then captures the latest date in the study that a subject physically 
took a dose of randomized treatment. 
• The eCRF allows for the possibility of partial or missing dates to be recorded for the last 
actual dose of randomized study treatment on the IP Discontinuation form (i.e., missing day, 
or day and month, or day and month and year). In such a case, or in case of subjects who 
have a non-missing treatment start date, but are missing an IP Discontinuation form, the 
following conventions will be applied in order to impute a last non-zero dose date: 
o Missing day: 
▪ The last day of the month will be used, unless the treatment stop date also 
occurs in the same month; in this case, the treatment stop date will be 
used. 
o Missing day and month; 
▪ ‘31’ will be used for the day and ‘Dec’ will be used for the month, unless the 
treatment stop date also occurs in the same year; in this case the treatment 
stop date will be used. 
o Missing day, month, and year: 
▪ Treatment stop date will be used only for subjects who have a non-missing 
treatment start date. 
 
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Treatment Stop Date 
• Calculated as the latest randomized treatment dose stop date for subjects who have a 
non-missing treatment start date. Note that this date could come from a randomized 
treatment exposure record with a missing or partial dose stop date if the associated 
dose start date for that exposure record is on or after the last non-missing randomized 
treatment dose stop date. 
• The eCRF allows for the possibility of missing or partial dates to be recorded for the 
dose stop date on the study treatment form (i.e., missing day, or day and month, or day 
and month and year). In such a case, the following conventions will be applied in order 
to impute a treatment stop date: 
o Missing day: 
▪ The last day of the month will be used, unless the study completion or 
withdrawal date also occurs in the same month; in the case, the study 
completion or withdrawal date will be used. 
o Missing day and month: 
▪ ‘31’ will be used for the day and ‘Dec’ will be used for the month, unless 
the study completion or withdrawal date also occurs in the same year; 
in this case, the study completion or withdrawal date will be used. 
o Missing day, month and year: 
▪ The study completion or withdrawal date will be used only for subjects 
who have a non-missing treatment start date. 
End of Treatment Value 
• Only defined for subjects with a non-missing treatment start date 
• Hgb, iron, transfusion and PRO parameters: the latest value on or before the treatment 
stop date + 1 day. 
• Blood pressure, central laboratory, and vital signs parameters: the latest value on or 
before the last non-zero dose date + 1 day. 
Study Completion/Withdrawal Date 
• Date of withdrawal for subjects withdrawing (i.e., subjects who actively withdraw or are 
deemed lost to follow-up) from study or date of completion of study for subjects who 
complete the study. 
o Note: Subjects who die while on study are considered as having completed the 
study 
• The eCRF allows for the possibility of missing or partial dates to be recorded for the 
study completion/withdrawal date on the Study Conclusion form (i.e., missing day, or 
day and month, or day and month and year). In such a case, or in case of subjects who 
are missing a Study Conclusion form, the following conventions will be applied in order 
to impute a study completion/withdrawal date: 
o Missing day: 
▪ The last day of the month will be used, unless the last study contact 
date also occurs in the same month; in the case, the last study contact 
date will be used. 
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o Missing day and month: 
▪ ‘31’ will be used for the day and ‘Dec’ will be used for the month, unless 
the last study contact date also occurs in the same year; in this case, 
the last study contact date will be used. 
o Missing day, month and year: 
▪ The last study contact date will be used. 
Planned/Actual Visit Dates 
• Planned/actual visit dates will be defined as follows: 
o Week 28 date: Non-missing Week 28 visit start date (from SV domain), 
otherwise randomization date + 28*7 
o Week 36 date: Non-missing Week 36 visit end date (from SV domain), 
otherwise randomization date + 36*7 
o Week 52 date: Non-missing Week 52 visit end date (from SV domain), 
otherwise randomization date + 52*7 
Stabilization Period 
• Defined as the period between and including the Randomization date + 1 day - <Week 
28 visit, using planned/actual dates. 
Alternative Evaluation Period (Alt. EP) 
• Defined as the period between and including Week 28 visit – Week 36 visit, using 
planned/actual dates.  
Evaluation Period (EP) 
• Defined as the period between and including Week 28 visit – Week 52 visit, using 
planned/actual dates. 
Study Day 
• Calculated as the number of days from randomization date : 
• Ref Date = Missing           → Study Day = Missing  
• Ref Date < Randomization Date  → Study Day = Ref Date – Randomization Date     
• Ref Date ≥ Randomization Date  → Study Day = Ref Date – (Randomization Date) + 
1     
Treatment Day 
• Calculated as the number of days from treatment start date: 
• Treatment Start Date = Missing   → Treatment Day = Missing  
• Ref Date < Treatment Start Date  → Treatment Day = Ref Date – Treatment Start 
Date  
• Ref Date ≥ Treatment Start Date  → Treatment Day = Ref Date – (Treatment Start 
Date) + 1     
Last Study Contact Date 
• Latest visit date from an unscheduled visit or a clinic, telephone, designated third party, 
healthcare provider or medical records, or other contact with subject (mail, email, text, social 
media, etc.) visit. 
Time Definitions (per GSK standard principles) 
• 1 week = 7 days 
• 1 month = 30.4375 days 
• 1 year = 365.25 days 
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Production of Two-Sided p-values 
• The majority of the efficacy and safety analyses in this study will use one-sided 2.5% p-
values to assess statistical significance. Should two-sided p-values be required for 
publication purposes after the study is complete, the corresponding two-sided p-values will 
be produced at that time. 
10.6.2. 
Study Population 
10.6.2.1. 
Subject Disposition 
Subject Disposition 
Screen Failures 
• Screen failures are defined as subjects who consent to participate in the clinical trial but are 
not subsequently randomized.  
o At the time of screening closure, there may have been subjects who had been 
consented but had not been entered into the eCRF. These subjects are not 
included in the clinical database, but will be noted in a footnote on the Summary 
of Screening Status and Reasons for Screen Failures. 
• Any subject that consented, was entered into the eCRF, and was not randomized, but is 
missing a screen failure record will have the following values imputed: 
o Was this subject a screen failure? = Yes 
o Reason for screen failure = Missing 
Randomized Treatment Discontinuation 
• Any randomized subject with a non-missing treatment start date that is missing an IP 
Discontinuation eCRF will have the following values imputed: 
o Date of last dose = See Last Non-Zero Dose Date in Section 10.6.1 
o Was the study treatment stopped permanently before the scheduled end of the 
treatment period? = Yes 
o Primary reason the treatment was stopped = Missing 
Study Completers/Withdrawals 
• Any randomized subject that is missing Study Conclusion eCRF will have the following 
values imputed: 
o Date of subject completion or withdrawal? = See Study Completion/Withdrawal 
Date in Section 10.6.1 
o Was the subject withdrawn from the study? = Yes 
o Primary reason for study withdrawal = Missing 
 
10.6.2.2. 
Demographic & Baseline Characteristics 
Demographic & Baseline Characteristics 
Age 
• GSK standard IDSL algorithms will be used for calculating age where birth date will be 
imputed as follows: 
o Any subject with a missing day will have this imputed as day ‘15’.  
o Any subject with a missing date and month will have this imputed as ‘30th June’. 
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Demographic & Baseline Characteristics 
• Birth date will be presented in listings as ‘YYYY’. 
High Level Race 
• Geographic ancestry data will be combined into the following high level race categories: 
o American Indian or Alaskan Native 
o Asian (Asian-East Asian Heritage, Asian-Japanese Heritage, Asian-
Central/South Asian Heritage, Asian-South East Asian Heritage, Mixed Asian 
Race) 
o Black or African American  
o Native Hawaiian or Other Pacific Islander 
o White (White-Arabic/North African Heritage, White-White/Caucasian/European 
Heritage, Mixed White Race) 
o Mixed Race (Multiple high level races are selected) 
Note: A subject will only be counted in one category. Mixed Asian Race includes subjects who 
have more than one Asian category selected, but no other categories. Mixed White Race 
includes subjects who have more than one White category selected, but no other categories. 
Race Detail 
• Geographic ancestry data will be combined into race detail categories: 
o American Indian or Alaskan Native 
o Asian-Central/South Asian Heritage 
o Asian-East Asian Heritage 
o Asian-Japanese Heritage 
o Asian-South East Asian Heritage 
o Mixed Asian Race (Only display if data exists) 
o Black or African American (African American/African Heritage) 
o Native Hawaiian or Other Pacific Islander 
o White-Arabic/North African Heritage 
o White-White/Caucasian/European Heritage 
o Mixed White Race (Only display if data exists) 
o Mixed Race (Multiple high level races are selected; only display if data exists) 
Note: A subject will only be counted in one category. Mixed Asian Race includes subjects who 
have more than one Asian category selected, but no other categories. Mixed White Race 
includes subjects who have more than one White category selected, but no other categories. 
Dialysis Type at Randomization 
• Dialysis type at randomization will use the subject’s randomization date and the dialysis type 
information recorded on the Dialysis Initiation and Dialysis Changes eCRF pages to 
determine the dialysis type on the randomization date and will be summarized as follows: 
o HD (which includes: HD – conventional and HDF/HF) 
o PD 
o Missing 
• Subjects may start dialysis up to 4 weeks after randomization. For subjects who have not yet 
started dialysis on the randomization date, the earliest dialysis type entered on the Dialysis 
Initiation eCRF page will be summarized. 
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Demographic & Baseline Characteristics 
Dialysis Start Manner 
• Dialysis start manner will use information recorded in the stratification level field of the 
Randomization eCRF page and the following two groups will be summarized: 
o Planned start 
o Unplanned (urgent) start 
Dialysis Status at Randomization 
• Dialysis status at randomization will use the subject’s randomization date and the dialysis 
type information recorded on the Dialysis Initiation and Dialysis Changes eCRF pages to 
determine the dialysis status on the randomization date and will be summarized as follows: 
o Dialysis not initiated 
o On dialysis  
Baseline Body Mass Index (BMI) 
• Calculated as baseline weight (kg) / [height (m)]2 
Note: For subjects with in-clinic dialysis, baseline post-dialysis weight is used. 
B12 Supplementation Required to Be Eligible for Randomization 
• If a randomized subject’s B12 value at screening is below the lower limit of the reference 
range, and there is a Vitamin B12 concomitant medication (any route) start date after the 
screening date, but before the randomization date, then the subject is considered to have 
required B12 supplementation to be eligible for randomization. 
IV Iron Supplementation Required to Be Eligible for Randomization 
• If a randomized subject has an IV iron concomitant medication record with a reason of ‘study 
eligibility’, then the subject is considered to have required IV iron supplementation to be 
eligible for randomization. 
Dosing Algorithm at Randomization 
• Protocol Amendment 1 updated the dosing algorithm used to assign doses of randomized 
treatment to subjects in both treatment arms. The number of subjects randomized under the 
original algorithm and under the updated algorithm will be summarized. 
• A subject’s randomization date will be compared to the site-specific ethics 
committee/regulatory protocol amendment approval date for their site. This date is stored in 
the IRT system as the Site Level Amendment Flag Date for each site.  
• Subjects randomized before their site’s non-missing Site Level Amendment Flag Date or 
who have a missing Site Level Amendment Flag Date will be considered to have been 
randomized under the original algorithm, and subjects randomized on or after their site’s 
non-missing Site Level Amendment Flag Date will be considered to have been randomized 
under the updated algorithm. 
History of Diabetes 
• Subjects are considered to have a history of diabetes if they have a yes response to any of 
the following medical history conditions: diabetes, diabetic autonomic neuropathy, diabetic 
neuropathy peripheral, diabetic dermopathy, diabetic renal disease, diabetic retinopathy. 
• If subjects have indicated that they do not have any of the listed diabetic medical history 
conditions above, they are considered not to have a history of diabetes. 
• If subjects have not been classified as either having or not having a history of diabetes, and 
are missing a response to any of the listed medical history conditions, their diabetes history 
status will be missing. 
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Demographic & Baseline Characteristics 
History of Stroke 
• Subjects are considered to have a history of stroke if they have a yes response to the stroke 
medical history condition. 
• Subjects who have indicated that they do not have a history of stroke will be summarized 
accordingly. 
• If a subject is missing a response to the stroke medical history condition, their stroke history 
status will be missing. 
History of MI 
• Subjects are considered to have a history of MI if they have a yes response to either of the 
following medical history conditions: myocardial infarction, cardiac arrest. 
• Subjects who have indicated that they do not have a medical history of myocardial infarction 
or cardiac arrest will be considered not to have a history of MI. 
• If subjects have not been classified as either having or not having a history of MI, and are 
missing a response to either the myocardial infarction or cardiac arrest medical condition, 
their MI history status will be missing. 
History of Cancer 
• Subjects are considered to have a history of cancer if they have a yes response to either of 
the following medical history conditions: neoplasms malignant or unknown/unspecified, 
allogenic bone marrow transplant. 
• Subjects who have indicated that they do not have a medical history of neoplasms malignant 
or unknown/unspecified or allogenic bone marrow transplant will be considered not to have 
a history of cancer. 
• If subjects have not been classified as either having or not having a history of cancer, and 
are missing a response to either the neoplasms malignant or unknown/unspecified or 
allogenic bone marrow transplant medical condition, their cancer history status will be 
missing. 
History of Heart Failure 
• Subjects are considered to have a history of heart failure if they have a yes response to any 
of the following medical history conditions: heart failure, left ventricular systolic dysfunction, 
left ventricular diastolic dysfunction, pulmonary hypertension. 
• Subjects who have indicated that they do not have a medical history of any of the terms 
listed above will be considered not to have a history of heart failure. 
• If subjects have not been classified as either having or not having a history of heart failure, 
and are missing a response to any of the medical condition terms listed above, their heart 
failure history status will be missing. 
History of Thromboembolic Events 
• Subjects are considered to have a history of thromboembolic events if they have a yes 
response to any of the following medical history conditions: pulmonary embolism, deep vein 
thrombosis, retinal vein occlusion, arteriovenous graft thrombosis, arteriovenous fistula 
thrombosis, central venous catheter thrombosis. 
• Subjects who have indicated that they do not have a medical history of any of the terms 
listed above will be considered not to have a history of thromboembolic events. 
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Demographic & Baseline Characteristics 
• If subjects have not been classified as either having or not having a history of 
thromboembolic events, and are missing a response to any of the medical condition terms 
listed above, their thromboembolic event history status will be missing. 
History of Cardiovascular Disease 
• Subjects are considered to have a history of cardiovascular disease if they have a yes 
response to any of the following medical history conditions: angina pectoris, myocardial 
infarction, stroke, coronary artery disease, transient ischaemic attack, heart failure, atrial 
fibrillation, cardiac arrest, valvular heart disease. 
• Subjects who have indicated that they do not have a medical history of any of the terms 
listed above will be considered not to have a history of cardiovascular disease. 
• If subjects have not been classified as either having or not having a history of cardiovascular 
disease and are missing a response to any of the medical condition terms listed above, their 
cardiovascular disease history status will be missing. 
Baseline Iron Use & Standardized Baseline IV Iron Dose 
• See Section 10.6.3. 
Dialysis Access Type Used at Randomization 
• Dialysis access type at randomization will use the subject’s randomization date and the 
dialysis access type information recorded on the Dialysis Access History and Dialysis 
Access Changes eCRF pages to determine the dialysis access type on the randomization 
date and will be summarized as follows: 
o Arteriovenous fistula 
o Arteriovenous graft 
o Central venous catheter – tunneled 
o Central venous catheter – non-tunneled 
o Peritoneal catheter 
o Other 
o Missing 
• Subjects may start dialysis up to 4 weeks after randomization. For subjects who have not yet 
started dialysis on the randomization date, the earliest dialysis access type entered on the 
Dialysis Access History eCRF page will be summarized. 
Phosphate Binder Use at Randomization 
• Phosphate binder use at randomization will be summarized as follows: 
o Iron-based phosphate binders 
o Calcium-based phosphate binders 
o Non-calcium and non-iron based phosphate binders 
o No phosphate binder use 
• Subjects will be counted in each applicable group, based on the concomitant medications 
they are receiving on the day of randomization. 
Concomitant Medication Use at Randomization 
• Concomitant medication records on the day of randomization will be used to determine the 
following classifications of concomitant medication use at randomization: 
o ACEI/ARB 
o Vitamin D 
o Beta blockers 
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o SGLT2i 
o Statin 
o Aspirin 
o Vitamin K 
o Insulin 
o Calcimimetics 
o Diabetic medication 
10.6.2.3. 
Randomized Treatment Discontinuation and Study Withdrawal 
Randomized Treatment Discontinuation and Study Withdrawal 
Randomized Treatment Discontinuation 
• Randomized Treatment Discontinuation Censored Time (days) = Treatment stop date – 
Treatment start date +1 
If the treatment stop date = death date for a subject, the subject will be censored and will not be 
counted as an event for treatment discontinuation summaries that exclude subjects who die 
while on treatment. 
• Time to Randomized Treatment Discontinuation (days) = Treatment stop date – Treatment 
start date +1 
• Randomized Treatment Person Years = (Cumulative total of time to randomized treatment 
discontinuation for subjects who discontinued randomized treatment + Cumulative total of 
randomized treatment discontinuation censoring time for subjects who did not discontinue 
randomized treatment) / 365.25 
• Randomized Treatment Discontinuation Incidence Rate (per 100 person years) = 100* 
Number of subjects who discontinued randomized treatment / randomized treatment person 
years 
Study Withdrawal 
• Study Censored Time (days) = Study completion date – Randomization date +1 
• Time to Study Withdrawal (days) = Study withdrawal date – Randomization date +1 
• Study Person Years = (Cumulative total time to study withdrawal for subjects withdrawing 
from the study + Cumulative total of study censoring time for subjects who did not withdraw 
from study) / 365.25 
• Study Withdrawal Incidence Rate (per 100 person years) = (100 * Number of subjects who 
have withdrawn from study) / Study Person Years 
 
