A 28-week, Randomized, Double-blind, Placebo-controlled, Parallel-group, Multi-center, Study in Recombinant Human Erythropoietin (rhEPO) naïve Non-dialysis Participants With Anemia Associated With Chronic Kidney Disease to Evaluate the Efficacy, Safety and Effects on Quality of Life of Daprodustat Compared to Placebo
Phase: PHASE3
Conditions: Anaemia
Sponsor: GlaxoSmithKline

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TITLE PAGE
Protocol Title: A 28-week, randomized, double-blind, placebo-controlled, parallelgroup, 
multi-center, study in recombinant human erythropoietin (rhEPO) naïve nondialysis 
participants with anemia associated with chronic kidney disease to evaluate the efficacy, 
safety and effects on quality of life of daprodustat compared to placebo.
Protocol Number: 205270/01
Short Title: Anemia Studies in CKD: Erythropoiesis via a Novel PHI Daprodustat in 
Non-Dialysis participants evaluating Hemoglobin and Quality of life (ASCEND-NHQ)
Compound Number:
GSK1278863
Sponsor Name and Legal Registered Address: 
GlaxoSmithKline Research & Development Limited
980 Great West Road
Brentford
Middlesex, TW8 9GS
UK
Medical Monitor Name and Contact Information:
Medical Monitor contact information can be found in the Study Reference Manual.
Regulatory Agency Identifying Number(s):
IND#: 101291
EudraCT:  2017-002270-39  
Approval Date: 23-AUG-2019
Copyright 2019 the GlaxoSmithKline group of companies.  All rights reserved.  
Unauthorised copying or use of this information is prohibited.

PPD
PPD
PPD

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PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE
DOCUMENT HISTORY
Document
Date
Protocol Amendment 1
23-Aug-2019
Country Specific Protocol ITA-1
02-Apr-2018
Original Protocol 
22-Aug-2017
Amendment Version 1 23-AUG-2019
Overall Rationale for Amendment: Amendment conducted to provide clarity regarding 
follow-up of participants with ADPKD and to incorporate new safety data provided in the 
Investigator’s Brochure. 
Section# and Name
Description of Change
Brief Rationale
Section 2: Schedule of 
Activities, Table 1
Added footnote #17 to state 
when study treatment should 
be dispensed. 
Footnote was added to clarify 
when study treatment is 
dispensed at study visits 
through the IRT system. 
Section 2: Schedule of 
Activities, Table 1
Revised footnote #9 to permit a
HemoCue Hgb retest with a 
new blood sample 
A re-test provides an 
opportunity for participants and 
sites to avoid the inappropriate 
screen-failures due to technical 
issues with the initial sample 
collection and analysis via the 
HemoCue device.  
Section 2: Schedule of 
Activities, Table 1
Revised footnote #12 to clarify 
the purpose of the participant 
reminder card
To clarify the purpose of the 
participant reminder card. 
Section 2: Schedule of 
Activities, Table 1 
Edited footnote #15 to add 
necessary ultrasound 
assessments for ADPKD 
participants at end of treatment
All participants with ADPKD 
will require an ultrasound 
within one month of study 
treatment discontinuation or as 
soon as clinically feasible as 
mandated by Dear Investigator 
Letter (DIL, dated 14 Dec 
2018)  
Section 2: Schedule of 
Activities for Patient Reported 
Outcomes and Actigraphy, 
Added row to conduct 
assessment regarding 
healthcare resource utilization 
Clarified timepoints for 
collection of the healthcare 
resource utilization data for all

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Section# and Name
Description of Change
Brief Rationale
Table 2 and
Schedule of Activities for 
Participants Permanently 
Discontinuing Study 
Treatment, Table 3
reported by participants at 
each visit starting with Day 1 
(randomization visit) and after 
study treatment discontinuation
participants in the study. 
Section 2: Schedule of 
Activities for Participants 
Permanently Discontinuing 
Study Treatment, Table 3 
Added renal ultrasound for 
ADPKD participants upon 
discontinuation of study 
treatment. 
Per the DIL, renal ultrasound is 
mandated for all participants 
with history of ADPKD who
have discontinued study 
treatment.
Section 3.3.1 Risk Assessment
Updated risk assessment table
with language related to 
Investigator Brochure update. 
Edited Risk Assessment 
information to align with 
version 10 of the Investigator’s 
Brochure. 
Section 4. Objectives and
Endpoints
Added secondary and 
exploratory endpoints and 
objectives related to BP 
exacerbations and concomitant 
medications 
New objectives and endpoints 
were added to evaluate the 
effect of study treatment on 
BP.  
Section 4. Objectives and 
Endpoints 
Revised secondary endpoints 
for work productivity and 
regular daily activity 
impairment to quantify 
participant employment status 
and remove mean hours 
captured on WPAI-ANS-CPV
Endpoints were revised to align 
with the type of data captured 
in WPAI-ANS-CPV 
questionnaire.  
Section 4. Objectives and 
Endpoints 
Amended exploratory 
objectives for Hgb change to 
evaluate participants achieving 
a Hgb increase of ≥1.0g/dL  
instead of ≥1.2g/dL  
Exploratory objective amended 
to fix the administrative error
(typo) from the initial protocol.  
Section 4. Objectives and 
Endpoints 
Updated the exploratory 
objective to capture time to first 
rhEPO and Transfusion use. 
Objective and endpoints were 
updated to additionally analyse 
the use of rhEPO and 
Transfusion in the study. 
Section 6.1 Inclusion Criteria 
#5
Edited inclusion crtierion #5 to 
provide clarity for requirements 
of compliance with oral iron 
Inclusion criterion to provide 
further clarity on appropriate 
compliance with type and dose 

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Section# and Name
Description of Change
Brief Rationale
dosing prior to Day 1, and 
removed the need for stable 
iron dose prior to screening. 
of oral iron prior to 
randomization. 
Section 6.2 Exclusion Criteria 
#13
Edited exclusion criterion #13 
edited to include use of 
investigational device 
Broadened exclusion to include 
participation in a study with an 
investigational agent or device
Section 6.2 Exclusion Criteria
#22
Added exclusion criterion #22 
for uncontrolled hypertension  
Additional criterion added to 
exclude participants with 
uncontrolled hypertension as 
worsening of hypertension has 
been added to the list of AESI 
for daprodustat per IB Version 
10
Table 6. Study Treatment 
Dosing Algorithm
Instructions to repeat and 
average HemoCue Hgb 
assessment for Hgb <8.5 g/dL
Language added to align with 
the IRT system programming. 
Section 8.1 Discontinuation of 
Study Treatment
Added information regarding 
discontinuation of study 
treatment in participants with 
ADPKD. 
Study treatment must be 
discontinued in participants 
with ADPKD who experience
greater than expected 
worsening of kidney function 
and/or cyst enlargement with 
no other cause or clinical 
scenario identified. 
Section 8.2 Withdrawal from 
the Study 
Added language related to
alternative methods of follow-
up
To align with the ICF and 
provide information regarding 
additional methods of follow-up 
for participants unwilling to 
perform study clinic visits. 
Section 8.3 Lost to Follow Up
Added language regarding 
alternative methods of follow-
up for participants potentially 
lost to follow up. 
To provide further guidance on 
evaluation of participant status 
after the participant is lost to 
follow up.
Section 9.1 Screening and 
Critical Baseline Assessments
Added language regarding 
retests with a new blood 
sample and entering HemoCue 
Hgb values into the IRT system
To ensure sites they may 
retest Hgb with a new blood 
sample for the day 1 visit. 
Additional clarification provided 
regarding data entry criteria to 
capture HemoCue Hgb values

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Section# and Name
Description of Change
Brief Rationale
in the IRT system.  
Section 9.3.7 Adverse Events 
of Special Interest 
Added “worsening of 
hypertension” as an additional 
adverse event of special 
interest 
AESI list of was updated to 
align with the changes in the 
Risk Assessment table and the 
IB version 10. 
Section 9.5.4 Ultrasound
Added guidance on conducting 
ultrasound for participants with 
ADPKD based on different 
clinical scenarios in the study. 
Added text related to 
requirements for ADPKD 
participants as mandated by 
the DIL (dated 14 Dec 2018)
Section 12.7, Appendix 7: 
Country specific requirement
Changes made to provide 
guidance regarding the 
conduct of the study at French 
site only. 
Updated French Administrative 
Considerations and Specifics 
Requirements based on an 
updated template
Entire protocol 
Minor editorial and document 
formatting revisions
Minor, therefore have not been 
summarized.

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TABLE OF CONTENTS
PAGE
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE.....................................3
1.
SYNOPSIS.............................................................................................................10
2.
SCHEDULE OF ACTIVITIES (SOA).......................................................................13
3.
INTRODUCTION....................................................................................................18
3.1.
Study Rationale ..........................................................................................18
3.2.
Background ................................................................................................19
3.3.
Benefit/Risk Assessment ............................................................................19
3.3.1.
Risk Assessment .........................................................................19
3.3.2.
Benefit Assessment.....................................................................33
3.3.3.
Overall Benefit:Risk Conclusion...................................................33
4.
OBJECTIVES AND ENDPOINTS...........................................................................33
5.
STUDY DESIGN ....................................................................................................36
5.1.
Overall Design ............................................................................................36
5.2.
Number of Participants ...............................................................................37
5.3.
Participant and Study Completion...............................................................37
5.4.
Scientific Rationale for Study Design ..........................................................38
5.5.
Dose Justification........................................................................................38
6.
STUDY POPULATION...........................................................................................39
6.1.
Inclusion Criteria.........................................................................................39
6.2.
Exclusion Criteria........................................................................................40
6.3.
Lifestyle Restrictions...................................................................................42
6.4.
Screen Failures...........................................................................................42
7.
TREATMENTS.......................................................................................................42
7.1.
Treatments Administered............................................................................42
7.2.
Dose Modification .......................................................................................43
7.3.
Method of Treatment Assignment ...............................................................45
7.4.
Blinding.......................................................................................................45
7.4.1.
Additional Considerations to Maintain the Blind ...........................45
7.5.
Preparation/Handling/Storage/Accountability..............................................46
7.6.
Treatment Compliance................................................................................46
7.6.1.
Study Treatment Extended Interruption .......................................46
7.7.
Standard of Care ........................................................................................47
7.7.1.
Iron Management Criteria ............................................................47
7.7.2.
Rescue Criteria............................................................................47
7.8.
Concomitant Therapy..................................................................................48
7.8.1.
Permitted Medications and Non-Drug Therapies..........................49
7.8.2.
Prohibited Medications and Non-Drug Therapies.........................49
7.9.
Treatment after the End of the Study ..........................................................50
8.
DISCONTINUATION CRITERIA.............................................................................50
8.1.
Discontinuation of Study Treatment ............................................................50
8.1.1.
Liver Chemistry Stopping Criteria ................................................50

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8.2.
Withdrawal from the Study..........................................................................52
8.3.
Lost to Follow Up........................................................................................53
9.
STUDY ASSESSMENTS AND PROCEDURES .....................................................53
9.1.
Screening and Critical Baseline Assessments ............................................54
9.2.
Efficacy Assessments.................................................................................55
9.3.
Adverse Events...........................................................................................55
9.3.1.
Time Period and Frequency for Collecting AE and SAE 
Information...................................................................................55
9.3.2.
Method of Detecting AEs and SAEs.............................................56
9.3.3.
Follow-up of AEs and SAEs.........................................................56
9.3.4.
Regulatory Reporting Requirements for SAEs .............................56
9.3.5.
Events Referred to the Clinical Events Committee (CEC)............57
9.3.6.
Other Cardiovascular (CV) Events...............................................57
9.3.7.
Adverse Events of Special Interest ..............................................58
9.3.8.
Possible Suicidality Related Adverse Events ...............................58
9.3.9.
Pregnancy ...................................................................................59
9.4.
Treatment of Overdose...............................................................................59
9.5.
Safety Assessments ...................................................................................59
9.5.1.
Height and Weight .......................................................................59
9.5.2.
Blood Pressure and Heart Rate ...................................................59
9.5.3.
Electrocardiograms......................................................................60
9.5.4.
Ultrasound ...................................................................................60
9.5.5.
Clinical Laboratory Assessments .................................................61
9.6.
Patient Reported Outcomes........................................................................62
9.6.1.
Chronic Kidney Disease - Anemia Questionnaire (CKD-
AQ)..............................................................................................63
9.6.2.
Patient Global Impression of Severity (PGI-S) and Patient 
Global Impression of Change (PGI-C) .........................................63
9.6.3.
Health Related Quality of Life (SF-36) .........................................63
9.6.4.
Health Status (EQ-5D-5L & EQ-VAS) ..........................................64
9.6.5.
Work Productivity and Activity Impairment (WPAI-ANS-
CPV)............................................................................................64
9.7.
Actigraphy...................................................................................................64
9.8.
Pharmacokinetics .......................................................................................65
9.9.
Genetics .....................................................................................................65
9.10.
Storage Biomarkers....................................................................................65
9.11.
Healthcare Resource Utilization and Economics.........................................65
9.12.
Patient Feedback Survey............................................................................66
10. STATISTICAL CONSIDERATIONS AND DATA ANALYSES .................................66
10.1.
Primary Hypothesis.....................................................................................66
10.2.
Sample Size Determination ........................................................................67
10.2.1.
Sample Size Assumptions ...........................................................67
10.2.2.
Sample Size Sensitivity................................................................67
10.2.3.
Sample Size Re-Estimation or Adjustment...................................68
10.3.
Data Analysis Considerations .....................................................................68
10.3.1.
Analysis Populations....................................................................68
10.4.
Key Elements of Analysis Plan ...................................................................68
10.4.1.
Primary Analyses.........................................................................68
10.4.2.
Secondary Analyses ....................................................................69
10.4.2.1.
Principal Secondary Efficacy Analyses.......................69

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10.4.2.2.
Safety Analyses..........................................................69
10.4.3.
Multiplicity Strategy......................................................................70
10.4.4.
Covariates and Subgroups of Interest..........................................70
10.4.5.
Interim Analyses ..........................................................................71
10.4.6.
Analysis of Patient-Reported Outcomes Measures and 
Actigraphy....................................................................................72
11. REFERENCES.......................................................................................................73
12. APPENDICES........................................................................................................74
12.1.
Appendix 1: Abbreviations and Trademarks................................................74
12.2.
Appendix 2: Study Governance Considerations..........................................77
12.2.1.
Regulatory and Ethical Considerations ........................................77
12.2.2.
Financial Disclosure.....................................................................78
12.2.3.
Informed Consent Process ..........................................................78
12.2.4.
Data Protection............................................................................78
12.2.5.
Quality Control (Study Monitoring) ...............................................78
12.2.6.
Data Quality Assurance ...............................................................79
12.2.7.
Source Documents ......................................................................80
12.2.8.
Study and Site Closure ................................................................80
12.2.9.
Records Retention.......................................................................80
12.2.10. Dissemination of Clinical Study Data ...........................................81
12.2.11. Publication Policy.........................................................................81
12.2.12. Clinical Events Committee ...........................................................82
12.2.13. Safety Review Team (SRT) .........................................................82
12.3.
Appendix 3: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting .......................................83
12.3.1.
Definition of Serious Adverse Events...........................................85
12.3.2.
Recording of AEs and SAEs ........................................................86
12.3.3.
Evaluating AEs and SAEs............................................................87
12.4.
Appendix 4: Female Eligibility Criteria, Contraceptive Guidance and 
Collection of Pregnancy Information ...........................................................89
12.5.
Appendix 5: Genetics..................................................................................92
12.6.
Appendix 6: Liver Safety: Required Actions and Follow-up 
Assessments ..............................................................................................95
12.7.
Appendix 7: Country Specific Requirements...............................................98
12.7.1.
French Administrative Considerations and Specifics
Requirements ..............................................................................98
12.8.
Appendix 8: Stratification by Region-Region Groupings............................102
12.9.
Appendix 9: Protocol Amendment History.................................................103

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1.
SYNOPSIS
Protocol Title: A 28-week, randomized, double-blind, placebo-controlled, parallel-
group, multi-center, study in rhEPO naïve non-dialysis participants with anemia 
associated with chronic kidney disease to evaluate the efficacy, safety and effects on 
quality of life of daprodustat compared to placebo.
Short Title: Anemia Studies in CKD: Erythropoiesis via a Novel PHI Daprodustat in 
Non-Dialysis participants evaluating Hemoglobin and Quality of life (ASCEND-NHQ)
Rationale:
Daprodustat (GSK1278863) is a hypoxia-inducible factor prolyl hydroxylase inhibitor 
(HIF-PHI) currently being investigated as a treatment for anemia associated with chronic 
kidney disease (CKD) in both dialysis and non-dialysis participants.
Blood hemoglobin (Hgb) concentration, transferrin saturation and ferritin levels are the 
primary markers for evaluation of anemia in CKD patients. Initially, non-dialysis CKD 
patients receive iron therapy, to ensure that sufficient iron is available for erythropoiesis 
prior to initiating therapy with recombinant human erythropoietin (rhEPO) for anemia. A 
one to three month trial of oral iron is generally recommended in rhEPO naïve patients 
with non-dialysis CKD. However, if poor compliance is seen with oral iron therapy due 
to lack of efficacy or gastrointestinal intolerance, IV iron may be administered in patients 
requiring iron repletion. rhEPO therapy is generally initiated in non-dialysis CKD 
patients once Hgb has dropped below 10 g/dL at which stage benefits outweigh the risks 
associated with this therapy. Thus, the question arises whether initiation of treatment with 
a PHI, such as daprodustat, in the rhEPO naïve and iron sufficient population might result 
in Hgb benefits that are reflected as benefits in symptoms and quality of life.
This Phase 3 double blind study will be conducted to assess efficacy, safety and effects 
on quality-of-life of daprodustat compared to placebo. Study participants will be rhEPO 
naïve and had limited IV iron exposure at baseline. The purpose of this study is to 
evaluate the effect of daprodustat, on hemoglobin response and quality of life, compared 
to placebo over 28 weeks.. The primary endpoint is Hgb superiority of daprodustat versus 
placebo, and a principal secondary endpoint includes measures of health related quality-
of-life.

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Objectives and Endpoints:
Objective
Endpoint
Primary

To compare the efficacy of daprodustat to 
placebo on mean change in Hgb levels  

Mean change in Hgb between baseline 
and the Evaluation Period (EP, mean 
over Week 24 to Week 28)
Principal Secondary

To compare the proportion of participants 
achieving increases in Hgb when treated 
with daprodustat versus placebo. 

% of participants having a Hgb increase 
of ≥1.0 g/dL to EP. 

To compare daprodustat to placebo for 
health related quality-of-life

Mean Change in 36-item Short Form 
health survey (SF-36) Vitality domain, 
between baseline and Week 28
Safety

To compare the safety and tolerability of 
daprodustat to placebo

Incidence and severity of adverse events 
(AEs) and serious adverse events (SAEs) 
including AEs of special interest and 
adjudicated Major Adverse 
Cardiovascular Events (MACE) 
(composite of all-cause mortality, non-fatal MI 
and non-fatal stroke)

Reasons for discontinuation of study 
treatment

Absolute values and changes from 
baseline in laboratory parameters, blood
pressure (BP) and heart rate (HR)
Overall Design:
This is a 28-week, randomized, double-blind, placebo-controlled, parallel-group, multi-
center Phase 3 study in participants with anemia associated with CKD who are not on 
dialysis.  This study will enroll participants with renal anemia who have a HemoCue Hgb 
8.5 to 10.0 g/dL, inclusive, as measured by a point-of-care Hgb analyser (HemoCue). 
These participants will also have limited history of IV iron use and are rhEPO naïve prior 
to screening and randomization.
Study treatment doses for participants in both treatment arms will be titrated based upon 
HemoCue Hgb.  Dose modifications for all participants will follow a protocol-specified 
dose adjustment algorithm to achieve and maintain Hgb within the target range of 11.0 to 
12.0 g/dL, inclusive. Dose changes will be made programmatically by the Interactive 
Response Technology (IRT) system for both randomized treatment arms.

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A rescue algorithm is provided to minimize participants having an inadequate response to 
treatment of their anemia after a fixed period of time and to enable rescue therapy to be 
provided to the participants based on local clinical practice.
A Clinical Events Committee (CEC) will adjudicate any event suspected to be a major 
adverse cardiovascular event (MACE).
Number of Participants:
Approximately 1200 participants will be screened to achieve approximately 600 
randomized and approximately 540 evaluable participants for an estimated total of 270 
evaluable participants per treatment arm.
Treatment Groups and Duration:
Participants will be randomized 1:1 to receive either daprodustat or matching placebo 
tablets, administered once daily.  
This study includes a 4-week Screening period, a 28-week Treatment period, and a 4-
week Follow-up period. The total duration of study participation for each participant will 
be approximately 36 weeks.

