A Randomized, Open-label Study to Evaluate the Effect of Daprodustat on Blood Pressure in Subjects With Anemia Associated With Chronic Kidney Disease on Hemodialysis Switched From a Stable Dose of an Erythropoiesis-stimulating Agent
Phase: PHASE2
Conditions: Anaemia
Sponsor: GlaxoSmithKline

2015N267693_04
CONFIDENTIAL
The GlaxoSmithKline group of companies
205665
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TITLE PAGE
Division: Worldwide Development
Information Type: Protocol Amendment
Title:
A randomized, open label study to evaluate the effect of 
daprodustat on blood pressure in subjects with anemia associated 
with chronic kidney disease on hemodialysis switched from a 
stable dose of an erythropoiesis-stimulating agent
Short Title:
Anemia Studies in CKD: Erythropoiesis via a Novel PHI 
Daprodustat – Blood Pressure (ASCEND-BP)
Compound Number:
GSK1278863
Development Phase:
IIB
Effective Date:
23-OCT-2019
Protocol Amendment Number:  04
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 can be found in the Study Reference
Manual (SRM).
Regulatory Agency Identifying Number(s): IND Number: 101,291
Copyright 2019 the GlaxoSmithKline group of companies.  All rights reserved.  
Unauthorised copying or use of this information is prohibited.

2015N267693_04
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The GlaxoSmithKline group of companies
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Revision Chronology
GlaxoSmithKline
Document Number
Date
Version
2015N267693_00
2016-AUG-02
Original
2015N267693_01
2016-NOV-21
Amendment No. 01
This protocol amendment was written to clarify specific biomarkers being drawn, modify 
time points of biomarkers, clarify safety laboratory studies, and clarify day/time of 
assessments.  An additional potential study visit is added.
2015N267693_02
2017-JUL-31
Amendment No. 2
This protocol amendment was written to clarify the descriptive statistics and include them 
in the objectives and endpoints table(s) as well as remove one blood pressure 
measurement. Additional minor changes were made for clarity of study procedures.
2015N267693_03
2018-MAY-21
Amendment No. 3
This protocol amendment was written to streamline recruitment of subjects into the study 
and maintain appropriate Hgb levels while in the study.  This includes removing study 
visits, altering entry requirements as well as stopping criteria, changing dosing and dose 
adjustments, and restructuring Hgb parameters.
2015N267693_04
2019-OCT-23
Amendment No. 4
This protocol amendment was written to remove the interim analysis from the statistical 
section due to more rapid recruitment than anticipated.  During the update, the objectives 
and endpoints were streamlined, the stratification variable of previous ESA dose was 
added to the models as it was inadvertently left out, the daprodustat dosing algorithm was 
updated, and exploratory endpoints were added to further clarify results.
During this time the safety language was updated as well as clarification of 
inclusion/exclusion criteria in response to an internal audit.

PPD
PPD

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PROTOCOL AGREEMENT PAGE
For protocol number 205665.
I confirm agreement to conduct the study in compliance with the protocol, as amended by 
this protocol amendment.
I acknowledge that I am responsible for overall study conduct. I agree to personally 
conduct or supervise the described study.
I agree to ensure that all associates, colleagues and employees assisting in the conduct of 
the study are informed about their obligations. Mechanisms are in place to ensure that site
staff receives the appropriate information throughout the study. 
Investigator Name:
Investigator Address:
Investigator Phone Number:
Investigator Signature
Date

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TABLE OF CONTENTS
PAGE
1.
PROTOCOL SYNOPSIS FOR STUDY 205665........................................................8
2.
INTRODUCTION....................................................................................................13
2.1.
Study Rationale ..........................................................................................14
2.2.
Brief Background ........................................................................................15
3.
OBJECTIVE(S) AND ENDPOINT(S) ......................................................................15
4.
STUDY DESIGN ....................................................................................................16
4.1.
Overall Design ............................................................................................16
4.2.
Treatment Arms and Duration.....................................................................18
4.3.
Type and Number of Subjects.....................................................................19
4.4.
Design Justification.....................................................................................19
4.5.
Dose Justification........................................................................................21
4.6.
Benefit:Risk Assessment ............................................................................22
4.6.1.
Risk Assessment .........................................................................22
4.6.2.
Benefit Assessment.....................................................................22
4.6.3.
Overall Benefit:Risk Conclusion...................................................22
5.
SELECTION OF STUDY POPULATION AND WITHDRAWAL CRITERIA .............22
5.1.
Hemoglobin Stability Criteria.......................................................................23
5.2.
Inclusion Criteria.........................................................................................23
5.3.
Exclusion Criteria........................................................................................24
5.4.
Screening/Baseline/Run-in Failures............................................................26
5.5.
Withdrawal/Stopping Criteria.......................................................................26
5.5.1.
Criteria for Permanent Discontinuation from Study 
Treatment and Early Withdrawal..................................................26
5.5.1.1.
Hemoglobin Stopping Criteria.....................................27
5.5.2.
Missed Clinic Visits/Lost to Follow-up ..........................................28
5.5.3.
Liver Chemistry Stopping Criteria ................................................29
5.5.3.1.
Study Treatment Restart or Rechallenge....................29
5.6.
Subject and Study Completion....................................................................30
6.
STUDY TREATMENT ............................................................................................30
6.1.
Investigational Product and Other Study Treatment....................................30
6.2.
Treatment Assignment................................................................................30
6.3.
Blinding.......................................................................................................31
6.4.
Starting Dose and Dose Adjustment Algorithm ...........................................31
6.4.1.
Subjects Randomized to Daprodustat..........................................31
6.4.2.
Subjects Randomized to Epoetin Alfa..........................................32
6.5.
Packaging and Labeling..............................................................................32
6.6.
Preparation/Handling/Storage/Accountability..............................................32
6.7.
Compliance with Study Treatment Administration.......................................33
6.8.
Treatment of Study Treatment Overdose....................................................33
6.9.
Treatment after the End of the Study ..........................................................33
6.10.
Lifestyle and/or Dietary Restrictions............................................................34
6.10.1.
Meals and Dietary Restrictions ....................................................34
6.11.
Concomitant Medications and Non-Drug Therapies....................................34

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6.11.1.
Weight and Antihypertensive Medication Changes ......................34
6.11.2.
Permitted Medications and Non-Drug Therapies..........................34
6.11.3.
Prohibited Medications and Non-Drug Therapies.........................34
6.11.4.
Standard of Care .........................................................................34
6.11.5.
Iron Protocol ................................................................................34
7.
STUDY ASSESSMENTS AND PROCEDURES .....................................................35
7.1.
Time and Events Table...............................................................................36
7.2.
Screening and Critical Baseline Assessments ............................................38
7.3.
Safety .........................................................................................................38
7.3.1.
Adverse Events (AE) and Serious Adverse Events (SAEs)..........38
7.3.1.1.
Time Period and Frequency for Collecting AE 
and SAE Information ..................................................38
7.3.1.2.
Method of Detecting AEs and SAEs ...........................39
7.3.1.3.
Follow-up of AEs and SAEs........................................39
7.3.1.4.
Adverse Events of Special Interest.............................39
7.3.1.5.
Cardiovascular and Death Events ..............................39
7.3.1.6.
Regulatory Reporting Requirements for SAEs............40
7.3.1.7.
Possible Suicidality Related Adverse Events..............40
7.3.2.
Pregnancy ...................................................................................40
7.3.3.
Physical Exams ...........................................................................40
7.3.4.
Vital Signs and Weight.................................................................41
7.3.5.
Electrocardiogram (ECG).............................................................41
7.3.6.
Clinical Safety Laboratory Assessments ......................................41
7.4.
Pharmacokinetics .......................................................................................42
7.4.1.
Blood Sample Collection..............................................................42
7.4.2.
Sample Analysis ..........................................................................43
7.5.
Biomarker(s)/Pharmacodynamic Markers ...................................................43
7.5.1.
Ambulatory Blood Pressure Monitoring (ABPM)...........................43
7.5.1.1.
ABPM Delay Due to High Hgb....................................44
7.5.2.
Blood Pressure Regulation Biomarkers .......................................44
7.6.
Genetics .....................................................................................................44
8.
DATA MANAGEMENT ...........................................................................................44
9.
STATISTICAL CONSIDERATIONS AND DATA ANALYSES .................................45
9.1.
Hypotheses.................................................................................................45
9.2.
Sample Size Considerations.......................................................................45
9.2.1.
Sample Size Assumptions ...........................................................45
9.2.2.
Sample Size Sensitivity................................................................46
9.2.3.
Sample Size Re-estimation or Adjustment...................................46
9.3.
Data Analysis Considerations .....................................................................46
9.3.1.
Analysis Populations....................................................................46
9.3.2.
Interim Analysis ...........................................................................47
9.4.
Key Elements of Analysis Plan ...................................................................47
9.4.1.
Primary Analyses.........................................................................47
9.4.2.
Secondary Analyses ....................................................................47
9.4.3.
Other Analyses ............................................................................47
10. STUDY GOVERNANCE CONSIDERATIONS........................................................48
10.1.
Posting of Information on Publicly Available Clinical Trial Registers............48

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10.2.
Regulatory and Ethical Considerations, Including the Informed 
Consent Process ........................................................................................48
10.3.
Quality Control (Study Monitoring) ..............................................................49
10.4.
Quality Assurance.......................................................................................49
10.5.
Study and Site Closure ...............................................................................49
10.6.
Records Retention......................................................................................50
10.7.
Provision of Study Results to Investigators, Posting of Information 
on Publicly Available Clinical Trials Registers and Publication....................51
11. REFERENCES.......................................................................................................52
12. APPENDICES........................................................................................................55
12.1.
Appendix 1 – Abbreviations and Trademarks..............................................55
12.2.
Appendix 2: Liver Safety Required Actions and Follow up 
Assessments ..............................................................................................58
12.3.
Appendix 3: Daprodustat Risk Assessment ................................................64
12.4.
Appendix 4: Definition of and Procedures for Recording, Evaluating, 
Follow-Up and Reporting of Adverse Events...............................................75
12.4.1.
Definition of Adverse Events........................................................75
12.4.2.
Definition of Serious Adverse Events...........................................76
12.4.3.
Definition of Cardiovascular Events .............................................77
12.4.4.
Recording of AEs and SAEs ........................................................78
12.4.5.
Evaluating AEs and SAEs............................................................78
12.4.6.
Reporting of SAEs to GSK...........................................................79
12.4.7.
Modified List of Highly Effective Methods for Avoiding 
Pregnancy in Females of Reproductive Potential (FRP) ..............80
12.4.8.
Collection of Pregnancy Information ............................................81
12.5.
Appendix 5 - Country Specific Requirements..............................................82
12.6.
Appendix 6 – Ambulatory Blood Pressure Monitoring Device......................83
12.7.
Appendix 7 – Protocol Changes..................................................................85
12.7.1.
Amendment 1 ..............................................................................85
12.7.2.
Amendment 2 ............................................................................108
12.7.3.
Amendment 3 ............................................................................135
12.7.4.
Amendment 4 ............................................................................164

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1.
PROTOCOL SYNOPSIS FOR STUDY 205665
Rationale
The purpose of this study is to compare the effects on blood pressure of daprodustat to 
epoetin alfa in hemodialysis-dependent (HD) subjects with anemia associated with 
chronic kidney disease (CKD).  The study will also assess various biomarkers associated 
with blood pressure physiology that may provide insight into the mechanism(s) of the 
hypertensive effects associated with erythropoiesis stimulating agent(s) (ESAs).
Objective(s)/Endpoint(s)
Objectives
Endpoints
Primary

To compare the effect of daprodustat to epoetin 
alfa on blood pressure (BP) after Acute 
Challenge 2 (8 weeks of hemoglobin [Hgb]
maintenance therapy)

Average of systolic blood pressure (SBP) as 
measured by ambulatory blood pressure 
monitoring (ABPM) over 6-hr post-dosing after 
8 weeks of Hgb maintenance therapy
Secondary

To compare the initial effect of daprodustat to 
epoetin alfa on BP after Acute Challenge 1 (2 
weeks of erythropoiesis-stimulating agent [ESA]
washout)

Average of SBP, diastolic blood pressure 
(DBP), mean arterial blood pressure (MAP), 
and heart rate (HR) as measured by ABPM 
over 6-hr post-dosing at Day 1

Area under the effect curve (AUEC) of SBP, 
DBP, MAP, and HR as measured by ABPM 
over 24-hr post-dosing at Day 1

To compare the effect of daprodustat to epoetin 
alfa on BP after Acute Challenge 2

Average of DBP, MAP, and HR as measured 
by ABPM over 6 hr post-dosing at Day 57.

AUEC of SBP, DBP, MAP, and HR as 
measured by ABPM over 24-hr post-dosing at 
Day 57.

To estimate the initial effect of daprodustat on 
SBP, DBP, HR and MAP after Acute Challenge 
1

Change from pre-dose in SBP, DBP, HR, and 
MAP at each timepoint at Day 1

To characterize the pharmacokinetics of 
daprodustat

Plasma concentrations of daprodustat and 
metabolites and derived pharmacokinetic 
parameters including maximum observed 
concentration (Cmax), time of occurrence of 
Cmax (tmax), terminal phase half-life (t½) and 
area under concentration-time curve from time 
zero to 24 hours (AUC[0-24]) as appropriate
Safety

To assess the safety and tolerability of 
daprodustat

Incidence and severity of adverse events (AEs)
and serious adverse events (SAEs)

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Objectives
Endpoints

Reasons for discontinuation of study treatment

Absolute values and changes from baseline 
over time in laboratory parameters, 
electrocardiograms (ECGs) and vital signs
Exploratory

To investigate the effect of daprodustat and 
epoetin alfa on vasoactive mediators of blood 
pressure

Plasma concentrations and derived 
parameters including Cmax, tmax, t½ and 
AUC(0-24) as appropriate (to include 
erythropoietin, endothelin-1, nitric oxide, 
asymmetric dimethylarginine, renin, 
angiotensin-II and metabolites, and 
noradrenalin) 

To summarize the effect of daprodustat and 
epoetin alfa on SBP after Acute Challenge 1 
and Acute Challenge 2

AUEC of SBP as measured by ABPM over 24-
hr post-dosing

To compare the effect of daprodustat to epoetin 
alfa on SBP after 8 weeks of Hgb maintenance 
therapy

Change from Day 1 pre-dose SBP to Day 57
pre-dose

To compare the effect of daprodustat to epoetin 
alfa on SBP at Cmax of each study treatment, 
as measured by ABPM. 

Change in SBP from pre-dose on Day 1 to 
Cmax of the study treatment on Day 1

Change in SBP from pre-dose on Day 1 to
Cmax of the study treatment on Day 57

Change in SBP from pre-dose on Day 57 to 
Cmax of the study treatment on Day 57

To compare the effect of daprodustat to epoetin 
alfa on SBP at respective Cmax of the 
erythropoietin level, as measured by ABPM.

Change in SBP from pre-dose on Day 1 to 
Cmax of erythropoietin on Day 1

Change in SBP from pre-dose on Day 1 to 
Cmax of erythropoietin on Day 57

Change in SBP from pre-dose on Day 57 to 
Cmax of erythropoietin on Day 57
Overall Design
This study will be an open-label, randomized, parallel-group design in HD subjects with 
anemia associated with CKD.  There will be a screening period, a 2-week ESA washout 
period, an initial 24-hour acute challenge, an 8-week Hgb-maintenance period, a second
24-hr acute challenge and a follow-up visit 14±3 days after completing treatment.  The 
study design is outlined below:

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Study Design
Subjects will be screened for eligibility within 7 - 30 days prior to the start of the ESA 
washout period.
Subjects that qualify for enrolment will be washed out of their ESA for 2 weeks; the start 
of the ESA washout should be timed to coincide as closely as possible with their next 
planned ESA dose.  Subjects are enrolled once they enter the ESA washout period.
Following the 2-week ESA washout, subjects will be randomized 1:1 and stratified by 
prior ESA dose, based on the average weekly (for epoetins or darbepoetin) or monthly 
(for methoxy polyethylene glycol (PEG)-epoetin beta) dosing during the 12 weeks prior 
to ESA washout as follows:

Low ESA dose: <100 U/kg/week epoetin alfa OR <0.5 µg/kg/week darbepoetin 
OR <0.6 µg/kg/week methoxy PEG-epoetin beta

High ESA dose: ≥100 U/kg/week epoetin alfa OR ≥0.5 µg/kg/week darbepoetin 
OR 0.6 µg/kg/week methoxy PEG-epoetin beta
On Day 1, subjects will be randomized and undergo Acute Challenge 1, a single dose 
challenge to compare the acute effects on BP of the highest planned once-daily 
maintenance dose of daprodustat (24 mg) to the highest starting dose of epoetin alfa 
(100 U/kg).  Subjects will have BP monitored for 24 hr using ABPM, and will have serial 
blood sampling to assess the pharmacokinetics of daprodustat and the time-course of 
various biomarkers.  Acute Challenge 1 will be started promptly following completion of 
a mid-week dialysis session.
After completing Acute Challenge 1, all subjects will enter the 8-week Hgb maintenance 
period where doses of either daprodustat or epoetin alfa will be administered and 
adjusted, as needed.
On Day 57, following the 8-week Hgb maintenance period, subjects will undergo Acute 
Challenge 2; this challenge will, similar to Acute Challenge 1, involve assessing the 
effect of daprodustat and epoetin alfa on BP as assessed by 24-hr ABPM measurement.  
The subjects will be administered the same dose of either daprodustat or epoetin alfa that 
was given in Acute Challenge 1, and serial blood sampling will be performed to assess 
Week -2: ESA 
Washout
Day 1: Randomize & 
Acute Challenge 1
Day 15, 29 & 43: Dose 
Adjustment (as needed)
Day 57: Acute Challenge 2
Hgb Maintenance Period 
Week 10: Follow-up
Screening: Between 7 and 30 
days prior to ESA Washout

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daprodustat pharmacokinetics and to characterize the time course of various biomarkers.  
Acute Challenge 2 will be started following completion of a mid-week dialysis session.
Subjects will attend a follow-up visit 2 weeks after completion of Acute Challenge 2.  
Subjects will be asked to not reinitiate anemia treatment until after the follow-up visit 
unless deemed medically necessary
After both Acute Challenge 1 and 2, the 24-hr ABPM results will be checked for data 
quality as defined in the Project Requirement Specification (PRS).  If the ABPM fails the 
QC criteria following Acute Challenge 2, one additional Acute Challenge may be made 
after a subsequent, mid-week dialysis visit 1 week later if the subject agrees. At that 
visit, the subject will receive the same study treatment for the repeat Acute Challenge 2 
as was administered on Day 57 as a single additional dose. No additional clinical 
chemistry, hematology, pharmacokinetic or biomarker sampling will be done, however 
all other procedures will be performed.
The Acute Challenge 2 may be delayed one week if the subject’s Hgb ≥11.5.  
Treatment Arms and Duration
The total maximum duration of subject involvement is up to 16 weeks (Screening to 
Follow-up) as described below:

Screening: Screening will occur at least one week prior to but not more than 30 
days prior to washout. 

ESA Washout: Subjects that meet eligibility criteria will begin the 2-week ESA 
washout.
o
This should be timed such that this day occurs on the date that would have 
been the next scheduled dose of ESA (or as close as practicable).
o
For subjects with a three-times weekly dialysis schedule, this day must not 
occur on the first dialysis session of the week (e.g., if Monday-Wednesday-
Friday schedule, the study visit cannot be on Monday).
o
For subjects with a four- to five-times weekly dialysis schedule, this day can 
be on any hemodialysis session of the week.

Randomization & Acute Challenge 1 (Day 1): Subjects will be randomized 1:1 to 
two treatment arms and will begin a 24-hr Acute Challenge where the acute BP 
effects of daprodustat and epoetin alfa will be evaluated.  This challenge will be 
initiated promptly following the subject’s dialysis session.

Hgb Maintenance Period: Subjects randomized to daprodustat will start an 8-week 
Hgb maintenance period based on a starting dose and dose adjustment algorithm.    
Subjects randomized to epoetin alfa will begin an 8-week Hgb maintenance 
period where Hgb will be managed in accordance with local labelling.

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
Acute Challenge 2 (Day 57): At the end of the 8-week Hgb maintenance period 
subjects will repeat the procedures of Acute Challenge 1 utilizing the same 
treatment dose administered in Acute Challenge 1.  This challenge will be 
initiated promptly following the subject’s dialysis session.

Follow-up: A Follow-up visit will be scheduled to occur 14 3 days after 
completing treatment.
Treatment Arm Descriptions
Treatment Arm
Acute Challenge 1
Hgb Maintenance Phase
Acute Challenge 2
A
100 U/kg IV epoetin 
alfa
IV epoetin alfa according to label
100 U/kg IV epoetin
alfa
B
24 mg daprodustat
QD daprodustat according to dose 
adjustment algorithm
24 mg daprodustat
Type and Number of Subjects

The study will enroll hemodialysis-dependent subjects with anemia associated with 
CKD currently treated with an ESA.  Subjects with Hgb values of 8.5 - 11.5 g/dL, 
inclusive at both Screening and Day 1, are eligible, and the subjects must currently be 
on an ESA product.

Approximately 124 subjects will be screened to achieve approximately 62 
randomized and 50 evaluable subjects for a total of 25 evaluable subjects per 
treatment group.

If subjects prematurely discontinue the study, additional replacement subjects may be 
randomized and assigned to the same treatment arm at the discretion of the Sponsor in 
consultation with the investigator.
Analysis

The primary endpoint for this study is average systolic blood pressure (SBP) over 6 
hours of measurements taken at 15-minute intervals after the administration of study 
treatment for the Acute Challenge 2.  The primary comparison of interest is 
daprodustat versus epoetin alfa for this challenge.

The primary analysis of average SBP over 6 hr post-dose during Acute Challenge 2 
will be an analysis of covariance (ANCOVA) with terms for treatment, prior ESA 
dose (low/high), post-HD/pre-Acute Challenge 1 SBP, difference between post-
HD/pre-Acute Challenge 2 SBP and post-HD/pre-Acute Challenge 1 SBP, and 
treatment by (difference in post-HD SBP between Acute Challenge 1 and 2) 
interaction.  Note that the pre-challenge SBP may change over time between Acute 
Challenge 1 and Acute Challenge 2 as a result of the maintenance therapy, and thus 
the pre-challenge SBP at Acute Challenge 2 is not a true pre-treatment covariate.  As 
a result, the interpretation of the effect of the Acute Challenge 2 may be confounded 
by the impact of treatment phase on the covariate. Therefore, if the interaction term in 
this model is significant at the 0.10 level, then the primary model will be ANCOVA 
with terms for treatment, prior ESA dose (low/high), and post-HD/pre-Acute 

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Challenge 1 SBP.  The primary model will provide a point estimate and two-sided 
95% CI for the treatment effect and a p-value for the superiority assessment.  
Superiority will be established if the p-value is <0.05.

The comparison of daprodustat versus epoetin alfa on 6 hr average SBP during Acute 
Challenge 1 is a secondary endpoint.  Average SBP over 6 hr post-dose in Acute 
Challenge 1 will be analyzed using ANCOVA with terms for treatment, prior ESA 
dose (low/high), and post-HD/pre-Acute Challenge 1 SBP.  Similar analyses will be 
performed for DBP, MAP, and HR.

ANCOVA using the primary model will be used for the analysis of average DBP, 
MAP, and HR over 6 hr post-dose in Acute Challenge 2 replacing the baseline SBP 
term with the analogous baseline measurement for DBP, MAP, and HR, respectively.

AUECs of SBP, DBP, MAP, and HR post Acute Challenge 2 and 1 will be analyzed 
using ANCOVA with terms for treatment and prior ESA dose (low/high) with 95% 
CIs and p-values provided for the treatment effect.

Null Hypothesis: The difference between 24 mg daprodustat versus 100 IU/kg
epoetin alfa on 6 hr average SBP under a background of treatment (i.e., during Acute 
Challenge 2) is zero.

Alternative Hypothesis: The difference between 24 mg daprodustat versus 100 IU/kg
epoetin alfa on 6 hr average SBP under a background of treatment (i.e. during Acute 
Challenge 2) is not zero.
2.
INTRODUCTION
Anemia is a common complication of chronic kidney disease (CKD).  The cause of 
anemia in this population is multi-factorial, including relative or absolute deficiency of 
erythropoietin (EPO), reduced iron availability related to chronic inflammation, and 
gastrointestinal blood loss.  Current treatments for anemia associated with CKD include 
erythropoiesis-stimulating agents (ESAs) such as recombinant human (rh) EPO, 
supplemental iron therapy (intravenous and/or oral), and blood transfusions.  However, 
each of these treatments has significant limitations:

ESAs: In order to achieve target hemoglobin (Hgb) levels (which are lower than 
normal Hgb levels), treatment with ESAs markedly increases plasma EPO 
concentrations to supra-physiologic levels.  Treatment with ESAs has also been 
associated with increased cancer-related morbidity and mortality and increased 
risk of major cardiovascular (CV) events (e.g., stroke, myocardial infarction and 
all-cause mortality) [FDA, 2011], as well as ESA-induced hypertension.

Iron: Poor compliance is seen with oral iron therapy due to gastrointestinal 
intolerance while intravenous (IV) iron may have an increased risk of infection 
and/or iron overload as well as an increased risk for congestive heart failure 
[Agarwal, 2015].

Blood transfusions: These are avoided when possible because of potential allo-
immunization, which can preclude the possibility of receiving a kidney transplant 
in addition to a risk of infection.
Hypoxia-inducible factor (HIF) prolyl hydroxylase inhibitors (PHIs) are an emerging new 
class of agents under investigation for the treatment of anemia associated with CKD.  

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These molecules stimulate erythropoiesis through inhibition of HIF-prolyl hydroxylase 
domain enzymes (PHD1, PHD2, PHD3).  This activity results in the accumulation of 
HIFα transcription factors which leads to increased transcription of HIF-responsive 
genes, stimulating components of the natural response to hypoxia.  During hypoxia, PHD 
enzymes are inhibited, resulting in the accumulation of unhydroxylated HIFα subunits, 
which dimerize with HIFβ subunits to affect the transcription of HIF-responsive genes, 
including EPO and others involved in increasing oxygen availability and utilization.  
Other functions regulated by HIFs include iron metabolism and utilization, angiogenesis, 
extracellular matrix metabolism, apoptosis, energy and glucose metabolism, vascular 
tone, cell adhesion, and motility [Haase, 2013].
Daprodustat (GSK1278863) is a small molecule, oral inhibiter of the HIF-PHD enzymes 
which may present several important advantages over other ESAs.  It is an oral 
medication and does not require cold-chain storage as do some ESAs, thus increasing 
ease of use for patients.  Moreover, data indicate that daprodustat can effectively raise 
Hgb concentrations with lower EPO levels than those observed after administration of 
ESAs [Provenzano, 2011].  Because of the increased CV risk associated with raising Hgb 
concentrations through large increases in EPO levels [Pfeffer, 2009], daprodustat has the 
potential to raise Hgb with less CV risk than other ESAs.  
 
.
2.1.
Study Rationale
Current labelling for all ESAs includes a contraindication in patients with uncontrolled 
hypertension, and increases in blood pressure (BP) and/or antihypertensive medication 
use has been observed in several clinical trials with ESAs.  While the mechanism for this 
hypertensive effect is not known, hypertension has been consistently observed in 
approximately 25 to 30% of CKD patients initiating ESA therapy, and varies between an 
average of approximately 5 to 8 mmHg in systolic blood pressure (SBP), and 4 to 6 
mmHg in diastolic blood pressure (DBP) reviewed in [Krapf, 2009].  Additionally, 
increases in BP are a well-recognized risk factor for CV events, in particular heart failure, 
ischemic stroke and myocardial infarction [Rodriguez, 2014].  Finally, treatment with 
ESAs has been associated with increased risk of major CV events including myocardial 
infarction, stroke and death.
Daprodustat has been shown to effectively raise and manage Hgb levels in subjects with 
CKD with lower levels of EPO than the ESAs.  As the hypertensive effects of ESAs 
appear dose-related [Abraham, 1991], there is the potential that daprodustat can treat 
anemia in CKD patients without the hypertensive effects observed with the ESAs.  This 
study will use two 24-hr Acute Challenges to compare the effect of daprodustat to rhEPO 
on BP as measured by ambulatory blood pressure monitoring (ABPM) following both a 
2-week ESA washout period (Acute Challenge 1) and an 8-week Hgb-maintenance 
period (Acute Challenge 2).
Therefore, the purpose of this study is to compare the effects on blood pressure of 
daprodustat to epoetin alfa in hemodialysis-dependent (HD) subjects with anemia 
associated with CKD.  The study will also assess various biomarkers associated with 
CCI
CCI
CCI

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blood pressure physiology that may provide insight into the mechanism(s) of the 
hypertensive effects associated with ESAs.
2.2.
Brief Background
Daprodustat is a HIF-PHI currently being investigated as a treatment for anemia 
associated with CKD in both hemodialysis dependent (HD) and non-dialysis dependent 
(ND) subjects, with adequate safety and efficacy demonstrated in clinical trials of up to 
24 weeks’ duration.  Both pre-clinical and clinical data show that daprodustat stimulates 
EPO production resulting in increased erythropoiesis and elevation in Hgb 
concentrations.  These increases in Hgb are achieved with peak EPO levels substantially 
lower than those observed with ESAs [Holdstock, 2016].  Data from completed clinical 
and pre-clinical studies are provided in the Daprodustat Investigator Brochure (IB) and 
IB Supplement 01 and 02 [GlaxoSmithKline Document Number RM2008/00267/07, 
GlaxoSmithKline Document Number 2015N266524_00, GlaxoSmithKline Document 
Number 2015N266524_01].
3.
OBJECTIVE(S) AND ENDPOINT(S)
Objectives
Endpoints
Primary

To compare the effect of daprodustat to epoetin 
alfa on blood pressure (BP) after Acute 
Challenge 2 (8 weeks of hemoglobin [Hgb]
maintenance therapy)

Average of systolic blood pressure (SBP) as 
measured by ambulatory blood pressure 
monitoring (ABPM) over 6-hr post-dosing after 
8 weeks of Hgb maintenance therapy
Secondary

To compare the initial effect of daprodustat to 
epoetin alfa on BP after Acute Challenge 1 (2
weeks of erythropoiesis-stimulating agent [ESA]
washout)

Average of SBP, diastolic blood pressure 
(DBP), mean arterial blood pressure (MAP), 
and heart rate (HR) as measured by ABPM 
over 6-hr post-dosing at Day 1

Area under the effect curve (AUEC) of SBP,
DBP, MAP, and HR as measured by ABPM 
over 24-hr post-dosing at Day 1

To compare the effect of daprodustat to epoetin 
alfa on BP after Acute Challenge 2

Average of DBP, MAP, and HR as measured 
by ABPM over 6 hr post-dosing at Day 57.

AUEC of SBP, DBP, MAP, and HR as 
measured by ABPM over 24-hr post-dosing at 
Day 57.

To estimate the initial effect of daprodustat on 
SBP, DBP, HR and MAP after Acute Challenge 
1

Change from pre-dose in SBP, DBP, HR and 
MAP at each timepoint at Day 1

To characterize the pharmacokinetics of 
daprodustat

Plasma concentrations of daprodustat and 
metabolites and derived pharmacokinetic 
parameters including maximum observed 
concentration (Cmax), time of occurrence of 

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Objectives
Endpoints
Cmax (tmax), terminal phase half-life (t½) and 
area under concentration-time curve from time 
zero to 24 hours (AUC[0-24]) as appropriate
Safety

To assess the safety and tolerability of 
daprodustat

Incidence and severity of adverse events (AEs)
and serious adverse events (SAEs)

Reasons for discontinuation of study treatment

Absolute values and changes from baseline 
over time in laboratory parameters, 
electrocardiograms (ECGs) and vital signs
Exploratory

To investigate the effect of daprodustat and 
epoetin alfa on vasoactive mediators of blood 
pressure

Plasma concentrations and derived 
parameters including Cmax, tmax, t½ and 
AUC(0-24) as appropriate (to include 
erythropoietin, endothelin-1, nitric oxide, 
asymmetric dimethylarginine, renin, 
angiotensin-II and metabolites, and 
noradrenalin) 

To summarize the effect of daprodustat and 
epoetin alfa on SBP after Acute Challenge 1 
and Acute Challenge 2

AUEC of SBP as measured by ABPM over 24-
hr post-dosing

To compare the effect of daprodustat to epoetin 
alfa on SBP after 8 weeks of Hgb maintenance 
therapy

Change from Day 1 pre-dose SBP to Day 57
pre-dose

To compare the effect of daprodustat to epoetin 
alfa on SBP at Cmax of each study treatment, 
as measured by ABPM

Change in SBP from pre-dose on Day 1 to 
Cmax of the study treatment on Day 1

Change in SBP from pre-dose on Day 1 to 
Cmax of the study treatment on Day 57

Change in SBP from pre-dose on Day 57 to 
Cmax of the study treatment on Day 57

To compare the effect of daprodustat to epoetin 
alfa on SBP at Cmax of the erythropoietin level, 
as measured by ABPM

Change in SBP from pre-dose on Day 1 to 
Cmax of erythropoietin on Day 1

Change in SBP from pre-dose on Day 1 to 
Cmax of erythropoietin on Day 57

Change in SBP from pre-dose on Day 57 to 
Cmax of erythropoietin on Day 57
4.
STUDY DESIGN
4.1.
Overall Design
This study will be an open-label, randomized, parallel-group design in HD subjects with 
anemia associated with CKD.  There will be a screening period, a 2-week ESA washout 

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period, an initial 24-hr Acute Challenge, an 8-week Hgb-maintenance period, a second
24-hr Acute Challenge and a follow-up visit 14±3 days after completing treatment.  The 
study design is outlined in Figure 1.
Figure 1
Study Design
Subjects will be screened for eligibility within 7-30 days prior to the start of an ESA 
washout period.
Subjects that qualify for enrolment will be washed out of their ESA for 2 weeks; the start 
of the ESA washout should be timed to coincide as closely as possible with their next 
planned ESA dose.  Subjects are enrolled once they enter the ESA washout period.
Following the 2-week ESA washout, subjects will be randomized 1:1 and stratified by 
prior ESA dose, based on the average weekly (for epoetins or darbepoetin) or monthly 
(for methoxy polyethylene glycol (PEG)-epoetin beta) dosing during the 12 weeks prior
to ESA washout as follows:

Low ESA dose: <100 U/kg/week epoetin alfa OR <0.5 µg/kg/week darbepoetin 
OR <0.6 µg/kg/week methoxy PEG-epoetin beta

High ESA dose: ≥100 U/kg/week epoetin alfa OR ≥0.5 µg/kg/week darbepoetin 
OR 0.6 µg/kg/week methoxy PEG-epoetin beta
On Day 1, subjects will be randomized and undergo Acute Challenge 1, a single dose 
challenge to compare the acute effects on BP of the highest planned once-daily 
maintenance dose of daprodustat (24 mg) to the highest starting dose of epoetin alfa 
(100 U/kg).  Subjects will have BP monitored for 24 hr using ABPM, and will have serial 
blood sampling to assess the pharmacokinetics of daprodustat and the time-course of 
various biomarkers.  Acute Challenge 1 will be started promptly following completion of 
a mid-week dialysis session.
After completing Acute Challenge 1, all subjects will enter the 8-week Hgb maintenance 
period where doses of either daprodustat or epoetin alfa will be administered and 
adjusted, as needed, based on dosing guidance as described in Section 6.4.
Week -2: ESA 
Washout
Day 1: Randomize & 
Acute Challenge 1
Day 15, 29 & 43: Dose 
Adjustment (as needed)
Day 57: Acute Challenge 2
Hgb Maintenance Period
Week 10: Follow-up
Screening: Between 7 and 30 
days prior to ESA Washout

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On Day 57, following the 8-week Hgb maintenance period, subjects will undergo Acute 
Challenge 2; this challenge will, similar to Acute Challenge 1, involve assessing the 
effect of daprodustat and epoetin alfa on BP as assessed by 24-hr ABPM measurement.  
The subjects will be administered the same dose of either daprodustat or epoetin alfa that 
was given in Acute Challenge 1, and serial blood sampling will be performed to assess 
daprodustat pharmacokinetics, and to characterize the time course of various biomarkers.  
Acute Challenge 2 will be started following completion of a mid-week dialysis session.
Subjects will attend a follow-up visit 2 weeks after completion of Acute Challenge 2.  
Subjects will be asked to not reinitiate anemia treatment until after the follow-up visit 
unless deemed medically necessary.
After both Acute Challenge 1 and 2, the 24-hr ABPM results will be checked for data 
quality as defined in the Project Requirement Specification (PRS).  If the ABPM fails the 
QC criteria following Acute Challenge 2, one additional Acute Challenge may be made 
after a subsequent, mid-week dialysis visit 1 week later if the subject agrees. At that 
visit, the subject will receive the same study treatment for the repeat Acute Challenge 2 
as was administered on Day 57 as a single additional dose. No additional clinical 
chemistry, hematology, pharmacokinetic or biomarker sampling will be done, however 
all other procedures will be performed as detailed in Table 4. 
The Acute Challenge 2 may be delayed one week if the subject’s Hgb ≥11.5.  See Section 
7.5.1.1 for guidance.
4.2.
Treatment Arms and Duration
The total duration of subject involvement is up to 16 weeks (Screening to Follow-up) as 
described below:

Screening: Screening will occur at least one week prior to but not more than 30 
days prior to washout.