10.6.2.4. 
Prior and Concomitant Medications 
Prior and Concomitant Medications 
Non-randomized ESA use during treatment period 
• Subjects will be considered to have non-randomized ESA use during the treatment 
period if they have any ESA concomitant medication records with one of the following 
two reasons for medication: 
o Non-randomized ESA treatment in addition to randomized treatment 
o Non-randomized ESA treatment instead of randomized treatment 
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Prior and Concomitant Medications 
Duration of non-randomized ESA use during treatment period 
• If there is only one concomitant medication record of non-randomized ESA use during 
the treatment period, then: 
o Duration (days) = earliest of (concomitant medication record end date, last non-
zero dose date + 1 day) – latest of (concomitant medication start date, 
treatment start date) + 1 day 
• If there are multiple concomitant medication records of non-randomized ESA use during 
the treatment period, then the duration of non-randomized ESA use will add the 
durations for all records, subtracting any overlapping days that may exist between the 
multiple records. 
10.6.2.4 
Exposure and Compliance 
Exposure and Compliance 
Exposure 
• Exposure (days) = Treatment stop date – treatment start date + 1 day 
Compliance 
• Compliance will be calculated based on data recorded in the Study Treatment Details eCRF 
pages and will only be calculated for subjects with a non-missing treatment start date, and 
will not be calculated after a subject’s treatment stop date, or study conclusion date for 
subjects who have a non-missing treatment start date and a missing treatment stop date. 
 
• A compliance category will be assigned to each randomized treatment exposure record 
according to the following tables. Exposure records corresponding to periods of dose 
hold/zero-dose as assigned by the IRT will be categorized in the compliant category and any 
gaps between exposure records will be categorized in the under compliant category. 
 
o Daprodustat Doses 
Under Compliant 
Compliant 
Over Compliant 
Compliance for the exposure 
record < 80% 
Compliance for the 
exposure record  80% 
and  120% 
Compliance for the exposure 
record > 120% 
Where compliance for the exposure record is calculated as 100% *  
[# dispensed – (# returned + # lost)] / # tablets per day / (dose stop date – dose start date +1) 
# tablets per day: 
1 tablet per day: 1mg, 2mg, 4mg, 6mg, 8mg, 10mg 
2 tablets per day: 12mg, 16mg 
3 tablets per day: 24mg 
o darbepoetin alfa Every 4 Week Exposure Records: Based on Number of Doses Given 
Duration of Exposure Record 
Under Compliant 
Compliant 
Over Compliant 
1 – 14 days 
< 1 dose 
1 dose 
> 1 dose 
15 – 42 days 
< 1 dose 
1 or 2 doses 
> 2 doses 
43 – 70 days 
< 2 doses 
2 or 3 doses 
> 3 doses 
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o darbepoetin alfa Every 2 Week Exposure Records: Based on Number of Doses Given 
Duration of Exposure Record 
Under Compliant 
Compliant 
Over Compliant 
1 – 7 days 
< 1 dose 
1 dose 
> 1 dose 
8 – 21 days 
< 1 dose 
1 or 2 doses 
> 2 doses 
22 – 35 days 
< 2 doses 
2 or 3 doses 
> 3 doses 
36 – 49 days 
< 3 doses 
3 or 4 doses 
> 4 doses 
50 – 63 days 
< 4 doses 
4 or 5 doses 
> 5 doses 
64 – 77 days 
< 5 doses 
5 or 6 doses 
> 6 doses 
78 – 91 days 
< 6 doses 
6 or 7 doses 
> 7 doses 
92 – 105 days 
< 7 doses 
7 or 8 doses 
> 8 doses 
Etc. 
 
 
 
 
o darbepoetin alfa Every Week Exposure Records: Based on Number of Doses Given 
Duration of Exposure 
Record 
Under Compliant 
Compliant 
Over Compliant 
1 – 3 days 
< 1 dose 
1 dose 
> 1 dose 
4 – 10 days 
< 1 dose 
1 or 2 doses 
> 2 doses 
11 days 
< 1 dose 
1 or 2 or 3 doses 
> 3 doses 
12 – 17 days 
< 2 doses 
2 or 3 doses 
> 3 doses 
18 days 
< 2 doses 
2 or 3 or 4 doses 
> 4 doses 
19 – 24 days 
< 3 doses 
3 or 4 doses 
> 4 doses 
25 days 
< 3 doses 
3 or 4 or 5 doses 
> 5 doses 
26 – 31 days 
< 4 doses 
4 or 5 doses 
> 5 doses 
32 days 
< 4 doses 
4 or 5 or 6 doses 
> 6 doses 
33 – 38 days 
< 5 doses 
5 or 6 doses 
> 6 doses 
39 days 
< 5 doses 
5 or 6 or 7 doses 
> 7 doses 
40 – 45 days 
< 6 doses 
6 or 7 doses 
> 7 doses 
46 days 
< 6 doses 
6 or 7 or 8 doses 
> 8 doses 
47 – 52 days 
< 7 doses 
7 or 8 doses 
> 8 doses 
53 days 
< 7 doses 
7 or 8 or 9 doses 
> 9 doses 
Etc. 
 
 
 
• Compliance will be summarized for the following time periods: Day 1 - < Week 28, Week 28 - 
< Week 52, and Day 1 - < Week 52 (Overall compliance). 
• Within each period, the percentage of time that a subject spent in each of the 3 categories 
above or with missing compliance data will be determined. 
• A subject’s compliance category will be the category that corresponds to the highest 
percentage of total time. In the unlikely event of a tie, the lower compliance category will be 
71 – 98 days 
< 3 doses 
3 or 4 doses 
> 4 doses 
99 – 126 days 
< 4 doses 
4 or 5 doses 
> 5 doses 
Etc. 
 
 
 
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Exposure and Compliance 
chosen (i.e., in a tie between under and compliant, under is chosen; in a tie between 
compliant and over, compliant is chosen; and in a tie between under and over, under is 
chosen; in a tie with missing, missing is chosen). 
 
10.6.3. 
Efficacy 
10.6.3.1. 
Hemoglobin Endpoints 
Hemoglobin Values 
Central Laboratory and HemoCue Hgb Values 
• When source of Hgb measurement is not specified: 
o For reporting purposes, central laboratory Hgb values will be used, unless 
otherwise specified. However, if a central laboratory Hgb value is missing, a 
corresponding non-missing HemoCue Hgb value will be used. This approach 
will be used for the primary Hgb analysis. 
• Some displays may be created for either central laboratory Hgb values only or HemoCue 
Hgb values only. The central laboratory summary will be considered the primary summary in 
this case. 
Evaluable Hemoglobin Values 
• Evaluable Hgb values are on-treatment Hgb values (see Section 10.4.1.1) that are not taken 
within the 8 weeks following a red blood cell transfusion, a whole blood transfusion, or a 
non-randomized ESA treatment which occurs on or after the randomization date. 
• Red blood cell transfusions, whole blood transfusions and non-randomized ESA treatments 
occurring on or after the randomization date are identified by comparing the start and stop 
date of the respective transfusion or ESA concomitant medication record to the 
randomization date. 
Imputed Hemoglobin Values 
• For each missing value between baseline to Week 52 (inclusive), 200 imputed values will be 
generated using the multiple imputation method (see Section 7.1.2). The average of these 
200 imputed values will be used as the value for this missing value in the summary tables 
and figures. 
• For the primary efficacy Hgb analysis and the corresponding subgroup analyses using all 
available observed and imputed Hgb values (on and off-treatment), Rubin’s rules [Rubin, 
1987] will be used to combine results of the imputed datasets using SAS PROC 
MIANALYZE procedure. 
EP Hemoglobin Value for Primary Hgb Analysis 
• For each subject, the mean of all available (on and off treatment) Hgb values during the EP 
(See Section 10.6.1) including any imputed and unscheduled Hgb values that were taken 
during this time period. 
• Should the assessment dates for Hgb values from the Early Treatment Discontinuation visit 
fall within the EP, then these values will be included as unscheduled Hgb values. Hgb 
values from the Follow-up visit will not be included in the EP mean. 
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Hemoglobin Values 
EP Hemoglobin Value for While On-Treatment Evaluable Hgb Supportive Analysis 
• For each subject, the mean of all evaluable Hgb values during the EP (See Section 10.6.1) 
including any evaluable unscheduled Hgb values that were taken during this time period. 
• Should the assessment dates for Hgb values from the Early Treatment Discontinuation visit 
fall within the EP, then these values will be included as unscheduled Hgb values. Hgb 
values from the Follow-up visit will not be included in the EP mean. 
EP Hemoglobin Value for Alternative EP Supportive Analyses 
• For each subject, the mean of all Hgb values during the Alt. EP (See Section 10.6.1) 
including any imputed and unscheduled Hgb values that were taken during this time period. 
This analysis will be conducted using all available (on and off treatment) Hgb values and 
separately using evaluable Hgb values only. 
• Should the assessment dates for Hgb values from the Early Treatment Discontinuation visit 
fall within the Alt. EP, then these values will be included as unscheduled Hgb values. Hgb 
values from the Follow-up visit will not be included in the Alt. EP mean. 
Use of Unscheduled Hemoglobin Values and Multiple Hgb Values on the Same Date 
• The scenarios outlined below provide guidance on the use of unscheduled Hgb values and 
multiple Hgb values occurring on the same date. Each row represents a single calendar 
date. 
• Rows outlining scenarios where there is at least one central lab Hgb and at least one 
HemoCue Hgb on the same date apply only for the derivation of Hgb values to be used in 
the primary Hgb analysis, where central lab values are used if they are available and if the 
central lab value is missing, then a corresponding non-missing HemoCue Hgb value is used. 
• Rows outlining scenarios involving combinations of scheduled and unscheduled Hgb values 
of the same type apply to all Hgb summaries and analysis. 
Scheduled 
Central Lab 
Hgb Value 
Unscheduled 
Central Lab 
Hgb Value 
Scheduled 
HemoCue 
Hgb Value 
Unscheduled 
HemoCue 
Hgb Value 
Value to Use 
Type/Label 
x 
 
 
 
Scheduled central lab 
Hgb value 
Scheduled visit 
 
x 
 
 
Unscheduled central lab 
Hgb value 
Unscheduled 
 
 
x 
 
Scheduled HemoCue 
Hgb value 
Scheduled visit 
 
 
multiple1 
 
Average of scheduled 
HemoCue Hgb values 
Scheduled visit 
 
 
 
x 
Unscheduled HemoCue 
Hgb value 
Unscheduled 
 
multiple 
 
 
Average of unscheduled 
central lab Hgb values 
Unscheduled 
 
 
 
multiple 
Average of unscheduled 
HemoCue Hgb values 
Unscheduled 
x 
x 
 
 
Average of central lab 
Hgb values 
Scheduled visit 
x 
 
x 
 
Scheduled central lab 
Hgb value 
Scheduled visit 
x 
 
 
x 
Scheduled central lab 
Hgb value 
Scheduled visit 
 
x 
x 
 
Unscheduled central lab 
Hgb value 
Unscheduled 
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x 
 
x 
Unscheduled central lab 
Hgb value 
Unscheduled 
 
 
x 
x 
Average of HemoCue 
Hgb values 
Scheduled visit 
1: The dose adjustment algorithm will require sites to obtain two HemoCue Hgb values at some visits. 
Time In Range 
Time in Range During the EP 
• Number of days that a subject’s evaluable Hgb is within the analysis range of 10-11.5 g/dL 
inclusive during the EP (See Section 10.6.1), including any unscheduled evaluable Hgb 
values that were taken during this time period. 
• Use of unscheduled Hgb values follows the scenarios for unscheduled and multiple Hgb 
values. 
• Linear interpolation is used to estimate Hgb between visits, accounting for any intermittent 
missing values (Rosendaal, 1993). 
Percent Time in Range During the EP 
• Time in Range During the EP / [Earlier of (Date of the last evaluable Hgb value, Week 52 
visit date) – Later of (Date of the first evaluable Hgb value that between Week 16 and Week 
52 inclusive, Week 28 visit date)] 
• Note: Percent time in/below/above range during the EP is only defined for subjects with a 
Treatment Stop Date that is on or after their Week 28 visit date, and have at least two 
evaluable Hgb values on different days, where at least one evaluable Hgb value is contained 
within the EP and another evaluable Hgb value occurs within the range of the Week 16 visit 
through 4 weeks following the Week 52 visit, inclusive. 
10.6.3.2. 
Iron Endpoints 
Iron Endpoints 
Iron Medications 
• During the study, subjects may be receiving iron in multiple routes, including: 
o IV iron 
o Oral iron 
o Other iron (including intramuscular, subcutaneous, and hemodialysis/dialysate) 
• Note: The iron route categories above will be determined using the route on the 
Prior/Concomitant Medication – Iron Therapy record. In addition, ferric citrate records 
recorded on the Prior/Concomitant Medication – Metabolic Bone Disease Therapy 
eCRF form will also be summarized as oral iron use. 
Baseline Iron Use 
• The number and percentage of subjects in the following iron use categories at baseline will 
be summarized: 
o IV iron use only 
o Oral iron use only 
o Other iron use only 
o IV and oral iron use only 
o IV and other iron use only 
o Oral and other iron use only 
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o IV, oral, and other iron use 
o No iron use 
• When determining baseline iron use, the gap factors mentioned below in the IV iron 
standardization algorithm will be applied to the end date for each iron record, and the 
baseline period of 10 weeks before the Randomization date until the day before the 
Randomization date will also be used. 
Standardized IV Iron Dose (mg/week) to Determine Iron Management Action 
• In order to compare between IV iron records, to determine the action taken with IV iron 
therapy in the 8 weeks following the date the IV management threshold was met, the dose 
of IV iron in each associated record will be standardized in terms of mg/month. 
• IV iron therapy concomitant medication records that occur or are ongoing during the 8 
weeks following the date the IV management threshold was met (inclusive), will be selected 
and ordered by start and end date. 
o If there is a record has a start date on the date the IV management threshold 
was met, and a prior record has an end date on the day before the IV 
management threshold was met, this prior record will be selected and 
considered as well. 
• The standardization will be carried out with the following formula: 
o Standardized IV iron dose (mg/week) = IV iron drug dose (mg) * frequency 
 
Note: Frequency defined as follows: 
Frequency (from eCRF) 
Frequency 
(for standardization formula) 
2 times per week 
2 
3 times per week 
3 
4 times per week 
4 
5 times per week 
5 
BID 
14 
Once daily 
7 
One time dose 
1 
Every 12 Hours 
14 
Every 2 weeks 
0.5 
Every 4 weeks 
0.25 
Once a month 
0.23 
Once a week 
1 
TID 
21 
Standardized Baseline IV Iron Dose (mg/month) 
• In order to calculate the baseline average monthly IV iron dose, the dose of IV iron will 
be standardized to obtain a continuous single unit IV iron dose in terms of mg/month for 
the period from 10 weeks before the Randomization date to the day before the 
Randomization date. 
• IV iron therapy concomitant medication records that occur or are ongoing during the 
period from the (the Randomization date – 10 weeks) to the Randomization date will be 
selected and ordered by start and end date. 
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Iron Endpoints 
• The standardization will be carried out with the following formula: 
o Standardized IV iron dose (mg/week) = IV iron drug dose (mg) * frequency 
 