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2.
SCHEDULE OF ACTIVITIES (SOA)
Table 1
Schedule of Activities
Protocol activity (visits ±1 week)
(Note: All visit timings are relative to Day 1)
Screening
Week -41
Treatment Period: Day 1 through Week 28
Follow-up Visit
(4 weeks post
treatment)
Screening
Week -2
Day 1
Week 2
Full study visit
Week 4, 16   
Abbreviated study visit 
Week 8, 12, 20, 24 
Week 28
Unscheduled
Informed Consent
X
Assess eligibility 
X
X
IRT system call 
X
X
X
X17
X
X
X
X17
X
Birth Year (demography)
X
History: medical, hospitalization, height, 
weight
X
X2
SBP/DBP and HR 3
X
X (triplicate)
X
X
X(triplicate)
X
X
ECG
X4
X
Ultrasound of kidney and adrenal glands (if 
able to be visualized)
X5
X15
Anemia therapy6
X
X
X
X
X
X
X
Rescue medication 7
X
X
X
X
Review concomitant medications
X
X
X
X
X
X
X
X
Females only: estradiol and FSH (if 
required and only for women whose 
menopausal status is unclear)
X
FRP only: urine pregnancy test8
X
X
X
X16
X
X
HemoCue Hgb
X
X (Duplicate)9
X
X
X
X
X
Hematology 10
X
X
X
Hgb only 
X
X
X
Clinical chemistry 10
X
X
X
X
X
X
Iron Panel 10
X
X
X 11
X
X
X
Hepcidin  
X
X
X
Lipids (non-fasting) 
X
X
hsCRP
X
X
Distribution of participant reminder tool12
X
Adverse Event Assessment 
X13
X13
X
X
X
X
X
X
X

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Protocol activity (visits ±1 week)
(Note: All visit timings are relative to Day 1)
Screening
Week -41
Treatment Period: Day 1 through Week 28
Follow-up Visit
(4 weeks post
treatment)
Screening
Week -2
Day 1
Week 2
Full study visit
Week 4, 16   
Abbreviated study visit 
Week 8, 12, 20, 24 
Week 28
Unscheduled
Genetic Sample 14
X
1.
SBP, systolic blood pressure; DBP, diastolic blood pressure; HR, heart rate; ECG, electrocardiogram; FSH, follicle stimulating hormone; FRP, Females of Reproductive Potential; 
WOCBP, woman of childbearing potential; hCG, human chorionic gonadotropin; UIBC, unsaturated iron binding capacity; hsCRP, high sensitivity C-reactive protein, serious 
adverse events (SAEs); ADPKD autosomal dominant polycystic kidney disease.If participants does not meet eligibility criteria during/after week -4, then week -2 visit should not be 
conducted.  
2.
Only history related to medical and hospitalization will be re-checked on Day 1 to confirm eligibility prior to randomization. 
3.
SBP/DBP, HR (single readings unless otherwise indicated)
4.
ECG can be conducted at Week -2 visit or at Day 1 prior to randomization. 
5.
Ultrasound of the kidneys and adrenal glands must be performed prior to randomization. The screening period may be extended up to 2 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 9.5.4.
6.
Record historical and current anemia therapy in eCRF, if applicable.
7.
See details on rescue in Section 7.7.2. 
8.
Repeat pregnancy test prior to study treatment re-administration if it is interrupted for >7 days and there was also a lapse in contraceptive use, regardless of the reason for the 
interruption. If a participant becomes post-menopausal (as defined in Section 12.4) during the study, pregnancy tests are no longer required.
9.
Participant are eligible for randomization if the initial HemoCue Hgb assessment is from 8.5 to 10.0 g/dL. Repeat a HemoCue Hgb assessment using the same sample and use 
the average of the two values for randomization only if the initial assessment is from 10.1 to 10.3 g/dL, or if the initial assessment is from 8.2 to 8.4 g/dL. If the average Hgb is also 
from 10.1 to 10.3 or from 8.2 to 8.4 g/dL then another HemoCue Hgb assessment can be performed using a new blood sample on the Day 1 visit date. All HemoCue Hgb 
assessments, starting after Day 1 to end of treatment visit, should be conducted at the end of the study visit, only prior to study medication or rescue medication dispensation. 
10. See details on hematology, clinical chemistry and other laboratory assessments in Section 9.5.5.
11. Ferritin, total iron and UIBC will be assessed at Week 16, but not at Week 4.
12. Participants will be provided a Visit Reminder Card (at Day 1) along with the verbal instruction to promptly inform site staff of any health changes. Health changes include new 
symptoms or medical problems (e.g., pregnancy, hospitalizations) and changes in medication .
13. Only SAEs assessed as related to study participation or a GSK product are collected at this visit. See Section 9.3.1 for additional details
14. 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.
15. France sites and participants with history of ADPKD only (to be performed at or after the week 28 study visit or as soon as clinically feasibile prior to the Follow-up visit (see 
Section 9.5.4) for additional details).
16. For Argentinian sites only and only in WOCB
17. New doses of study treatment will be provided to participants starting from Day 1 to week 24 visit as indicated by IRT System. Study treatment may be dispensed at week 2 or 
unscheduled visit only if indicated by IRT system, otherwise participants should continue on study treatment dispensed at prior study visit. 

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Table 2
Schedule of Activities for Patient Reported Outcomes and Actigraphy
Protocol Activity
(visits ±1 week)
(Note: All visit timings are relative to Day 1)
Screening 
Week -4
Treatment Period: Day 1 through Week 28 
Follow-up 
Visit
Week -2
Day 
1
Week 
4
Week
8
Week
12
Week
16
Week 
20
Week 
24
Week 
28
Dispense Actigraphy Device
X
X
X
X
Actigraphy (wearable)1,5,6
X
X
X
X
Patient Global Impression of Severity (PGI-S)2,3
X
X
X
X
X
Patient Global Impression of Change (PGI-C)2,3
X
X
X
Symptoms of aCKD questionnaire2
X
X
X
X
X
Short Form 36 (SF-36)2,3
X
X
X
X
EuroQol 5 Dimension 5 Level Health Utility 
Index (EQ-5D-5L) and EuroQol Visual 
Analogue Scale (EQ-VAS) 2,3,4
X
X
X
X
Work Productivity and Activity Impairment 
Questionnaire (WPAI-ANS-CPV) 2,3
X
X
X
X
Healthcare resource utilization (participants-
reported)
X
X
X
X
X
1. Actigraphy device should be worn for 7 days prior to the study visits indicated in Table 2 and as described in Section 9.7.  Data will be downloaded from device during the study visits
indicated in Table 2. 
2. Patient reported outcomes questionnaire should be completed as the first assessment, prior to conducting any other visit assessments (e.g. Adverse event assessment, HemoCue 
Hgb, etc.)
3. Subjects who are unable to or require assistance to read must not complete the questionnaires
4. Only in selected countries. See Section 12.8 (Appendix 8).
5. Sites can contact subjects to wear the actigraphy device 7 days prior to study visit. 
6. All efforts should be made to encourage participation in this activity monitoring assessment. If a participant is unable to take part, the reason should be documented, and they may 
continue in the study.

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Table 3
Schedule of Activities for Participants Permanently Discontinuing Study Treatment
Protocol Activity
(Note: All visit timings are relative to Day 1)
Early Treatment Discontinuation Visit
(within 2 weeks of discontinuing 
study treatment)
Day 1 through Week 28
Week 4, 16, 28 ± 2 weeks
Week 24
Unscheduled
IRT system call
X
X
X
X
SBP/DBP, HR  
X (Triplicate)
X
ECG
X
Rescue medication 1, 2
X
X
X
Urine (serum if transitioned to dialysis) 
pregnancy test (WOCBP only)
X 7
HemoCue Hgb
X
X
X
X
Hematology3
X
X
Hgb Only
Clinical chemistry3
X
X
Iron Panel 
X
Hospitalization1 , transition to dialysis1
X
X
X
X
hsCRP
X
Adverse event assessment 
X
X
X
X
Review concomitant medications
X
X
X
X
Actigraphy 4
X9
X
CKD-AQ 8
X
X
PGI-S, PGI-C 8
X
X
SF-36 8
X
X
EQ-5D-5L& EQ-VAS 6, 8
X
X
WPAI-ANS-CPV 5, 8
X
X
ADPKD participant only: Ultrasound
X10
Healthcare resource utilization (participant-
reported)
X
1. Record in eCRF, if applicable.
2.See details on rescue in Section 7.7.2.
3. See details on hematology and clinical chemistry in Section 9.5.5.
4. Actigraphy device could be worn for 7 days prior to the study visit indicated in Table 3 and as described in Section 9.7.  Data will be downloaded at the Discontinuation Visit.  
5. If local dialect or language is available. 
6. Only in selected countries. See Section 12.8 (Appendix 8).

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7. Additional pregnancy test required at subsequent visit. Must be at least 4 weeks after the end of randomized treatment.
8. Subjects who are unable to or require assistance to read must not complete the questionnaires.
9. If actigraphy device is available,participants should be instructed to wear actigraphy device for up to 7 days prior to early treatment discontinuation visit.
10 . Ultrasound of the kidneys will be performed within one month of discontinuing study treatment, or as soon as clinically feasible. See Section 9.5.4 for additional details. 

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3.
INTRODUCTION
3.1.
Study Rationale
Daprodustat (GSK1278863) is a hypoxia-inducible factor prolyl hydroxylase inhibitor 
(HIF-PHI) currently being investigated as a treatment for anemia associated with chronic 
kidney disease (CKD) in both dialysis and non-dialysis participants with safety and 
efficacy having been demonstrated in clinical trials up to 24 weeks duration. Both pre-
clinical and clinical data show that daprodustat-stimulated erythropoietin (EPO) 
production, increases erythropoiesis and thus elevates hemoglobin (Hgb) concentrations. 
These increases in Hgb are achieved with peak plasma EPO exposures substantially 
lower than those observed with recombinant human EPO (rhEPO). Data from completed 
clinical and preclinical studies are provided in the current Investigator Brochure [IB
GlaxoSmithKline Document number RM2008/00267/07] and IB supplement(s).  
Daprodustat has been evaluated as a treatment for anemia associated with CKD in non-
dialysis participants.  A Phase 2A clinical trial in non-dialysis participants with anemia 
associated with CKD demonstrated that fixed-dose daprodustat was better than placebo in 
increasing Hgb over 4 weeks [Holdstock, 2016].
Another Phase 2B, randomized, controlled 24-week parallel-group, multi-center study 
also evaluated daprodustat safety and efficacy in a non-dialysis population that were 
either naïve or previously treated with rhEPO [GlaxoSmithKline Document Number 
2014N219818_00]. Titration of daprodustat demonstrated efficacy by achieving mean
Hgb within target range with an adverse event rate consistent with the clinical events that 
generally occur in the CKD population. 
Blood Hgb concentration, transferrin saturation and ferritin levels are the primary 
markers for evaluation of anemia in CKD patients. Initially, non-dialysis CKD patients 
receive iron therapy, to ensure that sufficient iron is available for erythropoiesis prior to 
initiating rhEPO therapy for anemia treatment. A one to three month trial of oral iron is 
generally recommended in rhEPO naïve patients with non-dialysis CKD [KDIGO, 2012). 
However, if poor compliance is seen with oral iron therapy due to lack of efficacy or 
gastrointestinal intolerance, IV iron may be administered in patients requiring iron 
repletion. rhEPO therapy is generally initiated in non-dialysis CKD patients once Hgb 
has dropped below 10 g/dL and benefits outweigh the risks associated with this therapy
[KDIGO, 2012].Thus, the question arises whether initiation of treatment with a PHI, such 
as daprodustat, in the rhEPO naïve and iron sufficient population might result in Hgb 
benefits that are reflected as benefits in symptoms and quality of life.
This Phase 3 double blind study will be conducted to assess efficacy, safety and effects 
on quality-of-life of daprodustat compared to placebo. Study participants will be rhEPO 
naïve and had limited IV iron exposure at baseline. The purpose of this study is to 
evaluate the effect of daprodustat, on hemoglobin response and quality of life, compared 
to placebo over an extended period, i.e. 28 weeks, unlike the the previous study which 
evaluated the response over 4 weeks. The primary endpoint is Hgb superiority of 
daprodustat versus placebo, and a principal secondary endpoint includes measures of 
health related quality-of-life.

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3.2.
Background
Anemia is a common complication of CKD. The cause of anemia in this population is 
multi-factorial, including relative or absolute deficiency of EPO, reduced iron availability 
related to chronic inflammation or acute infection, and gastrointestinal blood loss. 
Anemia is further exacerbated by shortened erythrocyte survival that is associated with 
the uremic milieu and declining kidney function.
Current treatments for anemia associated with CKD include supplemental iron therapy 
(IV or oral), the use of rhEPO, and blood transfusions. While existing therapies are useful 
and effective in treating anemia, they each have significant limitations.
Thus, an unmet need exists for a safer alternative for treatment of anemia associated with 
CKD. 
 
 
 
 
 
3.3.
Benefit/Risk Assessment
More detailed information about the known and expected benefits and risks and 
reasonably expected adverse events of daprodustat may be found in the daprodustat IB
and IB supplements (if applicable).
Specific information regarding warnings, precautions, contraindications, adverse events 
(AEs), and other pertinent information on the randomized treatment is provided in the IB, 
IB supplement(s) (if applicable) and other pertinent documents (e.g., Study Reference 
Manual [SRM], informed consent).
3.3.1.
Risk Assessment
The potential risks of clinical significance including AEs of special interest 
(Section 9.3.7), and the mitigation strategies for this protocol taking into account the 
results of completed clinical and nonclinical studies with daprodustat, are outlined below.
CCI - This section contained Clinical Outcome Assessment data collection questionnaires or indices, which are 
protected by third party copyright laws and therefore have been excluded.

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Daprodustat 
Excessive erythropoiesis  leading to thrombosis 
and/or tissue ischemia
In animal studies, excessive erythropoiesis (Hgb/Hct > upper limit 
normal) attributed to daprodustat was associated with vascular 
congestion, microthrombi, and tissue ischemia in a number of organs.
In the phase 2 proof of concept study, a high incidence of 
discontinuation due to hemoglobin stopping criteria (Hgb > 13.5 g/dL 
or Hgb increased > 1 g/dL over any 2-week period) was observed.  In 
non-dialysis participants administered 10 mg, 25 mg, 50 mg or 100 mg 
of daprodustat daily, a total of 21 of 61 participants (34%) met these 
criteria.  In hemodialysis-dependent participants administered either 10 
mg or 25 mg of daprodustat daily, a total of 8 of 31 participants (26%) 
met these criteria.Phase 2 dose-ranging studies, and associated 
statistical and exposure response modelling has informed Phase 3 
dose rationale, starting doses, dose steps, and dose adjustment 
scheme to optimize Hgb management.
Integrated AE data [including 2 global phase 2b studies (24-week 
treatment duration) and 2 Japanese phase 3 studies (52-week 
treatment duration)]: Few participants experienced a possible 
thrombosis related adverse event in the setting of excessive 
erythropoiesis [3/688 (0.5%) participants on daprodustat vs. 0/404 on 
rhEPO].
Following review of clinical data received to date, this has not been 
identified as a safety concern for daprodustat when dose is managed 
appropriately according to target Hgb. However, experience with 
daprodustat is currently insufficient to fully characterize this risk.

Specific eligibility criteria related to 
requirements for entry Hgb are detailed in 
Section 6.1

Hgb will be closely monitored throughout the 
dosing period as outlined in the SoA Table 
Section 2.

Specific guidance for dose adjustment, dose 
interruption, or discontinuation of daprodustat 
based on achieved Hgb (including rate of 
change) is provided in Section 7.2 and Section
8.1.

Instream monitoring of safety data by internal 
safety review team.
Worsening of hypertension
In a dog cardiovascular study, single oral doses of daprodustat (up to 
90 mg/kg) did not produce effects on blood pressure.
Marketed rhEPO and its analogues have been associated with risks 
related to uncontrolled hypertension, including the need for initiation of 

Specific eligibility criteria related to current 
uncontrolled hypertension are outlined in 
Section 6.2

Blood pressure will be closely monitored 

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or increases in antihypertensive therapy when used in patients with 
anemia of CKD (i.e. 25% Epogen, 27% Mircera, and 40% Aranesp 
treated patients with renal anemia required initiation or increase in 
their anti-hypertensive medications; hypertensive encephalopathy and 
seizures have been reported. The contribution of rhEPO-associated 
hypertension to the unfavourable effects on cardiovascular outcomes 
remains uncertain).
Integrated AE data from clinical trials with daprodustat [including 2 
global phase 2b studies (24-week treatment duration) and 2 Japanese 
phase 3 studies (52-week treatment duration)]: 
o
The majority (>90%) of participants had a baseline history of 
hypertension.
o
No meaningful difference was seen between treatment groups in 
AEs (preferred term) of “hypertension” [29/688 (4%) daprodustat 
vs. 19/404 (4%) rhEPO; 0.91 relative risk (RR) (95% confidence 
interval: 0.5, 1.67)] or “blood pressure increased” [16 (2%) 
daprodustat vs. 7 (2%) rhEPO; RR 1.22 (0.48,3.11)]. Results 
were not substantively different between non-dialysis and 
haemodialysis participants.
o
Although no clinically meaningful changes in blood pressure were 
observed, participants in both treatment groups required 
increases in anti-HTN medications:
o
In the 24-week global phase 2b studies, 25/170 (15%) 
of ND participants receiving daprodustat vs. 18/80 
(14%) control and 22/177 (12%) of HD participants
receiving daprodustat vs. 2/39 (5%) control.
o
In the 52-week Japan phase 3 studies, 57/149 (38%) of 
ND participants receiving daprodustat vs. 68/150 
(45%)  rhEPO and 51/136 (38%) of HD participants
throughout the dosing period as outlined in the 
Schedule of Activities (Section 2) 

Instream monitoring of safety data by internal 
safety review team.

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Potential Risk of Clinical Significance
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receiving daprodustat vs. 66/135 (49%) for rhEPO.
The data received to date from completed clinical trials with 
daprodustat are insufficient to refute this risk.
Death, MI, stroke, heart failure, thromboembolic 
events, thrombosis of vascular access at Hgb levels 
which are within the normal range (i.e. not 
polycythemic conditions)
Marketed rhEPO/ Erythropoetin-stimulating agent (ESAs) have been 
associated with an increased risk for death and serious cardiovascular 
events when used in patients with anemia of CKD. Clinical studies with 
marketed rhEPO/analogs have suggested “higher” target hemoglobin, 
rate of hemoglobin rise of greater than 1 g/dL in any 2-week period, 
and/or higher doses may contribute to these risks.
In non-clinical studies conducted to date, not observed at tolerated 
doses when hemoglobin/hematocrit within normal range for species.
Integrated AE data from clinical trials with daprodustat [including 2 
global phase 2b studies (24-week treatment duration) and 2 Japanese 
phase 3 studies (52-week treatment duration)]: No meaningful 
difference was seen between treatment groups in the overall incidence 
of this AESI: [39/688 (5.5%) daprodustat vs. 25/404 (6%) rhEPO; 0.92 
relative risk (95% confidence interval: 0.55, 1.53)].  Within this 
composite AESI, the most frequent event types were heart failure (at 
least 12 events daprodustat vs. at least 13 events rhEPO) and 
thrombosis (at least 14 events daprodustat vs. at least 8 event 
rhEPO); and a numerical imbalance was noted in events of myocardial 
ischemia (at least 7 events daprodustat vs. at least 1 event rhEPO). 
The small number of events makes it difficult to draw any firm 
conclusions.
The clinical data received to date from completed clinical trials with 
daprodustat are insufficient to substantiate or refute this risk.

Specific eligibility criteria related to CV risk are 
outlined in Section 6.2.

Hgb will be closely monitored throughout the 
dosing period as outlined in the SoA (Section
2).

Instream monitoring of safety data by internal 
safety review team.
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 

Suspected GI bleeding or significant symptoms 
consistent with erosion or ulcers should be 
investigated diagnostically (i.e. endoscopic 

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daprodustat.
In rodents stomach erosions were observed with intravenous and oral 
administration of daprodustat.
Gender-averaged systemic exposure (AUC) at the no observed 
adverse effect levels (NOAEL) are 3.3 -fold (monkeys) and 737 -fold 
(rats) above human exposure (25 mg daprodustat).
In clinical trials to date with daprodustat, mild-moderate GI signs and 
symptoms represent the most frequently reported adverse event, 
however causal association has not been established.
Integrated AE data from clinical trials with daprodustat [including 2 
global phase 2b studies (24-week treatment duration) and 2 Japanese 
phase 3 studies (52-week treatment duration)]: No meaningful 
difference was seen between treatment groups in reports of this AESI 
[17 (2.7%) daprodustat vs. 10 (2.3%) rhEPO; 1.16 relative risk (95% 
confidence interval: 0.52, 2.58)].
Following review of clinical data received to date, GI erosions have not 
been identified as a safety concern for daprodustat.
examination) as clinically warranted.