ESA Washout: Subjects that meet eligibility criteria will begin the 2-week ESA 
washout at Week -2.
o
This should be timed such that this day occurs on the date that would have 
been the next scheduled dose of ESA (or as close as practicable).
o
For subjects with a three-times weekly dialysis schedule, this day must not 
occur on the first dialysis session of the week (e.g., if Monday-Wednesday-
Friday schedule, the study visit cannot be on Monday).
o
For subjects with a four- to five-times weekly dialysis schedule, this day can 
be on any hemodialysis session of the week.

Randomization & Acute Challenge 1 (Day 1): Subjects will be randomized 1:1 to 
two treatment arms as described in Table 1 and will begin a 24-hr Acute 
Challenge where the acute BP effects of daprodustat and epoetin alfa will be 

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evaluated.  This challenge will be initiated promptly following the subject’s 
dialysis session.

Hgb Maintenance Period: Subjects randomized to daprodustat will start an 8-week 
Hgb maintenance period based on a starting dose and dose adjustment algorithm 
as described in Section 6.4.1.  Subjects randomized to epoetin alfa will begin an 
8-week Hgb maintenance period where Hgb will be managed in accordance with 
local labelling.

Acute Challenge 2: At the end of the 8-week Hgb maintenance period, subjects 
will repeat the procedures of Acute Challenge 1 utilizing the same treatment 
administered in Acute Challenge 1.  This challenge will be initiated promptly
following the subject’s dialysis session.

Follow-up: A Follow-up visit will be scheduled to occur 14 3 days after 
completing treatment.
Table 1
Treatment Arm Descriptions
Treatment Arm
Acute Challenge 1
Hgb Maintenance Phase
Acute Challenge 2
A
100 U/kg IV epoetin 
alfa
IV epoetin alfa according to label
100 U/kg IV epoetin 
alfa
B
24 mg daprodustat
QD daprodustat according to dose 
adjustment algorithm (Section 6.4.1)
24 mg daprodustat
4.3.
Type and Number of Subjects
The study will enroll hemodialysis-dependent subjects with anemia associated with CKD 
currently treated with an ESA.  Subjects with Hgb values of 8.5 to 11.5 g/dL, inclusive at 
both Screening and Day 1, are eligible, and the subjects must currently be on an ESA 
product.
Approximately 124 subjects will be screened to achieve approximately 62 randomized 
and 50 evaluable subjects for a total of 25 evaluable subjects per treatment group.
If subjects prematurely discontinue the study, additional replacement subjects may be 
randomized and assigned to the same treatment arm at the discretion of the Sponsor in 
consultation with the investigator.
4.4.
Design Justification
This study will be an open-label, multi-center, randomized, parallel-group design in HD 
subjects with anemia associated with CKD.  There will be a screening period, a 2-week 
ESA washout period, an initial 24-hour Acute Challenge, an 8-week Hgb-maintenance 
period, a second 24-hr Acute Challenge, and a follow-up visit 14 ± 3 days after 
completing treatment.

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
This will be an open-label study since the primary endpoint (SBP by ABPM) is an 
objective measure and unlikely to be influenced by knowledge of the treatment 
received.  Additionally, blinding of an injectable comparator and oral study drug 
is impractical in this case.

A screening period will be used to assess Hgb stability in order to minimize the 
potential for enrolling patients with highly variable Hgb despite ESA treatment.

In our previous daprodustat study experience in Phase 2b, HD-dependent subjects 
with anemia associated with CKD were administered placebo for 4 weeks, with a 
mean decrease between 0.61 and 0.72 g/dL in Hgb.  No subject met either the 
Hgb stopping criterion or requiring rescue medication.  Therefore, the risk of a 
subject meeting Hgb withdrawal criteria is considered low during this phase.

The Acute Challenge days have been designed to be consistent with the 
methodology used in a published study [Kang, 1998] (See Figure 2).  Although 
the goal of the current study is to attempt to replicate the blood pressure results 
from the IV administration of epoetin alfa in that publication, SBP will be the 
primary endpoint rather than MAP since SBP is the overall best predictor of 
future cardiovascular risk in a hypertensive population, and MAP is biased toward 
DBP [Agarwal, 2015].

Acute Challenge 1 will assess whether there are any immediate effects of 
daprodustat or epoetin alfa on blood pressure.  This assessment will also 
determine the ability to replicate the findings in the published study and will 
provide information for an interim analysis (See Section 9.3.2).

The 8-week Hgb Maintenance Phase will replicate the management procedures 
planned for the Phase 3 studies as described in Section 6.4.  The duration was 
chosen to be consistent with the timeframe in which the hypertensive effects of 
ESAs have been observed (i.e., 4 to 8 weeks) [Samtleben,1988].

Acute Challenge 2 will again assess the effects of daprodustat or epoetin alfa on 
BP following 8 weeks of anemia treatment utilizing the same assessment as Acute 
Challenge 1. The purpose of Acute Challenge 2 is to assess any BP effects of 
ESA administration that may be potentiated (or possibly diminished) following 
long-term administration of an ESA.

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Figure 2
Changes in MAP after administration of rhEPO (rHuEPO) and control
Values are mean ± SD; *P<0.05 vs. Post-HD [Kang, 1998]
4.5.
Dose Justification
Daprodustat Treatment Group

Acute Challenge 1 & 2: The dose to be used for this group will be the highest planned 
maintenance dose for a once-daily regimen (i.e., 24 mg) for treatment of anemia 
associated with CKD.  In a previous GlaxoSmithKline (GSK) study (PHI112843), a 
single, oral dose of 150 mg daprodustat was administered to dialysis patients with no 
safety issues identified.  For Acute Challenge 2, stringent Hgb stopping criteria and 
dose hold have been defined at Day 57 to minimize marked increases in Hgb.

Hgb Maintenance Phase: Starting doses of daprodustat will be based on Hgb levels, 
as described in Section 6.4.1.  These doses have been chosen to minimize the 
potential for subjects to meet Hgb stopping criteria during the initial dosing period 
prior to the first dose adjustment, and are based on modelling and simulation of the 
dose-Hgb response results from Phase 2 studies.  
Epoetin alfa Treatment Group

Acute Challenge 1 & 2: The dose to be used for this group will be the highest labelled 
starting dose for epoetin alfa (100 U/kg, IV) which is consistent with the epoetin alfa 
dose used in the published study where an acute increase in MAP with rhEPO was 
observed [Kang, 1998].  As subjects in this group will have been washed off ESA for 
2 weeks prior to Acute Challenge 1 and only a single dose will be administered, the 
risk of a marked increase in Hgb levels is considered very low.  For Acute Challenge 
2, stringent Hgb-based stopping criteria and dose hold have been defined at Day 57 to 
minimize marked increases in Hgb (See Table 2).

Hgb Maintenance Phase: The dosage of epoetin alfa during the 8-week Hgb 

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maintenance phase will be adjusted (if necessary) according to the local labelling in 
order to manage the subject’s Hgb within the target range (10.0-11.0 g/dL). In a 
previous study (GSK Study PHI113633), HD subjects that had a 4-week ESA 
washout were initiated on a mean dose of rhEPO of 89 IU/kg/week (n=39), with the 
dose increased to a mean of 102 IU/kg/week 4 weeks later.
4.6.
Benefit:Risk Assessment
Summaries of findings from both clinical and non-clinical studies conducted with 
daprodustat can be found in the Daprodustat Investigator’s Brochure (IB) and IB 
Supplements, if applicable.
4.6.1.
Risk Assessment
The potential risks of clinical significance including AEs of special interest (Section 
7.3.1.4), and the mitigation strategies for this protocol taking into account the results of 
clinical and non-clinical studies with daprodustat, are outlined in Section 12.3.
4.6.2.
Benefit Assessment
In clinical trials of up to 24 weeks in duration, in subjects with anemia associated with 
CKD, daprodustat has been shown to treat Hgb to target range.  Data from prior studies 
with daprodustat suggest that the increases in Hgb are achieved with EPO exposure lower 
than those observed with rhEPO.
4.6.3.
Overall Benefit:Risk Conclusion
Daprodustat demonstrates a positive benefit vs. risk based on the evidence as follows.  In 
clinical trials up to 24 weeks in duration, daprodustat maintained Hgb to target range in 
subjects with anemia associated with CKD (both ND and HD) with a safety profile 
consistent with the patient population.
This protocol employs precautions to mitigate known and potential risks to enrolled 
subjects (See Section 12.3).  Given these precautions, as well as the potential benefit that 
daprodustat holds for the treatment of anemia associated with CKD compared to the 
current standard, the overall benefit risk balance is considered to be positive.
5.
SELECTION OF STUDY POPULATION AND 
WITHDRAWAL CRITERIA
Specific information regarding warnings, precautions, contraindications, adverse events, 
and other pertinent information on daprodustat that may impact subject eligibility is 
provided in the Daprodustat Investigator’s Brochure and IB Supplements, if applicable.
Deviations from inclusion and exclusion criteria are not allowed because they can 
potentially jeopardize subject safety, the scientific integrity of the study, or regulatory 
acceptability.  Adherence to the criteria as specified in the protocol is essential.

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5.1.
Hemoglobin Stability Criteria
Entry into the study requires a stable Hgb between 8.5 and 11.5 g/dL, inclusive.  This is 
confirmed from two Hgb values obtained at the Screening Visit and Washout Visit, with 
both values between 8.5 and 11.5 g/dL.  These will be taken via a validated point-of-care 
device to measure Hgb (i.e., HemoCue) prior to the dialysis session of the day.  The value 
at the Washout Visit must not have decreased by more than 1.0 g/dL from the Screening 
Visit value. For subjects with a three-times weekly dialysis schedule, Hgb values must 
not be obtained on the first dialysis session of the week (e.g., if Monday-Wednesday-
Friday schedule, the study visit cannot be on Monday).  For subjects with a four- to five-
times weekly dialysis schedule, Hgb values can be obtained on any hemodialysis session 
of the week.
5.2.
Inclusion Criteria
A subject will be eligible for inclusion in this study only if all of the following criteria 
apply:
AGE
1. ≥40 years of age, at the time of signing the informed consent.
TYPE OF SUBJECT AND DIAGNOSIS INCLUDING DISEASE SEVERITY
2. Hemoglobin: Stable Hgb 8.5 to 11.5 g/dL inclusive (See Section 5.1).
3. Dialysis frequency: On hemodialysis (HD, hemofiltration or hemodiafiltration) 
three-to five-times weekly for at least 4 weeks prior to screening.
4. Dialysis adequacy: A single pool Kt/Vurea 1.2 based on a historical value obtained 
within the 3 months prior to screening in order to ensure the adequacy of dialysis.  If 
Kt/Vurea is not available, then an average of the last 2 values of urea reduction ratio 
(URR) is at least 65%.  NOTE: Only needs confirming at screening.
5. ESA treatment: Treated with an ESA (epoetins or their biosimilars, darbepoetin, or 
methoxy PEG-epoetin beta) for at least 4 weeks prior to screening.
6. Iron replacement therapy: Subjects may be on stable (≤50% change in overall dose 
and compliance of 80% of prescribed doses in the 4 weeks prior to and including the 
screening period) maintenance oral or IV (≤100 mg/week) iron supplementation.  If 
subjects are on oral or IV iron, then doses must be stable for the 4 weeks prior to 
Washout.
7. Weight:  Mid-week weight change between dialysis treatments <5% as assessed 
post-dialysis at the Screening and Washout visits.
8. Antihypertensive Medication: Meets the following criteria:

On at least 1 antihypertensive medication [excluding diuretics]
AND

On that same medication and the same dose for at least 1 week prior to Washout

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INFORMED CONSENT
9. Capable of giving signed informed consent as described in Section 10.2 which 
includes compliance with the requirements and restrictions listed in the consent form 
and in this protocol.
10. Willing and able to wear ABPM device for at least 25 hours on two separate 
sessions.
5.3.
Exclusion Criteria
A subject will not be eligible for inclusion in this study if any of the following criteria 
apply:
CKD-RELATED CRITERIA
1. Dialysis modality: Planned change from HD to peritoneal dialysis within the study 
time period, or on home dialysis.
2. Renal transplant: Planned kidney transplant within the 16 weeks following the 
Screening visit.
3. High ESA dose: An epoetin alfa dose of ≥360 U/kg/week IV or ≥250 U/kg/week 
subcutaneous (SC), or darbepoetin dose of ≥1.8 µg/kg/week IV or SC, or methoxy 
PEG-epoetin beta dose of 2.2 µg/kg/week within the 8 weeks prior to screening 
through Week -4.
4. Mircera: Planned or recorded administration of Mircera (methoxy PEG-epoetin beta) 
within the 4 weeks prior to the Washout visit.
CARDIOVASCULAR DISEASE-RELATED CRITERIA
5. Myocardial infarction or acute coronary syndrome: Within the 3 months prior to 
Washout.
6. Stroke or transient ischemic attack: Within the 3 months prior to Washout.
7. Heart failure: Chronic Class IV heart failure (HF), as defined by the New York 
Heart Association (NYHA) functional classification system diagnosed prior to 
Washout.
8. QT interval corrected for heart rate using Bazett’s formula (QTcB): QTcB >500 
msec, or QTcB >530 msec in subjects with Bundle Branch Block.  There is no QTc 
exclusion for subjects with a predominantly paced rhythm.
9. Current uncontrolled hypertension: Resting post dialysis systolic blood pressure 
>160 mmHg; or diastolic blood pressure >100 mmHg at screening or uncontrolled 
hypertension as determined by the investigator.
10. Atrial Fibrillation: Presence of atrial fibrillation.
OTHER DISEASE-RELATED CRITERIA
11. Inflammatory disease: Active chronic inflammatory disease that could impact 
erythropoiesis (e.g., scleroderma, systemic lupus erythematosus, rheumatoid arthritis, 
celiac disease) diagnosed prior to Washout.
12. Aplasias: History of bone marrow aplasia or pure red cell aplasia.
13. Other causes of anemia: Pernicious anemia, thalassemia major, sickle cell disease or 

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myelodysplastic syndrome.
14. Liver disease (any one of the following):

Alanine transaminase (ALT) >2x upper limit of normal (ULN) (screening only)

Bilirubin >1.5xULN (screening only)
NOTE: Isolated bilirubin >1.5xULN is acceptable to keep in the study if bilirubin 
is fractionated and direct bilirubin <35%.

Current unstable liver or biliary disease per investigator assessment, generally 
defined by the presence of ascites, encephalopathy, coagulopathy, 
hypoalbuminaemia, esophageal or gastric varices, persistent jaundice, or cirrhosis.
NOTE: Stable chronic liver disease (including asymptomatic gallstones, chronic 
hepatitis B or C, or Gilbert’s syndrome) are acceptable if subject otherwise meets 
entry criteria.
15. Major surgery: Major surgery (excluding vascular access surgery) within the 3
months prior to Washout or planned during the study.
16. Transfusion: Blood transfusion within the 8 weeks prior to Washout, or an 
anticipated need for blood transfusion during the study.
17. Gastrointestinal (GI) bleeding: Evidence of actively bleeding gastric, duodenal, or 
esophageal ulcer disease OR clinically significant GI bleeding within the 8 weeks
prior to Washout.
18. Acute Infection: Clinical evidence of acute infection or history of infection requiring 
intravenous (IV) antibiotic therapy within the 8 weeks prior to Washout.
NOTE: IV antibiotics as prophylaxis are allowed.
19. Malignancy: History of malignancy within the two years prior to screening through 
Day 1 or currently receiving treatment for cancer, or has a known complex kidney 
cyst (e.g., Bosniak Category IIF, III or IV) 3 cm.
NOTE: ONLY exception is localized squamous cell or basal cell carcinoma of the 
skin that has been definitively treated more than 4 weeks prior to screening.
20. Blood Pressure Measurement: Subjects with an upper arm diameter which cannot 
be measured by oscillometer/ sphygmomanometer cuff OR for whom blood pressure 
cannot be measured in the opposite arm of current vascular access.
CONCOMITANT MEDICATIONS
21. Severe allergic reactions: History of severe allergic or anaphylactic reactions or 
hypersensitivity to excipients in the investigational product.
22. Drugs and supplements: Use of any prescription or non-prescription drugs or 
dietary supplements that are prohibited (See Section 6.11.3), from screening until 
Washout.
23. Prior investigational product exposure: The subject has participated in a clinical 
trial and has received an experimental investigational product within the 30 days prior 
to Day 1 or within 5 half lives of the investigational product prior to screening, 
whichever is longer.

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GENERAL HEALTH RELATED CRITERIA
24. Other conditions: Any other condition, clinical or laboratory abnormality, or 
examination finding that the investigator considers would put the subject at 
unacceptable risk, which may affect study compliance or prevent understanding of the 
aims or investigational procedures or possible consequences of the study.
25. Females ONLY: Subject is pregnant [as confirmed by a positive serum human 
chorionic gonadotrophin (hCG) test for females of reproductive potential (FRP) 
only], subject is breastfeeding, or subject is of reproductive potential and does not 
agree to follow one of the contraceptive options listed in the List of Highly Effective 
Methods for Avoiding Pregnancy in Section 12.4.7.
DIAGNOSTIC ASSESSMENTS AND OTHER CRITERIA
26. Vitamin B12: At or below the lower limit of the reference range (may rescreen in a 
minimum of 8 weeks, following treatment).
27. Folate: <2.0 ng/mL (4.5 nmol/L) (may rescreen in a minimum of 4 weeks, following 
treatment).
28. Ferritin: <100 ng/mL
29. Transferrin saturation (TSAT): <20%.
5.4.
Screening/Baseline/Run-in Failures
Screen failures are defined as subjects who consent to participate in the clinical trial but 
who never enter the washout period.  In order to ensure transparent reporting of screen 
failure subjects, meet the Consolidated Standards of Reporting Trials (CONSORT) 
publishing requirements, and respond to queries from Regulatory authorities, a minimal 
set of screen failure information is required including Demography, Screen Failure 
details, Eligibility Criteria, and Serious Adverse Events (see Section 7.3.1.6).
5.5.
Withdrawal/Stopping Criteria
A subject 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 or 
administrative reasons.  If a subject withdraws from the study, he/she may request 
destruction of any samples taken, and the investigator must document this in the site 
study records.
If a decision is made to withdraw a subject, he/she should return to the clinic as soon as 
possible to complete the Early Withdrawal assessments.  The Follow-up visit should be 
performed 14 ± 3 days after last dose (see Time and Events Table Section 7.1).
In all cases, the reason for withdrawal from the study and date of the last dose of study 
treatment will be recorded in the eCRF.
5.5.1.
Criteria for Permanent Discontinuation from Study Treatment and 
Early Withdrawal
Subjects must permanently discontinue study treatment and be withdrawn from the 
study for the following reasons:

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
Meets Hgb stopping criteria (See Section 5.5.1.1)

Receives a blood transfusion

Receives a kidney transplant

Becomes pregnant or intends to become pregnant during the study

Active GI bleeding

Diagnosis of cancer, with the exception of squamous cell or basal cell carcinoma

Liver chemistry abnormalities exceeding the threshold criteria (See Section 5.5.3)

Misses 2 consecutive dialysis sessions

Use of prohibited medication (See Section 6.11.3)

Myocardial infarction or acute coronary syndrome

Stroke or transient ischemic attack

New diagnosis of Class IV heart failure, as defined by the New York Heart 
Association (NYHA) functional classification system

Active chronic inflammatory disease that could impact erythropoiesis

Any new diagnosis of hematological disease including those affecting platelets, 
white or red blood cells, coagulation disorders, or any other cause of anemia of
chronic disease other than renal disease
5.5.1.1.
Hemoglobin Stopping Criteria
GSK will supply a point-of-care Hgb analyzer (HemoCue) to each site for rapid and 
convenient monitoring of Hgb levels and to ensure consistency of Hgb measurements 
across sites participating in the study.
Blood samples for measurement of Hgb concentrations via HemoCue will be collected 
(Table 2) and recorded in the eCRF.  The table below summarizes the Hgb values and 
corresponding action to be taken at each visit. If the subject meets the below condition(s), 
then IP must be permanently stopped.

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Table 2
Hgb Stopping Criteria
Day 1 (Prior to Acute Challenge 1)
Hgb at Visit
Action
<7.5
Repeat HemoCue assessment on the same sample at same study visit to confirm; take average of 2 
values.  If confirmed, withdraw subject from the study.
7.5-<11.5
decrease of 2.0 in Hgb 
over 2 weeks
Repeat HemoCue assessment on the same sample at same study visit 
to confirm; take average of 2 values.  If confirmed, permanently 
withdraw subject from the study.
11.5
Repeat HemoCue assessment on the same sample at same study visit to confirm; take average of 2 
values.  If confirmed, avoid dosing and continue washout for one additional week.  Progress with 
Acute Challenge 1 one week later if Hgb has decreased below 11.5; if not then withdraw subject from 
study.
Days 15, 29, & 43
Hgb at Visit
Action
<7.5
Repeat HemoCue assessment on the same sample at same study visit to confirm; take average of 2 
values.  If confirmed, permanently discontinue study treatment and withdraw subject from the study.
7.5-<12.0
decrease of 2.0 in Hgb 
over 2 weeks
Repeat HemoCue assessment on the same sample at same study visit 
to confirm; take average of 2 values.  If confirmed, permanently 
discontinue study treatment and withdraw subject from the study.
Day 57 (Prior to Acute Challenge 2)
Hgb at Visit
Action
<7.5
Repeat HemoCue assessment on the same sample at same study visit to confirm; take average of 2 
values.  If confirmed, permanently discontinue study treatment and withdraw subject from the study.
7.5-<11.5
decrease of 2.0 in Hgb 
over 2 weeks
Repeat HemoCue assessment on the same sample at same study visit 
to confirm; take average of 2 values.  If confirmed, permanently
discontinue study treatment and withdraw subject from the study.
11.5
Repeat HemoCue assessment on the same sample at same study visit to confirm; take average of 2 
values.  If confirmed, HOLD the dose for 1 week and progress with Acute Challenge 2 one week 
later. If Hgb remains above 11.5 one week later, then withdraw subject from the study.
5.5.2.
Missed Clinic Visits/Lost to Follow-up
The following actions must be taken when a subject fails to attend the clinic for a 
required study visit:

The site must attempt to contact the subject and re-schedule the missed visit as 
soon as possible.

The site must counsel the subject on the importance of maintaining the assigned 
visit schedule and ascertain whether or not the subject wishes to and/or should 
continue in the study.

In cases where the subject is deemed ‘lost to follow up’, the investigator or 
designee must make every effort to regain contact with the subject (where 
possible, 3 telephone calls and if necessary a certified letter to the subject’s last 
known mailing address or local equivalent methods).  These contact attempts 
should be documented in the subject’s medical record.

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
Should the subject continue to be unreachable, only then will he/she be considered 
to have withdrawn from the study with a primary reason of “Lost to Follow-up”.
5.5.3.
Liver Chemistry Stopping Criteria
Liver chemistry stopping and increased monitoring criteria have been designed to 
assure subject safety and evaluate liver event etiology (in alignment with the Food and 
Drug Administration [FDA] premarketing clinical liver safety guidance). 
Discontinuation of study intervention for abnormal liver tests is required when:

a participant meets one of the conditions outlined in the algorithm below.

when in the presence of abnormal liver chemistries not meeting protocol-specified 
stopping rules, the investigator believes study intervention discontinuation is in 
the best interest of the participant. 
Phase II Liver Chemistry Stopping and Increased Monitoring Algorithm
Continue Study Treatment 
Discontinue Study Treatment 
Plus
Bilirubin≥2x
ULN (>35% 
direct) 
or plus
INR>1.5, if 
measured*
Possible
Hy’s Law
ALT≥3xULN
ALT≥5xULN
ALT≥3xULN
Plus
Symptoms of 
liver injury
or 
hypersensitivity
ALT≥3xULN
but able to 
monitor 
weekly for 
4 weeks
No
Yes
Yes
Yes
Yes
No
No
No
No
Yes
ALT≥3xULN
persist for
4 weeks or 
stopping 
criteria 
met
Yes
No
*INR value not applicable to subjects on anticoagulants
Yes
If subject to be monitored weekly must refer to Liver Safety Required  Actions and  Follow  up 
Assessments  section  in  the  Appendix
Must refer to Liver Safety Required Actions and Follow  up Assessments section in the Appendix
Report as an SAE if possible Hy’s Law case: ALT≥3xULN and  Bilirubin≥2xULN (>35% direct)  or 
INR>1.5, if measured*
Liver Safety Required Actions and Follow up Assessments Section can be found in 
Section 12.2.
5.5.3.1.
Study Treatment Restart or Rechallenge
Study treatment restart or rechallenge after liver chemistry stopping criteria are met by 
any subject participating in this study is not allowed.

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5.6.
Subject and Study Completion
A completed subject is one who has completed all phases of the study including the 
Follow-up visit.
The end of the study is defined as the last subject’s last visit.
6.
STUDY TREATMENT
6.1.
Investigational Product and Other Study Treatment
The term ‘study treatment’ is used throughout the protocol to describe any combination 
of products received by the subject as per the protocol design.  Study treatment may 
therefore refer to the individual study treatments or the combination of those study 
treatments.
Product name:
Daprodustat
Dosage form:
Tablet
Unit dose strength(s)/Dosage level(s):
1 mg, 2 mg, 4 mg, 6 mg, 8 mg, 10 mg tablet strengths/1 mg, 2 mg, 4 mg, 
6 mg, 10 mg, 12 mg & 24 mg dosage levels
Route of Administration
Oral
Physical description:
1 mg, 2 mg & 4 mg tablets: 7.0 mm round, compound radius, white film 
coated tablets
6 mg, 8 mg & 10 mg tablets: 9.0 mm round, compound radius, white film 
coated tablets
Method for individualizing dosage:
See Section 6.4.1
For a description of epoetin alfa, please consult the local label.
All eligible subjects will discontinue their current ESA therapy and will undergo a 2-
week ESA washout period.  Following washout, subjects will be randomized to receive 
either daprodustat or epoetin alfa, on a dialysis day.  For subjects with a three-time 
weekly dialysis schedule, randomization must not occur on the first dialysis session of the 
week (e.g., if Monday-Wednesday-Friday schedule, the study visit cannot be on 
Monday).  For subjects with a four to five times weekly dialysis schedule, randomization 
can be on any hemodialysis session of the week.
Subjects can take their tablets without regard to food.  For all study visits, it is 
recommended for subjects not to eat a heavy meal before coming to the clinic in order to 
avoid lipemia of the blood sample collected for the analysis of transferrin, iron and total 
iron binding capacity (TIBC).
6.2.
Treatment Assignment
Subjects will be stratified by prior ESA dose (as outlined in Section 4.1) and randomized 
1:1 to receive open-label oral daprodustat or IV epoetin alfa.  A central randomization 
approach will be used due to the small sample size and to protect against potential 
selection bias due to the open-label design.  Once a randomization number has been 
assigned by an Interactive Voice/Web Response System (IVWRS) at time of 
Randomization, it must not be re-assigned.

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Subjects will be assigned to study medication in accordance with the randomization 
schedule generated by Clinical Statistics, prior to the start of the study, using validated 
internal software.
6.3.
Blinding
This will be an open-label study.  However, there are no plans to generate any aggregated 
unblinded summaries during the conduct of the study.
6.4.
Starting Dose and Dose Adjustment Algorithm
6.4.1.
Subjects Randomized to Daprodustat
Subjects randomized to daprodustat will have doses adjusted, as required, to target Hgb 
within the range of 10.0-11.0 g/dL.  Dose adjustments will be assigned automatically via 
the IVWRS based on the subject’s Hgb value via onsite HemoCue assessment according 
to the following algorithms:
Day 1 (HemoCue Prior to Acute Challenge 1)
Hgb (g/dL)
Action or Dose
<7.5
Repeat HemoCue assessment on the same sample at same study visit to confirm; take 
average of 2 values.  If confirmed, withdraw subject from the study.
7.5 and <10.0
6 mg daprodustat
10.0 and <11.5
4 mg daprodustat
11.5
Repeat HemoCue assessment on the same sample at same study visit to confirm; take 
average of 2 values.  If confirmed, avoid dosing and continue washout for one additional week.  
If Hgb remains above 11.5 then withdraw subject from study.
The 8 week Hgb maintenance dosing will begin on Day 2, following Acute Challenge 1.
Acute Challenge dosing is the same for all subjects on the daprodustat arm: 24 mg.
Days 15, 29, 43, & 57
The available dose steps for daprodustat are outlined below (highlighted boxes indicate 
starting doses).  Dose adjustments will result in the daprodustat dose being increased or 
decreased by one dose step.
Hgb (g/dL)
Hgb change since
previous study visit
Dose Adjustment
<7.5
Any change
Repeat HemoCue assessment on the same sample at same study 
visit to confirm; take average of 2 values.  If confirmed, permanently 
discontinue study drug and withdraw subject from the study.
7.5 to <9.5
Decreasing or No change1
Increase to the next higher dose step
7.5 to <9.5
Increasing2
Maintain dose

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9.5 to ≤11.5
Any change
Maintain dose
>11.5 to <12.0
Increasing or No change
Decrease to the next lower dose step
Decreasing
Maintain dose
≥12.0
Any change
Repeat HemoCue assessment on the same sample at same study 
visit to confirm; take average of 2 values.  If confirmed, HOLD dosing 
for 2 weeks until next study visit.3
7.5 to <12.0
increase of 1.3 in Hgb 
over 2 weeks4
Repeat HemoCue assessment on the same sample at same study 
visit to confirm; take average of 2 values. If confirmed, decrease to 
next lower dose step,
7.5 to <12.0
Increase of > 2.0 in Hgb 
over previous 4 weeks 
(Days 29, 43, 574 only)
Repeat HemoCue assessment on the same sample at same study 
visit to confirm; take average of 2 values. If confirmed, decrease to 
next lower dose step,
1No change is defined as an increase < 0.5 g/dL
2Increase is defined as an increase ≥ 0.5 g/dL
3 If Hgb remains ≥12.0 at next visit, the subject should be withdrawn from the study.  If the Hgb drops below 12.0, the 
subject should be restarted on the next lowest dose.
4 Only applies at Day 57 if a repeat AC2 is necessary.  The dose should be decreased for the 1 week between AC2 
and Additional AC2.
6.4.2.
Subjects Randomized to Epoetin Alfa
Subjects randomized to epoetin alfa will be administered according to local labelling and 
clinical practice guidelines to keep Hgb in the target range (10.0-11.0 g/dL).  For 
additional guidance on Hgb-based stopping criteria please refer to Section 5.5.1.1.
6.5.
Packaging and Labeling
Daprodustat tablets are packed in white, opaque high density polyethylene (HDPE) 
bottles with child-resistant closures.  The contents of the label will be in accordance with 
all applicable regulatory requirements.
6.6.
Preparation/Handling/Storage/Accountability
No special preparation of study treatment is required.

Only subjects 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 final disposition of unused study treatment 
are provided in the Study Reference Manual (SRM).