Note: Frequency and Gap Factors defined as follows: 
Frequency (from eCRF) 
Frequency 
(for standardization formula) 
Gap Factor 
2 times per week 
2 
2.5 days 
3 times per week 
3 
1.33 days 
4 times per week 
4 
0.75 day 
5 times per week 
5 
0.4 day 
BID 
14 
0 days 
Once daily 
7 
0 days 
One time dose 
1 
n/a 
Every 12 Hours 
14 
0 days 
Every 2 weeks 
0.5 
13 days 
Every 4 weeks 
0.25 
27 days 
Once a month 
0.23 
29 days 
Once a week 
1 
6 days 
TID 
21 
0 days 
 
• If the frequency of the record is not ‘one time dose’, then duration is calculated as 
follows: 
o If the concomitant medication record start date  Randomization date, the 
duration of the record is 0. 
o If the concomitant medication record end date + gap factor < (Randomization 
date – 10 weeks), the duration of the record is 0. 
o If the concomitant medication record end date + gap factor  (Randomization 
date – 10 weeks) or the record is ongoing, the duration of the record will be 
calculated as Stop Date – Start Date +1 day where: 
▪ Start date will be the latest of (concomitant medication record start date 
and the Randomization date – 10 weeks). 
▪ Stop date will be the earliest of (concomitant medication record stop 
date + gap factor and the day before randomization). 
• If the frequency of the record is ‘one time dose’, then: 
o If concomitant medication record start date < Randomization date – 10 weeks, 
or if Randomization date  concomitant medication record start date, then 
duration of the record is 0. 
o If Randomization date – 10 weeks  concomitant medication record start date < 
Randomization date, then: 
▪ Frequency (for standardization formula) = 1 
▪ Duration = 7 days 
• The total dose for each IV iron record will be: Standardized dose*duration/7 days 
• A weighted mean will then be used to obtain the baseline monthly IV iron dose: 
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o Mean baseline monthly IV iron dose = [(IV iron total doseRecord 1) + ... + (IV iron 
total doseRecord n)]/[( Randomization Date – Screening Week -2 Visit 
Date)/30.4375 days]. 
Standardized IV Iron Dose (mg/month) from Randomization to Week 52 
• In order to calculate the average monthly IV iron dose from Randomization to Week 52, the 
dose of IV iron will be standardized to obtain a continuous single unit IV iron dose in terms of 
mg/month for the period from the Randomization date to the Week 52 visit date while the 
subject is on treatment and before their first RBC or whole blood transfusion.  
o Note: Subjects who are randomized but never treated will not have a value for 
average monthly IV iron from Randomization to Week 52.  
• IV iron therapy concomitant medication records that occur or are ongoing during the period 
from the subject’s Randomization date – 10 weeks to the Week 52 visit date will be selected 
and ordered by start date and end date. 
• The standardization will be carried out with the following formula: 
o Standardized IV iron dose (mg/week) = IV iron drug dose (mg) * frequency 
 
Note: Frequency and Gap Factors defined as follows: 
Frequency (from eCRF) 
Frequency 
(for standardization formula) 
Gap Factor 
2 times per week 
2 
2.5 days 
3 times per week 
3 
1.33 days 
4 times per week 
4 
0.75 day 
5 times per week 
5 
0.4 day 
BID 
14 
0 days 
Once daily 
7 
0 days 
One time dose 
1 
n/a 
Every 12 Hours 
14 
0 days 
Every 2 weeks 
0.5 
13 days 
Every 4 weeks 
0.25 
27 days 
Once a month 
0.23 
29 days 
Once a week 
1 
6 days 
TID 
21 
0 days 
 
• If the frequency of the record is not ‘one time dose’, then duration is calculated as follows: 
o If the concomitant medication record start date > earliest of (treatment stop date +1 
and Week 52 visit date), the duration of the record is 0. 
o If the concomitant medication record end date + gap factor < Randomization date, 
the duration of the record is 0. 
o If the concomitant medication record end date + gap factor  Randomization date or 
the record is ongoing, the duration of the record will be calculated as Stop Date – 
Start Date +1 day where: 
▪ Start date will be the latest of (concomitant medication record start date, 
randomization date, treatment start date). 
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▪ Stop date will be the earliest of (concomitant medication record stop date + 
gap factor, first transfusion date (RBC or whole blood), treatment stop date 
+ 1, and the Week 52 visit date). 
• If the frequency of the record is ‘one time dose’, then: 
o If concomitant medication record start date < treatment start date, or if earliest of 
(first transfusion date (RBC or whole blood), treatment stop date +1 and Week 52 
visit date) < concomitant medication record start date, then duration of the record is 
0. 
o If latest of (Randomization date, treatment start date)  concomitant medication 
record start date  earliest of (first transfusion date (RBC or whole blood), treatment 
stop date + 1 and Week 52 visit date), then: 
▪ Frequency (for standardization formula) = 1 
▪ Duration = 7 days 
• The total dose for each IV iron record will be: Standardized dose*duration/7 days 
• A weighted mean will then be used to obtain the monthly IV iron dose from Randomization 
to Week 52: 
Mean monthly IV iron dose from Randomization to Week 52 while on treatment =  
[(IV iron total doseRecord 1) + ... + (IV iron total doseRecord n)] / {[earliest of (treatment stop date + 1, 
Week 52 Visit Date) – treatment start date + 1] / 30.4375 days}. 
Standardized Monthly IV Iron Dose (mg/month) from Week 28 to Week 52 (EP Average 
Monthly IV Iron Dose) 
• In order to calculate the average monthly IV iron dose from Week 28 to Week 52, the dose 
of IV iron will be standardized to obtain a continuous single unit IV iron dose in terms of 
mg/month for the period from the Week 28 visit date to the Week 52 visit date while the 
subject is on treatment and before their first RBC or whole blood transfusion. 
o Note: Subjects who are randomized but never treated, who have a RBC or 
whole blood transfusion, or who permanently discontinue randomized treatment 
on or before the Week 28 visit date will not have a value for average monthly IV 
iron from Week 28 to Week 52.  
• IV iron therapy concomitant medication records that occur or are ongoing during the period 
from the subject’s Week 24 visit date to the Week 52 visit date will be selected and ordered 
by start date and end date. 
• The standardization will be carried out with the following formula: 
o Standardized IV iron dose (mg/week) = IV iron drug dose (mg) * frequency 
 
Note: Frequency and Gap Factors defined as follows: 
Frequency (from eCRF) 
Frequency 
(for standardization formula) 
Gap Factor 
2 times per week 
2 
2.5 days 
3 times per week 
3 
1.33 days 
4 times per week 
4 
0.75 day 
5 times per week 
5 
0.4 day 
BID 
14 
0 days 
Once daily 
7 
0 days 
One time dose 
1 
n/a 
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Every 12 Hours 
14 
0 days 
Every 2 weeks 
0.5 
13 days 
Every 4 weeks 
0.25 
27 days 
Once a month 
0.23 
29 days 
Once a week 
1 
6 days 
TID 
21 
0 days 
 
• If the frequency of the record is not ‘one time dose’, then duration is calculated as follows: 
o If the concomitant medication record start date > earliest of (treatment stop date + 1 
and Week 52 visit date), the duration of the record is 0. 
o If the concomitant medication record end date + gap factor < Week 28 visit date, the 
duration of the record is 0. 
o If the concomitant medication record end date + gap factor  Week 28 visit date or 
the record is ongoing, the duration of the record will be calculated as Stop Date – 
Start Date +1 day where: 
▪ Start date will be the latest of (concomitant medication record start date, 
and the Week 28 visit date). 
▪ Stop date will be the earliest of (concomitant medication record stop date + 
gap factor, first transfusion date (RBC or whole blood), treatment stop date 
+ 1, and the Week 52 visit date). 
• If the frequency of the record is ‘one time dose’, then: 
o If concomitant medication record start date < Week 28 visit date, or if earliest of 
(first transfusion date (RBC or whole blood), treatment stop date + 1 and Week 52 
visit date) < concomitant medication record start date, then duration of the record is 
0. 
o If Week 28 visit date  concomitant medication record start date  earliest of (first 
transfusion date (RBC or whole blood), treatment stop date +1 and Week 52 visit 
date), then: 
▪ Frequency (for standardization formula) = 1 
▪ Duration = 7 days 
• The total dose for each IV iron record will be: Standardized dose*duration/7 days 
• A weighted mean will then be used to obtain the monthly IV iron dose from Week 28 to 
Week 52: 
Mean monthly IV iron dose from Week 28 to Week 52 while on treatment = 
[(IV iron total doseRecord 1) + ... + (IV iron total doseRecord n)] / {[earliest of (treatment stop 
date + 1, Week 52 Visit Date) – Week 28 Visit Date + 1]/30.4375 days}. 
Iron Use by Quarter 
• The number and percentage of subjects in the following iron use categories defined by route 
will be summarized by quarters listed below for Average Quarterly IV Iron Dose: 
o IV iron use only 
o Oral iron use only 
o Other iron use only 
o IV and oral iron use only 
o IV and other iron use only 
o Oral and other iron use only 
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Iron Endpoints 
o IV, oral, and other iron use 
o No iron use 
• When determining iron use by quarter, the gap factors mentioned in the IV iron 
standardization algorithm will also be applied to the end date for each iron record. 
• Although baseline iron use is defined based on a period of 10 weeks, it will also be included 
in summaries of iron use by quarter. 
Average Quarterly IV Iron Dose 
• The standardized IV iron (mg/month) dose will be summarized by quarters, where quarters 
will be defined using study visits as follows: 
o Baseline 
o For summaries of on & off treatment IV iron dose: 
▪ Quarter 1 = [Randomization date – Week 12)  
o For summaries of on-treatment IV iron dose: 
▪ Quarter 1 = [Treatment start date + 1 – Week 12)  
▪ Quarter 2 = [Week 12 – Week 24) 
▪ Quarter 3 = [Week 24 – Week 36) 
▪ Quarter 4 = [Week 36 – Week 48) 
• To determine the planned start date and end date of quarters, the visit end date (from the 
SV domain) will be used. If there is not a corresponding visit, or if the subject is missing that 
visit, the planned visit date (Randomization date + 7*x) will be used, where x is the 
scheduled week (e.g., Week 24, x = 24). 
• A subject’s quarterly average IV iron dose will end at the earliest of the following: 
o For summaries of on & off treatment IV iron dose: death date, study 
completion/withdrawal date, and the planned quarter end date. 
o For summaries of on-treatment IV iron dose: death date, first transfusion (RBC 
or whole blood), study completion/withdrawal date, treatment stop date + 1, and 
the planned quarter end date. 
• The standardization algorithm for IV iron described earlier in the table will be used to 
determine the standardized IV iron dose (mg/month) during each quarter. 
• Although the standardized baseline IV iron dose is defined based on a period of 10 weeks, it 
will also be included in summaries of average quarterly IV iron dose. 
TIBC 
• TIBC will be calculated automatically by the central laboratory using: 
o TIBC = UIBC + total iron 
TSAT 
• TSAT will be calculated automatically by the central laboratory using: 
o TSAT = 100 * (Serum Iron/TIBC) 
Average Quarterly TSAT and Ferritin 
• The average TSAT and Ferritin values will be summarized by quarters, where quarters will 
be defined as they are for Average Quarterly IV Iron Dose, with the following exception: 
o Baseline average quarterly ferritin and TSAT will take the average of all 
available records before or on randomization ferritin and TSAT values. 
 
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Iron Endpoints 
Note: any unscheduled values falling within these quarters will be used in the calculation of the 
quarterly average value. 
Meeting Iron Management Criteria 
Iron therapy will be administered if at any visit: 
• Ferritin  100 ng/mL and/or TSAT  20% 
All iron must be stopped if at any visit: 
• Ferritin > 800 ng/mL and TSAT >20%, or 
• TSAT > 40% 
Subjects meeting iron management criteria requiring starting and stopping of iron administration 
on the same day: 
• Ferritin 100 ng/mL and TSAT > 40% 
 
10.6.3.3. 
Time to Rescue 
Time to Stopping Randomized Treatment Due to Meeting Rescue Criteria 
Meeting Rescue Evaluation Criteria and Rescue Criteria 
• Subjects meeting evaluation criteria for rescue are identified from the Rescue Treatment 
eCRF. Subjects with a record on this form are considered to have met evaluation criteria for 
rescue. It is possible that a subject could be evaluated for rescue more than once, and in 
that case a subject would have multiple records on this form. 
• Subjects unable to be evaluated for rescue are subjects who met evaluation criteria for 
rescue, but were unable to be assessed at the 4 week check (e.g., subjects who died, 
permanently discontinued randomized treatment or withdrew from the study before the 4 
week check). The outcome of initial intervention eCRF field on the Rescue Treatment eCRF 
will be blank for these subjects. 
• Subjects meeting rescue are identified by the response ‘Met rescue criteria’ to the outcome 
of initial intervention question on the Rescue Treatment eCRF. 
Event Date 
• Treatment stop date when the primary reason and subreason for randomized treatment stop 
are: 
o Primary reason: Subject reached protocol-defined stopping criteria 
o Subreason: Rescue 
General Definitions 
• Time to event (days) = date of event – randomization date +1 
• Censored time (days) = censoring date – randomization date + 1 
• Rescue person years = (cumulative total time to stopping randomized treatment for subjects 
who stopped randomized treatment due to meeting rescue criteria + cumulative total of 
censoring time for subjects who did not stop randomized treatment due to meeting rescue 
criteria) / 365.25 
• Rescue incidence rate (per 100 person years) = (100 * number of subjects who stopped 
randomized treatment due to meeting rescue criteria) / rescue person years 
• Rescue absolute rate difference (per 100 person years) = daprodustat rescue incidence rate 
(per 100 person years) – darbepoetin alfa rescue incidence rate (per 100 person years) 
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Time to Stopping Randomized Treatment Due to Meeting Rescue Criteria 
Time Period for Treatment Discontinuation 
The period for treatment discontinuation begins at randomization. The end of this time period is 
defined as follows: 
• For subjects who did not take randomized treatment, use the date of randomization 
• For subjects whose treatment stop date is missing and who took randomized treatment, use 
study conclusion date 
• For subjects either continuing on study past treatment stop date or completing/withdrawing 
on the same day as treatment stop date, use treatment stop date 
 
Any events that occurred before the start of this time period are considered to be prior to the 
time period for treatment discontinuation, and any endpoints that occurred after the end of this 
time period are considered to be post the time period for treatment discontinuation. 
10.6.3.4. 
RBC and Whole Blood Transfusion Endpoints 
Number of RBC and Whole Blood Transfusions 
• The number of transfusions associated with each RBC and Whole Blood Transfusion record 
is determined by the frequency, start date, end date and number of units, as described 
below. 
• Only on-treatment transfusions are included. “End date” below refers to the end date defined 
for the transfusion, or the end of the on-treatment period, if sooner (see Section 10.4.1). 
• For records with a frequency of “Once only” or “Continuous infusion”, each record is 
considered to be a single transfusion (regardless of start and end dates or number of units). 
• For records with a frequency of “Once daily”, the number of transfusions will equal the 
duration (end date – start date +1). 
• For records with a frequency of “PRN”, or where the frequency is unknown, the number of 
transfusions for each record will be equal to the number of units recorded. 
• For other transfusion records, the number of transfusions will equal the duration (end date – 
start date +1) times a multiplier, as defined below: The number of transfusions should be 
rounded up to the nearest integer. 
 