Instream monitoring of safety data by internal 
safety review team.
Cancer-related mortality and tumor progression and 
recurrence
Marketed rhEPOs has been associated with increased risk of cancer 
related morbidity and mortality when used in patients with cancer.
Administration of 60mg/kg daprodustat to mice caused minimal 
increases in circulating VEGF while significant EPO increases were 
observed.
There were no daprodustat-related neoplastic findings in a 2-year rat 
oral carcinogenicity study.
In clinical studies conducted to date, administration of daprodustat has 
been associated with:
Once daily administration:

Specific eligibility criteria related to personal 
history of malignancy or participants with 
complex kidney cyst are outlined in Section
6.2.

Stopping criteria for participants with treatment 
emergent malignancy are outlined in Section
8.1

Instream monitoring of safety data by internal 
safety review team.

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
In studies up to 4 weeks duration, a dose-ordered increase 
in VEGF plasma concentrations, at doses ranging from 10 to 
150 mg.

In  studies up to 24 weeks duration at doses up to 25mg, 
changes in VEGF plasma concentrations were variable but 
similar relative to control.
Three times weekly administration:

In studies up to 4 weeks duration at doses of 10 to 30 mg:
o
Dose dependent increases in plasma VEGF and 
EPO concentrations were observed.
o
Pre-dose concentrations of EPO and VEGF were 
near or below baseline indicating no accumulation 
of EPO or VEGF after three times weekly dosing.
Integrated AE data [including 2 global phase 2b studies (24-week 
treatment duration) and 2 Japanese phase 3 studies (52-week 
treatment duration)]: No meaningful difference was seen between 
treatment groups in the occurrence of this AESI: [8/688 (1.1%) 
daprodustat vs. 4/404 (0.9%) rhEPO; 1.14 relative risk (95% 
confidence interval: 0.31, 4.28)].
Clinical experience to date is not yet sufficient to substantiate or refute 
this as a safety concern for daprodustat.
Pulmonary artery hypertension (PAH)
A role for HIF-regulated pathways in the pathophysiology of PAH has 
been suggested based on well established effects of acute and chronic 
hypoxia in man on the pulmonary vasculature (vasoconstriction), and
by findings in patients with naturally occurring mutations that result in 
decreased HIF degradation [Smith, 2006; Formenti, 2011].
There have been no histopathologic findings suggestive of PAH in pre-
clinical safety studies with daprodustat (up to 13 weeks duration in 

Instream monitoring of safety data by internal 
safety review team.

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Potential Risk of Clinical Significance
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mice and dogs, up to 26 weeks in rats, 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. These hypoxia-induced 
PRVP changes fall within the range of PRVP differences noted among 
non-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 systolic 
pulmonary artery pressure (sPAP) under either normoxic or hypoxic 
conditions.
ECHO assessments performed in Phase 2b studies (24 weeks 
treatment duration) did not identify any clinically meaningful changes in 
sPAP in participants not on dialysis for daprodustat. In hemodialysis 
participants, mean absolute change from baseline in sPAP was similar 
for both treatment groups; however, there was a numeric imbalance 
(Daprodustat: 8 [7%]; Control 0) in participants reaching the sPAP 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 participants with resolution 
of sPAP on safety follow-up ECHOs had confounding conditions that
could contribute to resolution other than discontinuation of study 
treatment; and there was no dose relationship for participants meeting 
the sPAP PCI criterion. Overall, there is insufficient evidence to 
conclude a relationship to treatment with daprodustat.

A post-hoc analysis was performed using a definition of PAH 
often cited in the literature [Navaneethan, 2016]. participants with 
sPAP >35 mmHg and/or tricuspid regurgitation maximum jet 
velocity (TRV) >2.5 m/s were considered as having 

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PAH.  Regardless of baseline status of PAH, there was no 
clinically meaningful difference in the proportion of participants
with on-treatment PAH between the two treatment groups:  
o
Participants with PAH at baseline: 35/113 (31%) vs. 
21/54 (39%) (ND) and 37/115 (32%) vs. 7/21 (33%) 
(HD), daprodustat vs. control, respectively.
o
Participants without PAH at baseline: 25/113 (22%) vs. 
12/54 (22%) (ND) and 22/115 (19%) vs. 6/21 (29%) 
(HD), daprodustat vs. control, respectively.
Integrated AE data [including 2 global phase 2b studies (24-week 
treatment duration) and 2 Japanese phase 3 studies (52-week 
treatment duration)]: Four (0.5%) non-serious AEs in the daprodustat 
group vs 0 in rhEPO. 

Review of participant level information did not suggest adverse 
treatment effect: 2 participants from phase2b that met protocol 
specified stopping criteria on scheduled ECHO had non-serious 
AEs of ‘pulmonary arterial pressure increased’ and 2 participants
from Japan Phase 3 had non-serious AE ‘pulmonary 
hypertension’ in setting of concurrent serious AEs of acute 
pulmonary embolus and mitral regurgitation (respectively) 
identified during hospitalization for coronary angiography.
Following review of clinical data received to date, this has not been 
identified as a safety concern for daprodustat.   
Cardiomyopathy
Published data suggest that cardiac effects of HIF stabilization are 
likely a function of the mechanism, extent, and duration of the effects, 
and can range from protective to detrimental depending upon the 
specific model and experimental conditions utilized.
With lifetime exposure to daprodustat in a 2-year rat oral 
carcinogenicity study, an exacerbation of rat spontaneous, progressive 
cardiomyopathy (PCM)(focal myofiber degeneration/necrosis with 

Instream monitoring of safety data by internal 
safety review team.

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inflammatory infiltrates) was observed at doses of 0.8 mg/kg/day and 
above, although total incidence and severity distribution within any 
daprodustat-group were within historical control ranges.  This is 
consistent with an equivocal threshold for exacerbation of 
spontaneous, progressive cardiomyopathy at 0.8 mg/kg/day which is 
also the threshold dose for observing increased Hct values in 
inndividual rats..
Cardiomyopathy has not been associated with naturally occurring 
mutation in man which results in increased HIF stabilization.
ECHO assessments performed in phase 2b studies (24 weeks 
treatment duration) did not identify any clinically meaningful changes in 
LVEF for daprodustat.
Integrated AE data from clinical trials with daprodustat [including 2 
global phase 2b studies (24-week treatment duration) and 2 Japanese 
phase 3 studies (52-week treatment duration)]: No meaningful 
difference was seen between treatment groups in reports of this AESI 
[1 (0.1%) daprodustat vs. 1 (0.2%) rhEPO; 0.64 relative risk (95% 
confidence interval: 0.02, 18.07)].
Following review of clinical data received to date, this has not been 
identified as a safety concern for daprodustat.
Proliferative retinopathy, macular edema, choroidal 
neovascularization
Increases in local (ocular) VEGF production with retinal 
neovascularization and macular edema observed in diabetic 
retinopathy and to choroidal leakage, edema and neovascularization 
seen in age-related macular degeneration [Campochiaro, 2006].
Administration of 60 mg/kg daprodustat to mice caused minimal 
increases in circulating VEGF while significant EPO increases were 
observed.
No ocular abnormalities with daprodustat were seen in non-clinical 
studies of up to 13 weeks duration in mice and dogs, 26 weeks in rats, 

Instream monitoring of safety data by internal 
safety review team.

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Potential Risk of Clinical Significance
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and 39 weeks in monkeys.
In clinical studies up to 4 weeks duration, a dose-ordered increase in 
VEGF plasma concentrations was observed at doses ranging from 10 
to 150 mg administered once daily and from 10 to 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 with daprodustat.
Integrated AE data [including 2 global phase 2b studies (24-week 
treatment duration) and 2 Japanese phase 3 studies (52-week 
treatment duration)]: No meaningful difference was seen between 
treatment groups in reports of this AESI [9 (2.9%) daprodustat vs. 6 
(2.5%) rhEPO; 1.19 relative risk; (95% confidence interval: 0.42, 
3.43)].
Following review of clinical data with daprodustat received to date, this 
has not been identified as a safety concern for daprodustat.
Exacerbation of rheumatoid arthritis
In inflamed rheumatic joints, activation of HIF- related genes 
secondary to decreased oxygen and pro-inflammatory cytokines has 
been postulated to contribute to the neo-angiogenesis, proliferation 
and infiltration of rheumatoid synovial fibroblasts [Westra, 2010; Muz, 
2009].
No abnormalities seen in non-clinical studies conducted to date for 
daprodustat.
Integrated AE data [including 2 global phase 2b studies (24-week 
treatment duration) and 2 Japanese phase 3 studies (52-week 
treatment duration)]: No meaningful difference was seen between 

Instream monitoring of safety data by internal 
safety review team.

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treatment groups in reports of this AESI [2 (0.3%) daprodustat vs. 1 
(0.2%) rhEPO; 1.20 relative risk; (95% confidence interval: 0.07, 
20.87) and the incidence of musculoskeletal AEs was generally lower 
in the daprodustat treatment group].
Following review of clinical data received to date, this has not been 
identified as a safety concern for daprodustat.
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. Although 
CYP2C8 induction studies were not performed, co-administration of 
daprodustat with an inducer of CYP2C8 may decrease the exposure of 
daprodustat.
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 IC50 value of 21 
µM.
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. Co-administration of daprodustat with BCRP 
inhibitors [e.g., cyclosporine, HIV antivirals (atazanavir, lopinavir, 
ritonavir, tipranavir), lapatanib and curcumin] ] is not expected to 
produce clinically relevant increases in daprodustat exposure
Daprodustat is an inhibitor of OATP1B1/1B3 in vitro, with IC50 values 

Co-administration of daprodustat with strong 
CYP2C8 inhibitors (e.g., gemfibrozil) and 
inducers (e.g., rifampin/rifampicin) is not 
permitted as outlined in Section 7.8.2.

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 7.8  
and Section 7.2.

Specific guidance on the management of 
potential drug-drug interactions and 
concomitant medications is provided in Section
7.8

Hgb will be closely monitored throughout the 
dosing period as outlined in the SoA in Section 
2.

Specific guidance for dose adjustment, dose 
interruption, or discontinuation of daprodustat 
based on achieved Hgb is provided in Section
7.2 and Section 8.1.

Instream monitoring of safety data by internal 

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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
of 6 µM and 11 µM, respectively. A clinical drug interaction study 
between 25mg and 100mg daprodustat with either a CYP2C8 
substrate or an OATP1B1/1B3 substrate showed no PK interaction at 
these doses of daprodustat.
safety review team.
Cyst progression in patients with autosomal dominant 
polycystic kidney disease (ADPKD)
Published data provide in vivo evidence for a potential role of HIF-1a in 
the growth of polycystic kidneys; Hif-1a deletion was sufficient to 
significantly mitigate a progressive polycystic phenotype in an ADPKD 
mouse model, while conversely pharmacologic HIF-1a stabilization 
was sufficient to convert a mild polycystic disease into a severely 
aggravated phenotype with marked loss of renal function. However, 
the dose of FG-2216 (a PHI) used resulted in a significant 
erythropoietic response as reflected by ≥10% relative increases in 
hematocrit over the course of the study (Kraus, 2018; Hofherr, 2018).
A review of the non-clinical data from toxicity studies conducted with 
daprodustat does not indicate an exacerbation in incidence or severity 
of kidney cysts in daprodustat-treated animals in comparison to 
controls.  However, the wild type animals used in these toxicity studies 
have a very low background incidence of renal cysts and are not 
comparable to the mice used in the Kraus article (Kraus, 2018) which 
are an inducible kidney epithelium-specific Pkd1-deletion model.
There is limited experience with daprodustat in participants with 
ADPKD in completed clinical trials. In the Japan phase 3 study in non-
dialysis participants, there were 5 participants with ADPKD (all CKD 
stage 5) in each treatment group.  Mean baseline eGFR was 10 
mL/min/1.73m2 in the daprodustat participants vs. 16 mL/min/1.73m2 
in the rhEPO participants.  The mean (SD) percent change from 
baseline at Week 52 in eGFR was: -18% (8) vs. -21% (14) in 
daprodustat vs. rhEPO, respectively.
Following review of clinical data received to date, this has not been 
identified as a safety concern for daprodustat.

Kidney function will be monitored throughout 
the study as outlined in SoA Section 2.

Ultrasounds will be performed as outlined in 
Section 9.5.4.

Monitoring of emerging safety data by an
internal safety review Team.

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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Other
Randomization to Placebo arm
Potential to receive no therapy due to the placebo-controlled design of 
the study can cause participants to be ineffectively treated for anemia 
associated with CKD. 

A rescue algorithm is provided to minimize 
participants having an inadequate response to 
the treatment for their anemia as outlined in 
Section 7.7.2

Instream monitoring of safety data by internal 
safety review team

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References
Brodie  M, Mitzer S, Pack A et al. Enzyme induction with antiepileptic drugs: Cause for 
concern? Epilepsia 2013. 54: 11 -27
Campochiaro PA and the First ARVO/Pfizer Institute Working Group2et al., Ocular 
versus Extraocular Neovascularization: Mirror Images or Vague Resemblances. Invest 
Ophthalmol & Vis Sci.2006. 47:462-474.
Formenti F, Beer PA, Croft QPP  et al., Cardiopulmonary function in two human 
disorders of the hypoxia-inducible factor (HIF) pathway: von Hippel-Lindau disease and 
HIF-2{alpha} gain-of-function mutation. FASEB J. 2011, 25(6): 2001-2011.
Hofherr, A., et al, HIF-1α drives cyst growth in advanced stages of autosomal dominant 
polycystic kidney disease; Kidney International (2018) 94, 849–851.
Kraus, A., et al, HIF-1α promotes cyst progression in a mouse model of autosomal 
dominant polycystic kidney disease; Kidney International, 2018.
Muz B, Khan MN, Kiriakidis S, Paleolog EM. The role of hypoxia and HIF-dependent 
signaling events in rheumatoid arthritis. Arthritis Research & Therapy 2009. 11:201-210.
Navaneethan SD, for CRIC investigators: Prevalence, Predictors, and Outcomes of 
Pulmonary Hypertension in CKD. J Am Soc Nephrol 2016, 27:877–886
Ohnhaus EE, Breckenridge AM, and Park BK. Urinary Excretion of 6β-Hydroxycortisol 
and the Time Course Measurement of Enzyme Induction in Man. Eur J Clin Pharmacol 
1989. 36: 39-46
Smith TG, Brooks JT, Balanos GM et.al., Mutation of von Hippel–Lindau Tumour 
Suppressor and Human Cardiopulmonary Physiology. PLoS MED 2006. 3:1176-1186.
Westra J, Molema, G and Kallenberg, CGM. Hypoxia-Inducible Factor-1 as Regulator of 
Angiogenesis in Rheumatoid Arthritis - Therapeutic Implications. Current Medicinal 
Chemistry 2010. 17(3):254-263.

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3.3.2.
Benefit Assessment
Generally, participants with non-dialysis dependent CKD undergo clinical assessment of 
anemia only every few months. This study may be beneficial to study participants by 
allowing participants access to anemia management and CKD care. Study participants 
will benefit from routine medical visits to the site and easy access to clinical facilities 
geared towards treatment of anemia in CKD. Study participants will also benefit from 
potentially obtaining a treatment for anemia in the form of an oral tablet which increases 
the ease of use for patients and health care providers. After administration of daprodustat, 
data suggest that the increases in Hgb are achieved with EPO exposure lower than those 
observed with rhEPOs.
 
3.3.3.
Overall Benefit:Risk Conclusion
Daprodustat demonstrates a positive benefit vs. risk based on the evidence as follows. In 
clinical trials up to 24 weeks in duration in non-dialysis CKD participants, daprodustat 
treats Hgb to target range, with a safety profile consistent with the patient population. 
Furthermore, this protocol employs precautions to mitigate known and potential risks to 
randomized participants (Section 3.3.1). 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.
4.
OBJECTIVES AND ENDPOINTS
Objectives
Endpoints
Primary

To compare the efficacy of daprodustat to 
placebo on mean change in Hgb levels 

Mean change in Hgb between baseline 
and the Evaluation Period(EP, mean over 
week 24 to week 28 inclusive)
Principal Secondary

To compare the proportion of participants
achieving increases in Hgb when treated 
with daprodustat versus placebo. 

% of participants having a Hgb increase 
of ≥1.0 g/dL from baseline to EP. 

To compare daprodustat to placebo for 
health related quality-of-life

Mean Change in SF-36 Vitality domain 
between baseline and Week 28
Safety

To compare the safety and tolerability of 
daprodustat to placebo

Incidence and severity of AEs and 
serious adverse events (SAEs) including 
AEs of special interest and adjudicated 
MACE (composite of all-cause mortality, 
non-fatal MI and non-fatal stroke)

Reasons for discontinuation of study 
treatment

Absolute values and changes from 
CCI - This section contained Clinical Outcome Assessment data collection questionnaires or indices, which are 
protected by third party copyright laws and therefore have been excluded.
CCI

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Objectives
Endpoints
baseline in laboratory parameters, Blood 
Pressure (BP) and heart rate (HR)
Secondary

To compare daprodustat to placebo on 
additional Hgb endpoints

N (%) responders, defined as mean Hgb 
within range. 

% time Hgb in range

Mean change in Hgb from baseline. 

To compare daprodustat to placebo on 
the time to rescue 

Time to stopping study treatment due to 
meeting rescue criteria

To compare daprodustat to placebo for 
improving symptoms of anemia of CKD

Mean change from baseline by domain 
and overall symptom score on the 
Chronic Kidney Disease - Anemia 
Questionnaire (CKD-AQ) symptom 
questionnaire

To compare daprodustat to placebo on 
the severity and change in symptoms

Change from baseline in PGI-S

To compare daprodustat to placebo for 
improving health related quality-of-life 

Mean Change in individual items of the 
SF-36 Vitality Domain from baseline.

Mean Change in SF-36 Physical 
Function domain from baseline.

To compare daprodustat to placebo on 
improving work productivity and regular 
daily activity impairment

N (%) of patients currently employed on 
the WPAI-ANS-CPV

Change from baseline in percent and 
mean hours work time missed on the 
WPAI-ANS-CPVChange from baseline in 
percent impaired (equivalent) on the 
WPAI-ANS-CPV

Change from baseline in overall percent 
work impairment (equivalent) on the 
WPAI-ANS-CPV

Change from baseline in percent activity 
impairment on the WPAI-ANS-CPV

To compare daprodustat to placebo on 
improving health status

Change in EQ-5D-5L utility score from 
baseline. 

Change in EQ-VAS score from baseline. 

To compare daprodustat to placebo on 
BP

Change from baseline in SBP, DBP, and 
MAP at week 28 

N (%) with at least one BP exacerbation 
event during the study 

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Objectives
Endpoints
Exploratory

Further evaluations to compare 
daprodustat to placebo on Hgb variability

% of time Hgb is above or below range.

Number (%) of participants with mean 
Hgb above and below range. 

Number (%) of participants with a 
Hgb<7.5 g/dL

Number (%) of participants with a >2 
g/dL increase in Hgb within any 4 week 
period up to EP

N (%) of participants with a Hgb value ≥ 
13 g/dL during the treatment period

Number of times Hgb ≥ 13 g/dL during 
the treatment period

% of time Hgb ≥ 13 g/dL during the 
treatment period. 

Further evaluation to compare 
daprodustat to placebo on Hgb change. 

% of participants who achieved a Hgb 
increase of ≥1.0g/dL  

% of time Hgb increase of ≥ 1.0 g/dL  
from baseline

% of participant having a Hgb increase of 
≥ 1.0 g/dL at each post-baseline visit.  

% of participants who achieved and 
maintained a Hgb increase of ≥1.0g/dL
between baseline and EP. 

To compare daprodustat to placebo on 
measures of iron status, rhEPO and 
Transfusion use

Observed and change from baseline in 
hepcidin, ferritin, transferrin saturation, 
serum iron, total iron binding capacity 
(TIBC)

Average monthly oral iron 
dose/participant (mg) to Week 28

N (%) of participants who reduced oral 
iron supplementation from baseline 

N (%) of participants requiring IV iron 
each month. 

Average monthly IV iron dose/participant
(mg) to Week 28

Time to first IV iron, rhEPO and 
Transfusion use 

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Objectives
Endpoints

Summary of frequency and dose of IV 
iron 

To compare daprodustat to placebo on 
renal function

Estimated Glomerular Filtration Rate 
(eGFR) observed and change from 
baseline 

Serum creatinine observed and change 
from baseline

N (%) transitioning to dialysis

Evaluate the dose adjustment schemes

Assigned dose by visit 

Most recent dose prior to Week 24, 
Week 28 and End of Treatment

Maximum achieved dose

Number (%) of participants with 0, 1, 2 or 
>2 dose adjustment 

Mean number of dose adjustments 

Time dose held for Hgb≥13 g/dL

To compare daprodustat to placebo on 
BP medication changes 

N (%) of subjects who had no change, 
an increase or a decrease in the number 
of BP medications from baseline to week 
28 or final visit for non-completers 

To compare daprodustat to placebo on 
the severity and change in symptoms

N(%) of participants within each PGI-C 
symptom change. 

To compare daprodustat to placebo for 
improving physical activity (actigraphy)

Change in percent and mean number of 
hours of daily activity from baseline.