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
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.
6.7.
Compliance with Study Treatment Administration
For subjects randomized to daprodustat, treatment dosing details including dates for dose 
increases/reductions, will be recorded in RAMOS NG.
For subjects randomized to daprodustat, for Acute Challenge 1 and 2, study site 
personnel will confirm compliance.  When daprodustat is administered at home (Hgb 
maintenance period), subjects will be instructed to return all unused randomized 
treatment at each clinic visit.  A record of the number of daprodustat tablets dispensed to 
and taken by each subject will be maintained and reconciled with randomized treatment 
and compliance records.
For subjects randomized to epoetin alfa, they will receive all study treatment directly 
from the investigator or designee, under medical supervision.  The date and time of each 
dose administered in the clinic will be recorded in the source documents.  The dose of 
study treatment and study subject identification will be confirmed at the time of dosing 
by a member of the study site staff other than the person administering the study 
treatment.
6.8.
Treatment of Study Treatment Overdose
There is no specific antidote for overdose with daprodustat.  The expected manifestations 
of daprodustat overdosage include signs and symptoms associated with an excessive 
and/or rapid increase in Hgb concentration.  Daprodustat is highly protein bound; thus, 
clearance of daprodustat by HD is very low and this is not an effective method to enhance 
the elimination of daprodustat.  Daprodustat metabolites are, in part, cleared via 
hemodialysis.  In the event of a suspected overdose, it is recommended that the 
appropriate supportive clinical care be instituted, as dictated by the subject’s clinical 
status.  Additionally, subjects should be monitored closely for CV events, increased heart 
rate and hematologic abnormalities.
Consult the approved product label for information on overdose for epoetin alfa.
6.9.
Treatment after the End of the Study
Subjects will not receive any additional treatment from GSK after completion of the 
study because the indication being studied is not life threatening or seriously debilitating 
and other treatment options are available.
The investigator is responsible for ensuring that consideration has been given to the post-
study care of the subject’s medical condition.

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6.10.
Lifestyle and/or Dietary Restrictions
6.10.1.
Meals and Dietary Restrictions
Daprodustat can be taken without regard to meals.
All subjects will be instructed to limit caffeine- or xanthine- containing products (e.g., 
coffee, tea, cola drinks, chocolate) for 24h prior to both Acute Challenge 1 and Acute 
Challenge 2.  
6.11.
Concomitant Medications and Non-Drug Therapies
Concomitant medications, including over-the-counter medications and supplements, 
taken during the study will be recorded in the eCRF.  Start/stop dates and route of 
administration will be recorded for general concomitant medications.
6.11.1.
Weight and Antihypertensive Medication Changes
It is preferred that changes to subject weight and antihypertensive medication(s) are not 
made while the subject is part of this study, however, subjects should remain in the study 
regardless of any changes.  All medication and dose changes should be recorded in the 
eCRF.
6.11.2.
Permitted Medications and Non-Drug Therapies
Unless specified as a prohibited medication in Section 6.11.3, all concomitant 
medications should be considered permitted provided they are not contraindicated for the 
individual subject concerned.
6.11.3.
Prohibited Medications and Non-Drug Therapies
Use of any of the following prescription drugs from Screening until 7 days after the last 
dose of randomized treatment is prohibited and will constitute a protocol violation.

Strong inhibitors of CYP2C8 (e.g., gemfibrozil, high dose clopidogrel [300 mg])

Strong inducers of CYP2C8 (e.g., rifampin/rifampicin)
6.11.4.
Standard of Care
During the study, investigators are expected to monitor the subject’s overall clinical 
status to ensure standards of care are met to enable consistency of practice with Kidney 
Disease Improving Global Outcomes (KDIGO) guidelines or local equivalent.
6.11.5.
Iron Protocol
Subjects must remain iron replete throughout the study.  If ferritin and TSAT are 
collected per local clinical practice while enrolled, the following is recommended.
Iron therapy will be administered if ferritin is ≤100 ng/mL and/or TSAT is ≤20%.  The 
investigator should choose the route of administration and dose of iron based on subject’s 
iron status and local clinical practice.  
All iron (excluding multivitamins) must be stopped and cannot be administered if:

Ferritin >800 ng/mL AND TSAT >20% OR

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
TSAT >40%
7.
STUDY ASSESSMENTS AND PROCEDURES
Protocol waivers or exemptions are not allowed with the exception of immediate safety 
concerns.  Therefore, adherence to the study design requirements, including those 
specified in the Time and Events Table (Section 7.1), are essential and required for study 
conduct.

If assessments are scheduled for the same nominal time, then the assessments 
should occur in the following order:
1. 12-lead ECG
2. vital signs
3. blood draws
Note: The timing of the assessments should allow the blood draw to occur at the 
exact nominal time.

The change in timing or addition of time points for any planned study 
assessments must be documented in a Note to File which is approved by the 
relevant GSK study team member and then archived in the study sponsor and 
site study files, but this will not constitute a protocol amendment.

The Institutional Review Board (IRB)/ Independent Ethics Committee (IEC)
will be informed of any safety issues that require alteration of the safety 
monitoring scheme or amendment of the Informed Consent Form.

No more than 550 mL of blood will be collected over the duration of the study, 
including any extra assessments that may be required.
Supplementary study conduct information is provided in the SRM.  The SRM provides 
administrative and detailed technical information that does not impact subject safety.

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7.1.
Time and Events Table
Table 3
Study Procedures and Assessments
Procedure1
Screening
Washout
Treatment Period2
Follow-up2
Day 1
Day 15
Day 29
Day 43
Day 57
Early WD
Week 10
Informed Consent
X
Entry Criteria
X
Physical, Medical History, Demography
X
HemoCue Hgb
X
X
X4
X
X
X
X4
X
X
Enrolment
X
IVWRS 
X
X
X
X
Randomization
X
Acute Challenge
X4
X4
ABPM Assessment
X4
X4
Dose Adjustment
X
X
X
Females Only: Serum Pregnancy Test
X
X
X
X
X
Females Only: Estradiol & FSH (if required)3
X
ECG
X
X4
X4
X
Vital signs & weight (Pre- & Post-dialysis)
X
X
X4
X
X4
X
Clinical Chemistry
X
X
X
X
X
Hematology
X
X
X
X
X
Folate and Vitamin B12
X
Ferritin, transferrin, total iron, TSAT, UIBC
X
Pharmacokinetic/Biomarker Assessments
X4
X4
Hgb Maintenance Period5
=======================================
Adverse Events Assessment
X6
X
X4
X
X
X
X4
X
Review Concomitant Medications
X
X
X4
X
X
X
X4
X
1 All assessments should be done predialysis/predose except as noted.
2 Allowable time window 2 days EXCEPT Follow-up Visit which is 3 days.
3 As detailed in Inclusion Criteria.
4 Detailed timings for assessments on Acute Challenge Days are given in Table 4.
5 From the end of Acute Challenge 1 to the beginning of Acute Challenge 2.
6 Only SAEs assessed as related to study participation are collected at this visit. See Section 12.4 for additional details.

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Table 4
Study Procedures and Assessments on Acute Challenge Days (Treatment Period Day 1 and Day 57)
Procedure
Pre-
Dialysis
Post-
Dialysis Predose
Time (in hours relative to dosing)
0
0.5
1
2
3
4
6
8
12
16
24
HemoCue Hgb1
X
X
IVWRS
X
ABPM Assessment1, 3
===========================================================================================
Administer Study Treatment1
X
Serum Pregnancy Test1
X
ECG1
X
X
Vital Signs and Weight1
X
X
X
X
X
Clinical Chemistry
X
Hematology
X
Pharmacokinetics4
X
X
X
X
X
X
X
X
X
X
X
Erythropoietin
X
X
X
X
X
X
X
X
X
X
X
Endothelin-1
X
X
X
X
X
X
X
Nitric Oxide
X
X
X
X
X
X
X
Asymmetric dimethylarginine
X
X
X
X
X
X
X
Renin
X
X
X
X
X
X
X
Angiotensin-II
X
X
X
X
X
X
X
Noradrenalin
X
X
X
X
X
X
X
Adverse Events Assessment1
X
X
X
X
X
X
X
X
X
X
X
Review Concomitant Medications1
X
X
Initiate Hgb maintenance dosing2
X
1 Procedures to be repeated if Acute Challenge 2 fails quality control criteria (For more detail refer to Section 7.5.1)
2 Applies to Acute Challenge 1 only
3 Timing of ABPM measurements does not correlate with specified time points in Table 4.
4 PK to be drawn from daprodustat subjects only.

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7.2.
Screening and Critical Baseline Assessments
Medical history, including cardiovascular disease and associated risk factors, (as detailed 
in the eCRF) will be assessed at screening.
The following demographic parameters will be captured: year of birth, sex, race and 
ethnicity.
Medical/medication/family history will be assessed as related to the inclusion/exclusion 
criteria listed in Section 5.
7.3.
Safety
7.3.1.
Adverse Events (AE) and Serious Adverse Events (SAEs)
The definitions of an AE or SAE can be found in Section 12.4.
The investigator and their designees are responsible for detecting, documenting and 
reporting events that meet the definition of an AE or SAE.
7.3.1.1.
Time Period and Frequency for Collecting AE and SAE Information

Any SAEs assessed as related to study participation (e.g., protocol-mandated 
procedures, invasive tests, or change in existing therapy) or related to a GSK 
product will be recorded from the time a subject consents to participate in the 
study up to and including any follow-up contact.

AEs will be collected from the start of washout until the follow-up contact (see 
Section 7.3.1.3), at the timepoints specified in the Time and Events Table (Section 
7.1).

Medical occurrences that begin prior to the start of washout but after obtaining 
informed consent may be recorded on the Medical History/Current Medical 
Conditions section of the CRF.

All SAEs will be recorded and reported to GSK within 24 hours, as indicated in 
Section 12.4.  The investigator will submit any updated SAE data to the sponsor 
within 24 hours of it being available.

Investigators are not obligated to actively seek AEs or SAEs in former study 
subjects.  However, if the investigator learns of any SAE, including a death, at any 
time after a subject has been discharged from the study, and he/she considers the 
event reasonably related to the study treatment or study participation, the 
investigator must promptly notify GSK.
NOTE: The method of recording, evaluating and assessing causality of AEs and SAEs 
plus procedures for completing and transmitting SAE reports to GSK are provided in 
Section 12.4.

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7.3.1.2.
Method of Detecting AEs and SAEs
Care must be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended 
and non-leading verbal questioning of the subject is the preferred method to inquire about 
AE occurrence.  Appropriate questions include:

“How are you feeling?”

“Have you had any (other) medical problems since your last visit/contact?”

“Have you taken any new medicines, other than those provided in this study, since 
your last visit/contact?”
7.3.1.3.
Follow-up of AEs and SAEs
After the initial AE/SAE report, the investigator is required to proactively follow each 
subject at subsequent visits/contacts.  All SAEs, and AEs of Special Interest (as defined 
in Section 7.3.1.4) will be followed until resolution, until the condition stabilizes, until 
the event is otherwise explained, or until the subject is lost to follow-up (as defined in 
Section 5.5).  Further information on follow-up procedures is given in Section 12.4.5.
7.3.1.4.
Adverse Events of Special Interest
The investigator or site staff will be responsible for detecting, documenting and reporting 
any AEs of special interest or any event that may potentially be one of the categories 
listed below (using preferred terms):

Death, myocardial infarction (MI), stroke, heart failure, thromboembolic events,
thrombosis of vascular access

Thrombosis and/or tissue ischemia secondary to excessive erythropoiesis

Cardiomyopathy

Pulmonary artery hypertension (see also Section 7.3.1.5)

Cancer-related mortality and tumor progression and recurrence

Esophageal and gastric erosions

Proliferative retinopathy, macular edema, choroidal neovascularization

Exacerbation of rheumatoid arthritis

Worsening of hypertension
The results of any investigation should be recorded in the relevant sections of the 
subject’s eCRF.
7.3.1.5.
Cardiovascular and Death Events
GSK has identified CV and death events of special interest for all clinical studies.  
Investigators will be required to fill out the specific CV event page of the eCRF for the 
CV AEs and SAEs or any event that may potentially be one of the categories listed in 
Section 12.4.3.

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7.3.1.6.
Regulatory Reporting Requirements for SAEs
Prompt notification by the investigator to GSK of SAEs related to study treatment is 
essential so that legal obligations and ethical responsibilities towards the safety of 
subjects and the safety of a product under clinical investigation are met.
GSK has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a product under clinical investigation.  GSK will 
comply with country specific regulatory requirements relating to safety reporting to the 
regulatory authority, Institutional Review Board (IRB)/Independent Ethics Committee 
(IEC) and investigators.
Investigator safety reports are prepared for suspected unexpected serious adverse 
reactions according to local regulatory requirements and GSK policy and are forwarded 
to investigators as necessary.
An investigator who receives an investigator safety report describing a SAE(s) or other 
specific safety information (e.g., summary or listing of SAEs) from GSK will file it with 
the IB and will notify the IRB/IEC, if appropriate according to local requirements.
7.3.1.7.
Possible Suicidality Related Adverse Events
If during the study there is an occurrence of an AE or SAE which in the investigator’s 
opinion, is possibly related to suicidality, the Possible Suicidality Related Adverse Events 
(PSRAE) eCRF form should be completed (in addition to the AE and SAE pages, as 
appropriate).
This event may include, but is not limited to, one that involves suicidal ideation, a 
preparatory act toward imminent suicidal behavior, a suicide attempt, or a completed 
suicide.  The investigator will exercise his or her medical and scientific judgment in 
deciding whether an event is possibly related to suicidality.
7.3.2.
Pregnancy
Details of all pregnancies in female subjects and the outcome for the neonate, if 
applicable, will be collected after the start of dosing and until 14 days post-last dose.  If a 
pregnancy is reported, then the investigator should inform GSK within 2 weeks of 
learning of the pregnancy and should follow the procedures outlined in Section 12.4.8.
7.3.3.
Physical Exams
A complete physical examination will include, at a minimum, assessment of the 
cardiovascular, respiratory, gastrointestinal and neurological systems.

Investigators should pay special attention to clinical signs related to previous 
serious illnesses.

For height and weight measurements, the subject is recommended to wear indoor, 
daytime clothing with no shoes.

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7.3.4.
Vital Signs and Weight
Vital signs will be measured with the subject in a semi-supine position after 5 minutes 
rest and will include temperature, systolic and diastolic blood pressure and heart rate, and
will be measured both pre- and post-dialysis.
Weight will be measured both pre- and post-dialysis and recorded as specified in the 
Time and Events Table (Section 7.1).
7.3.5.
Electrocardiogram (ECG)
ECG measurements will be taken at the time points specified in the Time and Events 
Table (Section 7.1).  Full 12-lead ECGs will be recorded with the subject in a supine 
position.  Heart rate (HR), PR interval, QRS duration, and QT (uncorrected) interval will 
be measured.  QTcB will be calculated (machine-read or manually).
At the Screening visit two additional ECGs are required if the initial ECG indicates 
prolonged QTc (see Section 5.3) using the automated or manually calculated QTcB 
value.  The average QTcB value of all three ECGs will be used to determine eligibility.  
Additional details are provided in the SRM.
ECG data will be read locally.
All ECGs will be performed before measurement of vital signs and collection of blood 
samples for laboratory testing.
7.3.6.
Clinical Safety Laboratory Assessments
All protocol required laboratory assessments, as defined in Table 5 must be conducted in 
accordance with the Laboratory Manual, and Protocol Time and Events Schedule.  
Laboratory requisition forms must be completed and samples must be clearly labelled 
with the subject number, protocol number, site/center number, and visit date.  Details for 
the preparation and shipment of samples will be provided by the laboratory and are 
detailed in the SRM.  Reference ranges for all safety parameters will be provided to the 
site by the laboratory responsible for the assessments.
If additional non-protocol specified laboratory assessments are performed at the 
institution’s local laboratory and result in a change in subject management or are 
considered clinically significant by the investigator (e.g., SAE or AE or dose 
modification) the results must be recorded in the eCRF.
Refer to the SRM for appropriate processing and handling of samples to avoid duplicate 
and/or additional blood draws.
All study-required laboratory assessments will be performed by a central laboratory, apart 
from HemoCue Hgb. The results of each HemoCue test must be entered into the eCRF.
NOTE:  Local laboratory results are only required in the event that the central laboratory 
results are not available in time for either a treatment and/or response evaluation to be 
performed.  If a local sample is required, it is important that the sample for central 

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analysis is obtained at the same time. Additionally if the local laboratory results are used 
to make either a treatment or response evaluation, the results must be entered into the 
eCRF.
Hematology, clinical chemistry, and additional parameters to be tested are listed in Table 
5.
Table 5
Protocol Required Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
Hematology
Platelet Count
RBC Indices:
WBC Count with 
Differential:
RBC Count
MCV
Neutrophils
Hemoglobin
MCH
Lymphocytes
Hematocrit
MCHC
Monocytes
WBC Count (absolute)
RDW
Eosinophils
Reticulocyte Count
CHr
Basophils
Clinical 
Chemistry
Potassium
AST (SGOT)
Total and direct/indirect 
bilirubin
Sodium
ALT (SGPT)
Total Protein
Glucose
Calcium (Albumin adjusted)
Alkaline Phosphatase
Albumin
Phosphate
Other Screening 
Tests
Serum hCG pregnancy test
Serum ferritin
Folate
Estradiol1
Serum iron
Vitamin B12
FSH1
Serum transferrin
UIBC
TSAT
NOTE: Details of Liver Chemistry Stopping Criteria and Required Actions and Follow-Up Assessments after liver 
stopping or monitoring event are given in Section 12.2.
1 As needed in women of non-child bearing potential only.
Abbreviations: ALT= Alanine transaminase; AST= Aspartate transaminase; CHr=Reticulocyte hemoglobin content; 
FSH=follicle stimulating hormone; MCH= Mean corpuscular hemoglobin; MCHC= Mean corpuscular hemoglobin 
concentration; MCV= Mean corpuscular volume; RBC= Red blood cell; RDW= Red blood cell distribution width; 
SGOT=Serum glutamic oxaloacetic transaminase; SGPT=Serum glutamic-pyruvic transaminase; TSAT = transferrin 
saturation; UIBC= unsaturated iron binding capacity; WBC= White blood cells;
All laboratory tests with values that are considered clinically significantly abnormal 
during participation in the study or within 14 (3) days after the last dose of study 
treatment should be repeated until the values return to normal or baseline.  If such values 
do not return to normal within a period judged reasonable by the investigator, the
etiology should be identified and the sponsor notified.
7.4.
Pharmacokinetics
7.4.1.
Blood Sample Collection
Blood samples for pharmacokinetic (PK) analysis of daprodustat and its metabolites 
(GSK2391220 [M2], GSK2531403 [M3], GSK2487818 [M4], GSK2506102 [M5], 
GSK2531398 [M6], and GSK2531401 [M13]) will be collected at the time points 
indicated in Section 7.1, Time and Events Table.  The actual date and time of each blood 

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sample collection will be recorded.  The timing of PK samples may be altered and/or PK 
samples may be obtained at additional time points to ensure thorough PK monitoring.
Details of PK blood sample collection (including volume to be collected), processing, 
storage and shipping procedures are provided in the SRM.
If the subject is unable to provide a sufficient blood quantity per time point or there is 
significant concern for this by the subject or investigator, these serial blood draws may be 
omitted.
7.4.2.
Sample Analysis
Plasma analysis will be performed under the control of Bioanalysis, Immunogenicity, and 
Biomarkers - In Vitro/In Vivo Translation Platform/Scinovo, GlaxoSmithKline, the 
details of which will be included in the SRM.  Concentrations of daprodustat and its 
metabolites (GSK2391220 [M2], GSK2531403 [M3], GSK2487818 [M4], GSK2506102 
[M5], GSK2531398 [M6], and GSK2531401 [M13]) will be determined in plasma 
samples using the currently approved bioanalytical methodology.  Raw data will be 
archived at the bioanalytical site (detailed in the SRM).
7.5.
Biomarker(s)/Pharmacodynamic Markers
7.5.1.
Ambulatory Blood Pressure Monitoring (ABPM)
Blood pressure and pulse will be measured during Acute Challenge 1 and 2 through the 
use of an ambulatory blood pressure monitoring device.  Subjects will wear the ABPM 
device for two sessions during the study (i.e., Acute Challenge 1 and 2), occurring at Day 
1 (randomization) and at Day 57.  The ABPM device will be placed prior to Acute 
Challenge dosing, and will remain on the subject’s arm until 24 hrs post-dosing.
ABPM measurements of systolic and diastolic blood pressure and heart rate will be 
automatically recorded every 15 minutes for the first 6 hrs post-dosing, and then every 20 
minutes thereafter until 24 hrs post-dosing.  The ABPM device will automatically 
calculate MAP.
The device planned for use in this study is the Mortara Ambulo 2400; a specification 
sheet for this device can be found in Section 12.6.
After both Acute Challenge 1 and 2, the 24-hr ABPM results will be checked for data 
quality as defined in the Project Requirement Specification (PRS).  If the ABPM fails the 
QC criteria following Acute Challenge 2, one additional Acute Challenge may be made 
in a subsequent, mid-week dialysis visit 1 week later if the subject agrees. At that visit, 
the subject will receive the same study treatment for the repeat Acute Challenge 2 as was 
administered on Day 57 as a single additional dose. No additional clinical chemistry, 
hematology, pharmacokinetic or biomarker sampling will be done, however all other 
procedures will be performed as detailed in Table 4.

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7.5.1.1.
ABPM Delay Due to High Hgb
Day 1:  If the HemoCue Hgb is confirmed to be ≥11.5 g/dL, then avoid dosing and 
continue washout for one additional week.  No other assessments should be performed 
for that subject during the visit.  When the subject returns 7 days later, re-draw the Hgb 
for HemoCue and assess.  If confirmed to be < 11.5 g/dL then progress with the 
remainder of assessments and perform Acute Challenge 1.  If the Hgb remains high, the 
subject must be withdrawn.
Day 57:   If the HemoCue Hgb is confirmed to be ≥11.5 g/dL, then hold the dose(s) of IP
for 1 week.  No other assessments should be performed for that subject during the visit.
When the subject returns 7 days later, re-draw the Hgb for HemoCue and assess.  If 
confirmed to be < 11.5 g/dL then progress with the remainder of assessments and 
perform Acute Challenge 2.  If the Hgb remains high, the subject must be withdrawn.
7.5.2.
Blood Pressure Regulation Biomarkers
Blood samples will be collected during this study to investigate the mechanism of the 
effect of daprodustat on blood pressure.  Biomarkers selected will explore the renin-
angiotensin-aldosterone axis, the nitric oxide and endothelin axes, sodium retention and 
HIF signalling.
Biomarkers may include erythropoietin, nitric oxide (NO), asymmetric dimethyarginine 
(ADMA), renin, angiotensin-II (1-8) and metabolites (1-7 and 1-5), endothelin-1 (ET-1), 
and noradrenalin. Samples will be collected as specified in the Time and Events Table 
(Section 7.1).  The timing of the collections may be adjusted on the basis of emerging 
pharmacokinetic or pharmacodynamic (PD) data from this study or other new 
information in order to ensure optimal evaluation of the PD endpoints.
If the subject is unable to provide a sufficient blood quantity per time point or there is 
significant concern for this by the subject or investigator, these serial blood draws may be 
omitted.
7.6.
Genetics
Genetics are not evaluated in this study.
8.
DATA MANAGEMENT

For this study, subject data will be entered into GSK defined electronic case report 
forms (eCRFs), transmitted electronically to GSK or designee and combined with 
data provided from other sources in a validated data system.

Management of clinical data will be performed in accordance with applicable 
GSK standards and data cleaning procedures to ensure the integrity of the data, 
e.g., removing errors and inconsistencies in the data.

Adverse events and concomitant medications terms will be coded using MedDRA 
(Medical Dictionary for Regulatory Activities) and an internal validated 
medication dictionary, GSKDrug.

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
CRFs (including queries and audit trails) will be retained by GSK, and copies will 
be sent to the investigator to maintain as the investigator copy.  Subject initials 
will not be collected or transmitted to GSK according to GSK policy.
9.
STATISTICAL CONSIDERATIONS AND DATA 
ANALYSES
The primary endpoint for this study is average systolic blood pressure (SBP) over 6 hours 
of measurements taken at 15-minute intervals after the administration of study treatment 
for the Acute Challenge 2.  The primary comparison of interest is daprodustat versus 
epoetin alfa for this challenge.
The comparison of daprodustat versus epoetin alfa on 6 hr average SBP during Acute 
Challenge 1 is a secondary endpoint.
9.1.
Hypotheses
Null Hypothesis: The difference between 24 mg daprodustat versus 100 IU/kg epoetin 
alfa on 6 hr average SBP under a background of treatment (i.e., during Acute Challenge 
2) is zero.
Alternative Hypothesis: The difference between 24 mg daprodustat versus 100 IU/kg 
epoetin alfa on 6 hr average SBP under a background of treatment (i.e. during Acute 
Challenge 2) is not zero.
9.2.
Sample Size Considerations
9.2.1.
Sample Size Assumptions
It is expected that 31 subjects will be randomized into each treatment arm.  Assuming a 
20% withdrawal rate during the Hgb Maintenance Period, there will be 25 subjects per 
treatment arm that will undertake Acute Challenge 2.  The study will continue to recruit 
subjects until it is projected that 25 subjects per treatment arm complete and pass QC for
Acute Challenge 2.
Assuming a 5% significance level and a true standard deviation (SD) of 16 mmHg for 
average SBP over 6 hours, a sample size of 25 subjects per treatment group will provide 
greater than 90% power to detect a -15 mmHg difference between treatment groups.  
Under these assumptions, statistical significance will be obtained if there is more than a 
9.1 mmHg mean difference observed in favor of daprodustat.

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Table 6
Power and Half-width of 95% CI for pair-wise comparisons, 
assuming a 16 mmHg SD for average SBP over 6 hours
Challenge
Expected Number of 
Subjects per Treatment 
Group
Power to detect 
15 mm Hg difference
Half-Width of 95% CI2
Acute Challenge 1
31
95%
8.1 mmHg
Acute Challenge 21
25
90%
9.1 mmHg
1 Primary Comparison
2 Minimal detectible effect
9.2.2.
Sample Size Sensitivity
Changes to power and the half-width of the 95% confidence interval for Acute Challenge 
2 due to varying assumptions on the SD for average SBP over 6 hr are explored in Table 
7 below.
Table 7
Half-width of 95% CI for pair-wise comparisons, assuming 25 
subjects per treatment group
Common SD for average SBP 
over 6 hours
Power to detect
15 mm Hg difference
Half-Width of 95% CI
14
96%
8.0 mmHg
16†
90%
9.1 mmHg
18
82%
10.2 mmHg
20
74%
11.4 mmHg
† Primary Comparison
9.2.3.
Sample Size Re-estimation or Adjustment
Subjects that withdraw prior to the Acute Challenge 2 assessment will be replaced so that 
25 subjects per treatment arm complete Acute Challenge 2.
9.3.
Data Analysis Considerations
9.3.1.
Analysis Populations
The primary population of interest is the intent to treat (ITT) population defined as all 
randomized subjects that received at least one dose of study treatment.
In addition, a per-protocol population may be investigated.  Details will be provided in 
the Reporting and Analysis Plan (RAP) for the study.

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9.3.2.
Interim Analysis
No interim analyses are currently planned for this study.
9.4.
Key Elements of Analysis Plan
9.4.1.
Primary Analyses
The primary analysis of average SBP over 6 hr post-dose during Acute Challenge 2 will 
be an analysis of covariance (ANCOVA) with terms for treatment, prior ESA dose
(low/high), and post-HD/pre-Acute Challenge 1 SBP, difference between post-HD/pre-
Acute Challenge 2 SBP and post-HD/pre-Acute Challenge 1 SBP, and treatment by 
(difference in post-HD SBP between Acute Challenge 1 and 2) interaction.  Note that the 
pre-challenge SBP may change over time between Acute Challenge 1 and Acute 
Challenge 2 as a result of the maintenance therapy, and thus the pre-challenge SBP at 
Acute Challenge 2 is not a true pre-treatment covariate.  As a result, the interpretation of 
the effect of the Acute Challenge 2 may be confounded by the impact of treatment phase 
on the covariate. Therefore, if the interaction term in this model is significant at the 0.10 
level, then the primary model will be ANCOVA with terms for treatment, prior ESA dose
(low/high), and post-HD/pre-Acute Challenge 1 SBP.  The primary model will provide a 
point estimate and two-sided 95% CI for the treatment effect and a p-value for the 
superiority assessment.  Superiority will be established if the p-value is <0.05.
9.4.2.
Secondary Analyses
Average SBP over 6 hr post-dose in Acute Challenge 1 will be analyzed using ANCOVA 
with terms for treatment, prior ESA dose (low/high), and post-HD/pre-Acute Challenge 1 
SBP.  Similar analyses will be performed for DBP, MAP, and HR.
ANCOVA using the primary model will be used for the analysis of average DBP, MAP, 
and HR over 6 hr post-dose in Acute Challenge 2 replacing the baseline SBP term with 
the analogous baseline measurement for DBP, MAP, and HR respectively.
AUECs of SBP, DBP, MAP, and HR post Acute Challenge 2 and 1 will be analyzed 
using ANCOVA with terms for treatment and prior ESA dose (low/high) with 95% CIs 
and p-values provided for the treatment effect.
9.4.3.
Other Analyses
The difference in SBP between pre-dose in Acute Challenge 1 and pre-dose in Acute 
Challenge 2 will be summarized by treatment group.  Similar summaries of DBP, MAP, 
and HR will be performed.
For each acute challenge, change from pre-challenge in SBP, DBP, MAP, and HR will be
summarized by treatment group at each timepoint.  In addition, for each acute challenge,
SBP, DBP, MAP, and HR will be summarized by treatment group at each timepoint.  
Line graphs of this information will be provided by treatment group for each acute 
challenge.

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For each acute challenge, the concentration of erythropoietin, endothelin-1, nitric oxide, 
asymmetric dimethylarginine, renin, angiotensin-II and metabolites, and noradrenalin
will be summarized by treatment group at each timepoint.  Line graphs of this 
information will be provided by treatment group for each acute challenge.
Further statistical considerations will be addressed in the RAP.
10.
STUDY GOVERNANCE CONSIDERATIONS
10.1.
Posting of Information on Publicly Available Clinical Trial 
Registers
Study information from this protocol will be posted on publicly available clinical trial 
registers before enrollment of subjects begins.
10.2.
Regulatory and Ethical Considerations, Including the 
Informed Consent Process
Prior to initiation of a site, GSK will obtain favorable opinion/approval from the 
appropriate regulatory agency to conduct the study in accordance with International 
Conference on Harmonization (ICH) Good Clinical Practice (GCP) and applicable 
country-specific regulatory requirements.
The study will be conducted in accordance with all applicable regulatory requirements, 
and with GSK policy.
The study will also be conducted in accordance with ICH Good Clinical Practice (GCP), 
all applicable subject privacy requirements, and the guiding principles of the current 
version of the Declaration of Helsinki.  This includes, but is not limited to, the following:

IRB/IEC review and favorable opinion/approval of the study protocol and 
amendments as applicable

Obtaining signed informed consent

Investigator reporting requirements (e.g., reporting of AEs/SAEs/protocol 
deviations to IRB/IEC)

GSK will provide full details of the above procedures, either verbally, in writing, 
or both

Signed informed consent must be obtained for each subject prior to participation 
in the study

The IEC/IRB, and where applicable the regulatory authority, approve the clinical 
protocol and all optional assessments, including genetic research.

Optional assessments (including those in a separate protocol and/or under separate 
informed consent) and the clinical protocol should be concurrently submitted for 
approval unless regulation requires separate submission.

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

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
If GSK determines 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.

If the study is suspended or prematurely discontinued for safety reasons, GSK will 
promptly inform all investigators, heads of the medical institutions (where 
applicable) and/or institution(s) conducting the study. GSK will also promptly 
inform the relevant regulatory authorities of the suspension or premature 
discontinuation of the study and the reason(s) for the action.

If required by applicable regulations, the investigator or the head of the medical 
institution (where applicable) must inform the IRB/IEC promptly and provide the 
reason for the suspension or premature discontinuation.
10.6.
Records Retention

Following closure of the study, the investigator or the head of the medical 
institution (where applicable) must maintain all site study records (except for 
those required by local regulations to be maintained elsewhere), in a safe and 
secure location.

The records must be maintained to allow easy and timely retrieval, when needed 
(e.g., for a GSK audit or regulatory inspection) and must be available for review 
in conjunction with assessment of the facility, supporting systems, and relevant 
site staff.

Where permitted by local laws/regulations or institutional policy, some or all of 
these records can be maintained in a format other than hard copy (e.g., microfiche, 
scanned, electronic); however, caution needs to be exercised before such action is 
taken.

The investigator must ensure that all reproductions are legible and are a true and 
accurate copy of the original and meet accessibility and retrieval standards, 
including re-generating a hard copy, if required.  Furthermore, the investigator 
must ensure there is an acceptable back-up of these reproductions and that an 
acceptable quality control process exists for making these reproductions.

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.

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10.7.
Provision of Study Results to Investigators, Posting of 
Information on Publicly Available Clinical Trials Registers 
and Publication
Where required by applicable regulatory requirements, an investigator signatory will be 
identified for the approval of the clinical study report.  The investigator will be provided 
reasonable access to statistical tables, figures, and relevant reports and will have the 
opportunity to review the complete study results at a GSK site or other mutually-
agreeable location.
GSK will also provide the investigator with the full summary of the study results.  The 
investigator is encouraged to share the summary results with the study subjects, as 
appropriate.
GSK will provide the investigator with the randomization codes for their site only after 
completion of the full statistical analysis.
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.
A manuscript will be progressed for publication in the scientific literature if the results 
provide important scientific or medical knowledge.