Frequency 
Multiplier 
QM 
0.033 
Every 2 weeks 
0.071 
Once a week 
0.14 
Q4D 
0.25 
2 times per week 
0.29 
Q3D 
0.33 
3 times per week 
0.43 
Every other day 
0.5 
4 times per week 
0.57 
5 times per week 
0.71 
BID 
2 
Q12H 
2 
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TID 
3 
Q8H 
3 
QID 
4 
Q6H 
4 
5 times per day 
5 
Q4H 
6 
Number of RBC and Whole Blood Transfusion Events 
• RBC and Whole Blood Transfusion Events are defined by grouping together on-treatment 
transfusion records. 
• Transfusion records are grouped into the same Transfusion Event if the transfusion start/end 
dates match with or are contained within an Admission/Discharge period, (based on the 
Hospitalization page in the eCRF). 
• For example, the following transfusion records would be grouped into a single Transfusion 
Event, because each transfusion is contained within the same hospital admission/discharge 
period:  
 
Dose 
Frequency 
Transfusion Dates 
Hospitalisation 
Comment 
Start Date 
End Date 
Admission 
Discharge 
1 unit 
Once only 
16FEB2019 16FEB2019 15FEB2019 26FEB2019 1 
Transfusion 
Event 
1 unit 
Once only 
19FEB2019 19FEB2019 15FEB2019 26FEB2019 
• Transfusion records not matching with an Admission/Discharge period are considered to be 
the same Transfusion Event if the gap between transfusions is 5 days or less, with further 
details provided below. For any subject where the frequency is PRN and the transfusion 
start date ≠ end date, the dates of individual transfusions are unknown and the number of 
transfusion events will be counted as one. 
• In the case of a sequence of more than two transfusions, transfusions are considered to be 
the same Transfusion Event if the gap between each transfusion and the start date of the 
first transfusion in the sequence (the “anchor” transfusion) is 5 days or less. The first 
transfusion that is greater than 5 days after the “anchor” transfusion is not included in the 
Transfusion Event, and it becomes the new “anchor” transfusion for a new Transfusion 
Event. 
• In the example below, transfusion records 1 and 2 would be grouped into a single 
Transfusion Event, because the gap between the transfusions (17JAN2019 to 18JAN2019) 
was 5 days or less. Record 3 falls outside this Transfusion Event because the gap between 
the start date (22JAN2019) and the previous anchor date (16JAN2019) is more than 5 days. 
Therefore, 22JAN2019 becomes the new “anchor” transfusion used to define the next 
Transfusion Event. This pattern is repeated, if necessary. N.B.  “anchor” transfusions are 
shown in bold. 
 
# 
Dose 
Frequency 
Transfusion Dates 
Comment 
Start Date 
End Date 
1 
1 unit 
Once only 
16JAN2019 
16JAN2019 
1 Transfusion Event 
2 
1 unit 
Once only 
19JAN2019 
19JAN2019 
3 
1 unit 
Once only 
22JAN2019 
22JAN2019 
1 Transfusion Event 
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4 
1 unit 
Once only 
25JAN2019 
25JAN2019 
5 
1 unit 
Once only 
28JAN2019 
28JAN2019 
1 Transfusion Event 
• Where a non-integer number of units has been entered on the eCRF, this will be rounded up 
to the nearest integer prior to any subsequent derivation (if necessary). 
Number of Units 
• The number of RBC and whole blood units are derived from blood transfusion records. The 
number of units associated with each record is determined by the frequency, start date, end 
date and dose (i.e. number of units recorded), as described below: 
• Only units associated with on-treatment transfusions are included. “End date” below refers 
to the end date defined for the transfusion, or the end of the on-treatment period, if sooner 
(see section 10.4.1). 
• For records with the frequency recorded as “Once only” or “Continuous infusion”, the total 
number of units associated with each record is the number of units recorded (regardless of 
start and end dates) 
• For records with the frequency recorded as “Once daily”, the total number of units 
associated with each record will equal the number of units recorded multiplied by the 
duration (end date – start date +1) 
• For records with the frequency recorded as “PRN”, the total number of units will be equal to 
the number of units recorded (regardless of start and end dates) 
• For other records, the number of units will be equal to the number of units recorded 
multiplied by the duration (end date – start date +1) times a multiplier, as defined for Number 
of RBC and Whole Blood Transfusions above 
• The table below provides multipliers for converting various reported units to Units (which 
should be rounded to up nearest integer).  For example, a transfusion of 450ml represents 
a single unit:  
(450 x 0.0025) = 1.125 (rounded up to 2 Units) 
 
 
• Where a non-integer number of units has been entered on the eCRF, this will be rounded up 
to the nearest integer prior to any subsequent derivation (if necessary). 
• Where a transfusion record has been entered with a missing number of units, the number of 
units associated with the record will be assumed to be 1 unit. 
Reported Units 
Multiplier 
Units 
1 
Milliliters (ml or CC) 
0.0025 
Milligram (mg) 
0.0025 
Milligrams/millilitres (mg/ml) 
0.0025 
Evaluation Period (Weeks 28 to 52) 
• Only transfusion events with a start date from date of week 28 visit to the date of the week 
52 visit will be included 
• Patient Years (PY) = (cumulative total time from date of week 28 visit to the date of the week 
52 visit, for subjects who did not withdraw from randomized treatment during the evaluation 
period + cumulative time from date of week 28 visit to the date of withdrawal from 
randomized treatment, for subjects who withdrew from randomized treatment during the 
evaluation period) / 365.25 
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• Transfusion Events per 100 PY = (100 * number of on-treatment RBC or whole blood 
transfusion events during the evaluation period) / Patient Years (PY) 
• Transfusions per 100 PY = (100 * number of on-treatment RBC or whole blood transfusions 
during the evaluation period) / Patient Years (PY) 
• Units per 100 PY = (100 * number of on-treatment RBC or whole blood transfusion units 
during the evaluation period) / Patient Years (PY) 
Randomization to Week 52 
• Only transfusion events with a start date from the date of randomization to the date of the 
week 52 visit will be included  
• Patient Years (PY) = (cumulative total time from date of randomization to the date of the 
week 52 visit, for subjects who did not withdraw from randomized treatment prior to week 52 
+ cumulative time from date of randomization to the date of withdrawal from randomized 
treatment, for subjects who withdrew from randomized treatment prior to week 52) / 365.25 
• Transfusion Events per 100 PY = (100 * number of on-treatment RBC or whole blood 
transfusion events from the date of randomization to the date of the week 52 visit) / Patient 
Years (PY) 
• Transfusions per 100 PY = (100 * number of on-treatment RBC or whole blood transfusions 
from the date of randomization to the date of the week 52 visit) / Patient Years (PY) 
• Units per 100 PY = (100 * number of on-treatment RBC or whole blood transfusion units 
from the date of randomization to the date of the week 52 visit) / Patient Years (PY) 
Time to First On-Treatment RBC or Whole Blood Transfusion 
• Event Date = Start date for the first on-treatment RBC or whole blood transfusion received 
after treatment start date 
• Censoring Date = date of stopping randomized treatment for subjects who stopped 
randomized treatment, or date of study completion for subjects who did not stop randomized 
treatment 
• Time to event (days) = date of event – treatment start date +1 
• Censored time (days) = censoring date – treatment start date + 1 
• Person years (PY) = (cumulative total time to event date, for subjects who received at least 
one on-treatment RBC or whole blood transfusion + cumulative total of censoring time for 
subjects who did not receive at least one on-treatment RBC or whole blood transfusion) / 
365.25 
• Incidence rate per 100 PY = (100 * number of subjects who received at least one on-
treatment RBC or whole blood transfusion) / person years 
• Absolute rate difference (per 100 person years) = daprodustat incidence rate (per 100 
person years) – darbepoetin alfa incidence rate (per 100 person years) 
 
Time Period for On-Treatment Transfusions 
• The period for capturing on-treatment transfusions begins on the treatment start date +1day. 
The end of this time period is defined as follows: 
o For subjects continuing on study past the (treatment stop date + 1day), use 
(treatment stop date + 1day) 
o For subjects whose study withdrawal/completion date is on or before (treatment 
stop date + 1day), use date of study withdrawal/completion 
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Model Specification 
• Analysis of time to first RBC or whole blood transfusion will be performed using an analysis 
model identical to that described for the time to stopping randomized treatment due to 
meeting rescue criteria (Section 8.1.2). 
• Analysis will include only transfusion occurring during the on-treatment period.. 
Model Results Presentation 
• The model results presentation will be identical to the co-primary MACE model results, with 
the following exception: 
• A single one-sided p-value for the test of superiority of daprodustat vs. darbepoetin alfa will 
be presented (i.e. there will be no test for non-inferiority). 
• A Kaplan-Meier plot will be produced showing the survival function for time to first RBC or 
whole blood transfusion. 
 
10.6.3.5. 
Dose Adjustment Scheme Endpoints 
Dose Adjustment Scheme Endpoints 
General 
• The IRT system assigns all randomized treatment doses in accordance with the dose 
adjustment scheme specified in the protocol.  
• During the study, it is possible for subjects to change randomized treatment doses at both 
scheduled and unscheduled visits.  
• Sites are instructed to complete an exposure record every time dosing instruction is received 
from the IRT, with the exception of re-dispensing situations where the subject is instructed to 
continue using the same randomized treatment. 
Daprodustat Doses 
Sites will enter the dose of daprodustat into exposure records – the daily frequency will be auto-
populated for this randomized treatment. The dose steps of daprodustat are shown below: 
 
 
 
 
 
 
 
 
 
  
Total Daily Dose 
How Administered 
1 mg 
single 1 mg tablet 
2 mg 
single 2 mg tablet 
4 mg 
single 4 mg tablet 
6 mg 
single 6 mg tablet 
8 mg 
single 8 mg tablet 
10 mg 
single 10 mg tablet 
12 mg 
two 6 mg tablets 
16 mg 
two 8 mg tablets 
24 mg 
three 8 mg tablets 
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Darbepoetin Alfa Doses 
Sites will enter the dose and frequency of each dose of darbepoetin alfa into exposure records. 
The dose steps of darbepoetin alfa (including the corresponding total 4-weekly doses) are 
shown below: 
 
 
 
 
 
 
 
 
 
 
 
 
 
Total 4-Weekly 
Dose 
Pre-filled Syringe Dose and 
Frequency 
20 µg 
20 µg every 4 weeks 
30 µg 
30 µg every 4 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 
Assigned Dose at A Scheduled Visit 
• The assigned dose at a particular visit refers to the dose the subject received at that visit, as 
recorded in the eCRF. The assigned dose at Visit X is the dose from the earliest exposure 
record with a start date on or after the Visit X date, but before the Visit X+1 date. 
o 
For example, the assigned dose at the Week 28 visit is the dose from the earliest 
exposure record with a start date on or after the Week 28 visit date, but before the 
Week 32 visit date. 
Most Recent Dose Prior to A Scheduled Visit / End of Treatment 
• The most recent dose prior to a particular visit refers to the dose the subject received in the 
period directly preceding the visit, as recorded in the eCRF. The most recent dose prior to 
Visit X is the dose from the latest exposure record with a start date that is on or after the 
Visit X-1 date and before the Visit X date. 
o 
For example, the most recent dose prior to Week 28 is the dose from the latest 
exposure record with a start date that is on or after the Week 24 visit date and 
before the Week 28 visit date. 
• If a subject permanently stops randomized treatment after Visit X-1 and on or before Visit X, 
the most recent dose prior to Visit X will be the dose from the subject’s final exposure 
record. 
Two Approaches to Dose Adjustment Summaries 
• The first approach counts all dose adjustments, including dose adjustments related to 
periods of dose holds (i.e., IRT assignment of a 0-dose). 
• The second approach does not count dose adjustments related to periods of dose holds. 
However, should the dose that a subject receives following a period of dose hold be 
different from the dose the subject received before the dose hold, this would still count as a 
dose adjustment in this approach. 
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10.6.4. 
Safety 
10.6.4.1. 
CV Safety Endpoints 
CV Safety Endpoints 
Dates for Investigator Reported CV Safety Endpoints 
• All-cause hospitalization: admission date 
• Death: date of death from the Death1 eCRF page 
• Myocardial infarction: date of onset of Myocardial Infarction/Unstable Angina symptoms 
from the MI/UA1 eCRF page 
• Stroke: start date of neurological symptoms from the Stroke/TIA eCRF page 
• Hospitalization for HF: Earliest of (ER admission date, Hospital admission date) from Heart 
Failure eCRF page 
• Thromboembolic event: date of onset of thromboembolic event from the Thromboembolic 
Event eCRF page 
Dates for Adjudicated CV Safety Endpoints 
• Death: event date reported by CEC 
• Myocardial infarction: event date reported by CEC 
o Fatal MI events only identified through a primary cause of death, without a 
corresponding positively adjudicated MI event: death event date reported by 
CEC 
• Stroke: event date reported by CEC 
o Fatal stroke events only identified through a primary cause of death, without a 
corresponding positively adjudicated stroke event: death event date reported by 
CEC 
• Hospitalization for HF: event date reported by CEC 
o Fatal heart failure/cardiogenic shock events only identified through a primary 
cause of death, without a corresponding heart failure event: death event date 
reported by CEC 
• Thromboembolic event (DVT, PE, VAT): event date reported by CEC 
o Fatal PE events only identified through a primary cause of death, without a 
corresponding positively adjudicated PE event: death event date reported by 
CEC 
Due to the design of the CRF, a fatal MI is reported as both an MI and a death. Both of these 
events will go through the adjudication process. It is possible that the MI could be negatively 
adjudicated, while the death is positively adjudicated with a primary cause of acute MI. The 
rationale for this is that the definition of a positively adjudicated MI (contained in the CEC 
charter) is more explicit than the definition of acute MI as a primary cause of death. Therefore, in 
analyses that include MI events without including all-cause mortality, the primary approach will 
be to include only those fatal MI events that correspond to a positively adjudicated MI event. 
These analyses will then be repeated for supportive purposes using all fatal MI events – 
including those fatal MI events only identified through a primary cause of death (i.e., acute MI) 
without a corresponding positively adjudicated MI event. 
 
Additionally, a fatal MI event could have an event date that differs from the death date because 
the subject may have died as a result of the MI but not on the same day. For analysis of first 
occurrence MACE, MI or any other composite endpoint that includes both MI and death, if both 
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the MI and death events are positively adjudicated, the MI date will be used as the event date. 
For analysis of CV mortality only and all-cause mortality only, the death date will be used. 
 
Similarly, fatal stroke events are reported as both a stroke and a death. In analyses that include 
stroke events without including all-cause mortality, the primary approach will be to include only 
those fatal stroke events that correspond to a positively adjudicated stroke event. These 
analyses will be repeated for supportive purposes using all fatal stroke events – including those 
fatal stroke events only identified through a primary cause of death (i.e., stroke) without a 
corresponding positively adjudicated stroke event. For analysis of first occurrence MACE, stroke, 
or any other composite endpoint that includes stroke and death, if both the stroke and death 
events are positively adjudicated, the stroke date will be used as the event date. For analysis of 
CV mortality only and all-cause mortality, the death date will be used. 
 
Fatal heart failure events are reported as both a heart failure and a death. In analyses that 
include hospitalization for heart failure events without including all-cause mortality, a single 
approach which includes only those fatal hospitalization for heart failure events that correspond 
to a positively adjudicated hospitalization for heart failure event will be used. The definition of the 
hospitalization for heart failure endpoint includes requirements around hospitalization which are 
not captured in the associated primary cause of death (heart failure/cardiogenic shock), so 
identification of hospitalization for heart failure events through only a primary cause of death is 
not possible. However, supportive analyses of the hospitalization for heart failure endpoint may 
include all heart failure events. These supportive analyses would then be able to include fatal 
heart failure events from the death page (i.e. primary cause of death = heart failure/cardiogenic 
shock) that do not correspond to a positively adjudicated heart failure event. For analysis of 
hospitalization for heart failure or any composite endpoint that includes hospitalization for heart 
failure and death, if both the hospitalization for heart failure and death events are positively 
adjudicated, the hospitalization for heart failure date will be used as the event date. For analysis 
of CV mortality only and all-cause mortality, the death date will be used. 
Fatal pulmonary embolism events are reported as both a pulmonary embolism and a death. In 
analyses that include pulmonary embolism events (i.e., thromboembolic events) without 
including all-cause mortality, the primary approach will be to include only those fatal pulmonary 
embolism events that correspond to a positively adjudicated pulmonary embolism event. These 
analyses will be repeated for supportive purposes using all pulmonary embolism events – 
including those fatal pulmonary embolism events only identified through a primary cause of 
death (i.e., pulmonary embolism) without a corresponding positively adjudicated pulmonary 
embolism event. For analysis of pulmonary embolism or any composite endpoint that includes 
pulmonary embolism and death, if both the pulmonary embolism and death events are positively 
adjudicated, the pulmonary embolism date will be used as the event date. For analysis of CV 
mortality only and all-cause mortality, the death date will be used. 
 