Change in percent sleep efficiency from 
baseline.
5.
STUDY DESIGN
5.1.
Overall Design
This is a 28-week, randomized, double-blind, placebo-controlled, parallel-group, multi-
center Phase 3 study in participants with anemia associated with chronic kidney disease 
(CKD) who are not on dialysis.  This study will enroll anemic participants who have a 
HemoCue Hgb 8.5 to 10.0 g/dL, inclusive. These participants will have limited history of 
IV iron and be rhEPO naïve prior to screening and randomization.    
This study includes a 4-week screening period, a 28-week treatment period, and a 4-week 
follow-up period (Figure 1). 

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The total duration of study participation for each participant will be approximately 36 
weeks.
Participants will be randomized 1:1 to receive either daprodustat or matching placebo 
tablets. Participants will not be provided with the results of their HemoCue Hgb 
assessment during their participation in the study. 
Daprodustat and placebo doses for participants will be titrated based upon HemoCue 
Hgb. Dose modifications for these participants will follow a protocol-specified dose 
adjustment algorithm to achieve and maintain Hgb within the target range of 11.0 to 12.0 
g/dL, inclusive. Dose changes will be made programmatically in a blinded fashion by the 
IRT system in order to ensure that investigators and participants stay blinded to the study 
treatment and the dose adjustments. 
A rescue algorithm is provided to minimize participants having an inadequate response to 
the treatment for their anemia for an extended period of time and to enable rescue therapy 
to be provided to the participants based on local clinical practice. (Section 7.7.2) 
Figure 1
Study Schematic
5.2.
Number of Participants
Approximately 1200 participants with anemia associated with CKD who are not on 
dialysis will be screened to achieve approximately 600 randomized and to target 
approximately 540 evaluable participants for an estimated total of 270 evaluable 
participants with a 1:1 randomization per study treatment group.
5.3.
Participant and Study Completion
A participant is considered to have completed the study if he/she has completed all 
phases of the study including the Follow-up visit, which takes place 4 weeks after the end 
of study treatment. 
The end of the study is defined as the date of the last visit of the last participant in the 
study or the last scheduled procedure shown in Table 1 of  Schedule of Activities (SoA).

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5.4.
Scientific Rationale for Study Design
This study has a 28-week Treatment Period ending with a 4-week evaluation period from 
Week 24 to Week 28. At the Day 1 visit the subjects will be randomized to the
daprodustat or placebo arm by the IRT system and the study treatment will be 
administered in a blinded manner. From Day 1 to Week 24 participant study treatment 
dosage will be adjusted, per the dosing algorithm (Section 7.2),in a blinded fashion, by 
the IRT system.. 
A placebo control will enable assessment of the magnitude of the daprodustat response 
and comparisons for safety data. Additionally, a placebo comparator   allows for an 
assessment of the extent to which any improvement in symptoms and HRQoL observed 
in the daprodustat treatment group is due to the drug’s effect.
The risk of drop-outs due to lack of treatment effect is estimated to also be low in this 
patient population since, prior clinical studies have indicated that non-dialysis, CKD 
patients can maintain, or even increase, their current level of Hgb value without requiring 
frequent interventional therapy with rhEPOs or IV iron for anemia [Skali, 2013]. 
Participants eligible for this study will be naïve to rhEPO therapies and have limited IV 
iron exposure at the time of screening and randomization, but may be receiving oral iron 
which will be allowed to continue during the course of the study. Participants may start 
treatment or change their dose of iron (oral, or IV if intolerable to oral) to maintain their 
iron levels during the study. Participants who experience worsening of their anemia 
during the study may receive rescue therapy based upon the protocol defined rescue 
algorithm.  Therefore, the use of a placebo arm in this study does not represent the 
absence of any treatment for anemia, but rather placebo in addition to appropriate
standard of care.
5.5.
Dose Justification
Daprodustat starting doses were selected to enable the majority of study participants to 
reach the target Hgb concentration after approximately one red blood cell (RBC) lifespan 
of treatment (almost 3 months, pharmacodynamic steady-state), without the need for any 
individual dose adjustments.  However, due to the between-participant variability in Hgb 
response to a given dose of daprodustat and the relatively narrow Hgb target range, 
individual dose adjustments of daprodustat are still expected during the first few months 
of treatment. 
The daprodustat starting doses and dose steps (including the highest dose level, 16 mg) 
were based on dose exposure-response longitudinal modeling of Hgb data collected 
across the Phase 2 program. 
In this study, the starting dose of daprodustat will be 2 or 4 mg based on baseline 
Hemocue Hgb, or a matching placebo dose, for all participants. The starting dose is 
estimated to increase steady-state Hgb on average by approximately 1g/dL. This starting 
dose is consistent with the dosing algorithm being evaluated in the Phase 3 study 
[GlaxoSmithKline Document Number 2015N230102_03] for non-dialysis dependent
participants who are not currently receiving rhEPO therapy.

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6.
STUDY POPULATION
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted.
6.1.
Inclusion Criteria
Participants will be eligible for inclusion in this study only if all of the following criteria 
apply at screening (Week -4 and Week -2) and randomization (Day 1), unless 
otherwise specified:
Age
1. ≥ 18 years of age at the time of signing the informed consent.
Type of Participant and Disease Characteristics
2. CKD: Have CKD, confirmed at screening: Kidney Disease Outcomes Quality 
Initiative (KDOQI) CKD stages 3, 4, or 5 defined by Estimated glomerular 
filtration rate  (eGFR) using the CKD Epidemiology Collaboration (CKD-EPI) 
formula [Levey, 2009].
3. Hgb: Stable HemoCue Hgb from 8.5 to 10.5 at screening visit (Week -4) and 
from 8.5 to 10.0 g/dL at randomization (Day 1) (Section 9.1). 
4. IV Iron: Participants may receive up to one IV iron dose within the 8 weeks prior 
to screening and NO IV iron use between screening visit and randomization (Day 
1).
5. Oral Iron: If needed, participant may be on stable maintenance oral iron 
supplementation.  There should be <50% change in overall dose and no change in 
type of iron prescribed doses in the 4 weeks prior to Day 1 randomization visit. 
Sex
6. Male and female participants are eligible. A female participant is eligible to 
participate if she is not pregnant (see Section 12.4), not breastfeeding, and at least 
one of the following conditions applies:
Not a woman of childbearing potential (WOCBP) as defined in Section 
12.4 (Appendix 4), or
A WOCBP who agrees to follow the contraceptive guidance in 
Appendix 4 during the treatment period and for at least 4 weeks after the 
last dose of study treatment.
Informed Consent
7. Capable of giving signed informed consent as described in Section 12.2
Appendix 2 which includes compliance with the requirements and restrictions 
listed in the informed consent form (ICF) and in this protocol.

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6.2.
Exclusion Criteria
Participants will not be eligible for inclusion in this study if any of the following criteria 
apply at screening (Week -4 and Week -2) and randomization (Day 1), unless 
otherwise specified: 
CKD Related Criteria 
1. Dialysis: On dialysis or clinical evidence of impending need to initiate dialysis 
within 180 days after randomization (Day 1).
2. Kidney Transplant: Planned living-related or living-unrelated kidney transplant 
within 28 weeks after randomization (Day 1).
Anemia-Related Criteria
3. Transferrin saturation (TSAT) <15% (Screening only) 
4. Ferritin <50 ng/mL (Screening only) 
5. rhEPO or rhEPO analogues: History of rhEPO or rhEPO analogue use within 
the 8 weeks prior to screening and rhEPO use between screening and 
randomization (Day 1).
6. Transfusion: History of transfusion within the 8 weeks prior to screening and 
transfusion between screening and randomization (Day 1).
7. Aplasias: History of bone marrow aplasia or pure red cell aplasia (PRCA)
8. Other causes of anemia: Megaloblastic anemia(untreated pernicious anemia and 
folate deficiency), thalassemia major, sickle cell disease or myelodysplastic 
syndrome
9. Gastrointestinal (GI) bleeding: Evidence of actively bleeding gastric, duodenal, 
or esophageal ulcer disease OR clinically significant GI bleeding ≤ 8 weeks prior 
to screening through to randomization (Day 1)
Concomitant medication and other study treatment-related criteria
10. Severe Allergic reaction: History of severe allergic or anaphylactic reactions or 
hypersensitivity to excipients in the investigational product.
11. Drugs and supplements: Use of strong inhibitor of CYP2C8 (e.g.,gemfibrozil) 
or strong inducers of CYP2C8 (e.g., rifampin/rifampicin).
12. Ferric Citrate: Ferric citrate use within 4 weeks prior to randomization (Day 1)
Prior Clinical Study Experience 
13. Other interventional study participation: Use of other investigational agent or 
device prior to screening through to randomization (Day 1).  
a.
Note:  at screening, this exclusion applies to use of the investigational 
agent within 30 days or within five half lives (whichever is longer).
14. Prior treatment with daprodustat:  Any prior treatment with daprodustat for a 
treatment duration of >30 days.

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Cardiovascular Disease-Related Criteria (see also other cardiovascular exclusion 
criteria #22)
15. MI or acute coronary syndrome:  within the 8 weeks prior to screening through 
to randomization. (Day 1)
16. Stroke or transient ischemic attack:  within the 8 weeks prior to screening
through to randomization. (Day 1)
17. Heart failure: Chronic Class IV heart failure, as defined by the New York Heart 
Association (NYHA) functional classification system
18. QTcB (Day 1): QTcB >500 msec or QTcB >530 msec in participants with bundle 
branch block.  There is no QTc exclusion for participants with a predominantly 
paced rhythm.
Other Disease Related Criteria 
19. Liver Disease-Related Criteria:
Alanine transaminase (ALT) >2x upper limit of normal (ULN) at 
screening (Week -4).
Bilirubin >1.5xULN at screening (Week -4). NOTE: Isolated bilirubin 
>1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin 
<35%.
Current unstable liver or biliary disease per investigator assessment, 
generally defined by the presence of ascites, encephalopathy, 
coagulopathy, hypoalbuminaemia, esophageal or gastric varices, 
persistent jaundice, or cirrhosis. NOTE: Stable chronic liver disease 
(including asymptomatic gallstones, chronic hepatitis B or C, or 
Gilbert’s syndrome) is acceptable if participant otherwise meets entry 
criteria.
20. Malignancy: History of malignancy within the 2 years prior to screening through 
to randomization (Day 1), or currently receiving treatment for cancer, or complex 
kidney cyst (e.g. Bosniak Category II F, III or IV) > 3cm. Note:  The only 
exception is localized squamous cell or basal cell carcinoma of the skin that has 
been definitively treated ≥8 weeks prior to screening.
Other Exclusion
21. Other Conditions:  Any other condition, clinical or laboratory abnormality, or 
examination finding that the investigator considers would put the participant at 
unacceptable risk, which may affect study compliance or prevent understanding 
of the aims or investigational procedures or possible consequences of the study.
Other cardiovascular exclusion criteria
22. Current uncontrolled hypertension: Current uncontrolled hypertension as 
determined by the investigator

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6.3.
Lifestyle Restrictions
There are no lifestyle restrictions required for this study.  Any restrictions of concomitant 
medications and non-drug therapies are described in Section 7.6.1.
6.4.
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study 
but are not subsequently randomized. A minimal set of screen failure information is 
required to ensure transparent reporting of screen failure participants to meet the 
Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to 
respond to queries from regulatory authorities. Minimal information includes 
demography, screen failure details, eligibility criteria, and any serious adverse events 
(SAEs).
Participants that fail screening are eligible to be rescreened up to two additional times as 
soon as the investigator assesses they may meet study entry criteria. If participants are 
rescreened, they must sign a new informed consent form. Rescreened participants will 
also be assigned a new participant number, while maintaining the link to the participant 
number used for the initial screening.
7.
TREATMENTS
Study treatment is defined as daprodustat or matching placebo, intended to be 
administered to a study participant according to the study protocol. Once daily oral 
daprodustat starting doses or matching placebo are assigned based on the HemoCue Hgb 
concentration at randomization (Day 1) (Table 4). 
Table 4
Daprodustat Starting Dose 
Baseline (Day 1)  
Hgb (g/dL)
Daprodustat Starting Dose (mg, once daily)
8.5 to <9
4
9 to 10
2
7.1.
Treatments Administered
Participants randomized on Day 1 to either daprodustat or placebo will receive 3 bottles, 
and will take one tablet from each bottle at each dose.  The study treatments to be 
administered in this study are described in Table 5.

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Table 5
Description of Daprodustat and Matching Placebo Tablets
Study Treatment Name:
Daprodustat (GSK1278863)
Placebo
Dosage formulation:
film-coated tablet
film-coated tablet
Unit dose
strength(s)/Dosage 
level(s):
Unit dose strength:
7mm tablet: 1mg, 2mg, 4mg
9mm tablet: 6mg, 8mg, 10mg
Dosage levels:
1, 2, 4, 6, 8, 10, 12, 16 mg
Unit dose strength:
Matching 7mm and 9mm tablets
Dosage levels:
Matching 1, 2, 4, 6, 8, 10, 12, 16 
mg
Route of Administration 
oral
oral
Dosing instructions:
3 Tablets are to be taken daily 
with water. Tablets can be taken 
without regard to food.
3 Tablets are to be taken daily 
with water.  Tablets can be taken 
without regard to food.
Packaging and Labeling
Study Treatment will be 
provided in white, opaque high 
density polyethylene (HDPE) 
bottles with child-resistant 
closures. Each bottle will be 
labeled as required per country 
requirement. 
Study Treatment will be provided 
in white, opaque high density 
polyethylene (HDPE) bottles with 
child-resistant closures. Each 
bottle will be labeled as required 
per country requirement.
Manufacturer
GlaxoSmithKline
GlaxoSmithKline
7.2.
Dose Modification
The available dose steps of daprodustat and placebo are outlined below. Dose 
adjustments (increase or decrease by one dose step, maintain, or withheld if ≥13 g/dL) 
will be made programmatically for both the daprodustat arm and the matching placebo 
arm by the IRT system to increase and maintain hemoglobin within the target range based 
on the HemoCue Hgb value measured at least every 4 weeks.  Those receiving the 
highest dose of daprodustat ,or dose matched placebo, who require a dose increase will 
maintain the same dose, while those receiving the lowest dose of daprodustat, or 
matching placebo, that require a dose decrease will receive placebo until such time as 
when study treatment can be restarted according to Table 6.  
10 mg
2 mg
1 mg
4 mg
6 mg
8 mg
12 mg
16 mg

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Dose adjustment decisions will be based on individual participant HemoCue Hgb 
response. The decision to proceed to the next dose (either an increase or a decrease) or 
maintain current dose will be conducted as follows:
Table 6
Study treatment dosing algorithm
HemoCue Hgb (g/dL) at 
current study visit1
HemoCue Hgb change since last 
study visit1
Study Treatment Dose Adjustment6
<8.52
Any change
Repeat Hgb and average values, if 
confirmed 8,Increase dose to next 
higher step AND evaluate for rescue 
criteria 7
8.5 to <10.5
Hgb increase <0.5 g/dL or any Hgb 
decrease or No change 
Increase dose to next higher step
8.5 to <10.5
Increase by ≥0.5 and ≤2 g/dL
Maintain dose
10.5 to 12.5
Any change ≤2 g/dL4
Maintain dose
10.5 to <11.0 at 2 
consecutive visits 
Decreasing or No change
Increase to the next higher dose step
>12.0 to ≤12.5 at 2 
consecutive visits
Increasing or No change
Decrease to the next lower dose step
>12.5 to <13
Decreasing 
Maintain dose
> 12.5 to <13 
Increasing or No change
Decrease to the next lower dose step
13.0 3
Any change 5  
Repeat Hgb and average values 8; if 
confirmed, temporarily hold the dose 
and re-check Hgb at next study visit 1; 
restart at one dose step lower when 
Hgb <12.0 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 weeks 2,5)
Repeat Hgb and average values 8; if 
confirmed, decrease to the next lower 
dose step
Any
>2  g/dL decrease over 4 weeks
(>1 g/dL decrease over 2 weeks 2,5)
Repeat Hgb and average values 8, if 
confirmed, increase to the next higher 
dose step 7
1.
“Study visit” refers to scheduled visits as outlined in SoA.
2.
This rule applies to any scheduled or unscheduled visit, provided it has been at least 2 weeks from 
the prior study visit.
3.
This rule applies to any scheduled or unscheduled visit
4.
Any change is defined as an increase, decrease or no change of 2g/dL, from prior study visit,
when Hgb is 10.5 or <12.5 g/dL.
5.
This rule applies to Week 2 visits as well. 
6.
Those receiving the highest dose of study treatment who require a dose increase will maintain the 
same dose, while those receiving the lowest dose of study treatment that require a dose decrease 
will have doses withheld.  
7.
If HemoCue Hgb <8.5 g/dL, then also consider participant for rescue criteria per protocol Section
7.7.2.
8.
Repeat HemoCue Hgb at the same study visit to confirm Hgb (using the same sample) and take 
average.

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7.3.
Method of Treatment Assignment

Subjects will be stratified by region (Section 12.8 Appendix 8). Region at study 
entry is considered a stratification factor that is potentially prognostic of study 
endpoints. Following stratification all participants will be centrally randomized in 
a 1:1 fashion to receive either oral daprodustat or oral placebo.

Once a randomization number has been assigned by the IRT system, it must not 
be re-assigned

Study treatment will be dispensed at the study visits summarized in the SoA
(Section 2).

Returned study treatment should not be re-dispensed to the participants.
7.4.
Blinding
This will be a double-blind study. The participant, investigator, site staff, and GSK study 
team are all blinded to the assigned study treatment.  
The IRT will be programmed with blind-breaking instructions. The investigator may 
unblind a participant’s study treatment assignment in case of an emergency or in the 
event of a serious medical condition when knowledge of the study treatment assignment 
is essential for the appropriate clinical management or welfare of the participant. In case 
of lack of efficacy, a participant should receive rescue therapy as per protocol Section
7.7.2, but the study treatment assignment should not be unblinded except in case of an 
emergency or serious medical condition as previously described. GSK must be notified 
before the blind is broken, unless identification of the study treatment is required for a 
medical emergency in which the knowledge of the specific blinded study treatment will 
affect the immediate management of the participant’s condition. In this case, GSK must 
be notified within 24 hours after the blind is broken. The investigator should not reveal 
the participant’s unblinded treatment assignment to GSK, unless that information is 
important for the safety of participants currently in the study. The date and reason that the 
blind was broken must be recorded in the source documentation and eCRF.
A participant may continue in the study if their treatment assignment blind is broken by 
the investigator. However the study treatment will be discontinued and the participant 
will be followed until the end of study on standard of care.
GSK’s Global Clinical Safety and Pharmacovigilance (GCSP) staff may unblind the 
treatment assignment for any participant with an SAE. If the SAE requires that an 
expedited regulatory report be sent to one or more regulatory agencies, a copy of the 
report, identifying the participant’s treatment assignment, may be sent to investigators in 
accordance with local regulations and/or GSK policy.
7.4.1.
Additional Considerations to Maintain the Blind
This study is double-blinded, such that the sponsor, investigator and participant will all 
be blinded to the study treatment assignment. Participants will not be provided with the 

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results of the HemoCue Hgb assessment during their pariticipation in the study. Subjects 
should be provided with the understanding to also not obtain Hgb information from local 
labs prior to study visits. Additionally, Investigators, site staff and participants will also 
be blinded to some of the central laboratory results during the study. 
7.5.
Preparation/Handling/Storage/Accountability
No preparation of study treatment is required.

The investigator or designee must confirm appropriate temperature conditions 
have been maintained during transit for all study treatment received and any 
discrepancies are reported and resolved before use of the study treatment.

Only participants enrolled in the study may receive study treatment and only 
authorized site staff may supply or administer study treatment. All study treatments 
must be stored in a secure, environmentally controlled, and monitored (manual or 
automated) area in accordance with the labelled 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 study treatment accountability, reconciliation, and 
record maintenance (i.e., receipt, reconciliation, and final disposition records).

Further guidance and information for the final disposition of unused study 
treatment are provided in the Study Reference Manual. 