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11.
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Agarwal R, Kusek JW, Pappas MK. A randomized trial of intravenous and oral iron in 
chronic kidney disease. Kidney Int 2015; 88: 905-914.
Brodie MJ, Mintzer S, Pack AM, Gidal Gary E, Vecht CJ, Schmidt D. Enzyme induction 
with antiepileptic drugs: Cause for concern? Epilepsia 2013: 54:11 – 27.
Campochiaro PA and the first ARVO/Pfizer Institute Working Group et al. Ocular versus 
extraocular neovascularization: Mirror images or vague resemblances. Invest Ophthalmol 
& Vis Sci. 2006; 47:462-474.
Chen H, Yu KD, Xu GZ. Association between Variant Y402H in Age-Related Macular 
Degeneration (AMD) Susceptibility Gene CFH and Treatment Response of AMD: A 
Meta-Analysis. PloS ONE 2012; 7: e42464 
FDA Drug Safety Communication: Modified dosing recommendations to improve the 
safe use of erythropoiesis-stimulating agents (ESAs) in chronic kidney disease. Safety 
Announcement issued June 24, 2011.  Link: 
http://www.fda.gov/Drugs/DrugSafety/ucm259639.htm#sa
Formenti F, Beer PA, Croft QPP, Dorrington KL, Gale DP, Lappin TRJ, Lucas GS, 
Maher ER, Maxwell PH, McMullin MF, O’Connor DF, Percy MJ, Pugh CW, Ratcliffe 
PJ, Smith TG, Talbot NP, Robbins PA. Cardiopulmonary function in two human 
disorders of the hypoxia-inducible factor (HIF) pathway: von Hippel-Lindau disease and 
HIF-2α gain-of-function mutation. FASEB J 2011; 25: 2001-2011.
Genetic insights into age-related macular degeneration: Controversies addressing risk, 
causality, and therapeutics. Mol. Asp. Med. 2012; 33: 467-486.
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OCT-2015.
Haase VH. Mechanisms of Hypoxia Responses in Renal Tissue. JASN 2013; 24: 537-
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Hofherr, A., et al, HIF-1α drives cyst growth in advanced stages of autosomal dominant 
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Holdstock L, Meadowcroft AM, Maier R, Johnson BM, Jones D, Rastogi A, Zeig S, 
Lepore JJ, Cobitz AR. Four-week studies of oral hypoxia-inducible factor-prolyl 
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James LP, Letzig L, Simpson PM, Capparelli E, Roberts DW, Hinson JA Davern TJ Lee 
WM. Pharmacokinetics of acetaminophen-protein adducts in adults with acetaminophen 
overdose and acute liver failure. Drug Metab Dispos 2009; 37: 1779-1784.
Kang D-H, Yoon K-I, Han, D-S. Acute effects of recombinant human erythropoietin on 
plasma levels of proendothelin-1 and endothelin-1 in haemodialysis patients. Nephrol 
Dial Transplant 1998; 13:2877-2883.
Krapf, R, Hulter, HN. Arterial hypertension by erythropoietin and erythropoiesis-
stimulating agents (ESA). Clin J Am Soc Nephrol 2009; 4: 470-480.
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 
signalling events in rheumatoid arthritis. Arthritis Research & Therapy 2009; 11: 201-
209.
Navaneethan SD, for CRIC investigators: Prevalence, Predictors, and Outcomes of 
Pulmonary Hypertension in CKD. J Am Soc Nephrol 2016, 27:877–886.
Ohnhaus EE, Breckenridge AM, Park BK. Urinary excretion of 6β-Hydroxycortisol and 
the Time Course Measurement of Enzyme Induction in Man.  Eur J Clin Pharmacol
1989:36:39-46.
Pfeffer MA, Burdmann EA, Chen C et al. for the TREAT Investigators. A Trial of 
Darbepoetin Alfa in Type 2 Diabetes and Chronic Kidney Disease. N Engl J Med 2009; 
361: 2019-2032.
Provenzano R, Tumlin J, Zabaneh R, et al. Pharmacokinetics of oral FG-4592 to treat 
anemia in hemodialysis patients. National Kidney Foundation Conference, 2011 
(Abstract #189).
Rodriguez CJ, Swett K, Agarwal SK, Folsom AR, Fox ER, Loehr LR, Ni H, Rosamond 
WD, Chang PP. Systolic blood pressure levels among adults with hypertension and 
incident cardiovascular events. The Atherosclerosis Risk in Communities Study. JAMA 
Intern Med 2014; 174: 1252-1261.
Samtleben W, Baldamus CA, Bommer J, Fassbinder W, Nonnast-Daniel B, Gurland HJ. 
Blood pressure changes during treatment with recombinant human erythropoietin. Contr 
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NP, Treacy M, Robbins PA. Mutation of von Hippel-Lindau tumour suppressor and 
human cardiopulmonary physiology. PLoS Med 2006;3: e290
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angiogenesis in rheumatoid arthritis - therapeutic implications. Curr Med Chem 2010; 17: 
254-63.

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12.
APPENDICES
12.1.
Appendix 1 – Abbreviations and Trademarks
Abbreviations
ABPM
Ambulatory blood pressure monitoring
ADMA
Asymmetric dimethyarginine
AE
Adverse event
ALT
Alanine transaminase
AMD
Age-Related Macular Degeneration
ANCOVA
Analysis of Covariance
AST
Aspartate transaminase
AUEC
Area under the effect curve
AUC (0-24)
Area under concentration-time curve from time zero to 24 hours
BP
Blood pressure
CHr
Reticulocyte hemoglobin content
CI
Confidence interval
CKD
Chronic kidney disease
Cmax
Maximum observed concentration
CPK
Creatine phosphokinase
CV
Cardiovascular
DBP
Diastolic blood pressure
dL
Deciliter
DNA
Deoxyribonucleic acid
ECG
Electrocardiogram
ECHO
Echocardiogram
eCRF
Electronic Case Report Form
EDW
Estimated Dry Weight
EPO
Erythropoietin
ESA
Erythropoiesis-stimulating agent
ET-1
Endothelin-1
FDA
Food and Drug Administration
FRP
Females of Reproductive Potential
FSH
Follicle Stimulating Hormone
GCP
Good Clinical Practice
G
Gram
GI
Gastrointestinal
GSK
GlaxoSmithKline
hCG
Human chorionic gonadotrophin
HD
Hemodialysis dependent
HDPE
High Density Polyethylene
HF
Heart Failure
Hgb
Hemoglobin
HIF
Hypoxia-inducible factor
HR
Hour/heart rate

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IB
Investigator’s Brochure
ICH
International Conference on Harmonization
IEC
Independent Ethics Committee
INR
International Normalized Ratio
IRB
Institutional Review Board
ITT
Intent-to-treat
IU
International Unit
IV
Intravenous
IVWRS
Interactive Voice/Web Response System
KDIGO
Kidney Disease Improving Global Outcomes
KG
Kilogram
LDH
Lactate dehydrogenase 
MAP
Mean Arterial Blood Pressure
MCH
Mean corpuscular hemoglobin
MCHC
Mean corpuscular hemoglobin concentration
MCV
Mean corpuscular volume
MedDRA
Medical Dictionary for Regulatory Activities
MG
Milligram
MI
Myocardial infarction
ML
Milliliter 
mmHG
Millimeter of mercury
MSDS
Material Safety Data Sheet
ND
Non-dialysis dependent
NO
Nitric Oxide
NOAEL
No Observed Adverse Effect Level
NYHA
New York Heart Association
PASP
Pulmonary Artery Systolic Pressure
PCI
Percutaneous Coronary Intervention
PD
Pharmacodynamic
PEG
Polyethylene glycol
PGI2
Prostaglandin I2
PHD
Prolyl hydroxylase domain
PHI
Prolyl hydroxylase inhibitor
PK
Pharmacokinetic
proADM
Proadrenomedullin
PRS
Project Requirement Specification
PRVP
Peak Right Ventricular Pressure
PSRAE
Possible suicidality related adverse event
QC
Quality Control
QTc
QT interval corrected for heart rate
QTcB
QT interval corrected for heart rate using Bazett’s formula
RAP
Reporting and Analysis Plan
RBC
Red blood cell
RDW
Red blood cell distribution width
rhEPO
Recombinant human erythropoietin 
RNA
Ribonucleic acid

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SAE
Serious adverse event
SBP
Systolic blood pressure
SC
Subcutaneous
SD
Standard deviation
SGOT
Serum glutamic oxaloacetic transaminase
SGPT
Serum glutamic-pyruvic transaminase
sPAP
Systolic Pulmonary Artery Pressure
SRM
Study Reference Manual
T1/2
Terminal phase half-life
TIBC
Total iron binding capacity
Tmax
Time of occurrence of Cmax
TSAT
Transferrin saturation
UG
Microgram
UIBC
Unsaturated iron binding capacity
ULN
Upper limit of normal
URR
Urea reduction ratio
WBC
White blood cells
Trademark Information
Trademarks of the GlaxoSmithKline 
group of companies
Trademarks not owned by the 
GlaxoSmithKline group of companies
NONE
Ambulo
HemoCue

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12.2.
Appendix 2: Liver Safety Required Actions and Follow up 
Assessments
The procedures listed below are to be followed if a subject meets the liver chemistry 
stopping criteria defined in Section 5.5.3:

Immediately withdraw the subject from study treatment

Notify the Medical Monitor within 24 hr of learning of the abnormality to confirm 
the subject’s study treatment cessation and follow-up.

Complete the “Safety Follow-Up Procedures” listed below.

Complete the liver event case report forms.  If the event also meets the criteria of an 
SAE (see Section 12.4), the SAE data collection tool will be completed separately 
with the relevant details.

Upon completion of the safety follow-up withdraw the subject from the study unless 
further safety follow up is required

Do not restart study treatment

Refer to the Flow chart for a visual presentation of the procedures listed below.
Safety Follow-Up Procedures for subjects with ALT 3xULN:

Monitor subjects weekly until liver chemistries (ALT, AST, alkaline phosphatase, 
bilirubin) resolve, stabilize or return to within baseline values.
Safety Follow-Up Procedures for subjects with ALT 3xULN and total bilirubin 
2xULN (>35% direct bilirubin); or ALT 3xULN and INR1 > 1.5:

This event is considered an SAE (see Section 12.4)  Serum bilirubin fractionation 
should be performed if testing is available.  If fractionation is unavailable, urinary 
bilirubin is to be measured via dipstick (a measurement of direct bilirubin, which 
would suggest liver injury).

Make every reasonable attempt to have subjects return to the clinic within 24 hr for 
repeat liver chemistries, additional testing, and close monitoring (with specialist or 
hepatology consultation recommended).

Monitor subjects twice weekly until liver chemistries (ALT, AST, alkaline 
phosphatase, bilirubin) resolve, stabilize or return to within baseline values.
1 INR testing not required per protocol and the threshold value does not apply to subjects receiving anticoagulants.

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In addition, for all subjects with ALT 3xULN, every attempt must be made to also 
obtain the following:

Viral hepatitis serology including:
o Hepatitis A IgM antibody.
o Hepatitis B surface antigen and Hepatitis B Core Antibody (IgM). 
o Hepatitis C ribonucleic acid (RNA).
o Cytomegalovirus IgM antibody.
o Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, obtain 
heterophile antibody or monospot testing).
o Hepatitis E IgM antibody.

Blood sample for pharmacokinetic (PK) analysis, obtained within 24 h of last dose. 
Record the date/time of the PK blood sample draw and the date/time of the last dose 
of study treatment prior to blood sample draw on the CRF.  If the date or time of the 
last dose is unclear, provide the subject’s best approximation.  If the date/time of the 
last dose cannot be approximated OR a PK sample cannot be collected in the time 
period indicated above, do not obtain a PK sample.  Instructions for sample 
handling and shipping are included in the SRM.

Serum creatine phosphokinase (CPK) and lactate dehydrogenase (LDH).

Fractionate bilirubin, if total bilirubin 2xULN.

Assess eosinophilia

Record the appearance or worsening of clinical symptoms of hepatitis (fatigue, 
nausea, vomiting, right upper quadrant pain or tenderness, fever, rash or eosinophilia) 
on the AE CRF.

Record use of concomitant medications, acetaminophen, herbal remedies, other over 
the counter medications, or putative hepatotoxins on the Concomitant Medications 
CRF.

Record alcohol use on the Liver Events CRF.
The following are required for subjects with ALT 3xULN and bilirubin 2xULN 
(>35% direct) but are optional for other abnormal liver chemistries:

Anti-nuclear antibody, anti-smooth muscle antibody, and Type 1 anti-liver kidney 
microsomal antibodies.

Serum acetaminophen adduct high performance liquid chromatography (HPLC)
assay (quantifies potential acetaminophen contribution to liver injury in subjects 
with definite or likely acetaminophen use in the preceding week [James, 2009].

Liver imaging (ultrasound, magnetic resonance, or computerized tomography) to 
evaluate liver disease.

The Liver Imaging and/or Liver Biopsy CRFs are also to be completed if these tests 
are performed.

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Refer to the diagram below for a visual presentation of the procedures listed above.

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Additional charts are provided below for reference.
Liver Chemistry Stopping Criteria – Liver Stopping Event
ALT-absolute
ALT 5xULN
ALT Increase
ALT 3xULN 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 3xULN 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 study treatment 
Report the event to GSK within 24 hours

Complete the liver event CRF and complete an 
SAE data collection tool if the event also meets 
the criteria for an SAE2

Perform liver event follow up assessments 

Monitor the subject until liver chemistries
resolve, stabilize, or return to within baseline 
(see MONITORING below)

Do not restart/rechallenge subject with study 
treatment. If restart/rechallenge not allowed 
per protocol or not granted, permanently 
discontinue study treatment and may 
continue subject in the study for any protocol 
specified follow up assessments 
MONITORING:
For bilirubin or INR criteria:

Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin) and perform 
liver event follow up assessments within 24 hrs

Monitor subjects twice weekly until liver 
chemistries resolve, stabilize or return to within 

Viral hepatitis serology4

Blood sample for pharmacokinetic (PK) 
analysis, obtained within 24 hours after 
last dose5

Serum creatine phosphokinase (CPK) 
and lactate dehydrogenase (LDH).

Fractionate bilirubin, if total 
bilirubin2xULN

Obtain complete blood count with 
differential to assess eosinophilia

Record the appearance or worsening of 
clinical symptoms of liver injury, or 
hypersensitivity, on the AE report form

Record use of concomitant medications 
on the concomitant medications report 
form including acetaminophen, herbal 
remedies, other over the counter 
medications.

Record alcohol use on the liver event 
alcohol intake case report form

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

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Liver Chemistry Increased Monitoring Criteria – Liver Monitoring Event
Criteria
Actions
ALT 3xULN and <5xULN and bilirubin 
<2xULN, without symptoms believed to 
be related to liver injury or 
hypersensitivity, and who can be 
monitored weekly for 4 weeks

Notify the GSK medical monitor within 24 hours of 
learning of the abnormality to discuss subject safety. 

Subject can continue study treatment.  Subject must 
return weekly for repeat liver chemistries (ALT, AST, 
alkaline phosphatase, bilirubin) until they resolve, 
stabilise or return to within baseline 

If at any time subject meets the liver chemistry 
stopping criteria, proceed as described above

If, after 4 weeks of monitoring, ALT <3xULN and 
bilirubin <2xULN, monitor subjects twice monthly 
until liver chemistries normalize or return to within 
baseline.

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12.3.
Appendix 3: Daprodustat Risk Assessment
Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Excessive erythropoiesis leading to 
thrombosis and/or tissue ischemia
In animal studies, excessive erythropoiesis (Hgb/Hct > upper limit normal) 
attributed to daprodustat was associated with vascular 
congestion/inflammation, microthrombi, and tissue ischemia in a number of 
organs.
In the phase 2 proof of concept study, a high incidence of discontinuation due 
to hemoglobin stopping criteria (Hgb > 13.5 g/dL or Hgb increased > 1 g/dL 
over any 2-week period) was observed.  In non-dialysis subjects administered 
10 mg, 25 mg, 50 mg or 100 mg of daprodustat daily, a total of 21 of 61 
subjects (34%) met these criteria.  In hemodialysis-dependent subjects 
administered either 10 mg or 25 mg of daprodustat daily, a total of 8 of 31 
subjects (26%) met these criteria.
Phase 2 dose-ranging studies, and associated statistical and exposure 
response modelling has informed Phase 3 dose rationale, starting doses, 
dose levels, and dose adjustment scheme to optimize Hgb management.
Integrated AE data [including 2 global phase 2b studies (24-week treatment 
duration) and 2 Japanese phase 3 studies (52-week treatment duration)]: Few 
subjects experienced a possible thrombosis related adverse event in the 
setting of excessive erythropoiesis [3/688 (0.5%) subjects on daprodustat vs. 
0/404 on rhEPO].
Following review of clinical data received to date, this has not been identified 
as a safety concern for daprodustat when dose is managed appropriately 
according to target Hgb. However, experience with daprodustat is currently 
insufficient to fully characterize this risk.

Specific eligibility criteria related to requirements 
for entry Hgb are detailed in Section 5

Hgb will be closely monitored throughout the 
dosing period as outlined in the Time and Events 
Table (Section 7.1)

Specific guidance for dose adjustment, dose 
interruption, or discontinuation of daprodustat 
based on achieved Hgb (including rate of 
change) is provided in Section 5.5.1.1

Instream monitoring of safety data by an internal  
safety review team
Worsening 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 

Specific eligibility criteria related to blood 
pressure, including exclusion of subjects with 
uncontrolled hypertension, are detailed in 
Section 6.2

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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
uncontrolled hypertension, including the need for initiation of or increases in 
antihypertensive therapy when used in patients with anemia of CKD (i.e. 25% 
Epogen, 27% Mircera, and 40% Aranesp treated patients with renal anemia 
required initiation or increase in their anti-hypertensive medications; 
hypertensive encephalopathy and seizures have been reported. The 
contribution of rhEPO-associated hypertension to the unfavourable effects on 
cardiovascular outcomes remains uncertain).
Integrated AE data from clinical trials with daprodustat [including 2 global 
phase 2b studies (24-week treatment duration) and 2 Japanese phase 3 
studies (52-week treatment duration)]: 
o
The majority (>90%) of subjects had baseline history of hypertension.
o
No meaningful difference was seen between treatment groups in AEs 
(preferred term) of “hypertension” [29/688 (4%) daprodustat vs. 19/404 
(4%) rhEPO; 0.91 relative risk (RR) (95% confidence interval: 0.5, 1.67)] 
or “blood pressure increased” [16 (2%) daprodustat vs. 7 (2%) rhEPO; 
RR 1.22 (0.48,3.11)]. Results were not substantively different between 
non-dialysis and haemodialysis subjects.
o
Although no clinically meaningful changes in blood pressure were 
observed, subjects in both treatment groups required increases in anti-
HTN medications:
o
In the 24-week global phase 2b studies, 25/170 (15%) of ND 
subjects receiving daprodustat vs. 18/80 (14%) control and 
22/177 (12%) of HD subjects receiving daprodustat vs. 2/39 
(5%) control.
o
In the 52-week Japan phase 3 studies, 57/149 (38%) of ND 
subjects receiving daprodustat vs. 68/150 (45%)  rhEPO and 
51/136 (38%) of HD subjects receiving daprodustat vs. 66/135 

Blood pressure will be closely monitored 
throughout the dosing period as outlined in the 
Time and Events Table Section 7.1.

Monitoring of emerging safety data by an 
internal GSK Safety Review Team.

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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
(49%) for rhEPO.
The data received to date from completed clinical trials with daprodustat are 
insufficient to refute this risk.
Death, MI, stroke, heart failure, 
thromboembolic events, thrombosis of 
vascular access at Hgb levels which are within 
the normal range (i.e. not polycythemic 
conditions)
Marketed rhEPO and its analogs have been associated with an increased risk 
for death and serious cardiovascular events when used in patients with 
anemia of CKD.  Clinical studies with marketed rhEPO/analogs have 
suggested “higher” target hemoglobin, rate of hemoglobin rise of greater than 
1 g/dL in any 2-week period, and/or higher doses may contribute to these 
risks.
In non-clinical studies conducted to date, not observed at tolerated doses 
when hemoglobin/hematocrit within normal range for species.
Integrated AE data from clinical trials with daprodustat [including 2 global 
phase 2b studies (24-week treatment duration) and 2 Japanese phase 3 
studies (52-week treatment duration)]: No meaningful difference was seen 
between treatment groups in the overall incidence of this AESI: [39/688 
(5.5%) daprodustat vs. 25/404 (6%) rhEPO; 0.92 relative risk (95% confidence 
interval: 0.55, 1.53)]. Within this composite AESI, the most frequent event 
types were heart failure (at least 12 events daprodustat vs. at least 13 events 
rhEPO) and thrombosis (at least 14 events daprodustat vs. at least 8 event 
rhEPO); and a numerical imbalance was noted in events of myocardial 
ischemia (at least 7 events daprodustat vs. at least 1 event rhEPO). The small 
number of events makes it difficult to draw any firm conclusions.
The clinical data received to date from completed clinical trials with 
daprodustat are insufficient to substantiate or refute this risk.
Specific eligibility criteria related to CV risk are 
outlined in Section 5.3
Hgb will be closely monitored throughout the 
dosing period as outlined in the Time and Events 
Table Section 7.1
Instream monitoring of safety data by an 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 daprodustat.
In rodents, stomach erosions were observed with intravenous and oral 
Suspected GI bleeding or significant symptoms 
consistent with erosion should be investigated 
diagnostically (i.e. endoscopic examination) as 
clinically warranted
Instream monitoring of safety data by an internal 

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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
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.
safety review team
Cancer-related mortality and tumor 
progression and recurrence
Marketed rhEPO and its analogs have been associated with increased risk of 
cancer related morbidity and mortality when used in patients with cancer.
Administration of 60mg/kg daprodustat to mice caused minimal increases in 
circulating VEGF while significant EPO increases were observed.
In clinical studies with daprodustat up to 4 weeks duration, a dose-ordered 
increase in VEGF plasma concentrations, an angiogenic factor that has been 
implicated in tumor growth, was observed at doses ranging from 10 to 150 
mg.  In clinical studies up to 24 weeks duration at doses up to 25 mg, changes 
in VEGF plasma concentrations were variable but similar relative to control.
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 
Specific eligibility criteria related to personal 
history of malignancy or subjects with complex 
kidney cyst are outlined in Section 5.3.
Stopping criteria for subjects with treatment 
emergent malignancy are outlined in Section 
5.5.1.
Instream monitoring of safety data by an internal 
safety review team

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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 (up to 13-weeks duration dogs, up to 2 years in rats and mice, 
and up to 39-weeks in monkeys.
Acute hypoxic challenge (rats): Daprodustat produced increases in peak right 
ventricular pressure (PRVP) during acute hypoxia that were slightly higher 
than the vehicle control group.  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 
echocardiographically (ECHO) estimates of pulmonary artery systolic 
pressure (PASP) under either normoxic or hypoxic conditions. ECHO 
assessments performed in Phase 2b studies (24 weeks treatment duration) 
did not identify any clinically meaningful changes in PASP in participants
not on dialysis for daprodustat. In hemodialysis participants, mean absolute 
change from baseline in PASP was similar for both treatment groups; 
however, there was a numeric imbalance (Daprodustat Total: 8 [7%]; 
Control 0) in participants reaching the PASP PCI (>20 mmHg increase from 
baseline). Regarding this imbalance, there were a number of confounding 
factors in the study, most notably a 4.5:1 randomization scheme and 
inconsistency in timing of ECHOs relative to dialysis day.  Additionally, 2 of 
3 participants with resolution of PASP on safety follow-up ECHOs had 
confounding conditions that could contribute to resolution other than 
discontinuation of study drug; and there was no dose relationship for 
participants meeting the PASP percutaneous coronary intervention(PCI)
Instream monitoring of safety data by an internal 
safety review team

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

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Small increases in cardiac troponin in 6 month rat study with daprodustat were 
consistent with the background finding of spontaneous rodent 
cardiomyopathy.  There were no elevations observed in cardiac troponin in 9 
month monkey study with daprodustat.
Cardiomyopathy has not been associated with naturally occurring mutation in 
man which results in increased HIF stabilization.
ECHO assessments performed in phase 2b studies (24 weeks treatment 
duration) did not identify any clinically meaningful changes in LVEF for 
daprodustat.
Integrated AE data from clinical trials with daprodustat [including 2 global 
phase 2b studies (24-week treatment duration) and 2 Japanese phase 3 
studies (52-week treatment duration)]: No meaningful difference was seen 
between treatment groups in reports of this AESI [1 (0.1%) daprodustat vs. 1 
(0.2%) rhEPO; 0.64 relative risk (95% confidence interval: 0.02, 18.07)].
Following review of clinical data received to date, this has not been identified 
as a safety concern for daprodustat.
Proliferative retinopathy, macular edema, 
choroidal neovascularization
Increases in local (ocular) VEGF production with retinal neovascularization 
and macular edema observed in diabetic retinopathy and to choroidal 
leakage, edema and neovascularization seen in age-related macular 
degeneration [Campochiaro, 2006]
Administration of 60 mg/kg daprodustat to mice caused minimal increases in 
circulating VEGF while significant EPO increases were observed.
No ocular abnormalities with daprodustat were seen in non-clinical studies of 
up to 13 weeks duration in mice and dogs, 26 weeks in rats, and 39 weeks in 
monkeys.
In clinical studies up to 4 weeks duration, a dose-ordered increase in VEGF 
plasma concentrations was observed at doses ranging from 10 to 150 mg
administered once daily and from 10 to 30 mg administered three times 
Instream monitoring of safety data by an internal 
safety review team

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weekly. In studies up to 24 weeks duration at doses up to 25 mg, changes in 
VEGF plasma concentrations were variable but similar relative to control.
Ophthalmologic assessments performed in phase 2b studies (24 weeks 
treatment duration) did not identify any clinically meaningful changes in 
proliferative retinopathy, macular edema, or choroidal neovascularization with 
daprodustat.
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 received to date, this has not been identified 
as a safety concern for daprodustat.
Exacerbation of rheumatoid arthritis
In inflamed rheumatic joints, activation of HIF- related genes secondary to 
decreased oxygen and pro-inflammatory cytokines has been postulated to 
contribute to the neo-angiogenesis, proliferation and infiltration of rheumatoid 
synovial fibroblasts [Westra, 2010; Muz, 2009].
No abnormalities seen in non-clinical studies conducted to date for
daprodustat.
Integrated AE data [including 2 global phase 2b studies (24-week treatment 
duration) and 2 Japanese phase 3 studies (52-week treatment duration)]: No 
meaningful difference was seen between treatment groups in reports of this 
AESI [2 (0.3%) daprodustat vs. 1 (0.2%) rhEPO; 1.20 relative risk; (95% 
confidence interval: 0.07, 20.87) and the incidence of musculoskeletal AEs 
was generally lower in the daprodustat treatment group].
Following review of clinical data received to date, this has not been identified 
as a safety concern for daprodustat.
Instream monitoring of safety data by an internal  
safety review team

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Drug-drug interactions
Daprodustat is a substrate of CYP2C8: Co-administration of daprodustat with 
a strong CYP2C8 inhibitor increased the maximum plasma concentration
(Cmax) and area under curve (AUC) of daprodustat, 4- and 19-fold, 
respectively, while co-administration of a weak inhibitor (i.e., trimethoprim) 
increased the Cmax and AUC of daprodustat by 1.3- and 1.5-fold, 
respectively. Population PK analysis from completed Phase 2 studies 
suggests that co-administration of daprodustat with a moderate CYP2C8 
inhibitor (i.e., clopidogrel) leads to a ~ 2-fold increase in AUC, with no 
clinically-significant increase in the measured Hb response. Although CYP2C8 
induction studies were not performed, co-administration of daprodustat with 
an inducer of CYP2C8 (e.g., rifampin/rifampicin) may decrease the exposure 
of daprodustat.
Daprodustat is an inhibitor of CYP2C8: A clinical drug interaction study 
between 25mg and 100mg daprodustat with a CYP2C8 substrate (i.e., 
pioglitazone) showed that there is no PK interaction at these doses of 
daprodustat.  
Daprodustat is a substrate of Breast cancer resistance protein (BCRP):  
Population PK analysis from Phase 2 studies suggested that while BCRP 
inhibitors were a covariate for daprodustat apparent total body clearance 
(CL/F) (8.6% lower clearance) the predicted change in exposure was not 
considered to be of clinical relevance.
Daprodustat is an inhibitor of organic anion transporter polypedtides
(OATP)1B1/1B3:  A clinical drug interaction study between 25mg and 100mg 
daprodustat with an OATP1B1/1B3 substrate (i.e., rosuvastatin) showed no 
PK interaction at these doses of daprodustat.
Co-administration of daprodustat with strong 
CYP2C8 inhibitors (e.g., gemfibrozil) and 
inducers (e.g., rifampin/rifampicin) is not 
permitted as outlined in Section 6.11.3.
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. Specific 
guidance on the management of potential drug-
drug interactions and concomitant medications is 
provided in Section 6.11.
Hgb will be closely monitored throughout the 
dosing period as outlined in the Time and Events 
Table (Section 7.1)
Specific guidance for dose adjustment, dose 
interruption, or discontinuation of daprodustat 
based on achieved Hgb is provided in Section 
5.5.1.1.
Instream monitoring of safety data by an internal  
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 

Kidney function  will be monitored throughout 
the dosing period as outlined in the Time and 
Events Table (Section 7.1).

Monitoring of emerging safety data by an 
internal GSK Safety Review Team.

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

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Mitigation Strategy
pressure management are outlined in Section 5.
Specific eligibility criteria related to personal 
history of pure red cell aplasia are outlined in 
Section 5.3

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12.4.
Appendix 4: Definition of and Procedures for Recording, 
Evaluating, Follow-Up and Reporting of Adverse Events
12.4.1.
Definition of Adverse Events
Adverse Event Definition:

An AE is any untoward medical occurrence in a patient or clinical investigation 
subject, temporally associated with the use of a medicinal product, whether or not 
considered related to the medicinal product.

NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a medicinal product.
Events meeting AE definition include:

Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) 
or other safety assessments (e.g., ECGs, radiological scans, vital signs 
measurements), including those that worsen from baseline, and felt to be clinically 
significant in the medical and scientific judgement of the investigator.

Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition.

New conditions detected or diagnosed after study treatment administration even 
though it may have been present prior to the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected interaction.

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
treatment or a concomitant medication (overdose per se will not be reported as an 
AE/SAE unless this is an intentional overdose taken with possible suicidal/self-
harming intent.  This should be reported regardless of sequelae).

"Lack of efficacy" or "failure of expected pharmacological action" per se will not be 
reported as an AE or SAE.  However, the signs and symptoms and/or clinical 
sequelae resulting from lack of efficacy will be reported if they fulfil the definition 
of an AE or SAE.
Events NOT meeting definition of an AE include:

Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the subject’s condition.

The disease/disorder being studied or expected progression, signs, or symptoms of 
the disease/disorder being studied, unless more severe than expected for the subject’s 
condition.

Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that 

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leads to the procedure is an AE.

Situations where an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).

Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present 
or detected at the start of the study that do not worsen.
12.4.2.
Definition of Serious Adverse Events
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met (e.g., hospitalization for signs/symptoms of the disease under study, 
death due to progression of disease, etc).
Serious Adverse Event (SAE) is defined as any untoward medical occurrence that, 
at any dose:
a.
Results in death
b.
Is life-threatening
NOTE:
The term 'life-threatening' in the definition of 'serious' refers to an event in which the 
subject was at risk of death at the time of the event.  It does not refer to an event, which 
hypothetically might have caused death, if it were more severe.
c.
Requires hospitalization or prolongation of existing hospitalization
NOTE:

In general, hospitalization signifies that the subject has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for 
observation and/or treatment that would not have been appropriate in the physician’s 
office or out-patient setting.  Complications that occur during hospitalization are 
AEs.  If a complication prolongs hospitalization or fulfills any other serious criteria, 
the event is serious.  When in doubt as to whether “hospitalization” occurred or was 
necessary, the AE should be considered serious.

Hospitalization for elective treatment of a pre-existing condition that did not worsen 
from baseline is not considered an AE.
d.
Results in disability/incapacity
NOTE:

The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.

This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (e.g. sprained ankle) which may interfere or prevent everyday 
life functions but do not constitute a substantial disruption
e.
Is a congenital anomaly/birth defect

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f.
Other situations:

Medical or scientific judgment should be exercised in deciding whether reporting is 
appropriate in other situations, such as important medical events that may not be 
immediately life-threatening or result in death or hospitalization but may jeopardize 
the subject or may require medical or surgical intervention to prevent one of the 
other outcomes listed in the above definition.  These should also be considered 
serious.

Examples of such events are invasive or malignant cancers, intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse
g.
Is associated with liver injury and impaired liver function defined as:

ALT 3xULN and total bilirubin* 2xULN (>35% direct), or

ALT 3xULN and International normalized ratio (INR)** >1.5.
* Serum bilirubin fractionation should be performed if testing is available; if unavailable, 
measure urinary bilirubin via dipstick.  If fractionation is unavailable and ALT 3xULN 
and total bilirubin 2xULN, then the event is still to be reported as an SAE.
** INR testing not required per protocol and the threshold value does not apply to 
subjects receiving anticoagulants.  If INR measurement is obtained, the value is to be 
recorded on the SAE form.
12.4.3.
Definition of Cardiovascular Events
Cardiovascular Events (CV) Definition:
Investigators will be required to fill out the specific CV event page of the CRF for the 
following AEs and SAEs or any event that may potentially be one of these categories:

Myocardial infarction/unstable angina

Congestive heart failure

Arrhythmias

Valvulopathy

Pulmonary hypertension

Cerebrovascular events/stroke and transient ischemic attack

Peripheral arterial thromboembolism

Deep venous thrombosis/pulmonary embolism

Revascularization

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12.4.4.
Recording of AEs and SAEs
AEs and SAE Recording:

When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (e.g., hospital progress notes, laboratory, and diagnostics reports) 
relative to the event.

The investigator will then record all relevant information regarding an AE/SAE in 
the CRF

It is not acceptable for the investigator to send photocopies of the subject’s medical 
records to GSK in lieu of completion of the GSK, AE/SAE CRF page.

There may be instances when copies of medical records for certain cases are 
requested by GSK.  In this instance, all subject identifiers, with the exception of the 
subject number, will be blinded on the copies of the medical records prior to 
submission of to 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.
12.4.5.
Evaluating AEs and SAEs
Assessment of Intensity
The investigator will make an assessment of intensity for each AE and SAE reported 
during the study and will assign it to one of the following categories:

Mild:  An event that is easily tolerated by the subject, causing minimal discomfort 
and not interfering with everyday activities.