In the situation that there is a fatal MI (or fatal stroke, hospitalization for heart failure, or 
pulmonary embolism) that does not have both an MI(or stroke, hospitalization for heart failure, or 
pulmonary embolism) endpoint and a death endpoint reported, the date of the event that is 
reported will be used in the analysis of all relevant endpoints. This would additionally apply to 
situations where the MI (or stroke, hospitalization for heart failure, or pulmonary embolism) may 
occur within an analysis period and the death may occur outside of the analysis period; the 
endpoint with the date in the analysis period will be used for all relevant endpoints. 
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Missing or Partial Endpoint Dates 
Missing of Partial Event (Start) Dates 
• If event dates are missing or partial and there is not sufficient information to classify the time 
period of the event, the event will be classified as occurring on-treatment and post-
randomization. The event will also be considered to have occurred during the follow-up for 
cardiovascular events as defined in Section 10.6.4. 
• The following rules for missing or partial event dates for events other than death will be 
implemented as long as the imputed date is after the randomization date. If the imputed date 
is prior to the randomization date, then the date of randomization will be imputed for the 
event date. 
o If only the day of the month is missing, impute the first day of the month (e.g., --
FEB2016 would impute as 01FEB2016) 
o If the month and day of the month are missing, impute 01JAN (e.g., -----2016 
would impute as 01JAN2016) 
o If the year, month, and day of month are missing, impute the randomization 
date 
• The following rules for missing or partial death dates will be implemented as long as the 
imputed date is after the randomization date. If the imputed date is prior to the 
randomization date, then the date of randomization will be imputed for the death date.  
o The latest clinic visit, telephone visit, other contact with subject visit, CV 
endpoint (other than death), AE or SAE date, or date last known to be alive will 
be determined. If the year, month, and day of month of the death are missing 
then the death date will be imputed as the latest of the dates. 
o If only the day of the month of death is missing, then impute the first day of the 
month (e.g., --FEB2016 would impute as 01FEB2016). However, if this imputed 
date results in a date that is prior to the latest clinic visit, telephone visit, other 
contact with subject visit, CV endpoint (other than death), AE or SAE date or 
date last known to be alive then impute the missing day of death as equal to this 
date instead. For example: 
▪ If –FEB2016 is given as the death date and there is a non-fatal MI on 
08FEB2016, then the imputed date of death would be 08FEB2016 
rather than 01FEB2016 such that the death is not before the non-fatal 
MI. 
▪ If –MAR2016 is give as the death date and the latest date is a non-fatal 
MI on 08FEB2016 then the imputed date of death would be 
01MAR2016. 
o If the month and day of the month of death are missing, then impute as 01JAN 
(e.g., -----2016 would impute as 01JAN2016). However, if this imputed date 
results in a date that is prior to the latest clinic visit, telephone visit, other 
contact with subject visit, CV endpoint (other than death), AE or SAE date, or 
date last known to be alive then impute the missing month and day of death as 
equal to this date instead. For example: 
▪ If -----2016 is given as the death date and the latest date is a non-fatal 
MI on 08FEB2016 then the imputed date of death would be 08FEB2016 
rather than 01JAN2016 such that the death is not before the non-fatal 
MI. 
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▪ If -----2017 is given as the death date and the latest date is a non-fatal 
MI on 08FEB2016 then the imputed date of death would be 
01JAN2017. 
o For deaths that occur after subjects have prematurely withdrawn from the study, 
missing or partial dates will be imputed as specified above except if the 
imputation places the death prior to or on the premature withdrawal date. In this 
case the death date will be imputed as the premature withdrawal date.  
 
Missing or Partial Hospitalization End Dates 
• If hospitalization end dates are missing or partial, the following rules for missing or partial 
dates will be implemented as long as the imputed date is before the next hospitalization start 
date or study completion/withdrawal date (if there is no next hospitalization start date). If the 
imputed date is after the next hospitalization start date, then the date of the next 
hospitalization start date – 1day will be used as the hospitalization end date. If the imputed 
date is after the study completion/withdrawal date, then the date of the study 
completion/withdrawal date will be used as the hospitalization end date. 
o If only the day of the month is missing, impute the last day of the month (e.g., --
MAR2016 would impute as 31MAR2016) 
o If the month and day of the month are missing, impute 31DEC (e.g., -----2016 
would impute as 31DEC2016) 
o If the year, month, and day of month are missing, impute the date of study 
completion/withdrawal. 
Order of CV Safety Endpoint Events 
• 
If multiple events occur on the same day or have imputed dates that place them on the 
same day, but it is not clear which event occurred first, then the following order will be 
applied: 
1. MI 
2. Stroke 
3. Hospitalization for Heart Failure 
4. Thromboembolic Event: DVT 
5. Thromboembolic Event: VAT 
6. Thromboembolic Event: PE 
7. Death 
CV Mortality 
• CV mortality includes all deaths indicated as having a cardiovascular primary cause of death 
(including fatal MI and fatal stroke events) as well as deaths with an undetermined primary 
cause of death that are indicated to be either presumed sudden death or presumed 
cardiovascular death. Deaths with an undetermined primary cause of death that are 
indicated to be an unknown death will not be included as a CV mortality event. 
Heart Failure Events 
• The primary heart failure event of interest in this study is hospitalization for heart failure. 
However, investigators are requested to report all potential heart failure events for 
adjudication, even if there was no hospitalization associated with the event. 
• The CEC will categorize heart failure events into one of the following adjudicated event 
types: 
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o Hospitalization for Heart Failure 
o Urgent ER/ED Visit for Heart Failure 
o Urgent Office/Practice Visit for Heart Failure 
o Negative adjudication (i.e., not one of the heart failure events above) 
• For purposes of endpoints that contain hospitalization for heart failure as a component, only 
the events adjudicated by the CEC as Hospitalization for Heart Failure will be included. 
• The concordance table for heart failure events will include the 4 adjudicated event types 
listed above. 
Investigator-reported Endpoint Events for Concordance 
• For purposes of concordance tables, events with an investigator-reported event date  
randomization date during the time period for follow-up of cardiovascular events, that meet 
the following final diagnosis criteria will be considered to be investigator-reported endpoint 
events: 
 
Endpoint 
Investigator-reported final diagnosis (from eCRF) 
Myocardial infarction 
Myocardial infarction 
Stroke 
Primary ischemic stroke (with or without hemorrhagic 
transformation), Primary intracranial hemorrhage, Retinal/ocular 
hemorrhage or infarction, Unknown type of stroke 
Hospitalization for 
Heart Failure 
Systolic heart failure, Diastolic heart failure, Heart failure - 
unspecified type 
 
Additional criteria: 
If admission/discharge times are non-missing, at least one of the 
following must be true (1-3):  
1. Time in hospital is ≥24 hours 
2. Time in ED/ER is ≥24 hours 
3. Consecutive time in hospital + time in ED/ER is ≥24 hours 
Or if admission/discharge times are missing, then at least one of the 
following must be true (4-6): 
4. Change in calendar date between hospital admission and 
discharge 
5. Change in calendar date between ED/ER admission and 
discharge 
6. Change in calendar date between consecutive hospital and 
ED/ER admission and discharge 
Thromboembolic Event 
(DVT, PE, VAT) 
Deep Vein Thrombosis (DVT), Pulmonary Embolism (PE), Vascular 
Access Thrombosis 
All-cause mortality 
Any death record 
CV mortality 
Any Cardiovascular primary cause of death 
Non-CV mortality 
Any Non-Cardiovascular primary cause of death 
All-cause Hospitalization 
• All-cause hospitalization events are defined to be hospital admissions recorded on the 
Hospitalization eCRF form with a hospitalization duration  24 hours. 
• Hospitalization rate (per year) across the study = number of all-cause hospitalization events 
/ [follow-up time (days) / 365.25]. 
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General Definitions 
• Time to event (days) = date of event – randomization date +1 
• Censored time (days) = censoring date – randomization date + 1 
• First event person years = (cumulative total time to first event for subjects who have the 
event + cumulative total of censoring time for subjects without the event) / 365.25 
• First event incidence rate (per 100 person years) = (100 * number of subjects with at least 1 
event) / first event person years 
• First event absolute rate difference (per 100 person years) = daprodustat incidence rate (per 
100 person years) – darbepoetin alfa incidence rate (per 100 person years) 
 
Evaluation Time Periods for CV Endpoints 
Time Period for Follow-up of Cardiovascular Endpoints 
The period for capturing CV safety endpoints begins at randomization. The end of this time 
period is the date of study completion/withdrawal, with the exception that if a death has been 
reported in the clinical database after this time, then the death will be included in the analysis. 
 
Any endpoints that occurred before the start of this time period are considered to be prior to the 
time period for follow-up of cardiovascular safety events, and any endpoints that occurred after 
the end of this time period are considered to be post the time period for follow-up of 
cardiovascular safety endpoints. 
Time Period for Vital Status 
The period for capturing vital status begins at the date of randomization. The end of this time 
period is defined as follows: 
• For all subjects known to have died, use the date of death 
• For all subjects who complete the study, use the study completion date (see Section 10.6.1) 
• For all subjects who withdraw from the study, but vital status has been ascertained, and are 
known to have not died – use the latest date last known to be alive. If vital status has not 
been ascertained following study withdrawal, use the study withdrawal date. 
 
Any endpoints that occurred before the start of this time period are considered to be prior to the 
time period for vital status, and any endpoints that occurred after the end of this time period are 
considered to be post the time period for vital status. 
 
10.6.4.2. 
Blood Pressure Endpoints 
Blood Pressure Endpoints 
Pre- and Post- Dialysis BP 
• For subjects undergoing dialysis in-clinic, both pre- and post- dialysis BP values will be 
measured. 
• Unless otherwise specified, for summaries and analyses of BP values, the post-dialysis BP 
values for subjects undergoing dialysis in-clinic will be used.  
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Blood Pressure Endpoints 
End of Treatment BP Value 
• See Section 10.6.1. 
Mean Arterial Pressure (MAP) 
• MAP = [(2*DBP)+SBP]/3 
Blood Pressure Exacerbations 
• BP exacerbations will be defined as ( 25 mmHg increase from baseline or SBP  180 
mmHg or DBP  15 mmHg increase from baseline or DBP  110 mmHg) and grouped by 
type as follows: 
o BP exacerbations 
▪ SBP exacerbations 
• 
 25 mmHg increase from baseline or  
• SBP  180 mmHg 
o SBP  180 mmHg and baseline SBP < 180 mmHg 
(including subjects with a missing baseline SBP) 
o SBP  180 mmHg and baseline SBP ≥180 mmHg 
▪ DBP exacerbations 
• 
 15 mmHg increase from baseline or  
• DBP  110 mmHg 
o DBP  110 mmHg and baseline DBP < 110 mmHg 
(including subjects with a missing baseline DBP) 
o DBP  110 mmHg and baseline DBP ≥110 mmHg 
Notes:  
• BP values used to assess BP exacerbations must be on-treatment (see Section 10.4.1), 
unless otherwise specified. 
• BP values used to assess BP exacerbations can be scheduled or unscheduled. 
• For visits where BP is measured in triplicate, the average of the 3 BP values will be 
used to assess BP exacerbations. 
• For subjects who have in-clinic dialysis, BP exacerbations identified using post-dialysis 
BP values will be used in summaries and analyses of BP exacerbations, unless 
otherwise specified. 
• Subjects with multiple exacerbation events on the same calendar date for each type 
defined above are considered to have one exacerbation event for event counts by type. 
For example, a subject with a SBP and a DBP exacerbation on the same date would 
count in each of the SBP and DBP types, but would only count as one BP exacerbation 
event in in the total BP exacerbation type. 
Blood Pressure Exacerbation Event Date 
• Date of BP exacerbation 
On-Treatment BP Medication 
• See Section 10.4.1 for treatment states for concomitant medications. 
General 
• Censored time (days) = last non-zero dose date treatment start date + 1 
• BP exacerbation person years = (cumulative total of censoring time for all subjects) / 365.25 
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• BP exacerbation event incidence rate (per 100 person years) = (100 * number of BP 
exacerbations) / BP exacerbation person years 
Changes in Blood Pressure Medications 
• No change: no new anti-hypertensive records since baseline (day before randomized 
treatment start date) and no change to anti-hypertensive records since baseline until date of 
visit while on randomized treatment 
• Increase: addition of new anti-hypertensive records for any reason or a change with primary 
reason for changing dose/frequency or stopping of ‘increased to…’ since baseline until date 
of visit while on randomized treatment 
• Decrease: discontinuation of an anti-hypertensive record with primary reason for change 
starting with “discontinued” or a change with a reason of ‘Decreased due to…’ since 
baseline until date of visit while on randomized treatment 
• Switch = change with a reason of ‘switched to another agent...’ since baseline until date of 
visit while on randomized treatment  
Cumulative Changes in Blood Pressure Medications 
• For the summary of cumulative changes excluding “Once only” and “PRN” records, 
cumulative change will be counted from the date of first randomized treatment to the 
Week 52 visit date while on randomized treatment. If a new anti-hypertensive 
medication is added during this time, it will be counted as one change. If the medication 
also stops during this period, then it will count as two changes (one change due to 
starting, and one change due to stopping). The cumulative number of changes will be 
calculated by adding up the changes for all records during this time period.  
• For the summary of cumulative changes for “Once only” records only, cumulative 
change will be counted from the date of first randomized treatment to the Week 52 visit 
date while on randomized treatment. Since “Once only” doses will have same start and 
stop dates, a new anti-hypertensive medication record during this period will be counted 
as one change. As “once only” doses are likely administered to control BP during 
dialysis, so they are considered part of a single titration regimen, hence multiple “once 
only” records on the same date will be counted as one change. 
10.6.4.3. 
Adverse Events 
Adverse Events 
AEs of Special Interest 
Adverse events of special interest are classified as follows: 
• Thrombosis and/or tissue ischemia secondary to excessive erythropoiesis  
• 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 
• Worsening of hypertension 
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Adverse Events 
Potential AESIs will be identified through a pre-defined terms of interest process in which pre-
defined lists of AE preferred terms corresponding with each AESI will be used to identify events 
considered to be potential AESIs. Sites will be prompted via query to complete any necessary 
additional information for these AESIs in the eCRF. 
 