Under normal conditions of handling and administration, study 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.
7.6.
Treatment Compliance
Given participants self-administer study treatment(s) at home, compliance with blinded 
study treatment will be assessed through querying the participant during the site visits 
and documented in the source documents and eCRF.  A record of the number of bottles 
of study treatment and the number of tablets from each bottle dispensed to and taken by 
each participant must be maintained and reconciled with study treatment and compliance 
records.  Treatment start and stop dates, including dates for treatment delays and/or 
treatmentinteruptions will also be recorded in the eCRF.
7.6.1.
Study Treatment Extended Interruption 
Sites should contact GSK if a subject will be away temporarily from the research site for 
>5 weeks during their participation in the study, in order to discuss options for continuing 
randomized treatment and completing study visits. Every effort must be made to continue 
randomized treatment; however if a subject will be off the study treatment, sites should 

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consult with GSK in order to determine if the subjects should be withdrawn from 
treatment and brought in for a treatment discontinuation visit. 
7.7.
Standard of Care
During the study (from screening), investigators are expected to monitor the participant’s 
overall clinical status to ensure standards of care are met to enable consistency of practice 
with Kidney Disease Improving Global Outcomes [KDIGO, 2012]guidelines or local 
equivalent (e.g, phosphate and albumin).
For this study, specific iron management criteria and a dose adjustment algorithm for 
randomized treatment will apply. These were developed to reflect global clinical practice.
7.7.1.
Iron Management Criteria
Investigators should make every effort to maintain participants’ serum TSAT ≥15% and 
ferritin ≥ 50 ng/mL from randomization (Day 1) to end of study. The investigator will 
follow the iron management criteria from randomization (Day 1) through end of study for 
all participants receiving study treatment. 
Iron therapy will be administered, starting with oral iron, if ferritin is <50 ng/mL and/or 
TSAT is <15%, to reestablish participant’s screening (Week -4) iron parameters.
Participants that are on oral iron at randomization may change their dose of oral iron in 
order to maintain their TSAT and ferritin levels as stated above. IV iron can be 
administered to participants who are intolerant to oral iron, otherwise IV iron should only 
be administered to participants being evaluated for rescue criteria (Section 7.7.2), please 
see the SRM for additional IV Iron administration requirements. Iron parameters will be 
assessed at scheduled study visits outlined in the SoA.  Iron therapy may be discontinued 
once screening ferritin and TSAT levels are reached

Only results for ferritin and TSAT measured by Q2 (central lab) should be used to 
inform if iron therapy is required.
7.7.2.
Rescue Criteria
A rescue algorithm is provided to minimize participants 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 7.
This rescue algorithm does not apply to participants with low Hgb as a result of an acute 
or subacute event with an identifiable cause (e.g., GI bleed, blood loss due to surgery or 
vascular access).  In these cases, treatment should be directed to the specific cause and 
randomized treatment will be continued at the current dose (unless Hgb is ≥13 g/dL 
which requires a dose hold).

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Table 7
Rescue Algorithm for Anemia Management
Evaluate Participant for Rescue starting from Week 4 if:  

HemoCue Hgb is <7.5g/dL, or

HemoCue Hgb is <8.5g/dL and participant is symptomatic1, or 

HemoCue Hgb is <8.5 g/dL on three consecutive visits 
Step 1:
Initial 
Intervention
Initial intervention depends on the participant’s iron status:

If participant has TSAT < 15% and/or Ferritin < 50 ng/mL from a prior study 
visit, then
o
continue with study treatment, and 
o
intervene with iron therapy: Single dose of IV iron up to 1000 mg (in 
addition to the iron management criteria)
At the next study visit in 4 ±1 weeks, recheck HemoCue Hgb. If HemoCue 
Hgb value continues to meet the evaluation criteria for rescue, then Proceed 
to Step 2.

If participant has TSAT ≥15% and Ferritin ≥ 50ng/mL, proceed to step 2.  
Step 2: 
Rescue 
Randomized treatment should be permanently discontinued (but participant 
should remain in study to monitor Hgb) and the participant should be 
rescued according to local clinical practice:

If HemoCue Hgb remains <8.5 g/dL despite Initial Intervention (Step 1) based 
on the average of two HemoCue Hgb values 2

Rescue can be considered IV iron, rhEPOs and/or Transfusions.
1.
Symptoms should be related to anemia of CKD. Further information regarding collecting this data will be stated in 
the SRM. 
2.
Repeat HemoCue Hgb at the same study visit to confirm Hgb (using the same sample); take average of 2 values.
The study site will supply any rescue medication that will be obtained locally. 
Although the use of rescue medications is allowable, if the participant meets rescue 
criteria, the use of rescue medications should be delayed, if possible, for at least 4 weeks 
following the initial administration of study treatment at randomization. The date of 
rescue medication administration as well as the name and dosage regimen of the rescue 
medication must be recorded in the eCRF 
7.8.
Concomitant Therapy
Any medication or vaccine (including over-the-counter or prescription medicines, 
vitamins, and/or herbal supplements) that the participant is receiving at the time of 
enrollment or receives during the study must be recorded along with:

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
reason for use

dates of administration including start and end dates

route of administration 
For any therapy related to anemia and hypertension, including iron, the following 
additional information should also be captured: 

Dosage information including:
o
Dose and frequency 
o
Formulation 
o
Reason for addition or termination 
o
Change in dose and reason for change in dose
The use of rescue medications is discussed in Section 7.7.2.
The Medical Monitor should be contacted if there are any questions regarding 
concomitant or prior therapy.
7.8.1.
Permitted Medications and Non-Drug Therapies 
Unless specified as a prohibited medication in Section 7.8.2, all concomitant medications 
should be considered permitted provided they are not contraindicated for the individual 
subject concerned.
Co-administration of daprodustat with moderate CYP2C8 inhibitors (e.g., clopidogrel, 
teriflunomide, deferasirox) should be performed with caution. If one of these 
medications is started, stopped or the dose is changed, Hgb should subsequently be 
monitored  at each visit for the following 12 weeks.
7.8.2.
Prohibited Medications and Non-Drug Therapies
Use of any of the following prescription drugs from screening (Week -4) 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)

Ferric Citrate
Except for randomized treatment administered for this study, no other investigational 
agents or devices are permitted from study entry through completion of the study.

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7.9.
Treatment after the End of the Study
Participants 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 participant’s medical condition.
8.
DISCONTINUATION CRITERIA
8.1.
Discontinuation of Study Treatment
Every effort should be made to keep participants in the study including those who
permanently stop randomized treatment. A participant 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. However, treatment should not be 
discontinued due to an inadequate hemoglobin response to the study treatment, by the 
investigator, since in such instances the study treatment dosing algorithm (Table 6) or the 
rescue criteria (Section 7.7.2) should be followed.
A participant must permanently discontinue study treatment for the following reasons, 
and should continue attending study visits as outlined in the SoA for participants that 
discontinued study treatment (Section 12.2 Appendix 2):

Participant receives a kidney transplant 

Participant initiates dialysis

Participant meets the criteria to receive rescue therapy (Section 7.7.2).

Participant becomes pregnant or intends to become pregnant during the study.

Liver chemistry abnormalities exceed the threshold criteria (Section 8.1.1).

Diagnosis of cancer (new or recurrent), with the exception of localized 
squamous cell or basal cell carcinoma of the skin.

Need for more than 14 days of prohibited medication (Section 7.8.2).

ADPKD participants only: following further imaging , condition of the cystic 
disease in the kidney(s) has worsened more than expected given the clinical 
scenario and no other cause for the kidney function decline and/or cyst 
enlargement can be identified (Section 9.5.4).
In all cases, the reason for study treatment discontinuation and the date of the last dose 
will be recorded in the participant’s eCRF.  
8.1.1.
Liver Chemistry Stopping Criteria
Liver chemistry stopping and increased monitoring criteria have been designed to 
assure participant safety and evaluate liver event etiology.
Discontinuation of study treatment for abnormal liver tests is required when:

A participant meets one of the conditions outlined in the algorithm 

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
In the presence of abnormal liver chemistries not meeting protocol-specified 
stopping rules, the investigator believes study treatment discontinuation is in the 
best interest of the participant. 
Algorithm A: Phase III-IV Liver Chemistry Stopping and Increased Monitoring 
Algorithm
Liver Safety Required Actions and Follow up Assessments Section can be found in 
Section 12.6 (Appendix 6).

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Algorithm B: Phase III-IV Liver Chemistry Increased Monitoring Algorithm with 
Continued Therapy for ALT 3xULN but <8xULN
Liver Safety Required Actions and Follow up Assessments Section can be found in
Section 12.6 (Appendix 6).
8.2.
Withdrawal from the Study
Specific wording is included in the informed consent form which permits participants to 
discontinue study treatment and study procedures, but states an expectation that follow up 
information will always be required. Participants will agree to this at the time of 
consenting.
Withdrawal of consent from the study is expected to be a rare occurrence.  If a participant
expresses a wish to withdraw consent from the study, the investigator will review the 
following contact options with the participant.

In-clinic and phone visits

Follow-up via medical records review and/or other treating physician

Follow-up via family member or other third party contact
If all of these options are refused, then no further study visits or study-related telephone 
contacts will be conducted and the participant will be considered to have withdrawn 
consent. The principal investigator will be required to document that all alternative 
options have been reviewed with the participant.

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For these participants, information regarding vital status will continue to be collected 
from available sources including those in the public domain based on accepted local laws 
and regulations. Where permitted, a third party may be used to obtain information.
In rare cases if a participant has been discontinued from the study without discussing all 
possible alternatives for follow-up the investigator may contact the participants to discuss
all of the alternative methods of follow-up described above. 
Participants may withdraw from the study at any time at his/her own request, or may be 
withdrawn at any time at the discretion of the investigator for safety, behavioral, 
compliance or administrative reasons.
If the participant withdraws consent for disclosure of future information, the sponsor may 
retain and continue to use any data collected before such a withdrawal of consent. 
If a participant withdraws from the study, he/she may request destruction of any samples 
taken and not tested, and the investigator must document this in the site study records.
Refer to the SoA (Section 2) for data to be collected at the time of study treatment 
discontinuation and follow-up and for any further evaluations that need to be completed.
8.3.
Lost to Follow Up
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. 
The following actions must be taken if a participant fails to return to the clinic for a 
required study visit:

Investigators should make every effort to contact participants who are deemed 
lost to follow-up and who have not withdrawn consent to follow-up contact . 
The site must attempt to contact the participant and reschedule the missed visit 
as soon as possible and counsel the participant on the importance of maintaining 
the assigned visit schedule and ascertain whether or not the participant wishes to 
and/or should continue in the study.

Before a participant is deemed lost to follow up, the investigator or designee 
must make every effort to regain contact with the participant (where possible, 
telephone calls, medical records review, third-part follow-up and/ora certified 
letter to the participant’s last known mailing address or local equivalent 
methods). These contact attempts should be documented in the participant’s 
medical record.
9.
STUDY ASSESSMENTS AND PROCEDURES

Study procedures and their timing are summarized in the SoA (Section 2). 

Protocol waivers or exemptions are not allowed with the exception of immediate 
safety concerns. 

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
Immediate safety concerns should be discussed with the sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or 
discontinue study treatment.

Adherence to the study design requirements, including those specified in the SoA
(Section 2), is essential and required for study conduct.

All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening 
log to record details of all participants screened and to confirm eligibility or record 
reasons for screening failure, as applicable. 

Procedures conducted as part of the participant’s routine clinical management (e.g., 
blood count) and obtained before signing of ICF may be utilized for screening or 
baseline purposes provided the procedure met the protocol-specified criteria and was 
performed within the time frame defined in the SoA (Section 2).

The maximum amount of blood collected from each participant over the duration of 
the study, including any extra assessments that may be required, will be 
approximately 150 mL. This amount does not take into account the blood that can be 
collected at unscheduled visits. 

Repeat or unscheduled samples may be taken for safety reasons or for technical 
issues with the samples.

This section lists the procedures and parameters of each planned study assessment. 
Post randomization visits should be referenced back to the Randomization visit (Day 
1). The allowable visit window is ±1 week. However, during the study, to ensure 
continuity of randomized treatment, study visits must be no more than 5 weeks apart.
In exceptional circumstances, minor changes to visit structure may be permitted after 
consultation with the Medical Monitor.

Supplementary study conduct information is provided in the SRM. The SRM 
provides administrative and detailed technical information that does not impact 
participant safety.
9.1.
Screening and Critical Baseline Assessments 

Before any study-specific procedure is performed, valid informed consent must be 
obtained at screening.

Demography and medical history (including cardiovascular medical history/risk 
factors) will be assessed at screening (Week -4).

A stable, HemoCue Hgb from 8.5 to 10.0 g/dL at Day 1 (randomization visit). 
o
If the initial HemoCue Hg assessment is from 10.1 – 10.3 g/dL or from 8.2 
to 8.4 g/dL, a repeat assessment should be conducted. The two Hemocue 
Hgb should be averaged and the average Hemocue Hgb value should be 
from 8.5 – 10.0 g/dL. 

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o
If the average Hgb is also from 10.1 to 10.3 or from 8.2 to 8.4 g/dL then 
another HemoCue Hgb assessment can be performed using a new blood 
sample on the Day 1 visit date.
o
Two values from one blood sample can be entered into the IRT system 
however only the first value or the average value will be used for 
randomization and dose modification algorithm. .

Full details of screening (Week -4) and Day 1 assessments are provided in the 
Schedule of Activities.
9.2.
Efficacy Assessments

Planned time points for all Hgb efficacy assessments are listed in the Schedule of 
Activities (Section 2).

GSK will supply a point-of-care Hgb analyzer (i.e. HemoCue) to each site for 
rapid measurement of Hgb. 

Blood samples for measurement of Hgb via HemoCue and also by the central 
laboratory will be collected as specified in the Schedule of Activities.

All HemoCue Hgb assessments after Day 1 visit to study completion should be 
conducted at the end of the study visit, prior to study medication or rescue 
medication administration. 
o
All efforts should be made to conduct the Hemocue Hgb measurements in 
a separate area away from the participants. 
9.3.
Adverse Events

The definitions of an AE or SAE can be found in Section 12.3 (Appendix 3).

The investigator and any designees are responsible for detecting, documenting, 
and reporting events that meet the definition of an AE or SAE and remain 
responsible for following up AEs that are serious, considered related to the study 
treatment or the study, or that caused the participant to discontinue the study 
treatment (see Section 8). 
9.3.1.
Time Period and Frequency for Collecting AE and SAE 
Information

All SAEs will be collected from the start of treatment until the follow-up visit at 
the time points specified in the SoA (Section 2).   However, any SAEs assessed 
as related to study participation (e.g., study treatment, protocol-mandated 
procedures, invasive tests, or change in existing therapy) or related to a GSK 
product will be recorded from the time a subject consents to participate in the 
study.

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
All AEs will be collected from the start of study treatment until the follow-up
visit at the time points specified in the SoA (Section 2).

Medical occurrences that begin before the start of study treatment but after 
obtaining informed consent will be recorded on the Medical History/Current
Medical Conditions section of the eCRF not the AE section.

All SAEs will be recorded and reported to GSK or designee immediately and 
under no circumstance should this exceed 24 hours, as indicated in Section 12.4
(Appendix 3). The investigator will submit any updated SAE data to GSK
within 24 hours of it being available.

Investigators are not obligated to actively seek AEs or SAEs in former study 
participants. However, if the investigator learns of any SAE, including a death, 
at any time after a participant has been discharged from the study, and he/she 
considers the event to be reasonably related to the study treatment or study 
participation, the investigator must promptly notify GSK.

The method of recording, evaluating, and assessing causality of AEs and SAEs
and the procedures for completing and transmitting SAE reports are provided in
Section 12.4 (Appendix 3).
9.3.2.
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 participant is the preferred method to inquire 
about AE occurrence. 
9.3.3.
Follow-up of AEs and SAEs
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. All SAEs and non-serious AEs of special 
interest (as defined in Section 9.3.6), will be followed until the event is resolved, 
stabilized, otherwise explained, or the participant is lost to follow-up (as defined in 
Section 8.3). Further information on follow-up procedures is given in Section 12.4
(Appendix 4).
9.3.4.
Regulatory Reporting Requirements for SAEs

Prompt notification by the investigator to GSK of an SAE related to placebo or 
daprodustat is essential so that legal obligations and ethical responsibilities 
towards the safety of participants and the safety of a study treatment 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 study treatment under clinical 
investigation. GSK will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, Institutional Review 
Boards (IRB)/Independent Ethics Committees (IEC), and investigators.

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
Investigator safety reports must be prepared for suspected unexpected serious 
adverse reactions (SUSAR) according to local regulatory requirements and GSK 
policy and forwarded to investigators as necessary.

An investigator who receives an investigator safety report describing an SAE or 
other specific safety information (e.g., summary or listing of SAE) from GSK 
will review and then file it along with the Investigator’s Brochure[IB
GlaxoSmithKline Document number RM2008/00267/07] and will notify the 
IRB/IEC, if appropriate according to local requirements.
9.3.5.
Events Referred to the Clinical Events Committee (CEC)
Investigators should refer any event suspected to be one of the events below to the CEC 
for adjudication, 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 HF

Thromboembolic events (vascular access thrombosis, deep vein thrombosis, 
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 by the committee differ, 
the committee’s decision will be considered final. The detailed descriptions of the 
endpoint definitions used for adjudication are contained within the CEC Charter 
(available on request). 
Source documentation required to support the adjudication of the events is described in 
the CEC site manual.  
9.3.6.
Other Cardiovascular (CV) Events
GSK has identified other CV events of interest for all clinical studies. Investigators will 
be required to fill out the specific CV event page of the eCRF for the following CV AEs 
and SAEs or any event that may potentially be one of the categories listed: 

Arrhythmias  

Pulmonary hypertension (also an AE of special interest see Section 9.3.7 for further 
details).

Valvulopathy

Revascularization 

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For any cardiovascular events detailed in Section 9.3.5 and Section 9.3.6 and all deaths, 
whether or not they are considered SAEs, specific Cardiovascular (CV) and Death 
sections of the CRF will be required to be completed. These sections include questions 
regarding cardiovascular (including sudden cardiac death) and non-cardiovascular death. 
The CV eCRFs are presented as queries in response to reporting of certain CV MedDRA 
terms. The CV information should be recorded in the specific cardiovascular section of 
the CRF within one week of receipt of a CV Event data query prompting its completion.
9.3.7.
Adverse Events of Special Interest
The investigator or site staff will be responsible for detecting, documenting and reporting 
any events that may represent the AEs of special interest listed below (using preferred 
terms):

Death, MI, stroke, heart failure, thromboembolic events, thrombosis of vascular 
access

Thrombosis and/or tissue ischemia secondary to excessive erythropoiesis

Worsening of hypertension

Cardiomyopathy  

Pulmonary artery hypertension (see also Section 9.3.2)

Cancer-related mortality or tumor progression and recurrence 

Esophageal and gastric erosions

Proliferative retinopathy, macular edema, choroidal neovascularization 

Exacerbation of rheumatoid arthritis
The Death CRF is provided immediately after the occurrence or outcome of death is 
reported. Initial and follow-up reports regarding death must be completed within one 
week of when the death is reported. 
The results of any investigation regarding adverse events of special interest should be 
recorded in the relevant sections of the participant’s eCRF.
9.3.8.
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 or 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.

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9.3.9.
Pregnancy

Details of all pregnancies in female participants will be collected after the start of 
study treatment and until seven days after the last dose.

If a pregnancy is reported, the investigator should inform Sponsor within 2 weeks of 
learning of the pregnancy and should follow the procedures outlined in Section 12.5
(Appendix 5) .

Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAEs.
9.4.
Treatment of Overdose
There is no specific antidote for overdose with daprodustat. The expected manifestations 
of daprodustat overdosage include signs and symptoms associated with an excessive 
and/or rapid increase in Hgb concentration. Daprodustat is highly protein bound; thus, 
clearance of daprodustat by hemodialysis (HD) or peritoneal dialysis (PD) is very low 
and these are not effective methods to enhance the elimination of daprodustat. 
Daprodustat metabolites are, in part, cleared via hemodialysis. In the event of a suspected 
overdose, it is recommended that the appropriate supportive clinical care be instituted, as 
dictated by the participant’s clinical status. Additionally, participants should be 
monitored closely for CV events, increased heart rate and hematologic abnormalities.
9.5.
Safety Assessments
Planned time points for all safety assessments are provided in the SoA (Section 2).
9.5.1.
Height and Weight 

Height and weight will be measured as specified in the SoA (Section 2). Weight 
should be measured with the participant wearing indoor daytime clothing with no 
shoes. 
9.5.2.
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 SoA (Section 2) 

One measurement each of SBP, DBP and HR will be taken except at Day 1 and 
Week 28 (or Early Treatment Discontinuation visit) when SBP, DBP and HR
will be measured in triplicate.

For measurements taken in triplicate, the readings can be averaged and the 
averaged value would be included in the eCRF. 

Measurements will be taken with participants in a seated position after at least a 
5-minute rest period, and will be before collection of blood samples for 
laboratory testing, where applicable.