Moderate:  An event that is sufficiently discomforting to interfere with normal 
everyday activities

Severe:  An event that prevents normal everyday activities. - an AE that is assessed 
as severe will not be confused with an SAE. Severity is a category utilized for rating 
the intensity of an event; and both AEs and SAEs can be assessed as severe.

An event is defined as ‘serious’ when it meets at least one of the pre-defined 
outcomes as described in the definition of an SAE.
Assessment of Causality

The investigator is obligated to assess the relationship between study 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.

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
Alternative causes, such as natural history of the underlying diseases, concomitant 
therapy, other risk factors, and the temporal relationship of the event to the study 
treatment will be considered and investigated.

The investigator will also consult the Investigator Brochure (IB) and/or Product 
Information, for marketed products, in the determination of his/her assessment.

For each AE/SAE the investigator must document in the medical notes that he/she 
has reviewed the AE/SAE and has provided an assessment of causality.

There may be situations when an SAE has occurred and the investigator has minimal 
information to include in the initial report to 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.
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.

If a subject dies during participation in the study or during a recognized follow-up 
period, the investigator will provide GSK with a copy of any post-mortem findings, 
including histopathology.

New or updated information will be recorded in the originally completed CRF.

The investigator will submit any updated SAE data to GSK within the designated 
reporting time frames.
12.4.6.
Reporting of SAEs to GSK
SAE reporting to GSK via electronic data collection tool

Primary mechanism for reporting SAEs to GSK will be the electronic data collection 
tool

If the electronic system is unavailable for greater than 24 hours, the site will use the 
paper SAE data collection tool and fax it to the Medical Monitor.

Site will enter the serious adverse event data into the electronic system as soon as it 
becomes available.

The investigator will be required to confirm review of the SAE causality by ticking 

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the ‘reviewed’ box at the bottom of the eCRF page within 72 hours of submission of 
the SAE.

After the study is completed at a given site, the electronic data collection tool (e.g., 
InForm system) will be taken off-line to prevent the entry of new data or changes to 
existing data

If a site receives a report of a new SAE from a study subject or receives updated data 
on a previously reported SAE after the electronic data collection tool has been taken 
off-line, the site can report this information on a paper SAE form or to the Medical 
Monitor by telephone.

Contacts for SAE receipt can be found at the beginning of this protocol on the 
Sponsor/Medical Monitor Contact Information page.
12.4.7.
Modified List of Highly Effective Methods for Avoiding Pregnancy 
in Females of Reproductive Potential (FRP)
This list does not apply to FRP with same sex partners, when this is their preferred and 
usual lifestyle or for subjects who are and will continue to be abstinent from penile-
vaginal intercourse on a long term and persistent basis.  Periodic abstinence (e.g., 
calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not 
acceptable methods of contraception.
1. Contraceptive subdermal implant.
2. Intrauterine device or intrauterine system.
3. Combined estrogen and progestogen oral contraceptive [Trussell, 2011].
4. Injectable progestogen [Trussell, 2011]
5. Contraceptive vaginal ring [Trussell, 2011]
6. Percutaneous contraceptive patches [Trussell, 2011]
7. Male partner sterilization prior to the female subject's entry into the study, and 
this male is the sole partner for that subject [Trussell, 2011]. The 
documentation on male sterility can come from the site personnel’s: review of 
subject’s medical records, medical examination and/or semen analysis, or 
medical history interview provided by her or her partner.
This is an all inclusive list of those methods that meet the GSK definition of highly 
effective: having a failure rate of less than 1% per year when used consistently and, 
correctly and, when applicable, in accordance with the product label.  For non-product 
methods (e.g.  male sterility), the investigator determines what is consistent and correct 
use. The GSK definition is based on the definition provided by the ICH.
The investigator is responsible for ensuring that subjects understand how to properly use 
these methods of contraception.

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References
Trussell J, Contraceptive Efficacy. In: Hatcher RA, Trussell J, Nelson AL, Cates W, 
Kowal D, and Policar M (editors). Contraceptive Technology: Twentieth Revised 
Edition. New York: Ardent Media, 2011.Table 26-1
12.4.8.
Collection of Pregnancy Information

Investigator will collect pregnancy information on any female subject, who becomes 
pregnant while participating in this study.

Information will be recorded on the appropriate form and submitted to GSK within 2 
weeks of learning of a subject's pregnancy.

Subject will be followed to determine the outcome of the pregnancy. The 
investigator will collect follow up information on mother and infant, which will be 
forwarded to 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 12.4.  While the investigator is not obligated to actively seek 
this information in former study participants, he or she may learn of an SAE through 
spontaneous reporting.
Any female subject who becomes pregnant while participating will discontinue 
study medication and be withdrawn from the study.

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12.5.
Appendix 5 - Country Specific Requirements
No country-specific requirements exist.

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12.6.
Appendix 6 – Ambulatory Blood Pressure Monitoring Device

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12.7.
Appendix 7 – Protocol Changes
12.7.1.
Amendment 1
Summary of Amendment Changes with Rationale
This protocol amendment applies to all centers where this study may be performed.  
This protocol amendment was written to clarify specific biomarkers being drawn, modify 
time points of biomarkers, clarify safety laboratory studies, and clarify day/time of 
assessments.  Additionally, a potential additional study visit has been added if necessary.
List of Specific Changes
Title Page
REVISED TEXT, where bolded text has been added
Authors:
 
 
Section 1 Protocol Synopsis for Study 205665
REVISED TEXT where bolded text has been added
The purpose of this study is to compare the effects on blood pressure of daprodustat to
epoetin alfa in hemodialysis-dependent (HD) subjects with anemia associated with 
chronic kidney disease (CKD).  The study will also assess various biomarkers associated 
with blood pressure physiology that may provide insight into the mechanism(s) of the 
hypertensive effects associated with erythropoiesis stimulating agent(s) (ESAs).
Exploratory Section of the Objective(s)/Endpoint(s) Table
REVISED TEXT, where text in strikethrough has been removed and bolded text has been 
added.
Objectives
Endpoints
Exploratory

To investigate the effect of daprodustat on 
vasoactive mediators of blood pressure

Plasma concentrations and derived 
parameters including Cmax, tmax, t½ and 
AUC(0-24) as appropriate (to include
erythropoietin, endothelin-1, proendothelin-1,
nitric oxide, asymmetric dimethylarginine, 
renin, angiotensin-II, aldosterone and MR-
proadrenomedullin [proADM] noradrenalin)

Evaluate exposure-response relationships for 
daprodustat and: erythropoietin, endothelin-1, 
proendothelin-1, nitric oxide, asymmetric 

Further models (as appropriate) to describe the 
daprodustat exposure-response relationship 
with: erythropoietin, endothelin-1, 
PPD

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Objectives
Endpoints
dimethylarginine, renin, angiotensin-II,
aldosterone and MR-proADM noradrenalin .
proendothelin-1, nitric oxide, asymmetric 
dimethylarginine, renin, angiotensin-II,
aldosterone and MR-proADM noradrenalin.

To summarize the effect of daprodustat and 
epoetin alfa on SBP after Acute Challenge 1 
and Acute Challenge 2

AUEC of SBP as measured by ABPM over 24-
hr post-dosing

To compare the effect of daprodustat to epoetin 
alfa on SBP after 8 weeks of Hgb maintenance 
therapy

Change from Day 1 pre-dose SBP to Week 8 
pre-dose
Section 1 Study Design
PREVIOUS IMAGE
REVISED IMAGE
REVISED TEXT where text in strikethrough has been removed and bolded text has been 
added.
Subjects will be screened for eligibility starting 4 weeks prior to the start of an ESA 
washout period (8 weeks prior to randomization/Day 1).
Subjects that qualify for enrolment will be washed out of their ESA for 4 weeks; the start 
of the ESA washout should be timed to coincide as closely as possible with their next 
planned ESA dose.
Following the 4-week ESA washout, subjects will be randomized 1:1 and stratified by 
prior ESA dose, based on the average weekly (for epoetins or darbepoetin) or monthly 

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(for methoxy polyethylene glycol (PEG)-epoetin beta) dosing during the 12 weeks prior 
to ESA washout (Week -4) as follows:

Low ESA dose: <100 IU/kg/week epoetin alfa OR <0.5 µg/kg/week darbepoetin 
OR <0.6 µg/kg/week methoxy PEG-epoetin beta

High ESA dose: ≥100 IU/kg/week epoetin alfa OR ≥0.5 µg/kg/week darbepoetin 
OR 0.6 µg/kg/week methoxy PEG-epoetin beta
On Day 1, subjects will be randomized and undergo Acute Challenge 1, a single dose 
challenge to compare the acute effects on BP of the highest planned once-daily 
maintenance dose of daprodustat (24 mg) to the highest starting dose of epoetin alfa 
(100 IU/kg).  Subjects will have BP monitored for 24 hr using ABPM, and will have 
serial blood sampling to assess the pharmacokinetics of daprodustat and the time-course 
of various biomarkers.  Acute Challenge 1 will be started immediately following 
completion of a mid-week dialysis session.
After completing Acute Challenge 1, all subjects will enter the 8-week Hgb maintenance 
period where doses of either daprodustat or epoetin alfa will be administered and 
adjusted, as needed.
On Day 57 At Week 8, following the 8-week Hgb maintenance period, subjects will 
undergo Acute Challenge 2; this challenge will, similar to Acute Challenge 1, involve 
assessing the effect of daprodustat and epoetin alfa on SBP as assessed by 24-hr ABPM 
measurement.  The subjects will be administered the same dose of either daprodustat or 
epoetin alfa that was given in Acute Challenge 1, and serial blood sampling will be 
performed to assess both daprodustat pharmacokinetics, and to characterize the time 
course of various biomarkers.  Acute Challenge 2 will be started following completion of 
a mid-week dialysis session.
Subjects will be asked to not reinitiate anemia treatment until after the follow-up visit 
unless deemed medically necessary.
Subjects will attend a follow-up visit 2 weeks after completion of Acute Challenge 2.
After both Acute Challenge 1 and 2, the 24-hr ABPM results will be checked for 
data quality as defined in the Project Requirement Specification (PRS).  If the 
ABPM fails the QC criteria following Acute Challenge 2, one additional Acute 
Challenge may be made in a subsequent, mid-week dialysis visit 1 week later if the 
subject agrees. At that visit, the subject will receive the same study treatment for 
the repeat Acute Challenge 2 as was administered on Day 57 as a single additional 
dose. No additional clinical chemistry, hematology, pharmacokinetic or biomarker 
sampling will be done, however all other procedures will be performed. 
Section 1 Treatment Arms and Duration
REVISED TEXT where the bolded text has been added

Acute Challenge 2 (Day 57) : At the end of the 8-week Hgb maintenance period 
subjects will repeat the procedures of Acute Challenge 1 utilizing the same 
treatment administered in Acute Challenge 1.  This challenge will be initiated 
immediately following the subject’s dialysis session.

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Section 3 OBJECTIVE(S) AND ENDPOINT(S)
REVISED TABLE where where text in strikethrough has been removed and bolded text 
has been added.
Exploratory

To investigate the effect of daprodustat on 
vasoactive mediators of blood pressure

Plasma concentrations and derived 
parameters including Cmax, tmax, t½ and 
AUC(0-24) as appropriate (to include
erythropoietin, endothelin-1, proendothelin-1,
nitric oxide, asymmetric dimethylarginine, 
renin, angiotensin-II, aldosterone and MR-
proadrenomedullin [proADM]) and 
noradrenalin)

Evaluate exposure-response relationships for 
daprodustat and: erythropoietin, endothelin-1, 
proendothelin-1, nitric oxide, asymmetric 
dimethylarginine, renin, angiotensin-II, 
aldosterone and MR-proAdm and 
noradrenalin.

Further models (as appropriate) to describe the 
daprodustat exposure-response relationship 
with: erythropoietin, endothelin-1, 
proendothelin-1, nitric oxide, asymmetric 
dimethylarginine, renin, angiotensin-II, 
aldosterone and MR-proAdm and 
noradrenalin.

To summarize the effect of daprodustat and 
epoetin alfa on SBP after Acute Challenge 1 
and Acute Challenge 2

AUEC of SBP as measured by ABPM over 24-
hr post-dosing

To compare the effect of daprodustat to epoetin 
alfa on SBP after 8 weeks of Hgb maintenance 
therapy

Change from Day 1 pre-dose SBP to Week 8 
pre-dose
Section 4.1 Overall Design
PREVIOUS FIGURE 1

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REVISED FIGURE 1
REVISED TEXT where text in strikethrough has been removed and bolded text has been 
added
Subjects will be screened for eligibility starting 4 weeks prior to the start of an ESA 
washout period (8 weeks prior to randomization/Day 1).
Subjects that qualify for enrolment will be washed out of their ESA for 4 weeks; the start 
of the ESA washout should be timed to coincide as closely as possible with their next 
planned ESA dose.
Following the 4-week ESA washout, subjects will be randomized 1:1 and stratified by 
prior ESA dose, based on the average weekly (for epoetins or darbepoetin) or monthly 
(for methoxy polyethylene glycol (PEG)-epoetin beta) dosing during the 12 weeks prior 
to ESA washout (Week -4) as follows:

Low ESA dose: <100 IU/kg/week epoetin alfa OR <0.5 µg/kg/week darbepoetin 
OR <0.6 µg/kg/week methoxy PEG-epoetin beta

High ESA dose: ≥100 IU/kg/week epoetin alfa OR ≥0.5 µg/kg/week darbepoetin 
OR 0.6 µg/kg/week methoxy PEG-epoetin beta
On Day 1, subjects will be randomized and undergo Acute Challenge 1, a single dose 
challenge to compare the acute effects on BP of the highest planned once-daily 
maintenance dose of daprodustat (24 mg) to the highest starting dose of epoetin alfa 
(100 IU/kg).  Subjects will have BP monitored for 24 hr using ABPM, and will have 
serial blood sampling to assess the pharmacokinetics of daprodustat and the time-course 
of various biomarkers.  Acute Challenge 1 will be started immediately following 
completion of a mid-week dialysis session.
After completing Acute Challenge 1, all subjects will enter the 8-week Hgb maintenance 
period where doses of either daprodustat or epoetin alfa will be administered and 
adjusted, as needed.
On Day 57 At Week 8, following the 8-week Hgb maintenance period, subjects will 
undergo Acute Challenge 2; this challenge will, similar to Acute Challenge 1, involve 
assessing the effect of daprodustat and epoetin alfa on SBP as assessed by 24-hr ABPM 
measurement.  The subjects will be administered the same dose of either daprodustat or 
epoetin alfa that was given in Acute Challenge 1, and serial blood sampling will be 
performed to assess both daprodustat pharmacokinetics, and to characterize the time 

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course of various biomarkers.  Acute Challenge 2 will be started following completion of 
a mid-week dialysis session.
Subjects will be asked to not reinitiate anemia treatment until after the follow-up visit 
unless deemed medically necessary.
Subjects will attend a follow-up visit 2 weeks after completion of Acute Challenge 2.
After both Acute Challenge 1 and 2, the 24-hr ABPM results will be checked for 
data quality as defined in the Project Requirement Specification (PRS).  If the 
ABPM fails the QC criteria following Acute Challenge 2, one additional Acute 
Challenge may be made in a subsequent, mid-week dialysis visit 1 week later if the 
subject agrees. At that visit, the subject will receive the same study treatment for 
the repeat Acute Challenge 2 as was administered on Day 57 as a single additional 
dose. No additional clinical chemistry, hematology, pharmacokinetic or biomarker 
sampling will be done, however all other procedures will be performed as detailed in 
Table 4. 
Section 5.1 Hemoglobin Stability Criteria
REVISED TEXT, where the text in strikethrough has been removed
Entry into the study requires a stable Hgb between 9.0 and 11.5 g/dL, inclusive.  This is 
confirmed from an average of three Hgb values obtained during the screening period at 
Weeks -8, -6 and -4 via a validated point-of-care device to measure Hgb (i.e., HemoCue) 
as outlined in Figure 3.  Calculations to determine eligibility will be performed 
automatically by an Interactive Voice/Web Response System (IVWRS).  For subjects 
with a three-times weekly dialysis schedule, Hgb values must not be obtained on the first 
dialysis session of the week (e.g., if Monday-Wednesday-Friday schedule, the study visit 
cannot be on Monday).  For subjects with a four- to five-times weekly dialysis schedule, 
Hgb values can be obtained on any hemodialysis session of the week.
Section 5.3 Exclusion Criteria
REVISED TEXT, where the text in strikethrough has been removed and bolded text has 
been added
4. Mircera: Planned or recorded administration of Mircera (methoxy PEG-epoetin beta) 
within the 4 weeks prior to start of washout screening through at Week -4.
Section 5.5.1.1 Hemoglobin Stopping Criteria
REVISED TABLE 2 where text in strikethrough has been removed and bolded text has 
been added

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Table 8
Hgb Stopping Criteria
Week -2 & Day 1 (Prior to Acute Challenge 1)
Hgb at Visit
Action
<7.5
Repeat HemoCue assessment on the same sample at same study visit to confirm; take average of 2 
values.  If confirmed, withdraw subject from the study.
7.5-<11.5
decrease of 2.0 in Hgb 
over 2 weeks
Repeat HemoCue assessment on the same sample at same study visit 
to confirm; take average of 2 values.  If confirmed, permanently 
withdraw subject from the study.
increase of 1.0 in Hgb 
over 2 weeks
Repeat HemoCue assessment on the same sample at same study visit 
to confirm; take average of 2 values.  If confirmed, withdraw subject 
from the study.
11.5
Repeat HemoCue assessment on the same sample at same study visit to confirm; take average of 2 
values.  If confirmed, permanently withdraw subject from the study.
Days 15, 29, &43 Weeks 2, 4 & 6
Hgb at Visit
Action
<7.5
Repeat HemoCue assessment on the same sample at same study visit to confirm; take average of 2 
values.  If confirmed, permanently discontinue study treatment and withdraw subject from the study.
7.5-<12.0
decrease of 2.0 in Hgb 
over 2 weeks
Repeat HemoCue assessment on the same sample at same study visit 
to confirm; take average of 2 values.  If confirmed, permanently 
discontinue study treatment and withdraw subject from the study.
increase of 1.0 in Hgb 
over 2 weeks
Repeat HemoCue assessment on the same sample at same study visit 
to confirm; take average of 2 values.  If confirmed, permanently 
discontinue study treatment and withdraw subject from the study.
12.0
Repeat HemoCue assessment on the same sample at same study visit to confirm; take average of 2 
values.  If cofirmed, permanently discontinue study treatment and withdraw subject from the study.
Day 57 Week 8 (Prior to Acute Challenge 2)
Hgb at Visit
Action
<7.5
Repeat HemoCue assessment on the same sample at same study visit to confirm; take average of 2 
values.  If confirmed, permanently discontinue study treatment and withdraw subject from the study.
7.5-<11.0
decrease of 2.0 in Hgb 
over 2 weeks
Repeat HemoCue assessment on the same sample at same study visit 
to confirm; take average of 2 values.  If confirmed, permanently 
discontinue study treatment and withdraw subject from the study.
increase of 1.0 in Hgb 
over 2 weeks
Repeat HemoCue assessment on the same sample at same study visit 
to confirm; take average of 2 values.  If confirmed, permanently 
discontinue study treatment and withdraw subject from the study.
11.0
Repeat HemoCue assessment on the same sample at same study visit to confirm; take average of 2 
values.  If confirmed, permanently discontinue study treatment and withdraw subject from the study.
Section 6.4.1 Subjects Randomized to Daprodustat
REVISED TEXT where text in strikethrough has been removed and bolded text has been 
added
Subjects randomized to daprodustat will have doses adjusted, as required, to target Hgb 
within the range of 10.0-11.0 g/dL.  Dose adjustments will be assigned automatically via 
the IVWRS based on the subject’s Hgb value via onsite HemoCue assessment according 
to the following algorithms:

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Day 1 2
Hgb (g/dL)
Action or Dose
<7.5
Repeat HemoCue assessment on the same sample at same study visit to confirm; take 
average of 2 values.  If confirmed, withdraw subject from the study.
7.5 and <9.0
8 mg daprodustat
9 and <10.0
6 mg daprodustat
10.0 and <11.5
4 mg daprodustat
11.5
Repeat HemoCue assessment on the same sample at same study visit to confirm; take 
average of 2 values.  If confirmed, withdraw subject from the study.
The 8 week Hgb maintenance dosing will begin on Day 2, following Acute Challenge 
1.
Day 29 Week 4
The available dose steps for daprodustat are outlined below (highlighted boxes indicate 
starting doses).  Dose adjustments will result in the daprodustat dose being increased or 
decreased by one dose step.
4 mg
10 mg
6 mg
8 mg
2 mg
Hgb (g/dL)
Hgb change since
Day 1 visit
Dose Adjustment
<7.5
Any change
Repeat HemoCue assessment on the same sample at same 
study visit to confirm; take average of 2 values.  If confirmed, 
permanently discontinue study drug and withdraw subject from 
the study.
7.5 to <9.5
Decreasing or No change
Increase to the next higher dose step
7.5 to <9.5
Increasing
Maintain dose
9.5 to ≤11.5
Any change
Maintain dose
>11.5 to <12.0
Increasing or No change
Decrease to the next lower dose step
Decreasing
Maintain dose
≥12.0
Any change
Repeat HemoCue assessment on the same sample at same 
study visit to confirm; take average of 2 values.  If confirmed, 
permanently discontinue study treatment and withdraw subject 
from the study.
Section 6.7 Compliance with Study Treatment Administration
REVISED TEXT where text in strikethrough has been removed and bolded text has been 
added.
Randomized treatment start and stop dates and dosing details, including dates for 
randomized treatment interruptions and/or dose increases/reductions, will be recorded in
the eCRF RAMOS NG.

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Section 7 STUDY ASSESSMENTS AND PROCEDURES
REVISED TEXT where test in strikethrough has been removed and bolded text has been 
added
Protocol waivers or exemptions are not allowed with the exception of immediate safety 
concerns.  Therefore, adherence to the study design requirements, including those 
specified in the Time and Events Table (Section 7.1), are essential and required for study 
conduct.

If assessments are scheduled for the same nominal time, then the assessments 
should occur in the following order:
1. 12-lead ECG
2. vital signs
3. blood draws
Note: The timing of the assessments should allow the blood draw to occur at the 
exact nominal time.

The change in timing or addition of time points for any planned study 
assessments must be documented in a Note to File which is approved by the 
relevant GSK study team member and then archived in the study sponsor and 
site study files, but this will not constitute a protocol amendment.

The Institutional Review Board (IRB)/ Independent Ethics Committee (IEC)
will be informed of any safety issues that require alteration of the safety 
monitoring scheme or amendment of the Informed Consent Form.

No more than 550 500 mL of blood will be collected over the duration of the 
study, including any extra assessments that may be required.
Supplementary study conduct information is provided in the SRM.  The SRM provides 
administrative and detailed technical information that does not impact subject safety.
Section 7.1 Time and Events Table
PREVIOUS TABLE 3

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Table 3
Study Procedures and Assessments
Procedure1
Screening
ESA Washout
Treatment Period2
Follow-up2
Week -8
Week -6
Week -4
Week -2
Day 1
Week 2
Week 4
Week 6
Week 8 Early WD
Week 10
Informed Consent
X
Entry Criteria
X
Physical, Medical History, Demography
X
HemoCue Hgb
X
X
X
X
X4
X
X
X
X4
X
IVWRS Call
X
X
X
X
X
X
X
X
X
X
X
Randomization
X
Acute Challenge
X4
X4
ABPM Assessment
X4
X4
Initiation of epoetin alfa/daprodustat dosing
X
Dose Adjustment
X
Females Only: Serum Pregnancy Test
X
X
X
X
X
X
Females Only: Estradiol & FSH (if required)3
X
ECG
X
X4
X4
X
X
Vital signs & weight (Pre- & Post-dialysis)
X
X
X
X4
X
X4
X
X
Clinical Chemistry
X
X
X
X
X
X
Hematology
X
X
X
X
X
X
Folate
X
Ferritin, transferrin, total iron, unsaturated iron 
binding capacity (UIBC)
X
X
Pharmacokinetic/Biomarker Assessments
X4
X4
Hgb Maintenance Period5
=======================================
Blood draw for PGx
X
Adverse Events Assessment
X6
X6
X6
X6
X4
X
X
X
X4
X
X
Review Concomitant Medications
X
X
X
X4
X
X
X
X4
X
X
1 All assessments should be done predialysis/predose except as noted.
2 Allowable time window 2 days EXCEPT Follow-up Visit which is 3 days.
3 As detailed in Inclusion Criteria.
4 Detailed timings for assessments on Acute Challenge Days are given in Table 4.
5 From the end of Acute Challenge 1 to the beginning of Acute Challenge 2.
6 Only SAEs assessed as related to study participation are collected at this visit. See Section 12.4 for additional details.

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REVISED TABLE 3
Table 3
Study Procedures and Assessments
Procedure1
Screening
ESA Washout
Treatment Period2
Follow-up2
Week -8
Week -6
Week -4
Week -2
Day 1
Day 15
Day 29
Day 43
Day 57
Early WD
Week 10
Informed Consent
X
Entry Criteria
X
Physical, Medical History, Demography
X
HemoCue Hgb
X
X
X
X
X4
X
X
X
X4
X
IVWRS 
X
X
Randomization
X
Acute Challenge
X4
X4
ABPM Assessment
X4
X4
Dose Adjustment
X
Females Only: Serum Pregnancy Test
X
X
X
X
X
X
Females Only: Estradiol & FSH (if required)3
X
ECG
X
X4
X4
X
X
Vital signs & weight (Pre- & Post-dialysis)
X
X
X
X4
X
X4
X
X
Clinical Chemistry
X
X
X
X
X
X
Hematology
X
X
X
X
X
X
Folate and Vitamin B12
X
Ferritin, transferrin, total iron,TSAT, UIBC
X
X
Pharmacokinetic/Biomarker Assessments
X4
X4
Hgb Maintenance Period5
=======================================
Adverse Events Assessment
X6
X6
X6
X6
X4
X
X
X
X4
X
X
Review Concomitant Medications
X
X
X
X4
X
X
X
X4
X
X
1 All assessments should be done predialysis/predose except as noted.
2 Allowable time window 2 days EXCEPT Follow-up Visit which is 3 days.
3 As detailed in Inclusion Criteria.
4 Detailed timings for assessments on Acute Challenge Days are given in Table 4.
5 From the end of Acute Challenge 1 to the beginning of Acute Challenge 2.
6 Only SAEs assessed as related to study participation are collected at this visit. See Section 12.4 for additional details
.

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Section 7.1 Time and Events Table
PREVIOUS TABLE 4
Table 4
Study Procedures and Assessments on Acute Challenge Days (Treatment Period Day 1 and Week 8 Visit)
Procedure
Predose
Time (in hours relative to dosing)
0
0.5
1
2
3
4
6
8
12
16
24
ABPM Assessment
===========================================================================================
Administer Study Treatment
X
HemoCue Hgb
X
X
ECG
X
X
Vitals
X
X
X
X
Pharmacokinetic/Biomarker Assessments
X
X
X
X
X
X
X
X
X
X
X
Adverse Events Assessment
X
X
X
X
X
X
X
X
X
X
X
Review Concomitant Medications
X
X

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REVISED TABLE 4
Table 4
Study Procedures and Assessments on Acute Challenge Days (Treatment Period Day 1 and Day 57)
Procedure
Pre-
Dialysis
Post -
Dialysis Predose
Time (in hours relative to dosing)
0
0.5
1
2
3
4
6
8
12
16
24
HemoCue Hgb1
X
X
IVWRS
X
ABPM Assessment1
X
===========================================================================================
Administer Study Treatment1
X
Serum Pregnancy Test1
X
ECG1
X
X
Vital Signs and Weight1
X
X
X
X
X
Clinical Chemistry
X
Hematology
X
Pharmacokinetics
X
X
X
X
X
X
X
X
X
X
X
Erythropoietin
X
X
X
X
X
X
X
X
X
X
X
Endothelin-1
X
X
X
X
X
X
X
Nitric Oxide
X
X
X
X
X
X
X
Asymmetric dimethylarginine
X
X
X
X
X
X
X
Renin
X
X
X
X
X
X
X
Angiotensin-II
X
X
X
X
X
X
X
Noradrenalin
X
X
X
X
X
X
X
Adverse Events Assessment1
X
X
X
X
X
X
X
X
X
X
X
Review Concomitant Medications1
X
X
Initiate Hgb maintenance dosing2
X
1 Procedures to be repeated if Acute Challenge 2 fails quality control criteria
2 Applies to Acute Challenge 1 only

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Section 7.3.6 Clinical Safety Laboratory Assessments
PREVIOUS TABLE 5
Table 5
Protocol Required Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
Hematology
Platelet Count
RBC Indices:
WBC Count with 
Differential:
RBC Count
MCV
Neutrophils
Hemoglobin
MCH
Lymphocytes
Hematocrit
MCHC
Monocytes
WBC Count (absolute)
RDW
Eosinophils
Reticulocyte Count
CHr
Basophils
Clinical 
Chemistry
Potassium
AST (SGOT)
Total and direct/indirect 
bilirubin
Sodium
ALT (SGPT)
Total Protein
Glucose
Calcium (Albumin adjusted)
Alkaline Phosphatase
Albumin
Phosphate
Other laboratory 
Tests
Erythropoietin
Vascular Endothelial 
Growth Factor
Hepcidin
Serum ferritin
Serum iron
Serum transferrin
Transferrin saturation (% 
saturation)
Unbound iron binding 
capacity
Folate
Vitamin B12
Other Screening 
Tests1
FSH
Estradiol
Serum hCG Pregnancy test
NOTE: Details of Liver Chemistry Stopping Criteria and Required Actions and Follow-Up Assessments after liver 
stopping or monitoring event are given in Section 12.2.
1 As needed in women of non-child bearing potential only.
Abrreviations: ALT= Alanine transaminase; AST= Aspartate transaminase; CHr=Reticulocyte haemoglobin content; 
FSH=follicle stimulating hormone; MCH= Mean corpuscular haemoglobin; MCHC= Mean corpuscular hemoglobin 
concentration; MCV= Mean corpuscular volume; RBC= Red blood cell; RDW= Red blood cell distribution width; 
SGOT=Serum glutamic oxaloacetic transaminase; SGPT=Serum glutamic-pyruvic transaminase; WBC= White blood 
cells;

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REVISED TABLE 5
Table 5
Protocol Required Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
Hematology
Platelet Count
RBC Indices:
WBC Count with 
Differential:
RBC Count
MCV
Neutrophils
Hemoglobin
MCH
Lymphocytes
Hematocrit
MCHC
Monocytes
WBC Count (absolute)
RDW
Eosinophils
Reticulocyte Count
CHr
Basophils
Clinical 
Chemistry
Potassium
AST (SGOT)
Total and direct/indirect 
bilirubin
Sodium
ALT (SGPT)
Total Protein
Glucose
Calcium (Albumin adjusted)
Alkaline Phosphatase
Albumin
Phosphate
Other Screening 
Tests
Serum hCG pregnancy test
Serum ferritin
Folate
Estradiol
Serum iron
Vitamin B12
FSH
Serum transferrin
UIBC
TSAT
NOTE: Details of Liver Chemistry Stopping Criteria and Required Actions and Follow-Up Assessments after liver 
stopping or monitoring event are given in Section 12.2.
1 As needed in women of non-child bearing potential only.
Abrreviations: ALT= Alanine transaminase; AST= Aspartate transaminase; CHr=Reticulocyte haemoglobin content; 
FSH=follicle stimulating hormone; MCH= Mean corpuscular haemoglobin; MCHC= Mean corpuscular hemoglobin 
concentration; MCV= Mean corpuscular volume; RBC= Red blood cell; RDW= Red blood cell distribution width; 
SGOT=Serum glutamic oxaloacetic transaminase; SGPT=Serum glutamic-pyruvic transaminase; TSAT = transferrin 
saturation;; UIBC = unsaturated iron binding capacity; WBC= White blood cells;
Section 7.5.1 Ambulatory Blood Pressure Monitoring (ABPM)
REVISED TEXT, where text in strikethrough has been removed and bolded text has been 
added
Blood pressure and pulse will be measured during Acute Challenge 1 and 2 through the 
use of an ambulatory blood pressure monitoring device.  Subjects will wear the ABPM 
device for two sessions during the study (i.e., Acute Challenge 1 and 2), occurring at Day 
1 (randomization) and at Day 57 Week 8.  The ABPM device will be placed 1 hr prior to 
completion of the dialysis session, and will remain on the subject’s arm until 24 hr post-
dosing.
ABPM measurements of systolic and diastolic blood pressure and pulse will be manually 
recorded at one hour prior to completion of the dialysis session, automatically 
recorded every 15 minutes for the first 6 hrs post-dosing, and then every 20 minutes 
thereafter until 24 hrs post-dosing.  The ABPM device will automatically calculate MAP.
The device planned for use in this study is the Mortara Ambulo 2400; a specification 
sheet for this device can be found in Section 12.6.