For the category of thrombosis and/or tissue ischemia secondary to excessive erythropoiesis, 
after the terms of interest list has been applied, the additional Hgb criteria described below will 
be applied to identify only those events that are considered to be secondary to excessive 
erythropoiesis as meeting the AESI definition for thrombosis and/or tissue ischemia secondary to 
excessive erythropoiesis. 
Thrombosis and tissue ischemia events will be considered to be secondary to excessive 
erythropoiesis if during the window of [AE start date – 30 days, AE start date +15 days] any one 
of the following 3 events occurs: 
• Any Hgb value  13 g/dL (measured pre-dialysis) 
• Hgb increase > 2 g/dL over 2 weeks (+1 week) 
o Note: for programming purposes, a +1 week window is applied, corresponding 
to the allowable visit window, to look for increases > 2 g/dL over 3 weeks 
• Hgb increase > 4 g/dL over 4 weeks (+1 week) 
o Note: for programming purposes, a +1 week window is applied, corresponding 
to the allowable visit window, to look for increases > 4 g/dL over 5 weeks 
 
To identify Hgb increases that meet the increase criterion above, all Hgb values taken within [AE 
start date – 58 days, AE start date + 15 days] will be identified. This corresponds to identifying 
Hgb values that occurred 4 weeks before the [AE start date – 30 days, AE start date +15 days] 
window of interest. HemoCue Hgb and central laboratory Hgb values will then be evaluated 
separately to identify increases, so that HemoCue and central laboratory Hgb values are not 
compared to each other to identify an increase. 
For HemoCue Hgb and separately for central laboratory Hgb values, if there is a Hgb value (or 
daily Hgb average) within the [AE start date – 30 days, AE start date +15 days] window and an 
earlier Hgb value (or daily Hgb average) that is within the larger [AE start date – 58 days, AE 
start date + 15 days] window, and the amount of time between the two Hgb values is: 
• Between 1 day and 3 weeks, inclusive, then the Hgb values will be compared to 
determine if there has been a Hgb increase > 2g/dL. 
• Between 15 days and 5 weeks, inclusive, then the Hgb values will be compared to 
determine if there has been a Hgb increase > 4g/dL. 
Unscheduled Hgb values will also be used in the assessment of secondary to excessive 
erythropoiesis following the guidance specified in Section 10.6.3 for unscheduled Hgb values 
and multiple Hgb values on the same date. 
Pre-defined Lists of AE Preferred Terms Corresponding with Each AESI 
Thrombosis and/or tissue ischemia secondary to excessive erythropoiesis 
• Narrow SMQ: Embolic and thrombotic events, arterial 
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• Narrow SMQ: Embolic and thrombotic events, venous 
• Narrow SMQ: Embolic and thrombotic events, vessel type unspecified and mixed arterial 
and venous 
• Broad SMQ: Thrombophlebitis 
• Additional Preferred Terms:  
o Vascular access site occlusion 
o Stoma site ischaemia 
o Vascular access site complication 
o Subendocardial ischaemia 
o Retinal vascular occlusion 
o Uterine ischaemia 
o Administration site ischaemia 
o Vaccination site ischaemia 
o Anterior segment ischaemia 
o Vestibular ischaemia 
o Application site ischaemia 
o Cerebral small vessel ischaemic disease 
o Biliary ischaemia 
o Colitis ischaemic 
o Bone marrow ischaemia 
o Delayed ischaemic neurological deficit 
o Brain stem ischaemia 
o Hypoxic-ischeaemic encephalopathy 
o Catheter site ischaemia 
o Ischaemic cardiomyopathy 
o Cerebellar ischaemia 
o Ischaemic cerebral infarction 
o Cerebral ischaemia 
o Ischaemic contracture of the left ventricle 
o ECG signs of myocardial ischaemia 
o Ischaemic enteritis 
o Gastrointestinal ischaemia 
o Ischaemic gastritis 
o Graft ischaemia 
o Ischaemic heart disease prophylaxis 
o Hepatic ischaemia 
o Ischaemic hepatitis 
o Implant site ischaemia 
o Ischaemic limb pain 
o Infusion site ischaemia 
o Ischaemic mitral regurgitation 
o Injection site ischaemia 
o Ischaemic nephropathy 
o Intestinal ischaemia 
o Ischaemic neuropathy 
o Ischaemia 
o Ischaemic pancreatitis 
o Macular ischaemia 
o Ischaemic skin ulcer 
o Medical device site ischaemia 
o Ischaemic stroke 
o Myocardial ischaemia 
o Necrosis ischaemic 
o Peripheral ischaemia 
o Ocular ischaemic syndrome 
o Renal ischaemia 
o Optic ischaemic neuropathy 
o Retinal ischaemia 
o Reversible ischaemic neurological deficit 
o Spinal cord ischaemia 
o Transient ischaemic attack 
 
Death, myocardial infarction, stroke, heart failure, thromboembolic events, thrombosis of 
vascular access 
• Death: all fatal SAEs 
• Myocardial infarction:  
o Broad SMQ: Myocardial infarction 
o Additional Preferred Terms: 
▪ Angina pectoris 
▪ Anginal equivalent 
▪ Cardiac arrest 
▪ Chest discomfort 
▪ Chest pain 
▪ Myocardial ischaemia 
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Adverse Events 
▪ Prinzmetal angina 
▪ Non-cardiac chest pain 
• Stroke:  
o Broad SMQ: Conditions associated with central nervous system haemorrhages 
and cerebrovascular accidents 
o Narrow SMQ: Ischaemic central nervous system vascular conditions 
o Narrow SMQ: Central nervous system vascular disorders, not specified as 
haemorrhagic or ischaemic 
• Heart failure: Narrow SMQ: Cardiac failure 
• Thromboembolic events & thrombosis of vascular access: 
• Narrow SMQ: Embolic and thrombotic events, arterial 
• Narrow SMQ: Embolic and thrombotic events, venous 
• Narrow SMQ: Embolic and thrombotic events, vessel type unspecified and mixed 
arterial and venous 
• Broad SMQ: Thrombophlebitis 
• Additional Preferred Terms:  
o Vascular access site occlusion 
o Vascular access site complication 
o Retinal vascular occlusion 
 
Cardiomyopathy 
• Narrow SMQ: Cardiomyopathy 
Pulmonary artery hypertension 
• High Level Term: Pulmonary hypertensions 
• Additional Preferred Terms: 
o Right ventricular dilatation 
o Right ventricular enlargement 
o Right ventricular dysfunction 
o Right ventricular failure 
o Right ventricular ejection fraction decreased 
o Right ventricular hypertrophy 
 
Cancer-related mortality and tumor progression and recurrence 
• Narrow SMQs: 
o Biliary malignant tumours 
o Myelodysplastic syndrome 
o Biliary tumours of unspecified 
malignancy 
o Oropharyngeal neoplasms 
o Breast malignant tumours 
o Ovarian malignant tumours 
o Breast tumours of unspecified 
malignancy 
o Ovarian tumours of unspecified 
malignancy 
o Liver malignant tumours 
o Prostate malignant tumours 
o Liver tumours of unspecified malignancy 
o Prostate tumours of unspecified 
malignancy 
o Malignancy related conditions 
o Tumour lysis syndrome 
o Haematological malignant tumours 
o Skin malignant tumours 
o Non-haematolgoical malignant tumours 
o Skin tumours of unspecified malignancy 
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Adverse Events 
o Haematological tumours of unspecified 
malignancy 
o Uterine and fallopian tube malignant 
tumours 
o Non-haematological tumours of 
unspecified malignancy 
o Uterine and fallopian tube tumours of 
unspecified malignancy 
o Malignant lymphomas 
 
 
• Additional Preferred Terms: 
o Aplastic anaemia 
o Pancytopenia 
o Cytopenia 
o Aplasia pure red cell 
 
Esophageal and gastric erosions 
• High Level Terms: 
o Duodenal ulcers and perforation 
o Oesophageal ulcers and perforation 
o Gastric ulcers and perforation 
o Peptic ulcers and perforation 
o Gastrointestinal ulcers and perforation, site 
unspecified 
 
• Additional Preferred Terms: 
o Haematemesis 
o Helicobacter duodenitis 
o Gastrointestinal haemorrhage 
o Helicobacter gastritis 
o Upper gastrointestinal haemorrhage 
o Melaena 
 
Proliferative retinopathy, macular edema, choroidal neovascularization 
• Broad SMQ: Retinal disorders 
Exacerbation of rheumatoid arthritis 
• High Level Term: Rheumatoid arthropathies 
• Additional Preferred Terms: 
o Rheumatoid factor increased 
o Rheumatoid factor quantatative increased 
o Rheumatoid factor positive 
 
 
Worsening of hypertension 
• Narrow SMQ: Hypertension 
Blood Pressure Events 
BP events will be identified during the study via programmatic sweeps of AE and SAE terms 
entered into the eCRF (using the narrow SMQ for hypertension). AEs identified this way will 
require an additional BP Exacerbation eCRF page to be completed that characterizes the event 
as clinically significant and/or symptomatic.  
In addition, subjects that experience BP values that meet the following criteria at any visit will 
also be considered to have a BP event and be required to complete the Blood Pressure 
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Adverse Events 
Exacerbation eCRF page: 
• SBP: an increase from baseline of  25 mmHg or SBP  180 mmHg 
• DBP: an increase from baseline of  15 mmHg or DBP  110 mmHg 
BP-related SAEs are those SAEs that have been identified via the BP Exacerbation eCRF page. 
General Definitions 
• 
Post-Randomization last contact date for censoring (subjects not having AE) will be defined 
as the study completion date. 
• Treatment emergent last contact date for censoring (subjects not having AE) will be defined 
as follows: 
o 1 day after last non-zero dose date (last non-zero dose date + 1) for subjects not 
having treatment emergent AE and continuing on study past (last non-zero dose 
date + 1) 
o Last non-zero dose date for all other subjects 
• AE Patient Years: (Cumulative total of time to AE for subjects who have the AE + 
Cumulative total of censoring time for subjects without the AE) / 365.25 
o For treatment emergent AEs, the start date of the patient year value for each subject 
should be the treatment start date. 
o For post-randomization AEs, the start date of the patient year value for each subject 
should be the randomization date. 
o For follow-up AEs, the start date of the patient year value for each subject should be 
2 days after the last non-zero dose date (last non-zero dose date + 2). 
• Incidence Rate (per 100 patient years): (100 * Number of subjects with at least 1 AE) / AE 
person years 
• For the analysis of the time to AE onset/worsening, if the AE onset/worsening date is 
missing then the time to AE onset/worsening will be counted as 1 day. 
10.6.4.4. 
Laboratory Parameters 
Laboratory Parameters 
• If a laboratory value which is expected to have a numeric value for summary purposes, has 
a non-detectable level reported in the database, where the numeric value is missing, but 
typically a character value starting with ‘<x’ or ‘>x’ (or indicated as less than x or greater than 
x in the comment field) is present, the number of significant digits in the observed values will 
be used to determine how much to add or subtract in order to impute the corresponding 
numeric value.  
o Example 1: 2 Significant Digits = ‘< x ‘ becomes x – 0.01 
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Laboratory Parameters 
o Example 2: 1 Significant Digit = ‘> x’ becomes x + 0.1 
o Example 3: 0 Significant Digits = ‘< x’ becomes x – 1     
• If there is more than one laboratory value on the same date for the same laboratory test, 
then the laboratory values associated with scheduled visits will be used. Hgb summaries 
and analyses are an exception and should use the data handling conventions outlined in 
Section 10.6.3. 
• For purposes of flagging worst-case post baseline laboratory values: 
o If there are multiple scheduled values on the same day, or only multiple 
unscheduled values on the same day, then the average of the values on that 
day should be used for the purpose of determining the worst-case value. 
• The following will be used to convert laboratory values from SI units to conventional units 
[Iverson, 2007]: 
• MCHC and Albumin: Divide the g/L value by 10 to get the g/dL value. 
• Albumin corrected calcium: Divide the mmol/L value by 0.25 to get the mg/dL value. 
• Creatinine: Divide the umol/L value by 88.4 to get the mg/dL value. 
• eGFR: Multiply the mL/sec/1.73m2 value by 60 to get the mL/min/1.73m2 value. 
• Phosphate: Divide the mmol/L value by 0.323 to get the mg/dL value. 
• BUN: Divide the mmol/L value by 0.357 to get the mg/dL value 
• Total cholesterol, LDL-C and HDL-C: Divide the mmol/L value by 0.0259 to get the 
mg/dL value. 
• Vitamin B9: Divide the nmol/L by 2.266 to get the ng/mL value 
Normal Range Categories, PCI Criteria Categories and Worst Case Values 
• Normal range categories are: To Low, To Normal or No Change, To High 
• PCI criteria categories are: To Low, To w/in Range or No Change, To High 
• Subjects with a missing baseline value are to be assumed to have a normal/within range 
baseline value. 
• The determination of the worst case post baseline value takes into account both planned 
and unscheduled assessments. 
• Worst case can be either High or Low.  
o If a subject has both a decrease ‘To Low’ and an increase ‘To High’, then the subject is 
counted in both the ‘To Low’ and ‘To High’ categories.  
o If a subject was High at baseline and decreases to Low during the time interval, then 
the subject is counted in the ‘To Low’ category. Likewise, if a subject was low at 
baseline and increases to high during the time interval, then the subject is counted in 
the ‘To High’ category. 
o Subjects are only counted in the ‘To Normal or No Change’ or ‘To w/in Range or No 
Change’ category if their values are: 
▪ 
When using normal ranges: Normal at baseline and have no high and no low 
values; When using PCI ranges: Within range at baseline and have no high and 
no low values 
▪ 
High at baseline and do not change to low 
▪ 
Low at baseline and do not change to high 
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10.6.4.5. 
Vital Signs 
Vital Signs 
Pre- and Post- Dialysis HR & Weight 
• For subjects undergoing dialysis in-clinic, both pre- and post- dialysis HR & weight values 
will be measured. 
• Unless otherwise specified, for summaries of HR & weight values, the post-dialysis HR & 
weight values for subjects undergoing dialysis in-clinic will be used.  
• If there is more than one vital sign value on the same date for the same vital sign value, then 
the vital sign values associated with scheduled visits will be used. 
• If there are multiple values from a scheduled visit on the same date, then the average of the 
scheduled values will be used. 
• For purposes of flagging worst-case post baseline vital sign values: 
o If there are multiple scheduled values on the same day, or only multiple 
unscheduled values on the same day, then the average of the values on that 
day should be used for the purpose of determining the worst-case value. 
10.6.4.6. 
COVID-19 
COVID-19 
Exposure Duration 
• For subjects who DO NOT experience the event, the exposure duration is calculated as: 
(last non-zero dose date or end date of time block, whichever occurs sooner – treatment 
start date or start date of time block, whichever occurs later + 1)/365.25 
• For subjects who DO experience the event, the exposure duration is calculated as: 
• (start date of AE – treatment start date or start date of time block, whichever occurs later + 
1)/365.25 
Exposure Adjusted Incidence Rate 
• Exposure adjusted incidence rate (rate/100 PY) = (number of subjects with the adverse 
event during the time block / total exposure duration across all subjects) * 100 
Time Periods 
• Pre COVID-19 pandemic period: the date of interest is prior to the country specific start date 
of COVID-19 pandemic measures. For example, for recruitment and demographic 
summaries, the subject will be counted in the pre COVID-19 period, if the randomization 
date of the subject is prior to the country specific start date of COVID-19 pandemic 
measures. 
• During COVID-19 period: the date of interest is after the country specific start date of 
COVID-19 pandemic measures. For example, for recruitment and demographic summaries, 
the subject will be counted in the during COVID-19 period, if the randomization date of the 
subject is after the country specific start date of COVID-19 pandemic measures. 
• There is currently no post COVID-19 period. 
 
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10.6.5. 
Patient Reported Outcomes 
SF-36 
General Information & Scoring 
• The SF-36 acute version 2 is a 36-item generic quality of life instrument designed to 
measure a subject’s level of performance in the following eight health domains: Physical 
Functioning, Role-Physical (role limitations caused by physical problems), Social 
Functioning, Bodily Pain, Mental Health, Role-Emotional (role limitations caused by 
emotional problems), Vitality, and General Perception of Health. 
• Scoring of the questionnaire data will be performed using Optum PRO CoRE scoring 
software version 1.4 using a norms-based scoring approach using 2009 norms and the 
maximum data recovery mode to handle missing data.  
• The 8 domain scores and scores for the physical and mental component summary 
measures will be provided by the Optum PRO CoRE software. 
EQ-5D-5L 
General 
• The EQ-5D-5L is a self-assessment questionnaire, consisting of five items covering five 
dimensions (mobility, self care, usual activities, pain/discomfort, and anxiety/depression). 
Each dimension is measured by a five-point Likert scale (no problems, slight problems, 
moderate problems, severe problems, and extreme problems). 
• The responses for the five dimensions together form a five-figure description of a health 
state (i.e., the score of 11112 describes the health state of no problems with mobility, self-
care, usual activities or pain/discomfort, but slight problems with anxiety/depression). Each 
of these five-figure health states has an attached valuation (index value), expressed as a 
single index on a scale from 0-1, where 1 is 
 and 0 is 
.  
• EQ-5D-5L health states are converted to a single summary index score by applying a 
country-specific value set formula that essentially attaches weights to each of the levels in 
each dimension. 
• The EuroQol Group’s United Kingdom (UK) value set for the health states will be used for all 
subjects, regardless of country. 
 
EQ-VAS 
General 
• The EQ-VAS is a self-assessment visual analogue scale, ranging from 0=
 – 
100=
.  
 