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
For subjects transitioning to dialysis, SBP, DBP and HR will be measured pre 
and post-dialysis, whenever possible (e.g., in-center HD). Otherwise these 
assessments will be done between dialysis sessions.
9.5.3.
Electrocardiograms
ECG measurements will be taken at the time points specified in the SoA (Section 2). Full 
12-lead ECGs will be recorded with the participant in a supine position. HR, PR interval, 
QRS duration, and QT (uncorrected) interval will be measured. QTcB will be calculated 
(machine-read or manually).
When an ECG is performed, two additional ECGs are required if the initial ECG 
indicates prolonged QTc (see Section 6.2) using the automated or manually calculated 
QTcB value.  The average QTcB value of all three ECGs will be used to determine 
eligibility (see Section 6.2). Additional details are provided in the SRM.
ECG data will be read locally by a physician with experience in reading and interpreting 
ECGs.  The over-read of the ECG will be required to confirm eligibility. Additional 
details are provided in the SRM.
All ECGs will be performed before measurement of SBP, DBP and HR and collection of 
blood samples for laboratory testing.
For subjects transitioning to dialysis, ECGs will be performed before measurement of 
SBP, DBP, HR and before collection of blood samples for laboratory testing, where 
applicable (e.g., would not apply if ECG is performed post-HD).
9.5.4.
Ultrasound
An ultrasound of the kidneys and adrenal glands will be performed prior to 
randomization. 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 a participant from 
randomization. Further details are provided in the SRM.
A documented ultrasound of the kidneys within the 6 months prior to screening may be 
used to assess entry criteria (see Section 6.2), provided the size and cyst category has 
been reported. If a more sensitive imaging study (e.g., MRI, CT) has been performed 
within this timeframe and a report is available, this may be used in place of the 
ultrasound.
For randomized participants with ADPKD:

An ultrasound of the kidneys will be performed when participants permanently 
discontinue study treatment, preferably within one month of discontinuation of study 
treatment as soon as clinically feasible. This may occur during the study OR at the 
end of study. See Table 1 and Table 3 for details.  

As clinically feasible, an ultrasound should be performed PRIOR to the following:
o
Transition to dialysis
o
Bilateral nephrectomy

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o
Kidney transplant.

An additional ultrasound may be performed at any time during the study based on 
investigator’s clinical judgment (e.g., deterioration of kidney function as measured by 
eGFR in the absence of other identifiable causes). Other imaging techniques (e.g., 
MRI) can be performed at the investigator’s discretion.  

If an additional imaging study is performed, and the condition of the cystic disease in 
the kidney(s) has worsened more than expected given the clinical scenario, then 
study treatment should be temporarily stopped.  Subsequently, if no other cause 
for the kidney function decline and/or cyst enlargement can be identified, study 
treatment should be permanently discontinued after consultation with the Medical 
Monitor.
9.5.5.
Clinical Laboratory Assessments

Refer to Table 8 for the list of clinical laboratory tests to be performed and to the 
SoA (Section 2) for the timing and frequency. 

The investigator must review the laboratory report, document this review, and 
record any clinically relevant changes occurring during the study in the AE 
section of the CRF. The laboratory reports must be filed with the source 
documents. Clinically significant abnormal laboratory findings are those which
are not associated with the underlying disease, unless judged by the investigator 
to be more severe than expected for the participant's condition.

All laboratory tests with values that are considered clinically significantly 
abnormal during participation in the study or within seven days after the last 
dose of randomized treatment should be repeated until the values return to 
normal or baseline.  If such values do not return to normal within a period 
judged reasonable by the investigator the sponsor should be notified.

If such values do not return to normal/baseline within a period of time judged 
reasonable by the investigator, the etiology should be identified and the sponsor 
notified.

All protocol-required laboratory assessments, as defined in Table 8, must be 
conducted in accordance with the laboratory manual and the SoA (Section
2). Laboratory assessments will be performed by a central laboratory with the 
exception of HemoCue Hgb and urine pregnancy tests which will be performed 
at the clinical site. The results of each HemoCue Hgb must be entered into the 
participant’s eCRF.

Local laboratory results are only required in the event that the central laboratory 
results are not available in time for either study treatment administration and/or 
response evaluation. If a local sample is required, it is important that the sample 
for central analysis is obtained at the same time.

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
Some of the central laboratory/analyte results which will not be reported to 
investigators, site staff and participants are Hgb, hematocrit, reticulocyte count, 
RBC count, etc. Additional details will be included in the SRM. 
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 
Chemistry 1
Sodium (serum)
AST
Carbon Dioxide (total)
Potassium (serum)
ALT
Albumin
Calcium (total and 
albumin-adjusted)
Inorganic phosphate 
Urea (serum)
Creatinine (serum)
Bilirubin (total and 
direct/indirect) 
Chloride (serum)
eGFR
Iron 
parameters
Iron (serum)
Ferritin
UIBC
Hepcidin
TIBC 
TSAT
Lipid 
parameters
Total cholesterol
LDL-C (direct)
HDL-C
Other 
laboratory 
tests
Urine/serum hCG 
pregnancy test 2,3
FSH 4
Estradiol 4
HemoCue Hgb
hsCRP
WBC, white blood cells; MCV, mean corpuscular volume; MCH, mean corpuscular hemoglobin; MCHC, mean 
corpuscular hemoglobin concentration; RDW, red blood cell distribution width, AST, aspartate transaminase; LDL-C, 
low density lipoprotein-C; HDL-C, high density lipoprotein-C; TIBC, total iron binding capacity; hCG, human chorionic 
gonadotropin; FSH, follicle-stimulating hormone.
1.
Details of Liver Chemistry Stopping Criteria and Required Actions and Follow-Up Assessments after liver stopping 
or monitoring event are given in Section 8.1.1 and Appendix 6.
2.
For women of childbearing potential only.
3.
Local urine testing will be standard for the protocol unless serum testing is required by local regulation or IRB/IEC, 
and for participants who transition to dialysis during the study.
4.
Screening only. As needed for postmenopausal women when their menopausal status is in doubt. See Inclusion 
Criteria Section 6.1.
9.6.
Patient Reported Outcomes 
The patient-reported effect of daprodustat and placebo on symptoms, health related 
quality of life (HR-QoL), health status (e.g., utility) and work productivity and activity 
impairment will be assessed. Symptoms will be assessed using a symptoms questionnaire 
which is specific to anemia of Chronic Kidney Disease - Anemia Questionnaire (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 
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Analogue Scale (EQ-VAS). Work productivity and regular daily activity impairment will 
be measured via the Work Productivity and Activity Impairment Questionnaire for the 
specific health problem of anemia, Clinical Practice Version 2.0 (WPAI-ANS- CPV; 
V2.0). 
All questionnaires used in this study have been translated and culturally adapted for use 
in local country languages and will be administered electronically only. Specific 
instructions on how the participant is to complete these questionnaires will be provided in 
the SRM. 
Patient reported outcomes questionnaires are to be administered at the beginning of the 
visits and the subjects should not be told the results of any diagnostic tests prior to 
completing the questionnaires. Adequate time must be allowed to complete all items on 
questionnaires, and if necessary, the subject must be encouraged to complete any missing 
items. So as to minimize the amount of missing data, the questionnaires should be 
completed by participants at a clinic visit, in the order specified: PGI-S, PGI-C, CKD-
AQ, SF-36, EQ-5D-5L and EQ-VAS, then the WPAI-ANS- CPV. Additional instructions 
on how investigators and site staff will be trained to provide participants with instructions 
will be provided in the SRM.
9.6.1.
Chronic Kidney Disease - Anemia Questionnaire (CKD-AQ)
A novel symptom questionnaire – CKD-AQ has been developed to collect concepts of 
interest for the anemia of CKD population. Unlike the Functional Assessment of Cancer 
Therapy – Anemia (FACT-AN) and Functional Assessment of Chronic Illness Therapy –
Fatigue (FACIT-Fatigue) which have not demonstrated content validity specific for the 
anemia of CKD population, the novel CKD-AQ instrument was developed to verify and 
ensure that concepts specific for anemia of CKD were captured and measured. It will 
measure both the frequency and/or severity in anemia of CKD concepts such as 
Weakness, Energy, Tiredness, Shortness of Breath, Exertion, Chest Pain, Memory, 
Concentration, Standing, Sleep and Distress over the past 7 days.
9.6.2.
Patient Global Impression of Severity (PGI-S) and Patient Global 
Impression of Change (PGI-C)
The PGI-S is a 1-item questionnaire designed to assess participant’s impression of 
disease severity of their anemia of CKD. It is measured on a 5-point disease severity 
scale (absent, mild, moderate, severe, or very severe) during the past 24 hours.
The PGI-C is a 1-item questionnaire designed to assess a participant’s impression of 
symptoms change of their anemia of CKD. It is measured on a 7-point Likert-type 
response scale (very much improved, moderately improved, minimally improved, no 
change, minimally worse, moderately worse, or very much worse) since they first started 
the study.
9.6.3.
Health Related Quality of Life (SF-36)
The SF-36 acute version is a general health status questionnaire designed to elucidate the 
participant’s self-perception of their health on several domains, including physical 

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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 participant to recall how they felt during the past seven days.
9.6.4.
Health Status (EQ-5D-5L & EQ-VAS)
EQ-5D-5L consists of 2 concepts – the EQ-5D-5L descriptive system and the EQ-VAS. 
The EQ-5D-5L is a self-reported descriptive system of health-related quality of life states 
consisting of five dimensions (mobility, self-care, usual activities, pain/discomfort, 
anxiety/depression) each of which can take one of five responses. The responses record 
five levels of severity (no problems/slight problems/moderate problems/severe 
problems/extreme problems) within a particular EQ-5D dimension. Self-reported health 
status captured by EQ-5D-5L relates to the participant’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’ at the time of completion. This information is used as a 
quantitative measure of health outcome as judged by individual participants.
9.6.5.
Work Productivity and Activity Impairment (WPAI-ANS-CPV)
The WPAI-ANS-CPV is an anemia specific questionnaire designed as a self-reported 
quantitative assessment of social functioning related to work and regular daily activities. 
It contains two main concepts- work productivity impairment measured via absenteeism 
(time missed from work), presenteeism (impairment at work) and regular daily activity 
impairment. The questionnaire contains 6 questions and asks the patient to recall work 
and activity impairment over the past 7 days.
9.7.
Actigraphy
Patients with anemia in CKD can experience decreased physical functioning and sleep 
disturbances [KDIGO, 2012]. Therefore, actigraphy assessment in this study will be 
conducted as a means to measure changes in the physical activity and sleep from a 
baseline measurement taken prior to Randomization (Day 1) to the end of study. The data 
collected may be used to conduct exploratory analyses of physical activity and sleep. 
ActiGraph GT9X Link is being piloted in this study to capture and record high resolution 
human activity information by using a validated solid state 3-axis MEMS accelerometer 
and proprietary filtering algorithm to report daily movement associated with physical 
activity and sleep. This device will capture patterns of activity throughout the day and 
night. 
Physical activity will be measured by subject activity metrics such as steps taken, 
physical activity intensity, and activity/sedentary bouts.
Sleep activity will be measured by subject sleep period metrics such as total sleep time, 
sleep latency and sleep efficiency. 

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Prior to the participant leaving the study site at the screening visit, the participant must 
have been trained on how to position the device to their arm, how to charge the battery 
and check the battery status. These topics are all covered in the Participant Information 
Leaflet and further instructions regarding distribution, operation, retrieval of ActiGraph 
GT9X Link devices will be provided in the SRM.
All efforts should be made to encourage participation in this activity monitoring 
assessment. If a participant is unable to take part, the reason should be documented, and 
they may continue in the study. 
The technical performance of the Actigraph device will also be closely monitored and 
assessed during the study and the Sponsor may elect to discontinue this assessment if 
device related difficulties are encountered.
9.8.
Pharmacokinetics
Pharmacokinetic parameters are not evaluated in this study.
9.9.
Genetics
A 6 mL blood sample for DNA isolation will be collected from participants who have 
consented to participate in the genetics analysis component of the study. Participation is 
optional. Participants who do not wish to participate in the genetic research may still 
participate in the study.
In the event of DNA extraction failure, a replacement genetic blood sample may be 
requested from the participant. Signed informed consent will be required to obtain a 
replacement sample unless it was included in the original consent.
See Section 12.5 (Appendix 5) for Information regarding genetic research. Details on 
processes for collection and shipment and destruction of these samples can be found in 
Q2 Solutions Investigator Manual
9.10.
Storage Biomarkers
Blood samples will not be stored for biomarker analysis in this study
9.11.
Healthcare Resource Utilization and Economics
Healthcare resource utilization and health economic data, associated with medical 
encounters, will be collected in the CRF by the investigator and study-site personnel for 
all participants throughout the study. Protocol-mandated procedures, tests, and encounters 
are excluded. 
The data collected may be used to conduct exploratory economic analyses and will 
include:

Number and duration of medical care encounters, including surgeries, and other 
selected procedures (inpatient and outpatient)

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
Duration of hospitalization (total days or length of stay, including duration by 
wards [eg, intensive care unit])

Number and type of diagnostic and therapeutic tests and procedures

Outpatient medical encounters and treatments (including physician or 
emergency room visits, tests and procedures, and medications).

Pharmacy utilization focused on anemia associated with CKD only, including 
rhEPO rescue, IV iron (use or rescue), blood pressure medications, and 
cholesterol lowering agents
9.12.
Patient Feedback Survey 
An optional smartphone App or website will be available during the study. Participants 
may be asked for feedback on their experience during the study, in the form of 
anonymized App or web based surveys. The purpose of this survey is for GSK to learn 
about participant experience in the study and possibly make future GSK trials more 
participant friendly and better focused on participant’s needs. 
10.
STATISTICAL CONSIDERATIONS AND DATA 
ANALYSES
10.1.
Primary Hypothesis
The primary Hgb efficacy objective will assess the estimand defined as the comparative
treatment effect in mean Hgb change between baseline and evaluation peorid (EP, i.e., 
week 24 to week 28 inclusive) in all randomized participants; defined as those who 
remain in follow-up throughout the period of stabilization and have at least one Hgb 
assessment during the EP regardless of adherence to study treatment. The analysis will 
test whether daprodustat is superior to placebo according to the following statistical
hypotheses:

Null: The difference in mean change in Hgb between baseline and EP, between 
treatment arms (daprodustat-placebo), is less than or equal to 0 g/dL.

Alternative: The difference in mean change in Hgb between baseline and EP 
between treatment arms (daprodustat-placebo), is greater than to 0 g/dL.
Statistical significance will be assessed at the one-sided 2.5% level. An analysis of 
covariance (ANCOVA) model including the randomization stratification factor, baseline 
hemoglobin and treatment will be used to obtain a point estimate and the two-sided 95% 
CI for the treatment difference (daprodustat-placebo) and generate the one-sided p-value 
for the superiority test.  Superiority will be established if the one-sided p-value is less 
than 0.025.

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10.2.
Sample Size Determination
10.2.1.
Sample Size Assumptions
The sample size of this study has been primarily determined in order to achieve sufficient 
power for the principal secondary endpoint SF-36 vitality sub-score, since the anticipated
effect size of this endpoint is less than that for the primary endpoint.
Approximately 600 participants are planned to be randomized (300 per arm) to receive 
daprodustat or placebo, who will be treated to achieve and maintain Hgb between 11 and 
12 g/dL. Under the assumption that up to 10% of participants will withdraw from the 
study before Week 24 (start of EP), 600 randomized participants will result in at least 540 
evaluable participants. 
For the primary endpoint, the expected difference in mean Hgb change from baseline and 
the EP, between arms, is 1.0 g/dL and the anticipated between participant standard 
deviation (SD) is 1.5 g/dL, based on historical rhEPO trials and daprodustat clinical trial 
experience to date. The planned study size provides more than 99% power for 
superiority. In addition, it is anticipated that the smallest difference in mean Hgb change 
between arms that would meet the statistical criterion for superiority would be 0.25 g/dL.  
For the first principal secondary endpoint of % of participants having a Hgb increase of 
≥1.0 g/dL from baseline to EP, 540 evaluable participants provides >90% power to detect 
a 20% difference between daprodustat and placebo, assuming 30% of placebo arm 
participants will have a Hgb increase of ≥1.0 g/dL. In that case the smallest difference 
between daprodustat and placebo that would meet the statistical criterion for superiority 
would be 8%.
For the second principal secondary endpoint of mean change in SF-36 vitality sub-score 
between baseline and week 28, 540 evaluable participants provides for 79% power to 
detect a difference between arms under the assumption of a between treatment effect of 5 
points in favor of daprodustat and a within-group standard deviation of 21 points. Prior 
research has determined that anemia is associated with a difference of 5.4 points from 
baseline for SF-36 vitality scores (Bjorner, 2007). It is expected that the smallest 
difference between arms that would meet the statistical criterion for superiority in this 
principal secondary endpoint is 3.5 points. 
10.2.2.
Sample Size Sensitivity
Since the sample size is primarily determined by the principal secondary endpoint SF-36 
vitality sub-score, the following table illustrates the impact on power for that endpoint 
based on alternative assumptions for the between participant SD and the number of 
evaluable participants.

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Between Participant SF-36 
Vitality Sub-score SD
Number of Evaluable Participants
300
400
500
540
19
62%
75%
84%
86%
20
58%
70%
80%
83%
21
54%
66%
76%
79%
22
50%
62%
72%
75%
23
47%
58%
68%
71%
10.2.3.
Sample Size Re-Estimation or Adjustment
The assumptions used to determine the planned sample size may be reassessed, if during 
the course of the study, information becomes available external to the trial that is 
informative with respect to clinically meaningful difference or variability estimates for 
the QoL principal secondary endpoint. If considered appropriate the planned sample size 
may be re-calculated and implemented via a protocol amendment as necessary. It is 
anticipated that the maximum sample size for the study will not exceed 800 patients.
10.3.
Data Analysis Considerations
10.3.1.
Analysis Populations 
The primary population for Hgb efficacy analyses will be the All Randomized Intent-to-
Treat (ITT) Population. Participants will be analyzed according to the treatment to which 
they were randomized.    
For analyses of quality of life endpoints, the All Randomized (ITT) Population will also 
be used. Participants will be analyzed according to the treatment to which they were 
randomized.
The primary population for safety (Safety Population) will consist of all randomized 
participants who receive at least one dose of randomized treatment. Participants will be 
analyzed according to the treatment received.
Additional populations may be defined in the Reporting and Analysis Plan (RAP).
10.4.
Key Elements of Analysis Plan
10.4.1.
Primary Analyses
Mean change in Hgb between baseline and EP (week 24 to week 28 inclusive): The 
primary efficacy estimand is to compare the effect of treatment for the evaluation of 
mean change from baseline in Hgb during the 4 week EP in all ITT participants with at 
least one Hgb during the EP. The ITT analysis of this endpoint will include all on and off 
treatment Hgb values of the ITT population, including values taken after rescue and IP 
discontinuation. The analysis will use an ANCOVA model.  For each participant, 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 week 24 to week 28 inclusive regardless of the use of rescue medication 

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or adherence to randomized treatment.  The ANCOVA model will include the
randomization stratification factor, baseline Hgb and treatment.  It will provide a point
estimate and two-sided 95% CI for the treatment effect, together with the one-sided p-
value.  There will be no imputation for missing data. 
Sensitivity Analysis: A sensitivity analysis that considers an “on-drug” efficacy 
estimand will be conducted.  In this analysis, only Hgb values measured while the 
participant was taking randomized study medication will be included. Missing Hgb 
values will be imputed based on the reasons of missing. Full details will be provided in 
the RAP.
10.4.2.
Secondary Analyses
10.4.2.1.
Principal Secondary Efficacy Analyses
Conditional on the primary endpoint achieving superiority at the one-sided 2.5% level, 
statistical testing will progress to the principal secondary endpoints which will evaluate 
superiority using a one-sided 2.5% significance level.
For the first principal secondary endpoint of % of participants having a Hgb increase of 
≥1.0 g/dL from baseline to EP, a Cochran-Mantel-Haenszel (CMH) chi-squared test, 
adjusting for treatment, baseline Hgb, and the prognostic randomization stratification 
factor, will be used to make comparisons between the treatment groups. An 
“effectiveness” estimand will be used in the analysis to include all on and off treatment 
Hgb values of the ITT populations, including values taken after rescue and IP 
discontinuation.
For the second principal secondary endpoint of mean change in SF-36 vitality sub-score 
between baseline and Week 28, an ANCOVA model will be used to compare the 
difference in this endpoint between arms, including factors for baseline score, treatment 
and the randomization stratification factor. An “efficacy” estimand will be used in the 
analysis in which we include only on-treatment values and exclude measures taken after 
IP disc/rescue medication.  For this endpoint, an alternative approach may be conducted 
that includes the development of a prior distribution for the effects of placebo based on 
external data to be combined with the data from this trial in a Bayesian framework in 
order to make inference on the effects of daprodustat.  If such an approach is undertaken 
it will be fully described in the RAP prior to the breaking of the study blind.
In addition, descriptive statistics for each individual item within the SF-36 vitality sub-
score will be generated. Of particular interest are the items assessing if patients have a lot 
of energy, feel tired, and feel worn out. These concepts have been found to be important 
and relevant concepts in this population[Martin, 2011] . 
Additional secondary/exploratory endpoints are listed in Section 4.  
10.4.2.2.
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 

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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. 
10.4.3.
Multiplicity Strategy
The primary endpoint will be tested first for superiority using a one-sided 2.5% 
significance level.  Conditional on achieving statistical significance, the first principal 
secondary endpoint will be tested for superiority using a one-sided 2.5% significance 
level. Finally, conditional on achieving statistical significance of both the primary 
endpoint, and the first principal secondary endpoint, the second principal secondary
endpoint will be tested for superiority using a one-sided 2.5% significance level. This 
three-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 Section 4 are of exploratory 
nature,and if tested, will not be adjusted for multiplicity. Summary statistics and nominal 
one-sided 2.5% significance levels will be used to describe the results of these treatment 
comparisons.
10.4.4.
Covariates and Subgroups of Interest
The primary and principal secondary endpoints will be evaluated for a set of pre-
specified subgroups.  Subgroup analyses are aimed to assess for consistency with the 
overall result, and they may have low power if the subgroup is small. Statistical models ( 
ANCOVA or CMH chi-squared test) will be adjusted for the covariates used in the 
original analysis, subgroup, treatment and treatment by subgroup interaction.  Point 
estimates and two-sided 95% CIs will be estimated (presented on Forest Plots) and the 
subgroup by treatment interaction p-value calculated. Subgroup analyses will not be 
adjusted for multiplicity.  Further subgroups/covariates may be defined in the RAP.