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After both Acute Challenge 1 and 2, the 24-hr ABPM results will be checked for 
data quality as defined in the Project Requirement Specification (PRS).  If the 
ABPM fails the QC criteria following Acute Challenge 2, one additional Acute 
Challenge may be made in a subsequent, mid-week dialysis visit 1 week later if the 
subject agrees. At that visit, the subject will receive the same study treatment for 
the repeat Acute Challenge 2 as was administered on Day 57 as a single additional 
dose. No additional clinical chemistry, hematology, pharmacokinetic or biomarker 
sampling will be done, however all other procedures will be performed as detailed in 
Table 4.
Section 7.5.2 Blood Pressure Regulation Biomarkers
REVISED TEXT where text in strikethrough has been removed and bolded text has been 
added
Blood samples will be collected during this study to investigate the mechanism of the 
effect of daprodustat on blood pressure.  Biomarkers selected will explore the renin-
angiotensin-aldosterone axis, the nitric oxide and endothelin axes, sodium retention and 
HIF signalling.
Biomarkers may include erythropoietin, nitric oxide (NO), asymmetric dimethyarginine 
(ADMA), renin, angiotensin-II, aldosterone, endothelin-1 (ET-1), proendothelin-1,
prostaglandin E2 (PGE2), prostaglandin I2 (PGI2),and noradrenalin, epinephrine, and MR-
proadrenomedullin.
Samples will be collected as specified in the Time and Events Table (Section 7.1).  The 
timing of the collections may be adjusted on the basis of emerging pharmacokinetic or 
pharmacodynamic (PD) data from this study or other new information in order to ensure 
optimal evaluation of the PD endpoints.
Section 7.6 GENETICS
Summary of changes:
All genetic research has been removed from this study.  
PREVIOUS TEXT:
Information regarding genetic research is included in Appendix 4.  
(Note: Appendix 4 has been deleted due to removal of genetic testing.  This may be 
referenced at the end of Appendix 7, within the eliminated genetics Section 12.4)
REVISED TEXT:
Genetics are not evaluated in this study.
Section 9.4.3 Other analyses
REVISED TEXT where text in strikethrough has been removed and bolded text has been 
added

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The difference in SBP between pre-dose in Acute Challenge 1 and pre-dose in Acute 
Challenge 2 will be summarized by treatment group.  Similar summaries of DBP and 
MAP will be performed.
For each acute challenge, change from pre-challenge in SBP, DBP, MAP, and pulse will 
be summarized by treatment group at each timepoint.  In addition, for each acute 
challenge, SBP, DBP, MAP, and pulse will be summarized by treatment group at each 
timepoint.  Line graphs of this information will be provided by treatment group for each 
acute challenge.
For each acute challenge, the concentration of PK parameters for erythropoietin, 
endothelin-1, proendothelin-1, nitric oxide, asymmetric dimethylarginine, renin, 
angiotensin-II, aldosterone, adrenomedullin and MR-proadrenomedullin and 
noradrenalin will be summarized by treatment group at each timepoint.  Line graphs of 
this information will be provided by treatment group for each acute challenge.
Further statistical considerations will be addressed in the RAP.
Section 12.2 Appendix 2 – Liver Safety Required Actions and Follow Up 
Assessments
PREVIOUS DIAGRAM
ALT≥3xULN ?
Bilirubin ≥ 2xULN
(or INR > 1.5 if 
measured)* ?
No
No
Yes
Yes
Continue investigational product (IP)
Instruct subject to stop IP
Notify GSK within 24 hrs 
Obtain weekly liver chemistries until resolved, stabilized or returned 
to baseline values
Perform liver event follow up assessments (serology, PK sample, etc 
as in protocol) 
Complete liver event CRF
Withdraw subject from study after liver chemistry monitoring 
complete + do not re-challenge with IP
Instruct subject to stop IP
Notify GSK and arrange clinical followup within 24 hrs
Perform liver event follow up assessments (serology, PK sample etc 
as in protocol) 
Report as SAE (excl. hepatic impairment or cirrhosis studies); 
complete SAE & liver event CRF + liver imaging  
and biopsy CRFs (if these tests are performed)
Obtain twice weekly liver chemistries until resolved, stabilized or 
returned to baseline values 
Consultation with hepatologist/specialist recommended
Withdraw subject from study after liver chemistry monitoring 
complete + do not re-challenge with IP
*INR threshold does not apply to 
subjects receiving anticoagulants.

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REVISED DIAGRAM

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ADDED CHARTS
The following two charts and corresponding text were added to Appendix 2 in their 
entirety.
Additional charts are provided below for reference.
Liver Chemistry Stopping Criteria – Liver Stopping Event
ALT-absolute
ALT 5xULN
ALT Increase
ALT 3xULN 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 3xULN 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  study treatment 
Report the event to GSK within 24 hours

Complete the liver event CRF and complete an 
SAE data collection tool if the event also meets 
the criteria for an SAE2

Perform liver event follow up assessments 

Monitor the subject until liver chemistries
resolve, stabilize, or return to within baseline 
(see MONITORING below)

Do not restart/rechallenge subject with study 
treatment. If restart/rechallenge not allowed 
per protocol or not granted, permanently 
discontinue study treatment and may 
continue subject in the study for any protocol 
specified follow up assessments 
MONITORING:
For bilirubin or INR criteria:

Repeat liver chemistries (include ALT, AST, 

Viral hepatitis serology4

Blood sample for pharmacokinetic (PK) 
analysis, obtained within 24 hours after 
last dose5

Serum creatine phosphokinase (CPK) 
and lactate dehydrogenase (LDH).

Fractionate bilirubin, if total 
bilirubin2xULN

Obtain complete blood count with 
differential to assess eosinophilia

Record the appearance or worsening of 
clinical symptoms of liver injury, or 
hypersensitivity, on the AE report form

Record use of concomitant medications 
on the concomitant medications report 
form including acetaminophen, herbal 
remedies, other over the counter 
medications.

Record alcohol use on the liver event 

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

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Liver Chemistry Increased Monitoring Criteria – Liver Monitoring Event
Criteria
Actions
ALT 3xULN and <5xULN and bilirubin 
<2xULN, without symptoms believed to 
be related to liver injury or 
hypersensitivity, and who can be 
monitored weekly for 4 weeks

Notify the GSK medical monitor within 24 hours of 
learning of the abnormality to discuss subject safety. 

Subject can continue study treatment  Subject must 
return weekly for repeat liver chemistries (ALT, AST, 
alkaline phosphatase, bilirubin) until they resolve, 
stabilise or return to within baseline 

If at any time subject meets the liver chemistry 
stopping criteria, proceed as described above

If, after 4 weeks of monitoring, ALT <3xULN and 
bilirubin <2xULN, monitor subjects twice monthly 
until liver chemistries normalize or return to within 
baseline.
Section 12.4 Appendix 4 – Genetic Research
Summary of changes:
Due to genetic research being removed from this study, this section was deleted in 
its entirety.  No revised text was created.
PREVIOUS TEXT:
Genetics – Background
Naturally occurring genetic variation may contribute to inter-individual variability in 
response to medicines, as well as an individual's risk of developing specific diseases. 
Genetic factors associated with disease characteristics may also be associated with 
response to therapy, and could help to explain some clinical study outcomes. For 
example, genetic variants associated with age-related macular degeneration (AMD) are 
reported to account for much of the risk for the condition with certain variants reported to 
influence treatment response [Chen, 2012]. Thus, knowledge of the genetic etiology of 
disease may better inform understanding of disease and the development of medicines. 
Additionally, genetic variability may impact the pharmacokinetics (absorption, 
distribution, metabolism, and elimination), or pharmacodynamics (relationship between 
concentration and pharmacologic effects or the time course of pharmacologic effects) of a 
specific medicine and/or clinical outcomes (efficacy and/or safety) observed in a clinical 
study.
Genetic Research Objectives and Analyses
The objectives of the genetic research are to investigate the relationship between genetic 
variants and: 

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
Response to medicine, including any treatment regimens under investigation in 
this study;

Anemia associated with chronic kidney disease

susceptibility, severity, and progression and related conditions
Genetic data may be generated while the study is underway or following completion of 
the study.  Genetic evaluations may include focused candidate gene approaches and/or 
examination of a large number of genetic variants throughout the genome (whole genome 
analyses). Genetic analyses will utilize data collected in the study and will be limited to 
understanding the objectives highlighted above.  Analyses may be performed using data 
from multiple clinical studies to investigate these research objectives.
Appropriate descriptive and/or statistical analysis methods will be used. A detailed 
description of any planned analyses will be documented in a Reporting and Analysis Plan 
(RAP) prior to initiation of the analysis. Planned analyses and results of genetic 
investigations will be reported either as part of the clinical RAP and study report, or in a 
separate genetics RAP and report, as appropriate.
Study Population
Any subject who is enrolled in the study can participate in genetic research.  Any subject 
who has received an allogeneic bone marrow transplant must be excluded from the 
genetic research.
Study Assessments and Procedures
A key component of successful genetic research is the collection of samples during 
clinical studies. Collection of samples, even when no a priori hypothesis has been 
identified, may enable future genetic analyses to be conducted to help understand 
variability in disease and medicine response.

A 6 ml blood sample will be taken for Deoxyribonucleic acid (DNA) extraction. 
A blood sample is collected at the baseline visit, after the subject has been 
randomized and provided informed consent for genetic research. Instructions for 
collection and shipping of the genetic sample are described in the laboratory 
manual. The DNA from the blood sample may undergo quality control analyses to 
confirm the integrity of the sample. If there are concerns regarding the quality of 
the sample, then the sample may be destroyed. The blood sample is taken on a 
single occasion unless a duplicate sample is required due to an inability to utilize 
the original sample.
The genetic sample is labelled (or “coded”) with the same study specific number used to 
label other samples and data in the study.  This number can be traced or linked back to 
the subject by the investigator or site staff. Coded samples do not carry personal 
identifiers (such as name or social security number).
Samples will be stored securely and may be kept for up to 15 years after the last subject 
completes the study, or GSK may destroy the samples sooner.  GSK or those working 
with GSK (for example, other researchers) will only use samples collected from the study 

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for the purpose stated in this protocol and in the informed consent form.  Samples may be 
used as part of the development of a companion diagnostic to support the GSK medicinal 
product.
Subjects can request their sample to be destroyed at any time.
Informed Consent
Subjects who do not wish to participate in the genetic research may still participate in the 
study.  Informed consent for genetic research must be obtained prior to any blood being 
taken.
Subject Withdrawal from Study
If a subject who has consented to participate in genetic research withdraws from the 
clinical study for any reason other than being lost to follow-up, the subject will be given a 
choice of one of the following options concerning the genetic sample, if already 
collected:

Continue to participate in the genetic research in which case the genetic DNA 
sample is retained

Discontinue participation in the genetic research and destroy the genetic DNA 
sample 
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.

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Provision of Study Results and Confidentiality of Subject’s Genetic Data
GSK may summarize the genetic research results in the clinical study report, or 
separately and may publish the results in scientific journals. 
GSK may share genetic research data with other scientists to further scientific 
understanding in alignment with the informed consent. GSK does not inform the subject, 
family members, insurers, or employers of individual genotyping results that are not 
known to be relevant to the subject’s medical care at the time of the study, unless 
required by law. This is due to the fact that the information generated from genetic 
studies is generally preliminary in nature, and therefore the significance and scientific 
validity of the results are undetermined.  Further, data generated in a research laboratory 
may not meet regulatory requirements for inclusion in clinical care.
Section 12.5, Section 12.6, and Section 12.7
Summary of changes:
Appendix 5, Appendix 6, and Appendix 7 re-numbered due to removal of Appendix 4.
12.7.2.
Amendment 2
Summary of Amendment Changes with Rationale
This protocol amendment applies to all centers where this study may be performed.
This protocol amendment was written to clarify the descriptive statistics and include them 
in the objectives and endpoints table(s) as well as remove one blood pressure 
measurement. Additional minor changes were made for clarity of study procedures.
List of Specific Changes
Section 1 Protocol Synopsis for Study 205665
Objective(s)/Endpoint(s) Table
REVISED TEXT, where text in strikethrough has been removed and bolded text has been 
added
Objectives
Endpoints
Primary

To compare the effect of daprodustat to epoetin 
alfa on blood pressure (BP) after Acute 
Challenge 2 (8 weeks of hemoglobin [Hgb]
maintenance therapy)

Average of systolic blood pressure (SBP) as 
measured by ambulatory blood pressure 
monitoring (ABPM) over 6-hr post-dosing after 
8 weeks of Hgb maintenance therapy
Secondary

To compare the initial effect of daprodustat to 
epoetin alfa on BP after Acute Challenge 1 (4 
weeks of erythropoiesis-stimulating agent [ESA]

Average of SBP, diastolic blood pressure 
(DBP), mean arterial blood pressure (MAP), 
and heart rate (HR) as measured by ABPM 

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Objectives
Endpoints
washout)
over 6-hr post-dosing at Day 1

Average of diastolic blood pressure (DBP) as 
measured by ABPM over 6-hr post-dosing at 
Day 1

Area under the effect curve (AUEC) of SBP,
DBP, MAP, and HR as measured by ABPM 
over 24-hr post-dosing at Day 1

To compare the effect of daprodustat to epoetin 
alfa on BP after Acute Challenge 2

Average of DBP, MAP, and HR as measured 
by ABPM over 6 hr post-dosing at Week 8 Day 
57.

AUEC of SBP, DBP, MAP, and HR as 
measured by ABPM over 24-hr post-dosing at 
Week 8 Day 57.

To estimate the initial effect of daprodustat on 
SBP, DBP, pulse HR and MAP mean arterial 
blood pressure (MAP) after Acute Challenge 1

Change from pre-dose in SBP, DBP, pulse HR
and MAP at each timepoint at Day 1

To characterize the pharmacokinetics of 
daprodustat

Plasma concentrations of daprodustat and 
metabolites and derived pharmacokinetic 
parameters including maximum observed 
concentration (Cmax), time of occurrence of 
Cmax (tmax), terminal phase half-life (t½) and 
area under concentration-time curve from time 
zero to 24 hours (AUC[0-24]) as appropriate

To assess the safety and tolerability of 
daprodustat

Incidence and severity of adverse events (AEs)
and serious adverse events (SAEs)

Reasons for discontinuation of study treatment

Absolute values and changes from baseline 
over time in laboratory parameters, 
electrocardiograms (ECGs) and vital signs
Exploratory

To investigate the effect of daprodustat on 
vasoactive mediators of blood pressure

Plasma concentrations and derived 
parameters including Cmax, tmax, t½ and 
AUC(0-24) as appropriate (to include 
erythropoietin, endothelin-1, nitric oxide, 
asymmetric dimethylarginine, renin, 
angiotensin-II and metabolites, and 
noradrenalin) 

Evaluate exposure-response relationships for 
daprodustat and: erythropoietin, endothelin-1, 
nitric oxide, asymmetric dimethylarginine, renin, 
angiotensin-II (and metabolites), and 
noradrenalin 

Further models (as appropriate) to describe the 
daprodustat exposure-response relationship 
with: erythropoietin, endothelin-1, nitric oxide, 
asymmetric dimethylarginine, renin, 
angiotensin-II (and metabolites), and 
noradrenalin. 

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Objectives
Endpoints

To summarize the effect of daprodustat and 
epoetin alfa on SBP after Acute Challenge 1 
and Acute Challenge 2

AUEC of SBP as measured by ABPM over 24-
hr post-dosing

To compare the effect of daprodustat to epoetin 
alfa on SBP after 8 weeks of Hgb maintenance 
therapy

Change from Day 1 pre-dose SBP to Week 8
Day 57 pre-dose
Section 1 Protocol Synopsis for Study 205665
Study Design
REVISED TEXT, where text in strikethrough has been removed and bolded text has been 
added
Subjects will be screened for eligibility starting 4 weeks prior to the start of an ESA 
washout period (8 weeks prior to randomization/Day 1).
Subjects that qualify for enrolment will be washed out of their ESA for 4 weeks; the start 
of the ESA washout should be timed to coincide as closely as possible with their next 
planned ESA dose.
Following the 4-week ESA washout, subjects will be randomized 1:1 and stratified by 
prior ESA dose, based on the average weekly (for epoetins or darbepoetin) or monthly 
(for methoxy polyethylene glycol (PEG)-epoetin beta) dosing during the 12 weeks prior 
to ESA washout (Week -4) as follows:

Low ESA dose: <100 IU/kg/week epoetin alfa OR <0.5 µg/kg/week darbepoetin 
OR <0.6 µg/kg/week methoxy PEG-epoetin beta

High ESA dose: ≥100 IU/kg/week epoetin alfa OR ≥0.5 µg/kg/week darbepoetin 
OR 0.6 µg/kg/week methoxy PEG-epoetin beta
On Day 1, subjects will be randomized and undergo Acute Challenge 1, a single dose 
challenge to compare the acute effects on BP of the highest planned once-daily 
maintenance dose of daprodustat (24 mg) to the highest starting dose of epoetin alfa 
(100 IU/kg).  Subjects will have BP monitored for 24 hr using ABPM, and will have 
serial blood sampling to assess the pharmacokinetics of daprodustat and the time-course 
of various biomarkers.  Acute Challenge 1 will be started immediately promptly
following completion of a mid-week dialysis session.
After completing Acute Challenge 1, all subjects will enter the 8-week Hgb maintenance 
period where doses of either daprodustat or epoetin alfa will be administered and 
adjusted, as needed.
On Day 57, following the 8-week Hgb maintenance period, subjects will undergo Acute 
Challenge 2; this challenge will, similar to Acute Challenge 1, involve assessing the 
effect of daprodustat and epoetin alfa on SBP as assessed by 24-hr ABPM measurement.  
The subjects will be administered the same dose of either daprodustat or epoetin alfa that 
was given in Acute Challenge 1, and serial blood sampling will be performed to assess 

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both daprodustat pharmacokinetics, and to characterize the time course of various 
biomarkers.  Acute Challenge 2 will be started following completion of a mid-week 
dialysis session.
Subjects will be asked to not reinitiate anemia treatment until after the follow-up visit 
unless deemed medically necessary.
Subjects will attend a follow-up visit 2 weeks after completion of Acute Challenge 2.
After both Acute Challenge 1 and 2, the 24-hr ABPM results will be checked for data 
quality as defined in the Project Requirement Specification (PRS).  If the ABPM fails the 
QC criteria following Acute Challenge 2, one additional Acute Challenge may be made 
in a subsequent, mid-week dialysis visit 1 week later if the subject agrees. At that visit, 
the subject will receive the same study treatment for the repeat Acute Challenge 2 as was 
administered on Day 57 as a single additional dose. No additional clinical chemistry, 
hematology, pharmacokinetic or biomarker sampling will be done, however all other 
procedures will be performed. 
Section 1 Protocol Synopsis for Study 205665
Treatment Arms and Duration
REVISED TEXT, where text in strikethrough has been removed and bolded text has been 
added
The total duration of subject involvement is up to 18 weeks (Screening to Follow-up) as 
described below:

Screening: Screening will be for at least 4 weeks prior to starting the ESA 
washout.

ESA Washout: Subjects that meet eligibility criteria will begin the 4-week ESA 
washout at Week -4.
o
This should be timed such that this day occurs on the date that would have 
been the next scheduled dose of ESA (or as close as practicable).
o
For subjects with a three-times weekly dialysis schedule, this day must not 
occur on the first dialysis session of the week (e.g., if Monday-Wednesday-
Friday schedule, the study visit cannot be on Monday).
o
For subjects with a four- to five-times weekly dialysis schedule, this day can 
be on any hemodialysis session of the week.

Randomization & Acute Challenge 1 (Day 1): Subjects will be randomized 1:1 to 
two treatment arms and will begin a 24-hr Acute Challenge where the acute BP 
effects of daprodustat and epoetin alfa will be evaluated.  This challenge will be 
initiated immediately promptly following the subject’s dialysis session.

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
Hgb Maintenance Period: Subjects randomized to daprodustat will start an 8-week 
Hgb maintenance period based on a starting dose and dose adjustment algorithm.  
Subjects randomized to epoetin alfa will begin an 8-week Hgb maintenance 
period where Hgb will be managed in accordance with local labelling.

Acute Challenge 2 (Day 57): At the end of the 8-week Hgb maintenance period 
subjects will repeat the procedures of Acute Challenge 1 utilizing the same 
treatment administered in Acute Challenge 1.  This challenge will be initiated 
immediately promptly following the subject’s dialysis session.

Follow-up: A Follow-up visit will be scheduled to occur 14 3 days after 
completing treatment.
Section 1 Protocol Synopsis
Analysis
REVISED TEXT, where text in strikethrough has been removed and bolded text has been 
added
The primary endpoint for this study is average systolic blood pressure (SBP) over 6 hours 
of measurements taken at 15-minute intervals after the administration of study treatment 
for the Acute Challenge 2.  The primary comparison of interest is daprodustat versus 
epoetin alfa for this challenge.
The primary analysis of average SBP over 6 hr post-dose during Acute Challenge 2 will 
be an analysis of covariance (ANCOVA) with terms for treatment, and post-HD/pre-
Acute Challenge 1 SBP, difference between post-HD/pre-Acute Challenge 2 SBP and 
post-HD/pre-Acute Challenge 1 SBP, and treatment by (difference in post-HD SBP 
between Acute Challenge 1 and 2) interaction.  Note that the pre-challenge SBP may 
change over time between Acute Challenge 1 and Acute Challenge 2 as a result of the 
maintenance therapy, and thus the pre-challenge SBP at Acute Challenge 2 is not a true 
pre-treatment covariate.  As a result, the interpretation of the effect of the Acute 
Challenge 2 may be confounded by the impact of treatment phase on the covariate.
Therefore, if the interaction term in this model is significant at the 0.10 level, then the 
primary model will be ANCOVA with terms for treatment and post-HD/pre-Acute 
Challenge 1 SBP.  The primary model will provide a point estimate and two-sided 95% 
CI for the treatment effect and a p-value for the superiority assessment.  Superiority will 
be established if the p-value is <0.05.
The comparison of daprodustat versus epoetin alfa on 6 hr average SBP during Acute 
Challenge 1 is a secondary endpoint.
Average SBP over 6 hr post-dose in Acute Challenge 1 will be analyzed using ANCOVA 
with terms for treatment and post-HD/pre-Acute Challenge 1 SBP.  Similar analyses will 
be performed for DBP, MAP, and pulse HR.

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ANCOVA using the primary model will be used for the analysis of average DBP, MAP, 
and pulse HR over 6 hr post-dose in Acute Challenge 2 replacing the baseline SBP term 
with the analogous baseline measurement for DBP, MAP, and pulse HR, respectively.
AUECs of SBP, DBP, and MAP, and HR post Acute Challenge 2 and 1 will be analyzed 
using ANCOVA with terms for treatment with 95% CIs and p-values provided for the 
treatment effect.
Null Hypothesis: The difference between 24 mg daprodustat versus 100 IU/kg epoetin 
alfa on 6 hr average SBP under a background of treatment (i.e., during Acute Challenge 
2) is zero.
Alternative Hypothesis: The difference between 24 mg daprodustat versus 100 IU/kg 
epoetin alfa on 6 hr average SBP under a background of treatment (i.e. during Acute 
Challenge 2) is not zero.
An interim analysis will be conducted after approximately 24 subjects have completed 
Acute Challenge 2.
If the mean change in SBP from pre-Acute Challenge 1 to the 6-hour mean following 
both Acute Challenge 1 and Acute Challenge 2 is less than 5 mmHg in the epoetin alfa 
group, then the study will be stopped.  However, if a clinically meaningful difference 
between the two treatment groups in mean change in SBP from pre-Acute Challenge 1 to 
the 6-hour mean following Acute Challenge 1 (i.e., >5 mmHg) is observed, then the 
study will be continued in order to further characterize the effects of daprodustat on blood 
pressure.
Simulations show that under assumptions of a true mean change in SBP of 0 mmHg and 
SD of 18 mmHg for both treatment groups at Acute Challenge 1 and the epoetin alfa 
group at Acute Challenge 2, this stopping guideline will result in stopping the trial >99% 
of the time.  Under the assumptions of a true mean change in SBP of 8 mmHg and SD of 
18 mmHg for both treatment groups at Acute Challenge 1 and the epoetin alfa group at 
Acute Challenge 2, this rule will result in stopping the trial <1% of the time.
While the above is a guideline for stopping the trial due to futility, the totality of the data 
will be considered when making the decision at the time of the interim analysis.
Section 3 OBJECTIVE(S) AND ENDPOINT(S)
REVISED TEXT, where text in strikethrough has been removed and bolded text has been 
added

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Objectives
Endpoints
Primary

To compare the effect of daprodustat to epoetin 
alfa on blood pressure (BP) after Acute 
Challenge 2 (8 weeks of hemoglobin [Hgb]
maintenance therapy)

Average of systolic blood pressure (SBP) as 
measured by ambulatory blood pressure 
monitoring (ABPM) over 6-hr post-dosing after 
8 weeks of Hgb maintenance therapy
Secondary

To compare the initial effect of daprodustat to 
epoetin alfa on BP after Acute Challenge 1 (4 
weeks of erythropoiesis-stimulating agent [ESA]
washout)

Average of SBP, diastolic blood pressure 
(DBP), mean arterial blood pressure (MAP), 
and heart rate (HR) as measured by ABPM 
over 6-hr post-dosing at Day 1

Average of diastolic blood pressure (DBP) as 
measured by ABPM over 6-hr post-dosing at 
Day 1

Area under the effect curve (AUEC) of SBP,
DBP, MAP, and HR as measured by ABPM 
over 24-hr post-dosing at Day 1

To compare the effect of daprodustat to epoetin 
alfa on BP after Acute Challenge 2

Average of DBP, MAP, and HR as measured 
by ABPM over 6 hr post-dosing at Week 8 Day 
57.

AUEC of SBP, DBP, MAP, and HR as 
measured by ABPM over 24-hr post-dosing at 
Week 8 Day 57.

To estimate the initial effect of daprodustat on 
SBP, DBP, pulse HR and MAP mean arterial 
blood pressure (MAP) after Acute Challenge 1

Change from pre-dose in SBP, DBP, pulse HR
and MAP at each timepoint at Day 1

To characterize the pharmacokinetics of 
daprodustat

Plasma concentrations of daprodustat and 
metabolites and derived pharmacokinetic 
parameters including maximum observed 
concentration (Cmax), time of occurrence of 
Cmax (tmax), terminal phase half-life (t½) and 
area under concentration-time curve from time 
zero to 24 hours (AUC[0-24]) as appropriate

To assess the safety and tolerability of 
daprodustat

Incidence and severity of adverse events (AEs)
and serious adverse events (SAEs)

Reasons for discontinuation of study treatment

Absolute values and changes from baseline 
over time in laboratory parameters, 
electrocardiograms (ECGs) and vital signs
Exploratory

To investigate the effect of daprodustat on 
vasoactive mediators of blood pressure

Plasma concentrations and derived 
parameters including Cmax, tmax, t½ and 
AUC(0-24) as appropriate (to include 
erythropoietin, endothelin-1, nitric oxide, 

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Objectives
Endpoints
asymmetric dimethylarginine, renin, 
angiotensin-II and metabolites, and 
noradrenalin) 

Evaluate exposure-response relationships for 
daprodustat and: erythropoietin, endothelin-1, 
nitric oxide, asymmetric dimethylarginine, renin, 
angiotensin-II (and metabolites), and 
noradrenalin 

Further models (as appropriate) to describe the 
daprodustat exposure-response relationship 
with: erythropoietin, endothelin-1, nitric oxide, 
asymmetric dimethylarginine, renin, 
angiotensin-II (and metabolites), and 
noradrenalin. 

To summarize the effect of daprodustat and 
epoetin alfa on SBP after Acute Challenge 1 
and Acute Challenge 2

AUEC of SBP as measured by ABPM over 24-
hr post-dosing

To compare the effect of daprodustat to epoetin 
alfa on SBP after 8 weeks of Hgb maintenance 
therapy

Change from Day 1 pre-dose SBP to Week 8
Day 57 pre-dose
Section 4.1 Overall Design
REVISED TEXT, where text in strikethrough has been removed and bolded text has been 
added
Subjects will be screened for eligibility starting 4 weeks prior to the start of an ESA 
washout period (8 weeks prior to randomization/Day 1).
Subjects that qualify for enrolment will be washed out of their ESA for 4 weeks; the start 
of the ESA washout should be timed to coincide as closely as possible with their next 
planned ESA dose.
Following the 4-week ESA washout, subjects will be randomized 1:1 and stratified by 
prior ESA dose, based on the average weekly (for epoetins or darbepoetin) or monthly 
(for methoxy polyethylene glycol (PEG)-epoetin beta) dosing during the 12 weeks prior 
to ESA washout (Week -4) as follows:

Low ESA dose: <100 IU/kg/week epoetin alfa OR <0.5 µg/kg/week darbepoetin 
OR <0.6 µg/kg/week methoxy PEG-epoetin beta

High ESA dose: ≥100 IU/kg/week epoetin alfa OR ≥0.5 µg/kg/week darbepoetin 
OR 0.6 µg/kg/week methoxy PEG-epoetin beta
On Day 1, subjects will be randomized and undergo Acute Challenge 1, a single dose 
challenge to compare the acute effects on BP of the highest planned once-daily 
maintenance dose of daprodustat (24 mg) to the highest starting dose of epoetin alfa 
(100 IU/kg).  Subjects will have BP monitored for 24 hr using ABPM, and will have 
serial blood sampling to assess the pharmacokinetics of daprodustat and the time-course 
of various biomarkers.  Acute Challenge 1 will be started immediately promptly 
following completion of a mid-week dialysis session.

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After completing Acute Challenge 1, all subjects will enter the 8-week Hgb maintenance 
period where doses of either daprodustat or epoetin alfa will be administered and 
adjusted, as needed, based on dosing guidance as described in Section 6.4.
On Day 57, following the 8-week Hgb maintenance period, subjects will undergo Acute 
Challenge 2; this challenge will, similar to Acute Challenge 1, involve assessing the 
effect of daprodustat and epoetin alfa on SBP as assessed by 24-hr ABPM measurement.  
The subjects will be administered the same dose of either daprodustat or epoetin alfa that 
was given in Acute Challenge 1, and serial blood sampling will be performed to assess 
both daprodustat pharmacokinetics, and to characterize the time course of various 
biomarkers.  Acute Challenge 2 will be started following completion of a mid-week 
dialysis session.
Subjects will be asked to not reinitiate anemia treatment until after the follow-up visit 
unless deemed medically necessary.
Subjects will attend a follow-up visit 2 weeks after completion of Acute Challenge 2.
After both Acute Challenge 1 and 2, the 24-hr ABPM results will be checked for data 
quality as defined in the Project Requirement Specification (PRS).  If the ABPM fails the 
QC criteria following Acute Challenge 2, one additional Acute Challenge may be made 
in a subsequent, mid-week dialysis visit 1 week later if the subject agrees. At that visit, 
the subject will receive the same study treatment for the repeat Acute Challenge 2 as was 
administered on Day 57 as a single additional dose. No additional clinical chemistry, 
hematology, pharmacokinetic or biomarker sampling will be done, however all other 
procedures will be performed as detailed in Table 4. 
Section 4.2 Treatment Arms and Duration
REVISED TEXT, where text in strikethrough has been removed and bolded text has been 
added
The total duration of subject involvement is up to 18 weeks (Screening to Follow-up) as 
described below:

Screening: Screening will be for at least 4 weeks prior to starting the ESA 
washout.

ESA Washout: Subjects that meet eligibility criteria will begin the 4-week ESA 
washout at Week 4.
o
This should be timed such that this day occurs on the date that would have 
been the next scheduled dose of ESA (or as close as practicable).
o
For subjects with a three-times weekly dialysis schedule, this day must not 
occur on the first dialysis session of the week (e.g., if Monday-Wednesday-
Friday schedule, the study visit cannot be on Monday).
o
For subjects with a four- to five-times weekly dialysis schedule, this day can 
be on any hemodialysis session of the week.

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
Randomization & Acute Challenge 1 (Day 1): Subjects will be randomized 1:1 to 
two treatment arms as described in Table 1 and will begin a 24-hr Acute 
Challenge where the acute BP effects of daprodustat and epoetin alfa will be 
evaluated.  This challenge will be initiated immediately promptly following the 
subject’s dialysis session.

Hgb Maintenance Period: Subjects randomized to daprodustat will start an 8-week 
Hgb maintenance period based on a starting dose and dose adjustment algorithm 
as described in Section 6.4.1.  Subjects randomized to epoetin alfa will begin an 
8-week Hgb maintenance period where Hgb will be managed in accordance with 
local labelling.

Acute Challenge 2: At the end of the 8-week Hgb maintenance period, subjects 
will repeat the procedures of Acute Challenge 1 utilizing the same treatment 
administered in Acute Challenge 1.  This challenge will be initiated immediately
promptly following the subject’s dialysis session.

Follow-up: A Follow-up visit will be scheduled to occur 14 3 days after 
completing treatment.
Section 4.4. Design Justification
REVISED TEXT, where text in strikethrough has been removed.
This study will be an open-label, multi-center, randomized, parallel-group design in HD 
subjects with anemia associated with CKD.  There will be a 4-week screening period, a 
4-week ESA washout period, an 8-week Hgb-maintenance period including two 24-hr 
acute challenges and a follow-up visit 14 ± 3 days after completing treatment.
It is preferred that no changes are made to estimated dry weight (EDW) and 
antihypertensive medications while the subject is participating in this study.  However, if 
changes in EDW and/or antihypertensive medications are necessary, these must be 
documented in the electronic case report form (eCRF) along with the reasons.  Subjects 
will remain in the study regardless of any changes.
(Note: No changes made to the bullet points within this section)
Section 6.7 Compliance with Study Treatment Administration
REVISED TEXT, where text in strikethrough has been removed and bolded text has been 
added
For subjects randomized to daprodustat, treatment start and stop dates and dosing 
details including dates for randomized treatment interruptions and/or dose 
increases/reductions, will be recorded in RAMOS NG.

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For subjects randomized to daprodustat, for Acute Challenge 1 and 2, study site 
personnel will confirm compliance.  When daprodustat is administered at home (Hgb 
maintenance period), subjects will be instructed to return all unused randomized 
treatment at each clinic visit.  A record of the number of daprodustat tablets dispensed to 
and taken by each subject will be maintained and reconciled with randomized treatment 
and compliance records.
For subjects randomized to epoetin alfa, they will receive all study treatment directly 
from the investigator or designee, under medical supervision.  The date and time of each 
dose administered in the clinic will be recorded in the source documents.  The dose of 
study treatment and study subject identification will be confirmed at the time of dosing 
by a member of the study site staff other than the person administering the study 
treatment.
Section 6.10.1 Meals and Dietary Restrictions
REVISED TEXT, where bolded text has been added
Daprodustat can be taken without regard to meals. 
All subjects will be instructed to limit caffeine- or xanthine- containing products 
(e.g., coffee, tea, cola drinks, chocolate) for 24h prior to both Acute Challenge 1 and 
Acute Challenge 2.  Should the Additional Acute Challenge 2 be necessary, the 
subject does not need to limit the products listed above.
Section 6.11 Concomitant Medications and Non-Drug Therapies
REVISED TEXT, where text in strikethrough has been removed.
Concomitant medications, including over-the-counter medications and supplements, 
taken during the study will be recorded in the eCRF.  Start/stop dates and route of 
administration will be recorded for general concomitant medications, while additional 
details will be recorded for certain medications (e.g., anti-hypertensive medications).
Section 6.11.1 Estimated Dry Weight and Antihypertensive Medication Changes
REVISED TEXT, where text in strikethrough has been removed.
It is preferred that changes to EDW and antihypertensive medication(s) are not made 
while the subject is part of this study.  If changes in EDW and/or antihypertensive 
medications are necessary, these changes as well as the reason(s) for the change must be 
documented in the eCRF.  Subjects should remain in the study regardless of any changes.
Section 7.1 Time and Events Table
Table 3 Study Procedures and Assessments
REVISED TEXT, where text in strikethrough has been removed.