PGI-S 
General 
• The PGI-S is a 1-item questionnaire designed to assess a subject’s impression of disease 
severity on a 5-point disease severity scale (absent, mild, moderate, severe, or very severe). 
• Scores range from 
 as follows: 
o 
o 
o 
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PGI-S 
General 
o 
o 
 
 
PGI-C 
General 
• The PGI-C is a 1-item questionnaire designed to assess a subject’s impression of change in 
their anemia of CKD on a 7-point Likert-type response scale (very much improved, 
moderately improved, minimally improved, no change, minimally worse, moderately worse, 
or very much worse). 
• Scores range from to
as follows: 
o 
o 
o 
o 
o 
o 
o 
 
CKD-AQ 
General 
• 
The CKD-AQ is a newly-developed 21-item PRO measure assessing symptoms and 
symptom impact in patients with anemia associated with CKD. An interim cut of blinded 
observations from approximately 400 participants, approximately 350 from study 200808 
(GSK Document Number 2015N230102_03) and approximately 50 from study 201410 (GSK 
Document Number. 2015N234534_01), who had completed the baseline (Day 1) CKD-AQ 
was taken to establish the scoring algorithm and any potential domains of the instrument. 
Further details of the scoring can be found in the psychometric report (GSK Document 
Number ). 
• CKD-AQ originally had 23 questions/items, the psychometric analysis identified three 
domains (multi-item scales) and four single items, which consist of 21 items. The three 
domains are: (1) a Tired/Low Energy/Weak scale consisting of ten items – Items 
.; (2) a Chest Pain/Shortness of Breath scale consisting of 
four items – Items
 
 This factor was labeled Chest Pain/Shortness of Breath.); and (3) a Cognitive scale 
consisting of three item – Items
 The four CKD-AQ 
single items are: Items
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CKD-AQ 
General 
 
, were retained based upon their CKD-relevant 
content. The CKD-AQ domains and single-item measures were recoded based on a 0-100 
scoring with 0 representing 
 and 100 
. 
• Scoring instruction:  
o Step 1: For items 1-8, 17-23, recode from 5-pt scale (
 
) to 0-100 (
 scale by using (5-raw score)*25; for items 9-
16, recode from 11-pt scale (
) to 0-
100 scale (
) by using (10-raw score)*10. 
o Step 2: calculate the domain and single item scores as follows: (items 16 and 23 
were NOT used currently based on the psychometric report.) 
▪ Tired/Low Energy/Weak domain: average items
(0-100 scale) 
▪ Chest Pain/Shortness of Breath domain: average items
(0-100 
scale) 
▪ Cognitive domain: average items
(0-100 scale) 
▪ 
 (0-100 
scale) 
▪ 
 (0-100 scale) 
▪ 
 (0-100 scale) 
▪ 
(0-100 scale) 
 
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10.7. 
Appendix 7: Premature Withdrawals & Handling of Missing 
Data 
10.7.1. 
Premature Withdrawals 
Element 
Reporting Detail 
General 
• Subject study completion (i.e. as specified in the protocol) was defined as 
completing all phases of the study through the End of Treatment visit (i.e. 
Week 52), with the following exception: subjects who die while on study are 
also considered as having completed the study.  
• Withdrawn subjects will not be replaced in the study. 
• All available data from subjects who were withdrawn from the study will be 
listed and all available planned data will be included in summary tables and 
figures, unless otherwise specified. 
• Per protocol, subjects may prematurely discontinue study drug but are 
encouraged to remain in the study. 
10.7.2. 
Handling of Missing Data 
Element 
Reporting Detail 
General 
• Missing data occurs when any requested data is not provided, leading to 
blank fields on the collection instrument : 
o These data will be indicated by the use of a “blank” in subject listing 
displays, unless all data for a specific visit are missing in which case the 
data is excluded from the table.  
o Answers such as “Not applicable” and “Not evaluable” are not considered 
to be missing data and should be displayed as such. 
Outliers 
• Any subjects excluded from the summaries and/or statistical analyses will be 
documented along with the reason for exclusion in the clinical study report. 
10.7.2.1. 
Handling of Missing and Partial Dates 
Element 
Reporting Detail 
General 
Partial dates will be displayed as captured in subject listing displays. 
Concomitant 
Medications 
• Partial dates for any concomitant medications recorded in the CRF will be 
imputed using the following convention: 
o If the partial date is a start date, a '01' will be used for the day and 'Jan' 
will be used for the month 
o If the partial date is a stop date, a '28/29/30/31' will be used for the day 
(dependent on the month and year) and 'Dec' will be used for the month. 
• The recorded partial date will be displayed in listings. 
Adverse 
Events 
• The eCRF allows for the possibility of partial dates (i.e., only month and year 
or only year) to be recorded for AE start/worsening and end dates. In such a 
case, the following conventions will be applied for calculating the time to 
onset and the duration of the event: 
• Imputing a Start/Worsening Date from a Partial Start/Worsening Date:  
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Element 
Reporting Detail 
o If an imputed worsening date is before the start date, then the start date 
will be used as the imputed worsening date.  
o Completely missing stop date: 
➢ If only the day is missing, the first of the month will be used unless 
the Screen Week -2 visit date or treatment start date also occurs 
in the same month.  
• If the treatment start date occurs in the same month, then 
the treatment start date will be used as the 
start/worsening date.  
• Otherwise, if the Screen Week -2 visit date occurs in the 
same month, then the Screen Week -2 visit date will be 
used as the start/worsening date. 
➢ If the day and month are missing, then ‘01’ will be used for the day 
and ‘Jan’ will be used for the month unless the Screen Week -2 
visit date or treatment start date also occurs in the same year. 
• If the treatment start date occurs in the same year, then 
the treatment start date will be used as the 
start/worsening date.  
• Otherwise, if the Screen Week -2 visit date occurs in the 
same year, then the Screen Week -2 visit date will be 
used as the start/worsening date. 
o Partial or non-missing stop date is before treatment start date:  
➢ If only the day is missing, then the first of the month will be used 
unless the Screen Week -2 Visit date also occurs in the same 
month; in this case the Screen Week -2 Visit date will be used as 
the start/worsening date. 
➢ If the day and month are missing, then '01' will be used for the day 
and 'Jan' will be used for the month unless the Screen Week -2 
Visit date also occurs in the same year; in this case the Screen 
Week -2 Visit date will be used as the start/worsening date. 
o Stop date is partial with the same year (or year and month) as the 
treatment start date or is on or after the treatment start date:  
➢ If only the day is missing, then the first of the month will be used 
unless the start date of study treatment also occurs in the same 
month; in this case the study treatment start date will be used as 
the start/worsening date. 
➢ If the day and month are missing, then '01' will be used for the day 
and 'Jan' will be used for the month unless the start date of study 
treatment occurs in the same year; in this case the study 
treatment start date will be used as the start/worsening date. 
• Imputing a Stop Date from a Partial Stop Date:  
o Latest of (start date and latest worsening date) is on or before the 
treatment stop date or is partial with the same year (or year and month) 
as the treatment stop date:  
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Element 
Reporting Detail 
➢ If only the day is missing, the last day of the month will be used 
unless the treatment stop date also occurs in the same month; in 
this case the treatment stop date will be used as the stop date. 
➢ If the day and month are missing, then '31' will be used for the day 
and 'Dec' will be used for the month, unless the stop date of study 
treatment also occurs in the same year; in this case the study 
treatment stop date will be used as the stop date. 
o Latest of (start date and latest worsening date) is partial or non-missing 
and is after treatment stop date:  
➢ If only the day is missing, the last day of the month will be used 
unless the study conclusion date also occurs in the same month; 
in this case, the study conclusion date will be used as the stop 
date. 
➢ If the day and month are missing, then '31' will be used for the day 
and 'Dec' will be used for the month, unless the study conclusion 
date also occurs in the same year; in this case, the study 
conclusion date will be used as the stop date. 
• Completely missing start or end dates (i.e. no year specified) will remain 
missing, with no imputation applied. Consequently, time to onset and 
duration of such events will be missing. 
CV Safety 
Endpoint 
Events 
Discussed in Section 10.6.4  
 
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10.8. 
Appendix 8: Values of Potential Clinical Importance 
10.8.1. 
Laboratory Values 
Clinical Chemistry 
Laboratory Parameter 
Units 
Clinical Concern Range 
Low Flag 
High Flag 
Albumin 
g/L 
< 30 g/L 
>55 g/L 
Aspartate Aminotransferase 
(AST) 
IU/L 
 
 3x ULRR 
Alanine Aminotransferase (ALT) 
IU/L 
 
 3x ULRR 
Bilirubin (total)  
mol/L 
 
 2x ULRR 
Calcium (albumin corrected) 
mmol/L 
< 1.87 mmol/L 
> 2.56 mmol/L  
Phosphate 
mmol/L 
< 0.81 mmol/L 
1.77 mmol/L 
Potassium (serum) 
mmol/L 
> 0.5 mmol/L below LLRR 
> 1.0 mmol/L above 
ULRR 
 
Hematology 
Laboratory Parameter 
 
Units 
Clinical Concern Range 
Low Flag  
High Flag  
Platelet Count  
GI/L 
< 80 GI/L 
> 500 GI/L 
Leukocytes (white blood cell 
count) 
GI/L 
< LLRR 
> 5x ULRR 
Neutrophils 
GI/L 
< 0.5x LLRR 
 
Lymphocytes 
GI/L 
< 0.5x LLRR 
 
 
Iron Parameters 
Laboratory Parameter 
Units 
Clinical Concern Range 
Low Flag 
High Flag 
Ferritin 
ng/mL 
< 100 ng/mL 
> 800 ng/mL 
TSAT 
% 
<15% 
> 40% 
 
Other PCI Values 
Laboratory Parameter 
Units 
Clinical Concern Range 
Low Flag  
High Flag  
iPTH 
ng/L 
 
> 9x ULRR 
 
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10.8.2. 
Vital Signs 
Vital Sign Parameter 
(Absolute) 
Units 
Clinical Concern Range 
Lower 
Upper 
Systolic Blood Pressure 
mmHg 
 85 mmHg 
 180 mmHg 
Diastolic Blood Pressure 
mmHg 
 45 mmHg 
 110 mmHg 
Heart Rate 
bpm 
 40 bpm 
 110 bpm 
Notes: 
• 
At visits where BP and HR are assessed in triplicate, the average of the 3 values will be used to 
assess PCI criteria. 
• 
For subjects who undergo in-clinic dialysis, the post-dialysis BP and HR values will be used to 
assess PCI criteria, unless otherwise specified. 
 
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10.9. 
Appendix 9: Multicenter Studies 
10.9.1. 
Methods for Handling Centres 
• 
In this multicentre global study, enrolment will be presented by investigative site, 
country, and the regions. 
 
Region 
Countries 
Region 1: 
USA 
USA1 
Region 2: 
Europe 
France, Germany, Italy, Spain1, United Kingdom1, Poland, Russia, South Africa1  
Region 3: 
Rest of 
World 
Australia1, Argentina, Brazil1, Canada1, India, Malaysia1, Mexico, South Korea1 
Note: countries that do not participate or do not randomize any subjects will be removed from 
the regional grouping. 
[1]: Countries which will collect the EQ-5D-5L and EQ-VAS. 
 
• 
For any summaries which include information related to a subject’s center or 
investigator, the most recent center and investigator at the time that the database is 
final will be used. 
 
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10.10. 
Appendix 10: Examination of Covariates, Subgroups & 
Other Strata 
10.10.1. 
Handling of Covariates, Subgroups & Other Strata 
• 
The following is a non-exhaustive list of covariates that may be used in summaries 
of demographics, descriptive summaries and statistical analyses.  
• 
Additional covariates of clinical interest may also be considered.  
• 
If the percentage of subjects is small within a particular subgroup, then the subgroup 
categories may be refined prior to unblinding the trial. 
• 
If the category cannot be refined further, then descriptive rather than statistical 
comparisons may be performed for the particular subgroup. Due to small sample 
sizes in American Indian or Alaskan Native, Native Hawaiian or Other Pacific 
Islander, and Mixed race categories, statistical comparison for race group will 
include Asian, Black, and White categories only. For baseline Hgb subgroup, if there 
are fewer than 25 subjects in the category >11 g/dL, the categories 10-11 g/dL and 
>11 g/dL will be combined to ≥ 10 g/dL. For any other subgroups, if there are less 
than 25 subjects in one of the subgroup categories, any subgroup statistical 
comparison should be interpreted with caution. 
• 
A pre-specified strategy for prioritizing subgroups/covariates is defined below (as 
recommended in the 2015 draft Committee for Medicinal Products for Human Use 
(CHMP) guidance on the investigation of subgroups in confirmatory clinical trials). 
• 
The primary and principal secondary endpoints will be evaluated for the subgroups 
below. Although subgroup analyses are aimed to assess for consistency with the 
overall results, they may have low power, especially if the subgroup is small or has a 
low number of events. Statistical models (ANCOVA) will be adjusted for the 
covariates used in the original analysis, subgroup, treatment and treatment by 
subgroup interaction. For the prognostic randomization stratification factors (dialysis 
type and dialysis start manner), the actual status of the factor derived from the eCRF 
will be used (see Section 0).  
• 
For Hgb and selected PRO endpoints using MMRM model in the original analysis, 
the statistical model for the corresponding subgroup analyses will have the following 
factors: dialysis type, dialysis start manner, baseline value, baseline value by time, 
and subgroup by treatment by time interaction terms. The model will be run without 
main effects (treatment, visit, and subgroup) and two-way interaction terms 
(subgroup by time, treatment by time, and subgroup by treatment) for computational 
ease since in SAS, the main effects and two-way interaction terms are included 
within the three-way interaction term, thus giving equivalent result. For the selected 
Hgb, BP, and PRO endpoints using MMRM in the original model that contain only 
main effects and two-way interaction terms, both the main effects and the two-way 
interaction terms will be included in the model statement. If any of the above 
MMRM models encounter convergence issues, then the following steps will be 
performed in this sequence: 
• 
Step 1: Use Fisher scoring method 
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• 
Scoring=0 will be used as the first option, which is equivalent to no scoring, 
and if the model fails to converge, the scoring will be updated to scoring=1 
• 
The scoring will be updated each time the model fails to converge until a 
maximum of scoring=4 is reached. At this point, if the model fails to 
converge, Step 2 will be utilized. 
• 
Step 2: If the model fails to converge, instead of unstructured, TOEPH variance-
covariance matrix will be used in conjunction with Step 1 
• 
Step 3: If the model fails to converge, denominator degrees of freedom will be 
changed from Kenward-Roger to Residual in conjunction with Steps 1 and 2.  
Please note that if any of the models still fail to converge after Step 3, model-
adjusted analyses will not be performed. The associated descriptive statistics will be 
displayed.  If the original model fails to converge, but it converges after one of the 
three steps, the output will display the changes made to the original model in a 
footnote. 
• 
When a subgroup category assesses the same or a similar parameter as one of the 
prognostic stratification variables, the randomization stratification variable will be 
removed from the model. 
• 
Point estimates and two-sided 95% CIs will be estimated within subgroups, the 
subgroup by treatment interaction two-sided p-value will be calculated and subgroup 
results will be graphically presented (e.g. Forest Plots). Directional consistency in 
subgroup treatment effects and a non-significant interaction p-value (two-sided 10% 
level) would support that the overall treatment effect is broadly applicable to the full 
study population. Subgroup analyses will not be adjusted for multiplicity. 
 