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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 
per Section 12.8 (Appendix 8).
BMI 
<30, ≥30 
Weight 
< 75kg, ≥75kg 
Baseline Hgb
8.5 - <9 g/dL, 9 – 10 g/dL 
Serum Iron levels 
TSATs ≥20% and Ferritins ≥100 ng/mL, others
IV Iron Therapy
Yes, or No  
hsCRP
Tertile analysis 
Diabetic
Yes or No
10.4.5.
Interim Analyses
An interim analysis to assess futility may be performed if the rate of the enrolment is 
considerably slower than expected. This analysis will only consist of the principal 
secondary endpoint of QoL SF-36 vitality sub-score, due to its considerably larger 
sample-size requirement for a powered analysis compared to the primary endpoint. The 
primary endpoint of mean change in Hgb between baseline and EP, and the principal 
secondary endpoint of % of participants having a Hgb increase of ≥1.0 g/dL from 
baseline at EPwill not be included in this interim analysis. The potential outcomes of this 
analysis include the continuation of the study with no change and the stopping of the 
enrolment. It is planned that the interim analysis will only be performed once 
approximately 200 participants have completed 28 weeks of study in order to preserve 
power for the primary endpoint should the study be discontinued.
If the observed difference for the QoL vitality endpoint between daprodustat and placebo 
is less than 2 points at the time of the interim analysis, study enrolment will be stopped. 
This decision guideline was determined to have favorable operating characteristics, such 
as an unconditional power of <30%, and an acceptably low probability of a false stop 
(<10%). Since the study will not be stopped for positive results, type I error will not be 
inflated. Inference on the aforementioned Hgb parameters will still be made as per 
Section 10.4, even if the study is stopped for futility based on QoL SF-36 vitality sub-
score. 
The interim analysis will be performed and the results reviewed by a small team who are 
not involved in the conduct of this study. Access to the interim results will be restricted to 
this small team until the study has been completed and the database is finalized and 
unblinded. Details regarding the justification for the interim analysis, including the 
blinding plan and associated measures to protect the integrity of the trial will be included 
in the RAP.

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10.4.6.
Analysis of Patient-Reported Outcomes Measures and 
Actigraphy
Analyses to compare the patient reported effects of daprodustat and placebo on 
symptoms, severity, HR-QoL, and health status, as discussed in Section 9.6, will be 
described in the RAP. Analyses regarding the effects of daprodustat and placebo on 
physical activity and sleep measured by the actigraphy assessment as discussed in Section 
9.7 will also be described in the RAP. 

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11.
REFERENCES
1. Bjorner J, Wallenstein G, Martin M, Lin P, Blaisdell-Gross B, Piech C, Mody S et 
al. Interpreting score differences in the SF-36 Vitality scale: using clinical conditions 
and functional outcomes to define the minimally important difference. Current 
Medical Research and Opinion, 2007;23(4):731-739. 
2. GlaxoSmithKline Document Number 2014N219818_00, GSK1278863, A 24-week, 
Phase 2B, randomized, controlled, parallel-group,multi-center study to evaluate the 
safety and efficacy of GSK1278863 in subjects with anemia associated with 
chronickidney disease who are not on dialysis. 13-JAN-2016
3. GlaxoSmithKline Document Number 2015N230102_03, GSK1278863, A phase 3 
randomized, open-label (sponsor-blind), active-controlled, parallel-group, multi-
center, event driven study in non-dialysis subjects with anemia associated with 
chronic kidney disease to evaluate the safety and efficacy of daprodustat compared 
to darbepoetin alfa (ASCEND-ND). 12-OCT-2016
4. GlaxoSmithKline Document Number RM2008/00267/07, Version 7 to GSK1278863 
Investigator's Brochure, 14-OCT-2015.
5. Holdstock L, Meadowcroft AM, Maier R, Johnson BM, Jones D, Rastogi A, et al. 
Four-Week Studies of Oral Hypoxia-Inducible Factor-Prolyl Hydroxylase Inhibitor 
GSK1278863 for Treatment of Anemia. J Am Soc Nephrol. 2016;27(4):1234-44.
6. KDIGO Clinical Practice Guidelines for Anemia in Chronic Kidney Disease. Kidney 
int. 2012; 2(4). 
http://www.kdigo.org/clinical_practice_guidelines/pdf/KDIGOAnemia%20GL.pdf
7. Levey AS, Stevens LA, Schmid CH, Zhang YL, Castro AF 3rd, Feldman HI et al; 
CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration). A New Equation 
to Estimate Glomerular Filtration Rate. Ann Intern Med 2009; 150(9):604-12.
8. Martin M, Patrick D, Shravanthi G, Bennett A, Leidy N, Nissenson A, et al. Content 
validation of two SF-36 subscales for use in type 2 diabetes and non-dialysis chronic 
kidney disease-related anemia. Qual Life Res. 2011;20:889–901. 
9. Skali H, Lin J, Pfeffer MA, Chen CY, Cooper ME, McMurray JJ, et al. Hemoglobin 
stability in patients with anemia, CKD, and type 2 diabetes: an analysis of the 
TREAT (Trial to Reduce Cardiovascular Events With Aranesp Therapy) placebo 
arm. Am J Kidney Dis. 2013;61(2):238-46.

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12.
APPENDICES
12.1.
Appendix 1: Abbreviations and Trademarks
Abbreviations
ADPKD
Autosomal dominant polycystic kidney disease
AE
Adverse event
ALT
Alanine transaminase
ANCOVA
Analysis of Covariance
ANSM
L'Agence nationale de sécurité du médicament et des 
produits de santé 
AST
Aspartate transaminase
BP
Blood pressure
CEC
Clinical Events Classification
CI
Confidence interval
CKD
Chronic kidney disease
CKD-AQ
Chronic Kidney Disease - Anemia Questionnaire
CKD-EPI
Chronic kidney disease Epidemiology Collaboration 
CNIL
Commission Nationale de I'Informatique et des Libertés
CPK
Creatine phosphokinase 
CRA
Clinical Research Assistant 
CTR
Clinical Trials Register
CT
Computed tomography
CV
Cardiovascular
DBP
Diastolic blood pressure
ECG
Electrocardiogram
eCRF
Electronic case report form
eGFR
Estimated glomerular filtration rate
EP
Evaluation period
EPO
Erythropoietin
EQ-5D-5L
EuroQol 5 Dimension 5 Level Health Utility Index
EQ-VAS
EuroQol Visual Analogue Scale 
ESA
Erythropoetin-stimulating agent
FDA
Food and Drug Administration
FRP
Females of reproductive potential
FSH
Follicle stimulating hormone
GCP
Good Clinical Practice
GI
Gastrointestinal
GSK
GlaxoSmithKline
hCG
Human chorionic gonadotrophin
HD
Hemodialysis 
HDL-c
High density lipoprotein-C
HDPE
High density polyethylene
Hgb
Hemoglobin
HIF
Hypoxia-inducible factor

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HR
Heart rate
HR-QoL
Health Related Quality of Life
HRT
Hormone replacement therapy
hsCRP
High sensitivity C-reactive protein
KDIGO
Kidney Disease Improving Global Outcomes
KDOQI
Kidney Disease Outcomes Quality Initiative
IB
Investigator’s Brochure
ICH
International Conference on Harmonization
IEC
Independent Ethics Committee
IRB
Institutional Review Board
IRT
Interactive Response Technology
ITT
Intent-to-treat
IV
Intravenous
LDH
Lactate dehydrogenase 
LDL-C (direct) 
Directly measured 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
MRI
Magnetic resonance imaging
MSDS
Material Safety Data Sheet
NYHA
New York Heart Association
PD
Peritoneal dialysis 
PGI-C
Patient Global Impression of Change
PGI-S
Patient Global Impression of Severity
PHI
Prolyl hydroxylase inhibitor
PK
Pharmacokinetic
PSRAE
Possible Suicidality Related Adverse Events 
RAP
Reporting and Analysis Plan
RBC
Red blood cell
RDW
Red blood cell distribution width
rhEPO
Recombinant human erythropoietin 
SAE
Serious adverse event
SBP
Systolic blood pressure
SD
Standard deviation
SF-36
Short Form -36
sPAP
Systolic pulmonary artery pressure
SRM
Study Reference Manual
TIBC
Total iron binding capacity
TSAT
Transferrin saturation
UIBC
Unsaturated iron binding capacity
U
Units
ULN
Upper limit of normal
WBC
White blood cells

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WPAI-ANS-CPV
Work Productivity and Activity Impairment Questionnaire:
Anemic Symptoms Clinical Practice Version 
Trademark Information
Trademarks of the GlaxoSmithKline 
group of companies
Trademarks not owned by the 
GlaxoSmithKline group of companies
NONE
ActiGraph GT9X Link
HemoCue

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12.2.
Appendix 2: Study Governance Considerations
12.2.1.
Regulatory and Ethical Considerations

This study will be conducted in accordance with the protocol and with:

Consensus ethical principles derived from international guidelines 
including the Declaration of Helsinki and Council for International 
Organizations of Medical Sciences (CIOMS) International Ethical 
Guidelines

Applicable International Conference on Harmonization (ICH) Good
Clinical Practice (GCP) Guidelines

Applicable laws and regulations

The protocol, protocol amendments, ICF, Investigator Brochure [IB
GlaxoSmithKline Document number RM2008/00267/07], and other relevant
documents (eg, advertisements) must be submitted to an IRB/IEC by the 
investigator and reviewed and approved by the IRB/IEC before the study is 
initiated. 

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

Any amendments to the protocol will require IEC/IRB approval before 
implementation of changes made to the study design, except for changes 
necessary to eliminate an immediate hazard to study participants. 

The investigator will be responsible for the following:

Providing written summaries of the status of the study to the IRB/IEC 
annually or more frequently in accordance with the requirements, policies, 
and procedures established by the IRB/EC

Notifying the IRB/IEC of SAE or other significant safety findings as 
required by IRB/IEC procedures

Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH guidelines, the IRB/IEC, European 
regulation 536/2014 for clinical studies (if applicable), and all other 
applicable local regulations

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12.2.2.
Financial Disclosure
Investigators and sub-investigators will provide the sponsor with sufficient, accurate 
financial information as requested to allow the sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate regulatory authorities. 
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study.
12.2.3.
Informed Consent Process

The investigator or his/her representative will explain the nature of the study to 
the participant or his/her legally authorized representative and answer all 
questions regarding the study. 
Participants must be informed that their participation is voluntary. Participants or 
their legally authorized representative will be required to sign a statement of 
informed consent that meets the requirements of 21 CFR 50, local regulations, 
ICH guidelines, Health Insurance Portability and Accountability Act (HIPAA) 
requirements, where applicable, and the IRB/IEC or study center.

The medical record must include a statement that written informed consent was 
obtained before the participant was enrolled in the study and the date the written 
consent was obtained. The authorized person obtaining the informed consent 
must also sign the ICF.

Participants must be re-consented to the most current version of the ICF(s) 
during their participation in the study. 

A copy of the ICF(s) must be provided to the participant or the participant’s 
legally authorized representative. 

Participants who are rescreened are required to sign a new ICF.
12.2.4.
Data Protection

Participants will be assigned a unique identifier by the sponsor. Any participant 
records or datasets that are transferred to the sponsor will contain the identifier 
only; participant names or any information which would make the participant 
identifiable will not be transferred. 

The participant must be informed that his/her personal study-related data will be 
used by the sponsor in accordance with local data protection law. The level of 
disclosure must also be explained to the participant. 

The participant must be informed that his/her medical records may be examined 
by Clinical Quality Assurance auditors or other authorized personnel appointed 
by the sponsor, by appropriate IRB/IEC members, and by inspectors from 
regulatory authorities.
12.2.5.
Quality Control (Study Monitoring)

In accordance with applicable regulations including GCP, and GSK procedures, GSK 
monitors will contact the site prior to the start of the study to review with the site staff 

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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.
GSK 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
12.2.6.
Data Quality Assurance

All participant data relating to the study will be recorded on printed or electronic 
CRF unless transmitted to the sponsor or designee electronically (e.g., 
laboratory data). The investigator is responsible for verifying that data entries 
are accurate and correct by physically or electronically signing the CRF. 

The investigator must maintain accurate documentation (source data) that 
supports the information entered in the CRF. 

The investigator must permit study-related monitoring, audits, IRB/IEC review, 
and regulatory agency inspections and provide direct access to source data 
documents. 

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.

The sponsor or designee is responsible for the data management of this study 
including quality checking of the data. 

Study monitors will perform ongoing source data verification to confirm that 
data entered into the CRF by authorized site personnel are accurate, complete, 
and verifiable from source documents; that the safety and rights of participants 
are being protected; and that the study is being conducted in accordance with the 
currently approved protocol and any other study agreements, ICH GCP, and all 
applicable regulatory requirements. 

Records and documents, including signed ICF, pertaining to the conduct of this 
study must be retained by the investigator for 25 years from the issue of the final 

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Clinical Study Report(CSR)/equivalent summary unless local unless local 
regulations or institutional policies require a longer retention period. No records 
may be destroyed during the retention period without the written approval of the 
sponsor. No records may be transferred to another location or party without 
written notification to the sponsor
12.2.7.
Source Documents

Source documents provide evidence for the existence of the participant and 
substantiate the integrity of the data collected. Source documents are filed at the 
investigator’s site.

Data reported on the CRF or entered in the eCRF that are transcribed from 
source documents must be consistent with the source documents or the 
discrepancies must be explained. The investigator may need to request previous 
medical records or transfer records, depending on the study. Also, current 
medical records must be available.
12.2.8.
Study and Site Closure
GSK or its designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of GSK. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study 
supplies have been collected and a study-site closure visit has been performed. If GSK 
determine such action is needed, GSK will discuss the reasons for taking such action with 
the investigator or the head of the medical institution (where applicable).  When feasible, 
GSK will provide advance notification to the investigator or the head of the medical 
institution, where applicable, of the impending action
The investigator may initiate study-site closure at any time, provided there is reasonable 
cause and sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the sponsor or investigator may include 
but are not limited to:
Failure of the investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the sponsor's procedures, or GCP guidelines
Inadequate recruitment of participants by the investigator
Discontinuation of further study treatment development
12.2.9.
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 

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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.
GSK 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, GSK 
standards/procedures, and/or institutional requirements.  
The investigator must notify GSK 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.
12.2.10.
Dissemination of Clinical Study Data
Study information from this protocol will be posted on publicly available clinical 
trial registers before enrollment of subjects begins
Where required by applicable regulatory requirements, an investigator signatory 
will be identified for the approval of the clinical study report.  The investigator 
will be provided reasonable access to statistical tables, figures, and relevant 
reports and will have the opportunity to review the complete study results at a 
GSK site or other mutually-agreeable location.
All study investigators will be provided with the full summary of the study 
results.  The investigator is encouraged to share the summary results with the 
study subjects, as appropriate.
The procedures and timing for public disclosure of the results summary and for 
development of a manuscript for publication will be in accordance with GSK 
Policy.
12.2.11.
Publication Policy

The results of this study may be published or presented at scientific meetings. If 
this is foreseen, the investigator agrees to submit all manuscripts or abstracts to 
the sponsor before submission. This allows the sponsor to protect proprietary 
information and to provide comments.

The sponsor will comply with the requirements for publication of study results. 
In accordance with standard editorial and ethical practice, the sponsor will 

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generally support publication of multicenter studies only in their entirety and not 
as individual site data. In this case, a coordinating investigator will be 
designated by mutual agreement.
Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements
12.2.12.
Clinical Events 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 9.3.5).
12.2.13.
Safety Review Team (SRT) 
An internal Safety Review Team, which includes GSK personal involved in the conduct 
of the study, will review periodically blinded safety data from this trial.

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12.3.
Appendix 3: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting
Definition of AE
AE Definition

An AE is any untoward medical occurrence in a clinical study participant, temporally 
associated with the use of a study treatment, whether or not considered related to the 
study treatment.

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 study treatment.
Events Meeting the AE Definition 

Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) 
or other safety assessments (eg, ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, considered clinically significant in the 
medical and scientific judgment of the investigator (ie, not related to progression of 
underlying disease).

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 study treatment administration even 
though it may have been present before the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
treatment or a concomitant medication. Overdose per se will not be reported as an 
AE/SAE unless it is an intentional overdose taken with possible suicidal/self-
harming intent. Such overdoses 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. Such instances will be captured in the efficacy 
assessments. However, the signs, symptoms, and/or clinical sequelae resulting from 
lack of efficacy will be reported as AE or SAE if they fulfill the definition of an AE 
or SAE. 

The signs, symptoms, and/or clinical sequelae resulting from lack of efficacy will be 
reported as AE or SAE if they fulfill the definition of an AE or SAE. Also, "lack of 
efficacy" or "failure of expected pharmacological action" constitutes an AE or SAE.

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Events NOT Meeting the AE Definition 

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 participant’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 
participant’s condition.

Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that 
leads to the procedure is the AE.

Situations in which 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.
Reporting of SAE to GSK
SAE Reporting to GSK via Electronic Data Collection Tool

The primary mechanism for reporting SAE to GSK will be the electronic data 
collection tool.

If the electronic system is unavailable, then the site will use the paper SAE data 
collection tool (see next section) in order to report the event within 24 hours.

The site will enter the SAE data into the electronic system as soon as it becomes 
available.

The investigator or medically-qualified sub-investigator must show evidence within 
the eCRF (e.g., check review box, signature, etc.) of review and verification of the 
relationship of each SAE to IP/study participation (causality) within 72 hours of SAE 
entry into the eCRF.

After the study is completed at a given site, the electronic data collection tool 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 participant or receives updated 
data on a previously reported SAE after the electronic data collection tool has been 
taken off-line, then the site can report this information on a paper SAE form (see 
next section) or to the medical monitor/SAE coordinator by telephone.

Contacts for SAE reporting can be found at the beginning of this protocol on the 
Medical Monitor Contact Information page. 

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12.3.1.
Definition of Serious Adverse Events
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met (e.g., hospitalization for signs/symptoms of the disease under study, 
death due to progression of disease, etc).
Serious Adverse Event (SAE) is defined as any untoward medical occurrence that, 
at any dose:
Results in death
Is life-threatening

NOTE: The term 'life-threatening' in the definition of 'serious' refers to an event in 
which the participant 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.
Requires hospitalization or prolongation of existing hospitalization

NOTE: In general, hospitalization signifies that the participant 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.
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 life functions but do not constitute a substantial disruption
Is a congenital anomaly/birth defect
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 participant 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 

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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
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 
participants receiving anticoagulants.  If INR measurement is obtained, the value 
is to be recorded on the SAE form.
12.3.2.
Recording of AEs and SAEs
AEs and SAE Recording:

When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (e.g., hospital progress notes, laboratory, and diagnostics reports) 
relative to the event.

The investigator will then record all relevant information regarding an AE/SAE in 
the eCRF

It is not acceptable for the investigator to send photocopies of the participant’s 
medical records to GSK in lieu of completion of the AE/SAE eCRF page.

There may be instances when copies of medical records for certain cases are 
requested by GSK.  In this instance, all participant identifiers, with the exception of 
the participant number, will be blinded on the copies of the medical records prior to 
submission to GSK.

The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information.  In such cases, the diagnosis will be 
documented as the AE/SAE and not the individual signs/symptoms.

Participant-completed Patient Reported Outcomes questionnaires and the collection 
of AE data are independent components of the study.

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12.3.3.
Evaluating AEs and SAEs
Assessment of Intensity
The investigator will make an assessment of intensity for each AE and SAE reported 
during the study and will assign it to one of the following categories:

Mild:  An event that is easily tolerated by the participant, 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 or 
randomized treatment will be considered and investigated.

The investigator will also consult the IB and/or Product Information, for marketed 
products, in the determination of his/her assessment.

For each AE/SAE the investigator must document in the medical notes that he/she 
has reviewed the AE/SAE and has provided an assessment of causality.

There may be situations when an SAE has occurred and the investigator has minimal 
information to include in the initial report to GSK.  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 GSK.

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.

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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 GSK to 
elucidate as fully as possible the nature and/or causality of the AE or SAE.

The investigator is obligated to assist.  This may include additional laboratory tests 
or investigations, histopathological examinations or consultation with other health 
care professionals.

New or updated information will be recorded in the originally completed eCRF.