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(Note: Changes are difficult to see on table.  Superscript 6 has been removed from 
Adverse Events Assessment in columns Weeks – 4 and Week – 2)

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Procedure1
Screening
ESA Washout
Treatment Period2
Follow-up2
Week -8
Week -6
Week -4
Week -2
Day 1
Day 15
Day 29
Day 43
Day 57
Early WD
Week 10
Informed Consent
X
Entry Criteria
X
Physical, Medical History, Demography
X
HemoCue Hgb
X
X
X
X
X4
X
X
X
X4
X
IVWRS 
X
X
Randomization
X
Acute Challenge
X4
X4
ABPM Assessment
X4
X4
Dose Adjustment
X
Females Only: Serum Pregnancy Test
X
X
X
X
X
X
Females Only: Estradiol & FSH (if required)3
X
ECG
X
X4
X4
X
X
Vital signs & weight (Pre- & Post-dialysis)
X
X
X
X4
X
X4
X
X
Clinical Chemistry
X
X
X
X
X
X
Hematology
X
X
X
X
X
X
Folate and Vitamin B12
X
Ferritin, transferrin, total iron,, TSAT, UIBC
X
X
Pharmacokinetic/Biomarker Assessments
X4
X4
Hgb Maintenance Period5
=======================================
Adverse Events Assessment
X6
X6
X6
X6
X4
X
X
X
X4
X
X
Review Concomitant Medications
X
X
X
X4
X
X
X
X4
X
X
1 All assessments should be done predialysis/predose except as noted.
2 Allowable time window 2 days EXCEPT Follow-up Visit which is 3 days.
3 As detailed in Inclusion Criteria.
4 Detailed timings for assessments on Acute Challenge Days are given in Table 4.
5 From the end of Acute Challenge 1 to the beginning of Acute Challenge 2.
6 Only SAEs assessed as related to study participation are collected at this visit. See Section 12.4 for additional details.
Table 4 Study Procedures and Assessments on Acute Challenge Days (Treatment Period Day 1 and Day 57)

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REVISED TEXT, where text in strikethrough has been removed and bolded text has been added.  
(Note: The box for ABPM Assessment in the Post-Dialysis column has been grayed out as well as the X removed)
Procedure
Pre-
Dialysis
Post -
Dialysis Predose
Time (in hours relative to dosing)
0
0.5
1
2
3
4
6
8
12
16
24
HemoCue Hgb1
X
X
IVWRS
X
ABPM Assessment1, 3
X
===========================================================================================
Administer Study Treatment1
X
Serum Pregnancy Test1
X
ECG1
X
X
Vital Signs and Weight1
X
X
X
X
X
Clinical Chemistry
X
Hematology
X
Pharmacokinetics4
X
X
X
X
X
X
X
X
X
X
X
Erythropoietin
X
X
X
X
X
X
X
X
X
X
X
Endothelin-1
X
X
X
X
X
X
X
Nitric Oxide
X
X
X
X
X
X
X
Asymmetric dimethylarginine
X
X
X
X
X
X
X
Renin
X
X
X
X
X
X
X
Angiotensin-II
X
X
X
X
X
X
X
Noradrenalin
X
X
X
X
X
X
X
Adverse Events Assessment1
X
X
X
X
X
X
X
X
X
X
X
Review Concomitant Medications1
X
X
Initiate Hgb maintenance dosing2
X
1 Procedures to be repeated if Acute Challenge 2 fails quality control criteria
2 Applies to Acute Challenge 1 only
3. Timing of ABPM measurements does not correlate with specified time points in Table 4.
4. PK to be drawn from daprodustat subjects only.

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Section 7.3.1.1 Time Period and Frequency for Collecting AE and SAE information
REVISED TEXT, where text in strikethrough has been removed and bolded text has been 
added

Any SAEs assessed as related to study participation (e.g., protocol-mandated 
procedures, invasive tests, or change in existing therapy) or related to a GSK 
product will be recorded from the time a subject consents to participate in the 
study up to and including any follow-up contact.

AEs will be collected from the start of washout (Week – 4) study treatment (Day 
1) until the follow-up contact (see Section 7.3.1.3), at the timepoints specified in 
the Time and Events Table (Section 7.1).

Medical occurrences that begin prior to the start of washout study treatment but 
after obtaining informed consent may be recorded on the Medical History/Current 
Medical Conditions section of the CRF.

All SAEs will be recorded and reported to GSK within 24 hours, as indicated in 
Section 12.4.

Investigators are not obligated to actively seek AEs or SAEs in former study 
subjects.  However, if the investigator learns of any SAE, including a death, at any 
time after a subject has been discharged from the study, and he/she considers the 
event reasonably related to the study treatment or study participation, the 
investigator must promptly notify GSK.
NOTE: The method of recording, evaluating and assessing causality of AEs and SAEs 
plus procedures for completing and transmitting SAE reports to GSK are provided in 
Section 12.4.
Section 7.3.1.4 Adverse Events of Special Interest 
REVISED TEXT, where text in strikethrough has been removed and bolded text has been 
added
The investigator or site staff will be responsible for detecting, documenting and reporting 
any AEs of special interest or any event that may potentially be one of the categories 
listed below (using preferred terms):

Death, myocardial infarction (MI), stroke, heart failure, thromboembolic events,
venous thromboembolism, thrombosis of vascular access

Thrombosis and/or tissue ischemia secondary to excessive erythropoiesis

Cardiomyopathy

Pulmonary artery hypertension (see also Section 7.3.1.5)

Cancer-related mortality and tumor progression and recurrence

Esophageal and gastric erosions

Proliferative retinopathy, macular edema, choroidal neovascularization

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
Exacerbation of rheumatoid arthritis
The results of any investigation should be recorded in the relevant sections of the 
subject’s eCRF.
Section 7.3.5 Electrocardiogram (ECG)
REVISED TEXT, where text in strikethrough has been removed and bolded text has been 
added
ECG measurements will be taken at the time points specified in the Time and Events 
Table (Section 7.1).  Full 12-lead ECGs will be recorded with the subject in a supine 
position.  Heart rate (HR), PR interval, QRS duration, and QT (uncorrected) interval will 
be measured.  QTcB will be calculated (machine-read or manually).
At the Screening visit (Week – 4 Week -8)  two additional ECGs are required if the 
initial ECG indicates prolonged QTc (see Section 5.3) using the automated or manually 
calculated QTcB value.  The average QTcB value of all three ECGs will be used to 
determine eligibility.  Additional details are provided in the SRM.
ECG data will be read locally.
All ECGs will be performed before measurement of vital signs and collection of blood 
samples for laboratory testing.
Section 7.5.1 Ambulatory Blood Pressure Monitoring (ABPM)
REVISED TEXT, where text in strikethrough has been removed and bolded text has been 
added
Blood pressure and pulse will be measured during Acute Challenge 1 and 2 through the 
use of an ambulatory blood pressure monitoring device.  Subjects will wear the ABPM 
device for two sessions during the study (i.e., Acute Challenge 1 and 2), occurring at Day 
1 (randomization) and at Day 57.  The ABPM device will be placed 1 hr prior to 
completion of the dialysis session prior to Acute Challenge dosing, and will remain on 
the subject’s arm until 24 hrs post-dosing.
ABPM measurements of systolic and diastolic blood pressure and pulse heart rate will 
be manually recorded at one hour prior to completion of the dialysis session,
automatically recorded every 15 minutes for the first 6 hrs post-dosing, and then every 20 
minutes thereafter until 24 hrs post-dosing.  The ABPM device will automatically 
calculate MAP.
The device planned for use in this study is the Mortara Ambulo 2400; a specification 
sheet for this device can be found in Section 12.6.
After both Acute Challenge 1 and 2, the 24-hr ABPM results will be checked for data 
quality as defined in the Project Requirement Specification (PRS).  If the ABPM fails the 

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QC criteria following Acute Challenge 2, one additional Acute Challenge may be made 
in a subsequent, mid-week dialysis visit 1 week later if the subject agrees. At that visit, 
the subject will receive the same study treatment for the repeat Acute Challenge 2 as was 
administered on Day 57 as a single additional dose. No additional clinical chemistry, 
hematology, pharmacokinetic or biomarker sampling will be done, however all other 
procedures will be performed as detailed in Table 4.
Section 7.5.2 Blood Pressure Regulation Biomarkers
REVISED TEXT, where bolded text has been added.
Blood samples will be collected during this study to investigate the mechanism of the 
effect of daprodustat on blood pressure.  Biomarkers selected will explore the renin-
angiotensin-aldosterone axis, the nitric oxide and endothelin axes, sodium retention and
HIF signalling.
Biomarkers may include erythropoietin, nitric oxide (NO), asymmetric dimethyarginine 
(ADMA), renin, angiotensin-II (1-8) and metabolites (1-7 and 1-5), endothelin-1 (ET-
1), and noradrenalin. Samples will be collected as specified in the Time and Events Table 
(Section 7.1).  The timing of the collections may be adjusted on the basis of emerging 
pharmacokinetic or pharmacodynamic (PD) data from this study or other new 
information in order to ensure optimal evaluation of the PD endpoints.
Section 9.4.2 Secondary Analyses
REVISED TEXT, where text in strikethrough has been removed and bolded text has been 
added
Average SBP over 6 hr post-dose in Acute Challenge 1 will be analyzed using ANCOVA 
with terms for treatment and post-HD/pre-Acute Challenge 1 SBP.  Similar analyses will 
be performed for DBP, MAP, and pulse HR.
ANCOVA using the primary model will be used for the analysis of average DBP, MAP, 
and pulse HR over 6 hr post-dose in Acute Challenge 2 replacing the baseline SBP term 
with the analogous baseline measurement for DBP, MAP, and pulse HR, respectively.
AUECs of SBP, DBP, and MAP, and HR post Acute Challenge 2 and 1 will be analyzed 
using ANCOVA with terms for treatment with 95% CIs and p-values provided for the 
treatment effect.
Section 9.4.3 Other Analyses
REVISED TEXT, where text in strikethrough has been removed and bolded text has been 
added
The difference in SBP between pre-dose in Acute Challenge 1 and pre-dose in Acute 
Challenge 2 will be summarized by treatment group.  Similar summaries of DBP, and 
MAP, and HR will be performed.

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For each acute challenge, change from pre-challenge in SBP, DBP, MAP, and pulse HR
will be summarized by treatment group at each timepoint.  In addition, for each acute 
challenge, SBP, DBP, MAP, and pulse HR will be summarized by treatment group at 
each timepoint.  Line graphs of this information will be provided by treatment group for 
each acute challenge.
For each acute challenge, the concentration of erythropoietin, endothelin-1, nitric oxide, 
asymmetric dimethylarginine, renin, angiotensin-II and metabolites, and noradrenalin
will be summarized by treatment group at each timepoint.  Line graphs of this 
information will be provided by treatment group for each acute challenge.
Further statistical considerations will be addressed in the RAP.

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Section 12.3 Appendix 3: Daprodustat Risk Assessment
REVISED TEXT, where text in strikethrough has been removed and bolded text has been added
Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Excessive erythropoiesis (polycythemia) leading 
to thrombosis and/or tissue ischemia
In animal studies, excessive erythropoiesis attributed to 
daprodustat was associated with vascular congestion, 
microthrombi, and tissue ischemia in a number of organs.
Following review of clinical data received to date, this has not 
been identified as a safety concern for daprodustat.
Phase 2 dose-ranging studies, and associated statistical and 
exposure response modelling has informed Phase 3 dose
rationale, starting doses, dose levels, and dose adjustment 
scheme to optimize Hgb management.

Specific eligibility criteria related to 
requirements for entry Hgb are detailed in 
Section 5

Hgb will be closely monitored throughout 
the dosing period as outlined in the Time 
and Events Table (Section 7.1)

Specific guidance for discontinuation of 
daprodustat based on achieved Hgb is 
provided in Section 5.5.1.1

Monitoring of emerging safety data by an 
internal GSK Safety Review Team
Death, MI, stroke, heart failure congestive HF, 
thromboembolic events venous 
thromboembolism, thrombosis of vascular 
access at Hgb levels which are within the normal 
range (i.e. not polycythemic conditions)
Marketed rhEPO/ESAs have been associated with an increased 
risk for death and serious cardiovascular events when used in 
patients with anemia of CKD.
Not observed at tolerated doses when 
hemoglobin/hematocrit within normal range for species.
The clinical data received to date are insufficient to 
conclude or refute this risk. Following review of clinical data 
received to date, this has not been identified as a safety concern 
for daprodustat.

Specific eligibility criteria related to CV risk 
are outlined in Section 5.3

Hgb will be closely monitored throughout 
the dosing period as outlined in the Time 
and Events Table Section 7.1

Monitoring of emerging safety data by an 
internal GSK Safety Review Team
Esophageal and gastric erosions
In animal studies, undesirable GI effects including emesis, 
abnormal feces and/or decreased food consumption/body 

Suspected GI bleeding or significant 
symptoms consistent with erosion should 

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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
weight loss and stomach erosions/ ulcers with hemorrhage were 
observed with daprodustat.
In rodents rats stomach erosions were observed with 
intravenous and oral administration of daprodustat.
Stomach erosions/ulcers also reported in rats with 
marketed rhEPOs/ESAs.
Gender-averaged systemic exposure (AUC) at the no observed 
adverse effect levels (NOAEL) are 3.3 -fold (monkeys) and 737 -
fold (rats) above human exposure (25 mg daprodustat).
In clinical trials to date with daprodustat, mild-moderate GI signs 
and symptoms represent the most frequently reported adverse 
event, however causal association has not been established.
Following review of clinical data received to date, GI erosions 
have not been identified as a safety concern for daprodustat.
be investigated diagnostically (i.e. 
endoscopic examination) as clinically 
warranted

Monitoring of emerging safety data by an 
internal GSK Safety Review Team
Cancer-related mortality and tumor progression 
and recurrence
Marketed reEPOs have been associated with increased risk of 
cancer related morbidity and mortality when used in patients 
with cancer.
Administration of 60mg/kg daprodustat to mice caused minimal 
increases in circulating VEGF while significant EPO increases 
were observed.
There were no daprodustat-related neoplastic findings in a 
2-year rat oral carcinogenicity study (lifetime 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 subjects 
with complex kidney cyst are outlined in 
Section 5.3.

Stopping criteria for subjects with 
treatment emergent malignancy are 
outlined in Section 5.5.1.

Monitoring of emerging safety data by an 
internal GSK Safety Review Team

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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy

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 concentration were 
variable but similar relative to control.

Systemic EPO concentrations within the physiologic 
range.
Three times weekly administration:

In studies up to 4 weeks duration at doses of 10 to 30 
mg:
o
Dose dependent increases in plasma VEGF 
and EPO concentrations were observed.
o
Pre-dose concentrations of EPO and VEGF 
were near or below baseline indicating no 
accumulation of EPO or VEGF after three times 
weekly dosing.
In clinical studies with daprodustat up to 4 weeks duration, a 
dose-ordered increase in VEGF plasma concentrations, an 
angiogenic factor that has been implicated in tumor growth, was 
observed at doses ranging from 10 to 150 mg. In clinical studies 
up to 24 weeks duration at doses up to 25 mg, changes in 
VEGF plasma concentrations were variable but similar relative 
to control.
Following review of clinical data received to date, this has not 
been identified as a safety concern for daprodustat.

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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 (up to 13-weeks duration in mice 
and dog, up to 26-weeks in rat, 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 has no clinically 
significant effect on echocardiographically estimated 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 subjects not on dialysis. In hemodialysis 
subjects, 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 subjects 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 

Monitoring of emerging safety data by an 
internal GSK Safety Review Team

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inconsistency in timing of ECHOs relative to dialysis day.  
Additionally, 2 of 3 subjects 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 subjects 
meeting the sPAP PCI criterion. Overall, there is insufficient 
evidence to conclude a relationship to treatment with 
daprodustat.
Following review of clinical data received to date, this has not 
been identified as a safety concern for daprodustat.
Cardiomyopathy
Published data suggest that cardiac effects of HIF stabilization 
are likely a function of the mechanism, extent, and duration of 
the effects, and can range from protective to detrimental 
depending upon the specific model and experimental conditions 
utilized.
With lifetime exposure to daprodustat in a 2-year rat oral 
carcinogenicity study, an exacerbation of rat spontaneous, 
progressive cardiomyopathy (PCM)(focal myofiber 
degeneration/necrosis with inflammatory infiltrates) was 
observed at doses of 0.8 mg/kg/day and above, although 
total incidence and severity distribution within any 
daprodustat-group were within historical control ranges.  
This is consistent with an equivocal threshold for 
exacerbation of spontaneous, progressive cardiomyopathy 
at 0.8 mg/kg/day which is also the threshold dose for 
observing increased Hct values in individual rats. Small 
increases in cardiac troponin in 6 month rat study were 
consistent with the background finding of spontaneous rodent 
cardiomyopathy.  There were no elevations observed in cardiac 

Monitoring of emerging safety data by an 
internal GSK Safety Review Team

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Mitigation Strategy
troponin in 9 month monkey study with daprodustat.
Cardiomyopathy has not been associated with naturally 
occurring mutation in man which results in increased HIF 
stabilization.
ECHO assessments performed in phase 2b studies (24 weeks 
treatment duration) did not identify any clinically meaningful 
changes in LVEF for daprodustat.
Following review of clinical data received to date, this has not 
been identified as a safety concern for daprodustat.
Proliferative retinopathy, macular edema, 
choroidal neovascularization
Increases in local (ocular) VEGF production with retinal 
neovascularization and macular edema observed in diabetic 
retinopathy and to choroidal leakage, edema and 
neovascularization seen in age-related macular degeneration
Administration of 60 mg/kg daprodustat to mice caused minimal 
increases in circulating VEGF while significant EPO increases 
were observed.
Aside from congestion of retinal vessels and optic disc 
hyperemia secondary to markedly increased red cell mass, 
there were no ocular abnormalities observed in non-clinical 
studies. No ocular abnormalities were seen in non-clinical 
studies of up to 13 weeks duration in mice and dogs, 26 weeks 
in rats, and 39-weeks in monkeys.  
In clinical studies up to 4 weeks duration, a dose-ordered 
increase in VEGF plasma concentrations was observed at 
doses ranging from 10 to 150 mg administered once daily and 
from 10 to 30mg administered three times weekly. In studies 

Suspected proliferative retinopathy, 
macular edema, choroidal 
neovascularization or symptoms 
consistent with these events should be 
investigated by ophthalmologic 
consultation as clinically warranted.

Monitoring of emerging safety data by an 
internal GSK Safety Review Team

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Mitigation Strategy
up to 24 weeks duration at doses up to 25 mg, changes in 
VEGF plasma concentrations were variable but similar relative 
to control.
Ophthalmologic assessments performed in phase 2b studies (24 
weeks treatment duration) did not identify any clinically 
meaningful changes in proliferative retinopathy, macular edema, 
or choroidal neovascularization with daprodustat.
Following review of clinical data received to date, this has not 
been identified as a safety concern for daprodustat.
Exacerbation of rheumatoid arthritis
In inflamed rheumatic joints, activation of HIF- related genes 
secondary to decreased oxygen and pro-inflammatory cytokines 
has been postulated to contribute to the neo-angiogenesis, 
proliferation and infiltration of rheumatoid synovial fibroblasts 
[Westra, 2010; Muz, 2009].
No abnormalities seen in non-clinical studies conducted to date 
for daprodustat.
Following review of clinical data received to date, this has not 
been identified as a safety concern for daprodustat.

Monitoring of emerging safety data by an 
internal GSK Safety Review Team
Drug-drug interactions
Co-administration of daprodustat with a strong CYP2C8 inhibitor 
increased the Cmax and AUC of daprodustat, 4- and 19-fold, 
respectively, while co-administration of a weak inhibitor 
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 (e.g., rifampin/rifampicin) may decrease 
the exposure of daprodustat. 

Co-administration of daprodustat with 
strong CYP2C8 inhibitors (e.g., 
gemfibrozil) and inducers (e.g., 
rifampin/rifampicin) is not permitted as 
outlined in Section 6.11.3.

Co-administration of daprodustat with 
moderate CYP2C8 inhibitors (i.e., 
clopidogrel, teriflunomide, deferasirox) 

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Although co-administration of daprodustat with strong 
inhibitors and inducers of CYP2C8 is prohibited, 
inadvertent co-administration may occur. Due to the known 
time delay in enhancing erythropoiesis by daprodustat, co-
administration with strong CYP2C8 inhibitors for up to 14 
days is not anticipated to lead to immediate marked 
increases in hemoglobin levels. Therefore, there is 
adequate time to change to alternate therapy that does not 
inhibit CYP2C8.
Additionally, as the time for maximum induction of CYP2C8 
occurs approximately 10-14 days of dosing with rifampin 
(Brodie et al, 2013 and Ohnhaus et al, 1989), daprodustat 
systemic exposure will decrease over time which will result 
in a lag period before an effect on Hgb is recognized and is 
of clinical concern.
Population PK analysis from completed Phase 2 studies 
suggests that co-administration of daprodustat with a moderate 
CYP2C8 inhibitor, 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 completed Phase 2 studies 
suggests that co-administration of daprodustat with clopidogrel 
(a moderate CYP2C8 inhibitor) leads to a ~ 2-fold increase in 
AUC, with no clinically-significant increase in the measured Hgb 
response
Co-administration of daprodustat with potent BCRP inhibitors 
should be performed with caution.Specific 
guidance on the management of potential 
drug-drug interactions and concomitant 
medications is provided in Section 6.11.

Hgb will be closely monitored throughout 
the dosing period as outlined in the Time 
and Events Table (Section 7.1)

Specific guidance for discontinuation of 
daprodustat based on achieved Hgb is 
provided in Section 5.5.1.1.

Monitoring of emerging safety data by an 
internal GSK Safety Review Team.

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Mitigation Strategy
has the potential to increase exposure of daprodustat.  Use of 
BCRP inhibitors (mostly weak) was found to result in a small
change in metabolite exposure (20% increase in AUC).
Daprodustat is an inhibitor of OATP1B1/1B3 in vitro, with IC50
values of 6 µM and 11 µM, respectively. A clinical drug 
interaction study between 25 mg daprodustat with either a 
CYP2C8 substrate or an OATP1B1/1B3 substrate showed that 
there is no PK interaction at this dose of daprodustat.
Other
rhEPO risks (Control)
See risks outlined in table for daprodustat for excessive 
erythropoiesis (polycythemia) leading to thrombosis and/or 
tissue ischemia, death, MI, stroke, heart failure, 
thromboembolic events venous thromboembolism, thrombosis 
of vascular access, and for cancer-related mortality and tumor 
progression.
Uncontrolled hypertension
Pure red cell aplasia

See mitigation strategies outlined in table 
for daprodustat for excessive 
erythropoiesis (polycythemia) leading to 
thrombosis and/or tissue ischemia; death, 
MI, stroke, heart failure, 
thromboembolic events venous 
thromboembolism, thrombosis of vascular 
access; and for cancer-related mortality 
and tumor progression.

Specific eligibility criteria related to blood 
pressure management are outlined in 
Section 5.

Specific eligibility criteria related to 
personal history of pure red cell aplasia 
are outlined in Section 5.3

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12.7.3.
Amendment 3
Summary of Amendment Changes with Rationale
This protocol amendment applies to all centers where this study may be performed.  
This protocol amendment was written to streamline recruitment of subjects into the study 
and maintain appropriate Hgb levels while in the study.  This includes removing study 
visits, altering entry requirements as well as stopping criteria, changing dosing and dose 
adjustments, and restructuring Hgb parameters.
List of Specific Changes
Title Page
A Short Title has been added:  
Short Title: Anemia Studies in CKD: Erythropoiesis via a Novel PHI Daprodustat –
Blood Pressure (ASCEND-BP)
Medical Monitor Page
REVISED TEXT, where text in strikethrough has been removed and bolded text has been 
added
Role
Name
Day Time Phone 
Number and email 
address
After-hours (Cell) 
Number
Fax Number
Primary 
Medical 
Monitor
, MD, 
PhD
Tel:
Secondary 
Medical 
Monitor
 MD, PhD
, MD, 
FACC
Tel:
Tertiary 
Medical 
Monitor
 MD
Tel:
Site and 
SAE 
Contact 
Address:
GlaxoSmithKline
1250 S. Collegeville Road, UP4400
Collegeville, PA 19426
Regulatory Agency Identifying Number(s): IND Number: 101,291
Section 1 
Protocol Synopsis for Study 205665
Objective(s)/Endpoint(s) Table
REVISED TEXT, where text in strikethrough has been removed and bolded text has been 
added.  (Within secondary endpoints, 4 weeks changed to 2 weeks)
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD

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Objectives
Endpoints
Primary

To compare the effect of daprodustat to epoetin 
alfa on blood pressure (BP) after Acute 
Challenge 2 (8 weeks of hemoglobin [Hgb] 
maintenance therapy)

Average of systolic blood pressure (SBP) as 
measured by ambulatory blood pressure 
monitoring (ABPM) over 6-hr post-dosing after 
8 weeks of Hgb maintenance therapy
Secondary

To compare the initial effect of daprodustat to 
epoetin alfa on BP after Acute Challenge 1 (4 2
weeks of erythropoiesis-stimulating agent [ESA]
washout)

Average of SBP, diastolic blood pressure 
(DBP), mean arterial blood pressure (MAP), 
and heart rate (HR) as measured by ABPM 
over 6-hr post-dosing at Day 1

Area under the effect curve (AUEC) of SBP, 
DBP, MAP, and HR as measured by ABPM 
over 24-hr post-dosing at Day 1

To compare the effect of daprodustat to epoetin 
alfa on BP after Acute Challenge 2

Average of DBP, MAP, and HR as measured 
by ABPM over 6 hr post-dosing at Day 57.

AUEC of SBP, DBP, MAP, and HR as 
measured by ABPM over 24-hr post-dosing at 
Day 57.

To estimate the initial effect of daprodustat on 
SBP, DBP, HR and MAP after Acute Challenge 
1

Change from pre-dose in SBP, DBP, HR, and 
MAP at each timepoint at Day 1

To characterize the pharmacokinetics of 
daprodustat

Plasma concentrations of daprodustat and 
metabolites and derived pharmacokinetic 
parameters including maximum observed 
concentration (Cmax), time of occurrence of 
Cmax (tmax), terminal phase half-life (t½) and 
area under concentration-time curve from time 
zero to 24 hours (AUC[0-24]) as appropriate

To assess the safety and tolerability of 
daprodustat

Incidence and severity of adverse events (AEs)
and serious adverse events (SAEs)

Reasons for discontinuation of study treatment

Absolute values and changes from baseline 
over time in laboratory parameters, 
electrocardiograms (ECGs) and vital signs
Exploratory

To investigate the effect of daprodustat on 
vasoactive mediators of blood pressure

Plasma concentrations and derived 
parameters including Cmax, tmax, t½ and 
AUC(0-24) as appropriate (to include 
erythropoietin, endothelin-1, nitric oxide, 
asymmetric dimethylarginine, renin, 
angiotensin-II and metabolites, and 
noradrenalin) 

Evaluate exposure-response relationships for 
daprodustat and: erythropoietin, endothelin-1, 
nitric oxide, asymmetric dimethylarginine, renin, 

Further models (as appropriate) to describe the 
daprodustat exposure-response relationship 
with: erythropoietin, endothelin-1, nitric oxide, 

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Objectives
Endpoints
angiotensin-II (and metabolites), and 
noradrenalin 
asymmetric dimethylarginine, renin, 
angiotensin-II (and metabolites), and 
noradrenalin. 

To summarize the effect of daprodustat and 
epoetin alfa on SBP after Acute Challenge 1 
and Acute Challenge 2

AUEC of SBP as measured by ABPM over 24-
hr post-dosing

To compare the effect of daprodustat to epoetin 
alfa on SBP after 8 weeks of Hgb maintenance 
therapy

Change from Day 1 pre-dose SBP to Day 57
pre-dose
Section 1 
Overall Design
REVISED TEXT, where text in strikethrough has been removed and bolded text has been 
added.
This study will be an open-label, randomized, parallel-group design in HD subjects with 
anemia associated with CKD.  There will be a 4-week screening period, a 4 2-week ESA 
washout period, an initial 24-hour acute challenge, an 8-week Hgb-maintenance period, 
two a second 24-hr acute challenges and a follow-up visit 14±3 days after completing 
treatment.  The study design is outlined below:
Section 1 
Study Design
PREVIOUS IMAGE
REVISED IMAGE
Week -2: ESA 
Washout
Day 1: Randomize & 
Acute Challenge 1
Day 29: Dose Adjustment 
(as needed)
Day 57: Acute Challenge 2
Hgb Maintenance Period 
Week 10: Follow-up
Screening: Between 7 and 30  
days prior to ESA Washout

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REVISED TEXT, where text in strikethrough has been removed and bolded text has been 
added.
Subjects will be screened for eligibility starting 4 weeks within 7 - 30 days prior to the 
start of an the ESA washout period (8 weeks prior to randomization/Day 1).
Subjects that qualify for enrolment will be washed out of their ESA for 4 2 weeks; the 
start of the ESA washout should be timed to coincide as closely as possible with their 
next planned ESA dose.  Subjects are enrolled once they enter the ESA washout 
period.
Following the 4 2-week ESA washout, subjects will be randomized 1:1 and stratified by 
prior ESA dose, based on the average weekly (for epoetins or darbepoetin) or monthly 
(for methoxy polyethylene glycol (PEG)-epoetin beta) dosing during the 12 weeks prior 
to ESA washout (Week -4) as follows:

Low ESA dose: <100 IU/kg/week epoetin alfa OR <0.5 µg/kg/week darbepoetin 
OR <0.6 µg/kg/week methoxy PEG-epoetin beta

High ESA dose: ≥100 IU/kg/week epoetin alfa OR ≥0.5 µg/kg/week darbepoetin 
OR 0.6 µg/kg/week methoxy PEG-epoetin beta
On Day 1, subjects will be randomized and undergo Acute Challenge 1, a single dose 
challenge to compare the acute effects on BP of the highest planned once-daily 
maintenance dose of daprodustat (24 mg) to the highest starting dose of epoetin alfa 
(100 IU/kg).  Subjects will have BP monitored for 24 hr using ABPM, and will have 
serial blood sampling to assess the pharmacokinetics of daprodustat and the time-course 
of various biomarkers.  Acute Challenge 1 will be started promptly following completion 
of a mid-week dialysis session.
After completing Acute Challenge 1, all subjects will enter the 8-week Hgb maintenance 
period where doses of either daprodustat or epoetin alfa will be administered and 
adjusted, as needed.
On Day 57, following the 8-week Hgb maintenance period, subjects will undergo Acute 
Challenge 2; this challenge will, similar to Acute Challenge 1, involve assessing the 
effect of daprodustat and epoetin alfa on SBP BP as assessed by 24-hr ABPM 
measurement.  The subjects will be administered the same dose of either daprodustat or 
epoetin alfa that was given in Acute Challenge 1, and serial blood sampling will be 
performed to assess both daprodustat pharmacokinetics, and to characterize the time 
course of various biomarkers.  Acute Challenge 2 will be started following completion of 
a mid-week dialysis session.
Subjects will be asked to not reinitiate anemia treatment until after the follow-up visit 
unless deemed medically necessary.
Subjects will attend a follow-up visit 2 weeks after completion of Acute Challenge 2.  
Subjects will be asked to not reinitiate anemia treatment until after the follow-up 
visit unless deemed medically necessary

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After both Acute Challenge 1 and 2, the 24-hr ABPM results will be checked for data 
quality as defined in the Project Requirement Specification (PRS).  If the ABPM fails the 
QC criteria following Acute Challenge 2, one additional Acute Challenge may be made 
in after a subsequent, mid-week dialysis visit 1 week later if the subject agrees. At that 
visit, the subject will receive the same study treatment for the repeat Acute Challenge 2 
as was administered on Day 57 as a single additional dose. No additional clinical 
chemistry, hematology, pharmacokinetic or biomarker sampling will be done, however 
all other procedures will be performed. 
The Acute Challenge 2 may be delayed one week if the subject’s Hgb ≥11.5.  
Section 1 
Treatment Arms and Duration
REVISED TEXT, where text in strikethrough has been removed and bolded text has been 
added.
The total maximum duration of subject involvement is up to 18 16 weeks (Screening to 
Follow-up) as described below:

Screening: Screening will occur at least one week prior to but not more than 
30 days prior to washout. Be for at least 4 weeks prior to starting the ESA 
washout

ESA Washout: Subjects that meet eligibility criteria will begin the 4 2-week ESA 
washout at Week -4.
o
This should be timed such that this day occurs on the date that would have 
been the next scheduled dose of ESA (or as close as practicable).
o
For subjects with a three-times weekly dialysis schedule, this day must not 
occur on the first dialysis session of the week (e.g., if Monday-Wednesday-
Friday schedule, the study visit cannot be on Monday).
o
For subjects with a four- to five-times weekly dialysis schedule, this day can 
be on any hemodialysis session of the week.

Randomization & Acute Challenge 1 (Day 1): Subjects will be randomized 1:1 to 
two treatment arms and will begin a 24-hr Acute Challenge where the acute BP 
effects of daprodustat and epoetin alfa will be evaluated.  This challenge will be 
initiated promptly following the subject’s dialysis session.

Hgb Maintenance Period: Subjects randomized to daprodustat will start an 8-week 
Hgb maintenance period based on a starting dose and dose adjustment algorithm.  
(See Section 6.4) Subjects randomized to epoetin alfa will begin an 8-week Hgb 
maintenance period where Hgb will be managed in accordance with local 
labelling.

Acute Challenge 2 (Day 57): At the end of the 8-week Hgb maintenance period 
subjects will repeat the procedures of Acute Challenge 1 utilizing the same 

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treatment dose administered in Acute Challenge 1.  This challenge will be 
initiated promptly following the subject’s dialysis session.