Category 
Covariates and / or 
Subgroups 
Summary of 
Demographics & 
Baseline 
Characteristics 
Note: Include 
'Missing' 
categories, if 
applicable. 
Subgroup 
Analysis for 
Primary Hgb & 
Principal 
Secondary 
Efficacy 
Endpoint 
Note: Do not 
include 'Missing' 
categories. 
Key Covariates/Subgroups of Regulatory/Clinical Interest or Potential Biological 
Plausibility for Different Subgroup Effects 
Age (years) 
Summary statistics of 
continuous values 
Yes 
No 
Age at 
randomization 
(Grouping 1) 
<65 years, 65-<75 years, 
≥75 years 
Yes 
Yes 
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Category 
Covariates and / or 
Subgroups 
Summary of 
Demographics & 
Baseline 
Characteristics 
Note: Include 
'Missing' 
categories, if 
applicable. 
Subgroup 
Analysis for 
Primary Hgb & 
Principal 
Secondary 
Efficacy 
Endpoint 
Note: Do not 
include 'Missing' 
categories. 
Age at 
randomization 
(Grouping 2) 
18 years, 19 - 64 years, ≥ 
65 years 
Yes 
No 
Age at 
randomization 
(Grouping 3) 
18-64 years, 65-84 years, 
≥85 years 
No (included in 
stand-alone age 
ranges table) 
No 
Gender 
Female, Male 
Yes 
Yes 
Ethnicity 
Hispanic or Latino, Not 
Hispanic or Latino 
Yes 
Yes 
High level race 
American Indian or Alaskan 
Native  
Asian 
Black or African American 
Native Hawaiian or Other 
Pacific Islander 
White 
Mixed Race 
Yes 
Yes  
(Asian, Black or 
African American, 
and White will be 
used in subgroup 
analyses due to 
small sample size 
in other groups) 
Race detail 
American Indian or Alaskan 
Native 
Asian – Central/South Asian 
Heritage 
Asian – East Asian Heritage 
Asian – Japanese Heritage 
Asian – South East Asian 
Heritage 
Black or African American 
Native Hawaiian or Other 
Pacific Islander 
White – Arabic/North African 
Heritage 
White – 
White/Caucasian/European 
Heritage 
Mixed Asian Race 
Mixed White Race 
Mixed Race 
Yes 
No 
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Category 
Covariates and / or 
Subgroups 
Summary of 
Demographics & 
Baseline 
Characteristics 
Note: Include 
'Missing' 
categories, if 
applicable. 
Subgroup 
Analysis for 
Primary Hgb & 
Principal 
Secondary 
Efficacy 
Endpoint 
Note: Do not 
include 'Missing' 
categories. 
Region 
Region 1: USA 
Region 2: Europe 
Region 3: Rest of World 
Yes 
Yes 
Regions combined 
USA, Non-USA 
Yes 
Yes 
Dialysis type at 
randomization1 
HD, PD (repeat using HD, 
HDF/HF, PD) 
Yes 
Yes (HD/PD only) 
Dialysis start 
manner 
Planned Start, Unplanned 
(Urgent) Start 
Yes 
Yes 
Dialysis status at 
randomization 
Dialysis not initiated, On 
dialysis 90 days 
Yes 
No 
Baseline Hgb (g/dL) 
Continuous covariate for 
Hgb co-primary analysis; 
summary statistics of 
continuous values 
Yes 
No 
Baseline Hgb group 
<9 g/dL, 9- <10g/dL, 10-
11g/dL, >11 g/dL, Missing 
Yes 
Yes 
(the last two 
subgroups will be 
combined into a 
single >=10 g/dL 
group if there are 
< 25 subjects in 
either group) 
Baseline body mass 
index (kg/m2) 2 
Summary statistics of 
continuous values 
Yes 
No 
Baseline body mass 
index group2 
<30 kg/m2, ≥30 kg/m2, 
Missing 
Yes 
Yes 
Baseline weight 
(kg)2 
Summary statistics of 
continuous values 
Yes 
No 
Baseline weight 
group2 
<75 kg, ≥75 kg, Missing 
Yes 
No 
Baseline weight 
quartiles2 
Overall ITT Population 
Quartile 1: < xx kg 
Overall ITT Population 
Quartile 2: xx kg - < xx kg 
Overall ITT Population 
Quartile 3: xx kg - < xx kg 
Yes 
Yes 
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Category 
Covariates and / or 
Subgroups 
Summary of 
Demographics & 
Baseline 
Characteristics 
Note: Include 
'Missing' 
categories, if 
applicable. 
Subgroup 
Analysis for 
Primary Hgb & 
Principal 
Secondary 
Efficacy 
Endpoint 
Note: Do not 
include 'Missing' 
categories. 
Overall ITT Population 
Quartile 4: ≥ xx kg 
Missing 
Baseline hsCRP 
(mg/L) 
Summary statistics of 
continuous values 
Yes 
No 
Baseline hsCRP 
group 
3 mg/L, >3 mg/L, Missing 
Yes 
No 
Baseline hsCRP 
quartiles 
Overall ITT Population 
Quartile 1: < xx mg/L 
Overall ITT Population 
Quartile 2: xx mg/L - < xx 
mg/L 
Overall ITT Population 
Quartile 3: xx mg/L - < xx 
mg/L 
Overall ITT Population 
Quartile 4: ≥xx mg/L 
Missing 
Yes 
Yes 
Required B12 
supplementation to 
be eligible for 
randomization 
No, Yes 
Yes 
No 
Required IV iron 
supplementation to 
be eligible for 
randomization 
No, Yes 
Yes 
No 
Dosing algorithm at 
randomization 
Original algorithm, Updated 
algorithm 
Yes 
No 
Other Exploratory Covariates/Subgroups where Biological Plausibility for Heterogeneous 
Effects Are Not Known or Anticipated 
History of diabetes 
No, Yes, Missing 
Yes 
Yes 
History of stroke 
No, Yes, Missing 
Yes 
Yes 
History of MI 
No, Yes, Missing 
Yes 
Yes 
History of cancer 
No, Yes, Missing 
Yes 
Yes 
History of HF 
No, Yes, Missing 
Yes 
Yes 
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Category 
Covariates and / or 
Subgroups 
Summary of 
Demographics & 
Baseline 
Characteristics 
Note: Include 
'Missing' 
categories, if 
applicable. 
Subgroup 
Analysis for 
Primary Hgb & 
Principal 
Secondary 
Efficacy 
Endpoint 
Note: Do not 
include 'Missing' 
categories. 
History of 
thromboembolic 
events 
No, Yes, Missing 
Yes 
Yes 
Hospitalization 
within 6 months 
prior to screening 
No, Yes, Missing 
Yes 
Yes 
Transfusion within 6 
months prior to 
screening 
No, Yes, Missing 
Yes 
Yes 
Baseline iron use 
No iron use 
IV iron use only 
Oral iron use only 
Other iron use only 
IV and oral iron use only 
IV and other iron use only 
Oral and other iron use only 
IV, oral and other iron use 
Yes 
No 
Standardized 
baseline IV iron 
dose (mg/month) 
Continuous covariate for 
monthly IV iron dose 
analysis; summary statistics 
of continuous values 
Yes 
No 
Standardized 
baseline IV iron 
dose (mg/month) 
for subjects using 
IV iron at baseline 
Continuous covariate for 
monthly IV iron dose 
analysis; summary statistics 
of continuous values 
Yes 
No 
Baseline SBP 
(mmHg) 2 
 
Continuous covariate for 
change from baseline in SBP 
analysis, summary statistics 
of continuous values 
Yes 
No 
Baseline DBP 
(mmHg) 2 
Continuous covariate for 
change from baseline in SBP 
analysis, summary statistics 
of continuous values 
Yes 
No 
Baseline MAP 
(mmHg) 2 
Continuous covariate for 
change from baseline in SBP 
Yes 
No 
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Category 
Covariates and / or 
Subgroups 
Summary of 
Demographics & 
Baseline 
Characteristics 
Note: Include 
'Missing' 
categories, if 
applicable. 
Subgroup 
Analysis for 
Primary Hgb & 
Principal 
Secondary 
Efficacy 
Endpoint 
Note: Do not 
include 'Missing' 
categories. 
analysis, summary statistics 
of continuous values 
Dialysis access 
type used at 
randomization 
Arteriovenous fistula 
Arteriovenous graft 
Central venous catheter – 
tunneled 
Central venous catheter – 
non-tunneled 
Peritoneal catheter 
Other 
Missing 
Yes 
No 
ACEI/ARB use at 
randomization 
No, Yes 
Yes 
No 
Phosphate binder 
use at 
randomization 
Iron-based phosphate 
binders 
Calcium-based phosphate 
binders 
Non-calcium and non-iron 
based phosphate binders 
No phosphate binder use 
Yes 
No 
Vitamin D use at 
randomization 
No, Yes 
Yes 
No 
History of 
cardiovascular 
disease 
No, Yes 
Yes 
No 
Beta blockers use 
at randomization 
No, Yes 
Yes 
No 
SGLT2i use at 
randomization 
No, Yes 
Yes 
No 
Statin use at 
randomization 
No, Yes 
Yes 
No 
Aspirin use at 
randomization 
No, Yes 
Yes 
No 
Vitamin K 
antagonist use at 
randomization 
No, Yes 
Yes 
No 
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Category 
Covariates and / or 
Subgroups 
Summary of 
Demographics & 
Baseline 
Characteristics 
Note: Include 
'Missing' 
categories, if 
applicable. 
Subgroup 
Analysis for 
Primary Hgb & 
Principal 
Secondary 
Efficacy 
Endpoint 
Note: Do not 
include 'Missing' 
categories. 
Insulin use at 
randomization 
No, Yes 
Yes 
No 
Calcimimetics use 
at randomization 
No, Yes 
Yes 
No 
Diabetic medication 
use at 
randomization 
No, Yes 
Yes 
No 
Baseline estimated 
dry weight (kg) 
Summary statistics of 
continuous values 
Yes 
No 
NOTES: 
[1]: Subjects who change dialysis modalities during the study will be counted in the subgroup 
corresponding to their dialysis modality at randomization. 
[2]: Note: For subjects with in-clinic dialysis, post-dialysis value are used. 
 
10.10.2. 
Randomization Stratification 
Randomization is stratified by dialysis type (HD or PD) and dialysis start manner 
(whether their dialysis start is planned or unplanned (urgent)) to ensure balance across 
treatment groups for the overall study. The prognostic stratification factors (i.e., dialysis 
type and dialysis start manner) will be taken into account within the analysis models.  
Baseline dialysis type strata and baseline dialysis start manner strata will be identified by 
two data sources: 
• 
PPD’s IRT dataset 
• 
eCRF  
The proposed approach is to use the IRT strata in the adjusted analysis models in order to 
provide a randomization-based test statistic in accordance with the principle of ‘analyze 
as randomized’. In summaries of subgroups however, the actual status of the factor for 
stratification derived from the eCRF form will be used. Additionally, subjects who 
change dialysis modality during the study will remain in the dialysis modality strata that 
was assigned at randomization. 
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10.11. 
Appendix 11: Multiple Comparisons & Multiplicity 
10.11.1. 
Handling of Multiple of Comparisons & Multiplicity 
10.11.1.1. Interim Analyses 
There is no formal intent to evaluate the interim data from this study for the purpose of 
stopping early for Hgb efficacy or futility.  
10.11.1.2. Final Analyses 
The multiplicity strategy for this trial will use the gatekeeper approach on the primary 
endpoint. First, the primary endpoint will be evaluated for non-inferiority by two-sided 
95% CI to the appropriate non-inferiority margin. Conditional on primary endpoint 
achieving non-inferiority (i.e., passing the gatekeeper), the principal secondary analysis 
will be formally tested for superiority using a one-sided 2.5% significance level. 
10.11.1.3. Subgroup Analyses 
Subgroup analyses will not be adjusted for multiplicity. 
 
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10.12. 
Appendix 12: Model Checking and Diagnostics for 
Statistical Analyses 
10.12.1. 
Statistical Analysis Assumptions 
Endpoint(s) • Hgb Change from Baseline to the EP 
Analysis 
• ANCOVA 
• Distributional assumptions underlying the model used for analysis will be examined by 
obtaining a normal probability plot of the residuals and a plot of the residuals versus the 
fitted values (i.e. checking the normality assumption and constant variance assumption of 
the model respectively) to gain confidence that the model assumptions are reasonable. 
• If there are any departures from the distributional assumptions, alternative models will be 
explored using appropriate transformed data. 
• Models will be examined for treatment interactions with baseline Hgb and stratification 
factors. 
Analysis 
• Multiple Imputation/Tipping Point Analysis 
• Intermittent missing data imputation: 
o If there are error and or warning messages related to the by statement (e.g. not 
enough observations to fit regression models), try to impute by randomized 
treatment and dialysis start manner, then by randomized treatment only until no 
error/warning messages. 
o If convergence issue still occurs, the convergence precision may be set to 1E-3.  
• Monotone missing data imputation: 
o When imputing for each of the monotone missing dataset (out of the 200), if 
there are error and or warning messages related to the by statement and/or 
regression model (e.g. not enough observations with the Monotone statement), 
try 1) impute by randomized treatment and dialysis start manner, with baseline 
Hgb and dialysis type as covariates, 2) impute by randomized treatment, with 
baseline Hgb, dialysis start manner, and dialysis type as covariates, 3) impute 
by randomized treatment, with baseline Hgb, and dialysis start manner use as 
covariates, 4) impute by randomized treatment with baseline Hgb as a 
covariate, until no error/warning messages. 
 
 
 
 
 
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10.13. 
Appendix 13: Abbreviations & Trade Marks 
10.13.1. 
Abbreviations 
Abbreviation 
Description 
ADaM 
Analysis Data Model 
AE 
Adverse Event 
AESI 
Adverse Event of Special Interest 
ALT 
Alanine Aminotransferase 
ANCOVA 
Analysis of Covariance 
AST 
Aspartate Aminotransferase 
ATC 
Anatomical Therapeutic Chemical 
BP 
Blood Pressure 
CDISC 
Clinical Data Interchange Standards Consortium 
CEC 
Clinical Endpoint Committee 
CFB 
Change from Baseline 
CHMP 
Committee for Medicinal Products for Human Use 
CI 
Confidence Interval 
CKD 
Chronic Kidney Disease 
CKD-AQ 
Chronic kidney disease anemia symptoms questionnaire 
CKD-EPI 
Chronic kidney disease epidemiology collaboration 
CMH 
Cochran-Mantel-Haenszel 
CSR 
Clinical Study Report 
CV 
Cardiovascular 
DBP 
Diastolic Blood Pressure 
DP 
Decimal Places 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Record Form 
EP 
Evaluation Period 
EQ-5D-5L 
EuroQoL 5 Dimension 5 Level Health Utility Index 
EQ-VAS 
EuroQol Visual Analogue Scale 
ERI 
Erythropoietin Resistance Index 
ESA 
Erythropoiesis Stimulating Agent 
FDA 
Food and Drug Administration 
FSH 
Follicle-stimulating Hormone 
GSK 
GlaxoSmithKline 
HbA1c 
Hemoglobin A1c 
HBPM 
Home Blood Pressure Monitoring 
HD 
Hemodialysis 
HDF 
Hemodiafiltration 
HDL-C 
High Density Lipoprotein Cholesterol 
HF 
Heart Failure 
HF 
Hemofiltration 
Hgb 
Hemoglobin 
HR 
Heart Rate 
HRQoL 
Health Related Quality of Life 
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Abbreviation 
Description 
hsCRP 
High-sensitivity C-reactive Protein 
ICH 
International Conference on Harmonisation 
IDMC 
Independent Data Monitoring Committee  
IDSL 
Integrated Data Standards Library 
IG 
Implementation Guide 
IMMS 
International Modules Management System 
iPTH 
Intact Parathyroid Hormone 
IRT 
Interactive Response Technology 
ITT 
Intent-To-Treat 
IV 
Intravenous 
KM 
Kaplan-Meier 
LDL-C 
Low Density Lipoprotein Cholesterol 
LS 
Least Squares 
MACE 
Major Adverse Cardiovascular Event 
MAP 
Mean Arterial Pressure 
MAR 
Missing at Random 
MCH 
Mean Corpuscular Hemoglobin 
MCHC 
Mean Corpuscular Hemoglobin Concentration 
MCS 
Mental Component Summary 
MCV 
Mean Corpuscular Volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
MI 
Myocardial Infarction 
MMRM 
Mixed Model Repeated Measures 
NI 
Non-inferiority 
PCI 
Potential Clinical Importance  
PCS 
Physical Component Summary 
PD 
Pharmacodynamic 
PGI-S 
Patient Global Impression of Change 
PGI-C 
Patient Global Impression of Severity 
PGx 
Pharmacogenetics 
PhRMA 
Pharmaceutical Research and Manufacturers of America 
PK 
Pharmacokinetic 
PP 
Per-Protocol 
PPD 
Pharmaceutical Product Development 
PRO 
Patient Reported Outcome 
PT 
Preferred Term 
QC 
Quality Control 
RAP 
Reporting & Analysis Plan 
RBC 
Red Blood Cell  
RDW 
Red Cell Distribution Width 
RTF 
Rich Text Format 
SAE 
Serious Adverse Event 
SBP 
Systolic Blood Pressure 
SC 
Subcutaneous 
SDTM 
Study Data Tabulation Model 
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Abbreviation 
Description 
SE 
Standard Error 
SI 
System Independent 
SMQ 
Standard MedDRA Query 
SOC 
System Organ Class 
SPERT 
Safety Planning Evaluation Reporting Team 
TC 
Total Cholesterol 
TFL 
Tables, Figures & Listings  
TIBC 
Total Iron Binding Capacity 
TIR 
Time in Range 
TSAT 
Transferrin Saturation 
UK 
United Kingdom 
US 
United States 
VAS 
Visual Assessment Scale 
WBC 
White Blood Cell 
 
10.13.2. 
Trademarks 
Trademarks of the GlaxoSmithKline 
Group of Companies 
 
Trademarks not owned by the 
GlaxoSmithKline Group of Companies 
CKD-AQ 
 
EQ-5D-5L 
 
 
SAS 
 
 
SF-36 
 
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