The investigator will submit any updated SAE data to GSK within the designated 
reporting time frames.

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12.4.
Appendix 4: Female Eligibility Criteria, Contraceptive 
Guidance and Collection of Pregnancy Information
Woman of Childbearing Potential (WOCBP)

A woman is considered fertile following menarche and until becoming post-
menopausal unless permanently sterile (see below)

A female subject is eligible to participate if she is not pregnant (as confirmed by a 
negative urine FRP test for females of reproductive potential only), not 
breastfeeding, or at least one of the following conditions applies:
o
Reproductive potential and agrees to follow one of the options listed in the 
List of Highly Effective Contraceptive Methods (Table 9) in WOCBP 
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 SoA (Section 2)
Women in the following categories are not considered WOCBP

Premenarchal

Premenopausal female with ONE of the following:

Documented hysterectomy

Documented bilateral salpingectomy

Documented bilateral oophorectomy

Documented tubal ligation
Note:  Documentation can come from the site personnel’s: review of participant’s 
medical records, medical examination, or medical history interview.

Postmenopausal female

Postmenopausal defined as 12 months of spontaneous amenorrhea. In 
questionable cases, a blood sample with simultaneous FSH and estradiol 
consistent with menopause is confirmatory ≥23 MIU/mL (≥23 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.

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Contraception Guidance
Women of childbearing potential are eligible to participate if they agree to use a highly 
effective method of contraception consistently and correctly as described in Table 9. 
Table 9
Highly Effective Contraceptive Methods
Highly Effective Contraceptive Methods That Are User Dependent a
Failure rate of <1% per year when used consistently and correctly. 
Combined (estrogen- and progestogen-containing ) hormonal contraception associated with 
inhibition of ovulation 

oral

intravaginal 

transdermal 
Progestogen-only hormonal contraception associated with inhibition of ovulation 

injectable 
Highly Effective Methods That Are User Independent 

Implantable progestogen-only hormonal contraception associated with inhibition of 
ovulationb

Intrauterine device (IUD)

Intrauterine hormone-releasing system (IUS)

bilateral tubal occlusion
Vasectomized partner 
(A vasectomized partner is a highly effective contraception method provided that the partner is 
the sole male sexual partner of the WOCBP and the absence of sperm has been confirmed. If 
not, an additional highly effective method of contraception should be used.)
Sexual abstinence 
(Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study drug. The 
reliability of sexual abstinence needs to be evaluated in relation to the duration of the study and 
the preferred and usual lifestyle of the participant.)
NOTES: 
a.
Typical use failure rates may differ from those when used consistently and correctly. Use should be consistent 
with local regulations regarding the use of contraceptive methods for participants in clinical studies. 
Pregnancy Testing

WOCBP should only be included after a confirmed menstrual period and a negative 
urine FRP test. 

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
Additional pregnancy testing should be performed per SoA (Section 2) during the 
treatment period and 30 days after the last dose of study treatment and as required 
locally 

Pregnancy testing will be performed whenever a menstrual cycle is missed or when 
pregnancy is otherwise suspected.
Collection of Pregnancy Information

Investigator will collect pregnancy information on any female participant, who 
becomes pregnant while participating in this study. 

Information will be recorded on the appropriate form and submitted to GSK within 2 
weeks of learning of a participant's pregnancy. 

Participant will be followed to determine the outcome of the pregnancy. The 
investigator will collect follow up information on participant and neonate, which will 
be forwarded to GSK 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 study treatment by the investigator, will be reported to GSK 
as described in Section 12.3 (Appendix 3). 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 participant who becomes pregnant while participating must 
permanently discontinue randomized treatment. Participants 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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12.5.
Appendix 5: Genetics
USE/ANALYSIS OF DNA

Genetic variation may impact a participant’s response to therapy, susceptibility, 
severity and progression of disease. Variable response to therapy may be due to 
genetic determinants that impact drug absorption, distribution, metabolism, and 
excretion; mechanism of action of the drug; disease etiology; and/or molecular 
subtype of the disease being treated. Therefore, where local regulations and IRB/IEC 
allow, a blood sample will be collected for DNA analysis

DNA samples will be used for research related to daprodustat or anemia associated 
with CKD and related diseases. They may also be used to develop tests/assays 
(including diagnostic tests) related to daprodustat (or study treatments of this drug 
class), and anemia associated with CKD. Genetic research may consist of the 
analysis of one or more candidate genes or the analysis of genetic markers 
throughout the genome.

DNA samples will be analyzed if it is hypothesized that this may help further 
understand the clinical data. 

DNA samples will be analyzed initially using genome-wide genotyping and 
performing genome-wide and candidate gene analysis of efficacy measures. 
Additional analyses may be conducted if it is hypothesized that this may help further 
understand the clinical data, such as investigating PK and/or safety endpoints as well 
as sequencing of the DNA. 

The samples may be analyzed as part of a multi-study assessment of genetic factors 
involved in the response to daprodustat or study treatments of this class. The results 
of genetic analyses may be reported in the clinical study report or in a separate study 
summary.

GSK will store the DNA samples in a secure storage space with adequate measures 
to protect confidentiality. 

The samples will be retained while research on daprodustat (or study treatments of 
this class) or anemia associated with CKD continues but no longer than 15 years 
after the last subject last visit or other period as per local requirements.
Study Population
Any subject who is randomized in the study can participate in genetic research.  Any 
subject who has received an allogeneic bone marrow transplant must be excluded from 
the genetic research.
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.  

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
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). 
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 
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

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
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.

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12.6.
Appendix 6: Liver Safety: Required Actions and Follow-up 
Assessments
Phase 3-4 liver chemistry stopping and increased monitoring criteria have been 
designed to assure participant safety and evaluate liver event etiology (in alignment with 
the FDA premarketing clinical liver safety guidance).  
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM174090.pdf
Phase 3-4 liver chemistry stopping criteria and required follow up assessments 
Liver Chemistry Stopping Criteria - Liver Stopping Event
ALT-absolute
ALT 8xULN
ALT Increase
ALT 5xULN but <8xULN  persists for 2 weeks
ALT 3xULN but <5xULN  persists for 4 weeks
Bilirubin1, 2
ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin) 
INR2
ALT 3xULN and INR>1.5, if INR measured
Cannot 
Monitor
ALT 5xULN but <8xULN and cannot be monitored weekly for 2 weeks
ALT 3xULN but <5xULN and cannot be monitored weekly for 4 weeks
Symptomatic3
ALT  3xULN associated with symptoms (new or worsening) believed to be 
related to  liver injury or hypersensitivity
Required Actions and Follow up Assessments following ANY Liver Stopping Event
Actions
Follow Up Assessments

Immediately discontinue randomized 
treatment

Report the event to GSK within 24 hours

Complete the liver event eCRF and complete 
an SAE data collection tool if the event also 
meets the criteria for an SAE2

Perform liver event follow up assessments 

Monitor the participant until liver chemistries 
resolve , stabilize, or return to within baseline 
(see MONITORING below)

Viral hepatitis serology4

Only in those with underlying chronic 
hepatitis B at study entry (identified by 
positive hepatitis B surface antigen) 
quantitative hepatitis B DNA and hepatitis 
delta antibody5.

Blood sample for PK analysis, obtained 
within 24 hour after last dose6

Serum creatine phosphokinase (CPK) and 
lactate dehydrogenase (LDH).

Fractionate bilirubin, if total 
bilirubin2xULN

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MONITORING:
For bilirubin or INR criteria:

Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin) and perform 
liver event follow up assessments within  24 
hours

Monitor participants twice weekly until liver 
chemistries resolve, stabilize or return to 
within baseline

A specialist or hepatology consultation is 
recommended
For All other criteria:

Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin) and perform 
liver event follow up assessments within  24-
72 hours 

Monitor participants weekly until liver 
chemistries resolve, stabilize or return to 
within baseline

Obtain complete blood count with 
differential to assess eosinophilia

Record the appearance or worsening of 
clinical symptoms of liver injury, or 
hypersensitivity, on the AE report form

Record use of concomitant medications on 
the concomitant medications report 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 participants
with definite or likely acetaminophen use in 
the preceding week [James, 2009]). 

Liver imaging (ultrasound, magnetic 
resonance, or computerised tomography) 
and /or liver biopsy to evaluate liver 
disease; complete Liver Imaging and/or 
Liver Biopsy eCRF forms.
1.
Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin fractionation is not 
immediately available, discontinue randomized treatment for that participant 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 participants receiving anticoagulants
3.
New or worsening symptoms believed to be related to liver injury (such as fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, or jaundice) or believed to be related to hypersensitivity (such as fever, rash or 
eosinophilia)   
4.
Includes: Hepatitis A IgM antibody; Hepatitis B surface antigen and Hepatitis B Core Antibody (IgM); Hepatitis C 
RNA; Cytomegalovirus IgM antibody;  Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, obtain 
heterophile antibody or monospot testing);  Hepatitis E IgM antibody 
5.
If hepatitis delta antibody assay cannot be performed, it can be replaced with a PCR of hepatitis D RNA virus 
(where needed) Le Gal, 2005].
6.
Record the date/time of the PK blood sample draw and the date/time of the last dose of randomized treatment 
prior to blood sample draw on the eCRF. If the date or time of the last dose is unclear, provide the participant’s 

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best approximation. If the date/time of the last dose cannot be approximated OR a PK sample cannot be collected 
in the time period indicated above, do not obtain a PK sample. Instructions for sample handling and shipping are 
in the SRM.  
Phase 3-4 liver chemistry increased monitoring criteria with continued therapy
Liver Chemistry Increased Monitoring Criteria – Liver Monitoring Event
Criteria
Actions
ALT 5xULN and <8xULN and bilirubin 
<2xULN without symptoms believed to 
be related to liver injury or 
hypersensitivity, and who can be 
monitored weekly for 2 weeks.
OR
ALT 3xULN and <5xULN and bilirubin 
<2xULN without symptoms believed to 
be related to liver injury or 
hypersensitivity, and who can be 
monitored weekly for 4 weeks.

Notify GSK within 24 hours of learning of the 
abnormality to discuss participant safety. 

Participant can continue randomized treatment 

Participant 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 participant 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 participants twice monthly 
until liver chemistries normalize or return to within 
baseline.
References
James LP, Letzig L, Simpson PM, Capparelli E, Roberts DW, Hinson JA, Davern TJ, Lee 
WM. Pharmacokinetics of acetaminophen-adduct in adults with acetaminophen overdose 
and acute Liver failure. Drug Metab Dispos 2009; 37:1779-1784.
Le Gal F, Gordien E, Affolabi D, Hanslik T, Alloui C, Dény P, Gault E.  Quantification 
of hepatitis delta virus RNA in serum by consensus real-time PCR indicates different 
patterns of virological response to interferon therapy in chronically infected patients J 
Clin Microbiol. 2005;43(5):2363–2369. 

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12.7.
Appendix 7: Country Specific Requirements
12.7.1.
French Administrative Considerations and Specifics
Requirements
This appendix includes all applicable requirements of French Public Health Code / 
specific local GSK requirements and identifies, item per item, the mandatory 
modifications or additional information to the study protocol.
1. Concerning the « SELECTION OF STUDY POPULATION AND 
WITHDRAWAL CRITERIA»

A subject will be eligible for inclusion in this study if he /she is either affiliated to 
or beneficiary of a social security category (French Public Health Code law 
L.1121-8-1). (exception for a participant to a non-interventional study if 
authorised by the Ethics Committee).
It is the investigator’s responsibility to ensure and to document (in the source 
document - subject notes) that the subject:
-
is either affiliated to or beneficiary of a social security category; 
-
has got an authorisation by the Ethics Committee.
2.
Concerning the “STATISTICAL CONSIDERATIONS AND DATA 
ANALYSES” and specially in the “SAMPLE SIZE ASSUMPTIONS”
The expected number of subjects to be recruited in France is declared to the French 
regulatory authority.
3.
Concerning the “STUDY GOVERNANCE CONSIDERATIONS” 
In section “Regulatory and Ethical Considerations, including the Informed Consent 
Process”
Concerning the process for informing the subject and/or his/her legally authorized 
representative, the following text is added:
French Patient Informed Consent is a document which summarizes the main features 
of the study and allows collection of the subject and/or his/her legally authorized 
representative written consent. It also contains a reference to the authorisation of 
ANSM and the approval from the French Ethics Committee.
Concerning the management of the Patient Informed Consent Forms, the 
following text is added: 
French Patient Informed Consent Form is in triplicate (quadruplicate for minor subject)
The first page of the Patient Informed Consent Form is given to the investigator. The 
second copy is kept by the Medical Direction of GlaxoSmithKline France and the last 
copy is kept by the patient or legally authorized representative.
Maintenance of confidentiality of the returned consent form by GlaxoSmithKline 
France is specified on the form.

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The second copy of all the consent forms will be collected by the Clinical Research 
Assistant (CRA) under the Investigator’s control, and placed in a sealed envelope 
bearing only:
-
the study number, 
-
the identification of the Centre: name of the principal investigator and centre 
number,
-
the number of informed consents,
-
the date, 
-
and the principal investigator’s signature.
Then, the CRA hands the sealed envelope over to the Medical Direction, for 
confidential recording, under the responsibility of the Medical Director.

NOTIFICATION TO THE HOSPITAL DIRECTOR
In accordance with Article L1123-13 of the French Public Health Code, the Hospital 
Director is informed of the commitment to the trial in her/his establishment. The 
Hospital Director is supplied with the protocol and any information needed for the 
financial disposition, the name of the investigator(s), the number of sites involved in 
his establishment and the estimated time schedule of the trial (R.1123-69).

INFORMATION TO THE HOSPITAL PHARMACIST the following text is 
added:
In accordance with Article R.1123-70 of the French Public Health Code, the Hospital 
Pharmacist is informed of the commitment to the trial in her/his establishment. The 
Pharmacist is supplied with a copy of the protocol (which allows her/him to dispense 
the drug(s) of the trial according to the trial methodology), all information 
concerning the product(s) of the trial (e.g. included in the CIB), the name of the 
investigator(s), the number of sites involved in her/his establishment and the 
estimated time schedule of the trial.
4. Concerning the “ DATA MANAGEMENT ” the following text is added:
Within the framework of this clinical trial, data regarding the identity of the 
investigators and/or co-investigators and/or the pharmacists if applicable, involved 
in this clinical trial, and data regarding the subjects recruited in this clinical trial 
(subject number, treatment number, subjects status with respect to the clinical trial, 
dates of visit, medical data) will be collected and computerized in 
GlaxoSmithKline data bases by GlaxoSmithKline Laboratory or on its behalf, for 
reasons of follow up, clinical trial management and using the results of said 
clinical trial. According to the Data Protection French Law n° 78-17 of 6th January 
1978, each of these people aforesaid has a right of access, correction and 
opposition on their own data through GlaxoSmithKline Laboratory (Clinical 
Operations Department).
DEMOGRAPHIC DATA
In accordance with the Data Protection French Law n° 78-17 of 6th January 1978 –
article 8, the ethnic origin can only be collected if the collection of this data is 
strictly necessary and relevant for the purpose of the study.

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TESTING OF BIOLOGICAL SAMPLES
In accordance with the French Public Health Code law – article L1211-2, a 
biological sample without identified purpose at the time of the sample and 
subject’s preliminary information is not authorized.
5. SAE 
In case of paper notification, the SAE Reports have to be transmitted to the 
GlaxoSmithKline France Drug Safety Department, which name, address and 
phone number are: 
Département de Pharmacovigilance
Laboratoire GlaxoSmithKline
23, rue François Jacob 
92 500 Rueil-Malmaison
Tel : 
Fax :
6. Monitoring visits
The Health Institution and the Investigator agree to receive on a regular basis a 
Clinical Research Assistant (CRA) of GLAXOSMITHKLINE or of a service 
provider designated by GLAXOSMITHKLINE. The Health Institution and the 
Investigator agree to be available for any phone call and to systematically answer 
to all correspondence regarding the Study from GLAXOSMITHKLINE or from 
a service provider designated by GLAXOSMITHKLINE. In addition, the Health 
Institution and the Investigator agree that the CRA or the service provider 
designated by GLAXOSMITHKLINE have direct access to all the data 
concerning the Study (test results, medical record, etc …). This consultation of 
the information by GLAXOSMITHKLINE is required to validate the data 
registered in the electronic Case Report Form (eCRF), in particular by comparing 
them directly to the source data. In accordance with the legal and regulatory 
requirements, the strictest confidentiality will be respected.
7. Data entry into the eCRF
The Health Institution and the Investigator agree to meet deadlines, terms and 
conditions of the Study’s electronic Case Report Form (eCRF) use here below:
The Health Institution and the Investigator undertake:
1. That the Investigator and the staff of the investigator center make themselves 
available to attend the training concerning the computer system dedicated to 
the  electronic Case Report Form (eCRF) of the Study provided by 
GLAXOSMITHKLINE or by a company designated by 
GLAXOSMITHKLINE.
2. That the Investigator and the staff of the investigator center use the IT 
Equipment loaned and/or the access codes only for the purpose of which they 
PPD
PPD

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are intended and for which they have been entrusted to them, namely for the 
Study achievement, to the exclusion of any other use.
3. That the Investigator and the staff of the investigator center use the IT 
Equipment loaned according to the specifications and manufacturer’s 
recommendations which will have been provided by GLAXOSMITHKLINE.
4. To keep the IT Equipment and/or access codes in a safe and secure place and 
to authorize only the use of this IT Equipment by investigator center staff 
designated by the principal investigator to enter the data of the Study.
5. To be responsible for the installation and payment of the required Internet 
connections needed for the use of the IT Equipment, Computer systems 
and/or access codes.
6. To return at the end of the Study the IT Equipment and/or access codes to 
GLAXOSMITHKLINE or to any company designated by 
GLAXOSMITHKLINE and any training material and documentation. The IT 
Equipment cannot under any circumstances be kept by the Health Institution 
or the Investigator for any reason whatsoever. 
8. CTR publication
It is expressly specified that GLAXOSMITHKLINE and/or the Sponsor can 
make available to the public the results of the Study by the posting of the said 
results on a website of the GLAXOSMITHKLINE GROUP named Clinical Trial 
Register (CTR) including the registration of all the clinical trials conducted by 
the GLAXOSMITHKLINE Group and this before or after the publication of such 
results by any other process.
9. Data Protection French Law of 6th January 1978 (CNIL)
In accordance with the Data Protection French Law of 6 January 1978 updated 
the 20th of June 2018, personal data are processed in a manner that ensures 
appropriate security, including protection against unauthorized or unlawful 
processing and against accidental loss, destruction or damage, using appropriate 
technical or organizational measures. The processing is whether deemed to be 
compliant with one of the methodology of reference (MR-001) or has been the 
subject of a request for authorization to the CNIL. The Investigator has, 
regarding the processing data related to her/him, a right of access, of 
rectification, erasure and of opposition with GLAXOSMITHKLINE in 
accordance with the legal provisions. Personal information can be transferred or 
be accessed to/by other entities of GLAXOSMITHKLINE Group, what the 
Investigator agrees by the signature of the present Protocol.

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12.8.
Appendix 8: Stratification by Region-Region Groupings
Region
Countries2
1

Republic of 
Korea1
2

Poland

Czech 
Rebuplic

Romania

Hungary

Russian 
Federation

South Africa
3

Australia1

Canada1

Italy

Germany

France

Netherlands1

United 
Kingdom1

Spain1

Sweden1
4

Argentina

Brazil1

Mexico
5

US1
1. Countries which will collect the EQ-5D-5L and EQ VAS
2. Countries that do not participate or do not randomize any participants will be 
removed from the regional grouping. 

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12.9.
Appendix 9: Protocol Amendment History
The Protocol Amendment Summary of Changes Table for the current amendment is 
located directly before the Table of Contents (TOC).
Prot-ITA-1: 02-Apr-2018
Overall Rationale for the Amendment: A country specific amendment has been 
published per the Italian regulatory request.
Protocol Amendment Summary of Changes
Section# and Name
Description of Change
Brief Rationale
Section 2: Schedule of 
Activites
Edited footnote #11 to include 
evaluation of all iron 
parameters at week 4
A check of all iron parameters at 
week 4 was requested by AIFA
Section 6.1 Exclusion Criteria 
Exclusion #18
Exclude participants with a 
lower ECG criteria based on 
QTcF and not QTcB.
. 
Exclude participants with 
second or third degree 
atrioventricular (AV) block
AIFA recommended a lower 
threshold for inclusion of 
participants with prolonged QTc 
measured by Fridericia equation. 
AIFA recommended to exclude 
participants with second or third 
degree AV block. 
Section 9.5.3 
Electrocardiograms
Replaced QTcB with QTcF 
Based on change to exclusion 
criteria #18. 
Type of Protocol Amendment
Numbering
Type of changes
Country-specific
Amendment ITA-1
Changes requested by Italian 
regulatory agency added to original 
protocol to create Italy Specific 
Protocol. 
DOCUMENT HISTORY
Document
Date
Country Specific Protocol ITA-1
02-Apr-2018
Original Protocol 
22-Aug-2017