Follow-up: A Follow-up visit will be scheduled to occur 14 3 days after 
completing treatment.
Section 1 
Type and Number of Subjects
REVISED TEXT, where text in strikethrough has been removed and bolded text has been 
added.

The study will enroll hemodialysis-dependent subjects with anemia associated with 
CKD currently treated with an ESA.  Subjects with Hgb values of 9.0 8.5 - 11.5 g/dL, 
inclusive at both Screening and Day 1, are eligible, and the subjects must currently 
be on an have received the same ESA product. with total weekly doses that varied by 
no more than 50% during the 4 weeks prior to the Screening visit.

Approximately 124 subjects will be screened to achieve approximately 62 
randomized and 50 evaluable subjects for a total of 25 evaluable subjects per 
treatment group.

If subjects prematurely discontinue the study, additional replacement subjects may be 
randomized and assigned to the same treatment arm at the discretion of the Sponsor in 
consultation with the investigator
Section 1 
Analysis
This section was bulleted for clarity only.  No text was changed.
Section 2 
Introduction
REVISED TEXT, where text in strikethrough has been removed and bolded text has been 
added.
After the bulleted section:
Hypoxia-inducible factor (HIF) prolyl hydroxylase inhibitors (PHIs) are an emerging new 
class of agents under investigation for the treatment of anemia associated with CKD.  
These molecules stimulate erythropoiesis through inhibition of HIF-prolyl hydroxylase 
domain enzymes (PHD1, PHD2, PHD3).  This activity results in the accumulation of 
HIFα transcription factors which leads to increased transcription of HIF-responsive 
genes, stimulating components of the natural response to hypoxia.  During hypoxia, the
PHD enzymes are inhibited, resulting in the accumulation of unhydroxylated HIFα 
subunits, which dimerize with HIFβ subunits to effect affect the transcription of HIF-
responsive genes, including EPO and others involved in increasing oxygen availability 
and utilization.  Other functions regulated by HIFs include iron metabolism and 
utilization, angiogenesis, extracellular matrix metabolism, apoptosis, energy and glucose 
metabolism, vascular tone, cell adhesion, and motility [Haase, 2013].
Daprodustat (GSK1278863) is a small molecule, oral inhibiter of the HIF-PHD enzymes 
which may present several important advantages over other ESAs.  It is an oral 
medication and does not require cold-chain storage as do some ESAs, thus increasing 
ease of use for patients.  Moreover, data indicate that daprodustat can effectively raise 

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Hgb concentrations with lower EPO levels than those observed after administration of 
ESAs [Provenzano, 2011].  Because of the increased CV risk associated with raising Hgb 
concentrations through large increases in EPO levels [Pfeffer, 2009], daprodustat has the 
potential to raise Hgb with less CV risk than other ESAs. 
.
Section 2.1 
Study Rationale
REVISED TEXT, where text in strikethrough has been removed and bolded text has been 
added.
Current labelling for all ESAs includes a contraindication in patients with uncontrolled 
hypertension, and increases in blood pressure (BP) and/or antihypertensive medication 
use has been observed in several clinical trials with ESAs.  While the mechanism for this 
hypertensive effect is not known, hypertension has been consistently observed in 
approximately 25 to 30% of CKD patients initiating ESA therapy, and varies between an 
average of approximately 5 to 8 mmHg in systolic blood pressure (SBP), and 4 to 6 
mmHg in diastolic blood pressure (DBP) reviewed in [Krapf, 2009].  Additionally, 
increases in BP are a well-recognized risk factor for CV events, in particular heart failure, 
ischemic stroke and myocardial infarction [Rodriguez, 2014].  Finally, treatment with 
ESAs has been associated with increased risk of major CV events including myocardial 
infarction, stroke and death.
Daprodustat has been shown to effectively raise and manage Hgb levels in subjects with 
CKD with lower levels of EPO than the ESAs.  As the hypertensive effects of ESAs 
appear dose-related [Abraham, 1991], there is the potential that daprodustat can treat 
anemia in CKD patients without the hypertensive effects observed with the ESAs.  This 
study will use two 24-hr Acute Challenges to compare the effect of daprodustat to rhEPO 
on BP as measured by ambulatory blood pressure monitoring (ABPM) following both a 4 
2-week ESA washout period (Acute Challenge 1) and an 8-week Hgb-maintenance 
period (Acute Challenge 2).
The Therefore, the purpose of this study is to compare the effects on blood pressure of 
daprodustat to epoetin alfa in hemodialysis-dependent (HD) subjects with anemia 
associated with CKD.  The study will also assess various biomarkers associated with 
blood pressure physiology that may provide insight into the mechanism(s) of the 
hypertensive effects associated with ESAs.
Section 2.2 
Brief Background
A reference was added here. (Holdstock 2016)
Section 3 
Objectives and Endpoints
REVISED TEXT, where text in strikethrough has been removed and bolded text has been 
added.  (Within secondary endpoints, 4 weeks changed to 2 weeks)
CCI
CCI
CCI
CCI

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Objectives
Endpoints
Primary

To compare the effect of daprodustat to epoetin 
alfa on blood pressure (BP) after Acute 
Challenge 2 (8 weeks of hemoglobin [Hgb] 
maintenance therapy)

Average of systolic blood pressure (SBP) as 
measured by ambulatory blood pressure 
monitoring (ABPM) over 6-hr post-dosing after 
8 weeks of Hgb maintenance therapy
Secondary

To compare the initial effect of daprodustat to 
epoetin alfa on BP after Acute Challenge 1 (4 2
weeks of erythropoiesis-stimulating agent [ESA]
washout)

Average of SBP, diastolic blood pressure 
(DBP), mean arterial blood pressure (MAP), 
and heart rate (HR) as measured by ABPM 
over 6-hr post-dosing at Day 1

Area under the effect curve (AUEC) of SBP, 
DBP, MAP, and HR as measured by ABPM 
over 24-hr post-dosing at Day 1

To compare the effect of daprodustat to epoetin 
alfa on BP after Acute Challenge 2

Average of DBP, MAP, and HR as measured 
by ABPM over 6 hr post-dosing at Day 57.

AUEC of SBP, DBP, MAP, and HR as 
measured by ABPM over 24-hr post-dosing at 
Day 57.

To estimate the initial effect of daprodustat on 
SBP, DBP, HR and MAP after Acute Challenge 
1

Change from pre-dose in SBP, DBP, HR, and 
MAP at each timepoint at Day 1

To characterize the pharmacokinetics of 
daprodustat

Plasma concentrations of daprodustat and 
metabolites and derived pharmacokinetic 
parameters including maximum observed 
concentration (Cmax), time of occurrence of 
Cmax (tmax), terminal phase half-life (t½) and 
area under concentration-time curve from time 
zero to 24 hours (AUC[0-24]) as appropriate

To assess the safety and tolerability of 
daprodustat

Incidence and severity of adverse events (AEs)
and serious adverse events (SAEs)

Reasons for discontinuation of study treatment

Absolute values and changes from baseline 
over time in laboratory parameters, 
electrocardiograms (ECGs) and vital signs
Exploratory

To investigate the effect of daprodustat on 
vasoactive mediators of blood pressure

Plasma concentrations and derived 
parameters including Cmax, tmax, t½ and 
AUC(0-24) as appropriate (to include 
erythropoietin, endothelin-1, nitric oxide, 
asymmetric dimethylarginine, renin, 
angiotensin-II and metabolites, and 
noradrenalin) 

Evaluate exposure-response relationships for 
daprodustat and: erythropoietin, endothelin-1, 
nitric oxide, asymmetric dimethylarginine, renin, 

Further models (as appropriate) to describe the 
daprodustat exposure-response relationship 
with: erythropoietin, endothelin-1, nitric oxide, 

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Objectives
Endpoints
angiotensin-II (and metabolites), and 
noradrenalin 
asymmetric dimethylarginine, renin, 
angiotensin-II (and metabolites), and 
noradrenalin. 

To summarize the effect of daprodustat and 
epoetin alfa on SBP after Acute Challenge 1 
and Acute Challenge 2

AUEC of SBP as measured by ABPM over 24-
hr post-dosing

To compare the effect of daprodustat to epoetin 
alfa on SBP after 8 weeks of Hgb maintenance 
therapy

Change from Day 1 pre-dose SBP to Day 57
pre-dose
Section 4.1 
Overall Design
REVISED TEXT, where text in strikethrough has been removed and bolded text has been 
added.  
This study will be an open-label, randomized, parallel-group design in HD subjects with 
anemia associated with CKD.  There will be a 4-week screening period, a 4 2-week ESA 
washout period, an initial 24-hour Acute Challenge, an 8-week Hgb-maintenance 
period, two a second 24-hr Acute Challenges and a follow-up visit 14±3 days after 
completing treatment.  The study design is outlined in Figure 1.
Figure 1
PREVIOUS IMAGE
REVISED IMAGE
Week -2: ESA 
Washout
Day 1: Randomize & 
Acute Challenge 1
Day 29: Dose Adjustment 
(as needed)
Day 57: Acute Challenge 2
Hgb Maintenance Period 
Week 10: Follow-up
Screening: Between 7 and 30  
days prior to ESA Washout

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Subjects will be screened for eligibility starting 4 weeks within 7 - 30 days prior to the 
start of an the ESA washout period (8 weeks prior to randomization/Day 1).
Subjects that qualify for enrolment will be washed out of their ESA for 4 2 weeks; the 
start of the ESA washout should be timed to coincide as closely as possible with their 
next planned ESA dose.  Subjects are enrolled once they enter the ESA washout 
period.
Following the 4 2-week ESA washout, subjects will be randomized 1:1 and stratified by 
prior ESA dose, based on the average weekly (for epoetins or darbepoetin) or monthly 
(for methoxy polyethylene glycol (PEG)-epoetin beta) dosing during the 12 weeks prior 
to ESA washout (Week -4) as follows:

Low ESA dose: <100 IU/kg/week epoetin alfa OR <0.5 µg/kg/week darbepoetin 
OR <0.6 µg/kg/week methoxy PEG-epoetin beta

High ESA dose: ≥100 IU/kg/week epoetin alfa OR ≥0.5 µg/kg/week darbepoetin 
OR 0.6 µg/kg/week methoxy PEG-epoetin beta
On Day 1, subjects will be randomized and undergo Acute Challenge 1, a single dose 
challenge to compare the acute effects on BP of the highest planned once-daily 
maintenance dose of daprodustat (24 mg) to the highest starting dose of epoetin alfa 
(100 IU/kg).  Subjects will have BP monitored for 24 hr using ABPM, and will have 
serial blood sampling to assess the pharmacokinetics of daprodustat and the time-course 
of various biomarkers.  Acute Challenge 1 will be started promptly following completion 
of a mid-week dialysis session.
After completing Acute Challenge 1, all subjects will enter the 8-week Hgb maintenance 
period where doses of either daprodustat or epoetin alfa will be administered and 
adjusted, as needed.
On Day 57, following the 8-week Hgb maintenance period, subjects will undergo Acute 
Challenge 2; this challenge will, similar to Acute Challenge 1, involve assessing the 
effect of daprodustat and epoetin alfa on SBP BP as assessed by 24-hr ABPM 
measurement.  The subjects will be administered the same dose of either daprodustat or 
epoetin alfa that was given in Acute Challenge 1, and serial blood sampling will be 
performed to assess both daprodustat pharmacokinetics, and to characterize the time 
course of various biomarkers.  Acute Challenge 2 will be started following completion of 
a mid-week dialysis session.
Subjects will be asked to not reinitiate anemia treatment until after the follow-up visit 
unless deemed medically necessary.
Subjects will attend a follow-up visit 2 weeks after completion of Acute Challenge 2.  
Subjects will be asked to not reinitiate anemia treatment until after the follow-up 
visit unless deemed medically necessary
After both Acute Challenge 1 and 2, the 24-hr ABPM results will be checked for data 
quality as defined in the Project Requirement Specification (PRS).  If the ABPM fails the 
QC criteria following Acute Challenge 2, one additional Acute Challenge may be made  
in after a subsequent, mid-week dialysis visit 1 week later if the subject agrees. At that 

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visit, the subject will receive the same study treatment for the repeat Acute Challenge 2 
as was administered on Day 57 as a single additional dose. No additional clinical 
chemistry, hematology, pharmacokinetic or biomarker sampling will be done, however 
all other procedures will be performed as detailed in Table 4. 
The Acute Challenge 2 may be delayed one week if the subject’s Hgb ≥11.5.  See 
Section 7.5.1.1 for guidance.
Section 4.2 
Treatment Arms and Duration 
REVISED TEXT, where text in strikethrough has been removed and bolded text has been 
added.
The total duration of subject involvement is up to 18 16 weeks (Screening to Follow-up) 
as described below:

Screening: Screening will occur at least one week prior to but not more than 
30 days prior to washout.  Be for at least 4 weeks prior to starting the ESA 
washout

ESA Washout: Subjects that meet eligibility criteria will begin the 4 2-week ESA 
washout at Week -4.
o
This should be timed such that this day occurs on the date that would have 
been the next scheduled dose of ESA (or as close as practicable).
o
For subjects with a three-times weekly dialysis schedule, this day must not 
occur on the first dialysis session of the week (e.g., if Monday-Wednesday-
Friday schedule, the study visit cannot be on Monday).
o
For subjects with a four- to five-times weekly dialysis schedule, this day can 
be on any hemodialysis session of the week.

Randomization & Acute Challenge 1 (Day 1): Subjects will be randomized 1:1 to 
two treatment arms and will begin a 24-hr Acute Challenge where the acute BP 
effects of daprodustat and epoetin alfa will be evaluated.  This challenge will be 
initiated promptly following the subject’s dialysis session.

Hgb Maintenance Period: Subjects randomized to daprodustat will start an 8-week 
Hgb maintenance period based on a starting dose and dose adjustment algorithm.  
(See Section 6.4) Subjects randomized to epoetin alfa will begin an 8-week Hgb 
maintenance period where Hgb will be managed in accordance with local 
labelling.

Acute Challenge 2 (Day 57): At the end of the 8-week Hgb maintenance period 
subjects will repeat the procedures of Acute Challenge 1 utilizing the same 
treatment dose administered in Acute Challenge 1.  This challenge will be 
initiated promptly following the subject’s dialysis session.

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
Follow-up: A Follow-up visit will be scheduled to occur 14 3 days after 
completing treatment.
Section 4.3 
Type and Number of Subjects
REVISED TEXT, where text in strikethrough has been removed and bolded text has been 
added.
The study will enroll hemodialysis-dependent subjects with anemia associated with CKD 
currently treated with an ESA.  Subjects with Hgb values of 9.0 8.5 to 11.5 g/dL, 
inclusive at both Screening and Day 1, are eligible, and the subjects must have received 
the currently be on an same ESA product. with total weekly doses that varied by no 
more than 50% during the 4 weeks prior to the Screening visit.
Approximately 124 subjects will be screened to achieve approximately 62 randomized 
and 50 evaluable subjects for a total of 25 evaluable subjects per treatment group.
If subjects prematurely discontinue the study, additional replacement subjects may be 
randomized and assigned to the same treatment arm at the discretion of the Sponsor in 
consultation with the investigator.
Section 4.4 
Design Justification
REVISED TEXT, where text in strikethrough has been removed and bolded text has been 
added.  Note: no change was made to Figure 2 at the end of this section.
This study will be an open-label, multi-center, randomized, parallel-group design in HD 
subjects with anemia associated with CKD.  There will be a 4-week screening period, a 4
2-week ESA washout period, an 8-week Hgb-maintenance period including two 24-hr 
acute challenges and a follow-up visit 14 ± 3 days after completing treatment.
It is preferred that no changes are made to estimated dry weight (EDW) and 
antihypertensive medications while the subject is participating in this study.  Subjects 
will remain in the study regardless of any changes.

This will be an open-label study since the primary endpoint (SBP by ABPM) is an 
objective measure and unlikely to be influenced by knowledge of the treatment 
received.  Additionally, an open label design will facilitate the conduct of the 
interim analysis.  Lastly, blinding of an injectable comparator and oral study 
drug is impractical in this case.

A 4-week screening period will be used to assess Hgb stability in order to 
minimize the potential for enrolling patients with highly variable Hgb despite 
ESA treatment.

A 4-week ESA washout will be used as this is the timeframe which was used in a 
published study which demonstrated an acute increase in MAP following IV 
administration of epoetin alfa as measured using ABPM over a 24-hr period 
starting from the end of the dialysis session following a single dose of epoetin 
alfa(both subcutaneous and intravenous) [Kang, 1998].  The results of the 

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published MAP assessments are demonstrated in Figure 2.  Of note, in In a our
previous daprodustat study (PHI113633)experience in Phase 2b, HD-dependent 
subjects with anemia associated with CKD were administered placebo for 4 
weeks, with a mean decrease of between 0.61 and 0.72 g/dL in Hgb.  No subject 
met either the Hgb stopping criterion or requiring rescue medication.  Therefore, 
the risk of a subject meeting Hgb withdrawal criteria is considered low during this 
phase.

The Acute Challenge days have been designed to be consistent with the 
methodology used in a published study [Kang, 1998] (See Figure 2).  Although 
the goal of the current study is to attempt to replicate the blood pressure results 
from the IV administration of epoetin alfa in the that publication by. [Kang, 
1998], in order to compare the response to daprodustat,SBP will be the primary 
endpoint rather than MAP since SBP is the overall best predictor of future 
cardiovascular risk in a hypertensive population, and MAP is biased toward DBP 
[Agarwal, 2015].

Acute Challenge 1 will assess whether there are any immediate effects of 
daprodustat or epoetin alfa on blood pressure.  This assessment will also 
determine the ability to replicate the findings in the published study and will 
provide information for an interim analysis (See Section 9.3.2).

The 8-week Hgb Maintenance Phase will replicate the management procedures 
planned for the Phase 3 studies as described in Section 6.4.  The duration was 
chosen to be consistent with the timeframe in which the hypertensive effects of 
ESAs have been observed (i.e., 4 to 8 weeks) [Samtleben, 1988].

Acute Challenge 2 will again assess the effects of daprodustat or epoetin alfa on 
BP following 8 weeks of anemia treatment utilizing the same assessment as Acute 
Challenge 1.  The purpose of Acute Challenge 2 is to assess any BP effects of 
ESA administration that may be potentiated (or possibly diminished) following 
long-term administration of an ESA.
Section 4.5 
Dose Justification
REVISED TEXT, where text in strikethrough has been removed and bolded text has been 
added.
Daprodustat Treatment Group

Acute Challenge 1 & 2: The dose to be used for this group will be the highest planned 
maintenance dose for a once-daily regimen (i.e., 24 mg) for treatment of anemia 
associated with CKD.  In a previous GlaxoSmithKline (GSK) study (PHI112843), a 
single, oral dose of 150 mg daprodustat was administered to dialysis patients with no 
safety issues identified.  For Acute Challenge 2, stringent Hgb stopping criteria and 
dose hold have been defined at Week 8 Day 57 to minimize marked increases in 
Hgb.

Hgb Maintenance Phase: Starting doses of daprodustat will be based on Hgb levels, 

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as described in Section 6.4.1.  These doses have been chosen to minimize the 
potential for subjects to meet Hgb stopping criteria during the initial 4-week dosing 
period prior to the first dose adjustment, and are based on modelling and simulation 
of the dose-Hgb response results from Phase 2 studies.  Additionally, Hgb levels will 
be assessed at 2 and 6 weeks after start of the maintenance period with specific Hgb 
stopping criteria (See Table 2).
Epoetin alfa Treatment Group

Acute Challenge 1 & 2: The dose to be used for this group will be the highest labelled 
starting dose for epoetin alfa (100 U/kg, IV) which is consistent with the epoetin alfa 
dose used in the published study where an acute increase in MAP with rhEPO was 
observed [Kang, 1998].  As subjects in this group will have been washed off ESA for 
4 2 weeks prior to Acute Challenge 1 and only a single dose will be administered, the 
risk of a marked increase in Hgb levels is considered very low.  For Acute Challenge 
2, stringent Hgb-based stopping criteria and dose hold have been defined at Week 8
Day 57 to minimize marked increases in Hgb (See Table 2).

Hgb Maintenance Phase: The dosage of epoetin alfa during the 8-week Hgb 
maintenance phase will be adjusted (if necessary) according to the local labelling in 
order to manage the subject’s Hgb within the target range (10.0-11.0 g/dL).  In a 
previous study (GSK Study PHI113633), HD subjects that had a similar 4-week ESA 
washout were initiated on a mean dose of rhEPO of 89 IU/kg/week (n=39), with the 
dose increased to a mean of 102 IU/kg/week 4 weeks later.
Section 5.1 
Hemoglobin Stability Criteria
REVISED TEXT, where text in strikethrough has been removed and bolded text has been 
added.  Note: Figure 3 has been removed from the end of this section.  There is no 
revised figure to insert.  As some values were already in bold, they are underlined below 
to indicate addition of this text.
Entry into the study requires a stable Hgb between 9.0 8.5 and 11.5 g/dL, inclusive.  
This is confirmed from an average of three two Hgb values obtained during at the 
Sscreening Visit and Washout Visit, with both values between 8.5 and 11.5 g/dL.  
period at Weeks -8, -6 and -4 These will be taken via a validated point-of-care device to 
measure Hgb (i.e., HemoCue) prior to the dialysis session of the day. as outlined in 
Figure 3.  The value at the Washout Visit must not have decreased by more than 1.0 
g/dL from the Screening Visit value. For subjects with a three-times weekly dialysis 
schedule, Hgb values must not be obtained on the first dialysis session of the week (e.g., 
if Monday-Wednesday-Friday schedule, the study visit cannot be on Monday).  For 
subjects with a four- to five-times weekly dialysis schedule, Hgb values can be obtained 
on any hemodialysis session of the week.
Section 5.2 
Inclusion Criteria
REVISED TEXT, where text in strikethrough has been removed and bolded text has been 
added.  Already bolded text has been underlined to show addition.

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A subject will be eligible for inclusion in this study only if all of the following criteria 
apply:
AGE
1.   ≥40 years of age, at the time of signing the informed consent.
TYPE OF SUBJECT AND DIAGNOSIS INCLUDING DISEASE SEVERITY
2.   Hemoglobin: Stable Hgb 9.0 8.5 to 11.5 g/dL inclusive (See Section 5.1).
3.   Dialysis frequency: On hemodialysis (HD, hemofiltration or hemodiafiltration) 
three-to five-times weekly for at least 4 weeks prior to screening.
4.  Dialysis adequacy: A single pool Kt/Vurea 1.2 based on a historical value obtained 
within the 3 months prior to screening in order to ensure the adequacy of dialysis.  If 
Kt/Vurea is not available, then an average of the last 2 values of urea reduction ratio 
(URR) is at least 65%.  NOTE: Only needs confirming at screening.
5.   ESA dose treatment: Treated with the same an ESA (epoetins or their biosimilars, 
darbepoetin, or methoxy PEG-epoetin beta) with total weekly dose varying by no 
more than 50% during the for at least 4 weeks prior to screening.
6.  Iron replacement therapy: Subjects may be on stable maintenance oral or IV 
(≤100 mg/week) iron supplementation.  If subjects are on oral or IV iron, then doses 
must be stable for the 4 weeks prior to screening through Day 1Washout.
7.  Estimated Dry Weight (EDW):  Mid-week average weight gain between dialysis 
treatments <5% as assessed pre- and post-dialysis from screening to WashoutDay 1.
8. Antihypertensive Medication: Meets the following criteria:

On at least 2 1 different antihypertensive medications of different classes
[excluding diuretics]
AND

On that same medication and the same dose for at least 1 week prior to 
Washout a stable dose and number of hypertensive medications for the 4 weeks 
prior to screening through Day 1.
INFORMED CONSENT
9. Capable of giving signed informed consent as described in Section 10.2 which 
includes compliance with the requirements and restrictions listed in the consent form 
and in this protocol.
10. Willing and able to wear ABPM device for at least 25 hours on two separate 
sessions.
Section 5.3 
Exclusion Criteria
REVISED TEXT, where text in strikethrough has been removed and bolded text has been 
added.  
A subject will not be eligible for inclusion in this study if any of the following criteria 
apply:

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CKD-RELATED CRITERIA
1. Dialysis modality: Planned change from HD to peritoneal dialysis within the study 
time period, or on home dialysis.
2. Renal transplant: Planned for kidney transplant within the 18 16 weeks following 
the Screening visit.
3. High ESA dose: An epoetin alfa dose of ≥360 IU/kg/week IV or ≥250 IU/kg/week 
subcutaneous (SC), or darbepoetin dose of ≥1.8 µg/kg/week IV or SC, or methoxy 
PEG-epoetin beta dose of 2.2 µg/kg/week within the 8 weeks prior to screening 
through Week -4.
4. Mircera: Planned or recorded administration of Mircera (methoxy PEG-epoetin beta) 
within the 4 weeks prior tostart of the Wwashout visit at Week -4.
CARDIOVASCULAR DISEASE-RELATED CRITERIA
5. Myocardial infarction or acute coronary syndrome: Within the 4 weeks 3 months
prior to screening through Day 1 Washout.
6. Stroke or transient ischemic attack: Within the 4 weeks 3 months prior to 
screening through Day 1 Washout.
7. Heart failure: Chronic Class IV heart failure (HF), as defined by the New York 
Heart Association (NYHA) functional classification system diagnosed prior to 
screening through Day 1 Washout.
8. QT interval corrected for heart rate using Bazett’s formula (QTcB): QTcB >500 
msec, or QTcB >530 msec in subjects with Bundle Branch Block.  There is no QTc 
exclusion for subjects with a predominantly paced rhythm.
9. Current uncontrolled hypertension: Resting systolic blood pressure >160 mmHg; 
or diastolic blood pressure >100 mmHg at screening.
10. Atrial Fibrillation: Presence of atrial fibrillation or a history of atrial fibrillation.
OTHER DISEASE-RELATED CRITERIA
11. Inflammatory disease: Active chronic inflammatory disease that could impact 
erythropoiesis (e.g., scleroderma, systemic lupus erythematosus, rheumatoid arthritis, 
celiac disease) diagnosed prior to screening through Day 1 Washout.
12. Aplasias: History of bone marrow aplasia or pure red cell aplasia.
13. Other causes of anemia: Pernicious anemia, thalassemia major, sickle cell disease or 
myelodysplastic syndrome.
14. Liver disease (any one of the following):

Alanine transaminase (ALT) >2x upper limit of normal (ULN) (screening only)

Bilirubin >1.5xULN (screening only)
NOTE: Isolated bilirubin >1.5xULN is acceptable if bilirubin is fractionated and 
direct bilirubin <35%.

Current unstable liver or biliary disease per investigator assessment, generally 
defined by the presence of ascites, encephalopathy, coagulopathy, 
hypoalbuminaemia, esophageal or gastric varices, persistent jaundice, or cirrhosis.
NOTE: Stable chronic liver disease (including asymptomatic gallstones, chronic 

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hepatitis B or C, or Gilbert’s syndrome) are acceptable if subject otherwise meets 
entry criteria.
15. Major surgery: Major surgery (excluding vascular access surgery) within the 8 
weeks 3 months prior to screening through Day 1 Washout, or planned during the 
study.
16. Transfusion: Blood transfusion within the 8 weeks prior to screening through Day 1
Washout, or an anticipated need for blood transfusion during the study.
17. Gastrointestinal (GI) bleeding: Evidence of actively bleeding gastric, duodenal, or 
esophageal ulcer disease OR clinically significant GI bleeding within the 4 8 weeks
prior to screening through Day 1 Washout.
18. Acute Infection: Clinical evidence of acute infection or history of infection requiring 
intravenous (IV) antibiotic therapy within the 4 8 weeks prior to Screening through 
Day 1 Washout.
NOTE: IV antibiotics as prophylaxis are allowed.
19. Malignancy: History of malignancy within the two years prior to screening through 
Day 1 or currently receiving treatment for cancer, or has a known complex kidney 
cyst (e.g., Bosniak Category IIF, III or IV) 3 cm.
NOTE: ONLY exception is localized squamous cell or basal cell carcinoma of the 
skin that has been definitively treated more than 4 weeks prior to screening.
20. Blood Pressure Measurement: Subjects with an upper arm diameter which cannot 
be measured by oscillometer/ sphygmomanometer cuff OR for whom blood pressure 
cannot be measured in the opposite arm of current vascular access.

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CONCOMITANT MEDICATIONS
21. Severe allergic reactions: History of severe allergic or anaphylactic reactions or 
hypersensitivity to excipients in the investigational product (see Daprodustat IB for 
list of excipients [GlaxoSmithKline Document Number RM2008/00267/07]).
22. Drugs and supplements: Use of any prescription or non-prescription drugs or 
dietary supplements that are prohibited (See Section 6.11.3), from screening until Day 
1 Washout.
23. Prior investigational product exposure: The subject has participated in a clinical 
trial and has received an experimental investigational product within the 30 days prior 
to screening through Day 1 or within 5 half lives of the investigational product 
prior to screening, whichever is longer.
GENERAL HEALTH RELATED CRITERIA
24. Other conditions: Any other condition, clinical or laboratory abnormality, or 
examination finding that the investigator considers would put the subject at 
unacceptable risk, which may affect study compliance or prevent understanding of the 
aims or investigational procedures or possible consequences of the study.
25. Females ONLY: Subject is pregnant [as confirmed by a positive serum human 
chorionic gonadotrophin (hCG) test for females of reproductive potential (FRP) 
only], subject is breastfeeding, or subject is of reproductive potential and does not 
agree to follow one of the contraceptive options listed in the List of Highly Effective 
Methods for Avoiding Pregnancy in Section 12.4.7.
DIAGNOSTIC ASSESSMENTS AND OTHER CRITERIA
26. Vitamin B12: At or below the lower limit of the reference range (may rescreen in a 
minimum of 8 weeks, following treatment).
27. Folate: <2.0 ng/mL (4.5 nmol/L) (may rescreen in a minimum of 4 weeks, following 
treatment).
28. Ferritin: <100 ng/mL
29. Transferrin saturation (TSAT): <20%.
Section 5.4 
Screening/Baseline/Run-in Failures
REVISED TEXT, where text in strikethrough has been removed and bolded text has been 
added.  
Screen failures are defined as subjects who consent to participate in the clinical trial but 
who never enter the washout period are never subsequently randomized.  In order to 
ensure transparent reporting of screen failure subjects, meet the Consolidated Standards 
of Reporting Trials (CONSORT) publishing requirements, and respond to queries from 
Regulatory authorities, a minimal set of screen failure information is required including 
Demography, Screen Failure details, Eligibility Criteria, and Serious Adverse Events (see 
Section 7.3.1.6).
Section 5.5 
Withdrawal/Stopping Criteria
REVISED TEXT, where text in strikethrough has been removed and bolded text has been 
added.  

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A subject 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 or 
administrative reasons.  If a subject withdraws from the study, he/she may request 
destruction of any samples taken, and the investigator must document this in the site 
study records.
If a decision is made to withdraw a subject, he/she should return to the clinic as soon as 
possible to complete the Early Withdrawal assessments.  The and Follow-up visit should 
be performed 14 ± 3 days after last dose. (see Time and Events Table Section 7.1).
In all cases, the reason for withdrawal from the study and date of the last dose of study 
treatment will be recorded in the eCRF.
Section 5.5.1.1 
Hemoglobin Stopping Criteria
REVISED TEXT, where text in strikethrough has been removed and bolded text has been 
added.  
GSK will supply a point-of-care Hgb analyzer (HemoCue) to each site for rapid and 
convenient monitoring of Hgb levels and to ensure consistency of Hgb measurements 
across sites participating in the study.
Blood samples for measurement of Hgb concentrations via HemoCue will be collected 
(Table 2 3) and recorded in the eCRF.  The table below summarizes the Hgb values and 
corresponding action to be taken at each visit. If the subject meets the below 
condition(s), then IP must be permanently stopped.
Table 2 Hgb Stopping Criteria
Week 2 & Day 1 (Prior to Acute Challenge 1)
Hgb at Visit
Action
<7.5
Repeat HemoCue assessment on the same sample at same study visit to confirm; take average of 2 
values.  If confirmed, withdraw subject from the study.
7.5-<11.5
decrease of 2.0 in Hgb 
over 2 weeks
Repeat HemoCue assessment on the same sample at same study visit 
to confirm; take average of 2 values.  If confirmed, permanently 
withdraw subject from the study.
increase of 1.0 3 in Hgb 
over 2 weeks
Repeat HemoCue assessment on the same sample at same study visit 
to confirm; take average of 2 values.  If confirmed, withdraw subject 
from the study.
11.5
Repeat HemoCue assessment on the same sample at same study visit to confirm; take average of 2 
values.  If confirmed, permanently withdraw subject from the study avoid dosing and continue 
washout for one additional week.  Progress with Acute Challenge 1 one week later if Hgb has 
decreased below 11.5; if not then withdraw subject from study.

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Days 15, 29, & 43
Hgb at Visit
Action
<7.5
Repeat HemoCue assessment on the same sample at same study visit to confirm; take average of 2 
values.  If confirmed, permanently discontinue study treatment and withdraw subject from the study.
7.5-<12.0
decrease of 2.0 in Hgb 
over 2 weeks
Repeat HemoCue assessment on the same sample at same study visit 
to confirm; take average of 2 values.  If confirmed, permanently 
discontinue study treatment and withdraw subject from the study.
increase of 1.0 3 in Hgb 
over 2 weeks
Repeat HemoCue assessment on the same sample at same study visit 
to confirm; take average of 2 values.  If confirmed, permanently 
discontinue study treatment and withdraw subject from the study.
12.0
Repeat HemoCue assessment on the same sample at same study visit to confirm; take average of 2 
values.  If confirmed, permanently discontinue study treatment and withdraw subject from the study.
Day 57 (Prior to Acute Challenge 2)
Hgb at Visit
Action
<7.5
Repeat HemoCue assessment on the same sample at same study visit to confirm; take average of 2 
values.  If confirmed, permanently discontinue study treatment and withdraw subject from the study.
7.5-<11.50
decrease of 2.0 in Hgb 
over 2 weeks
Repeat HemoCue assessment on the same sample at same study visit 
to confirm; take average of 2 values.  If confirmed, permanently 
discontinue study treatment and withdraw subject from the study.
increase of 1.0 3 in Hgb 
over 2 weeks
Repeat HemoCue assessment on the same sample at same study visit 
to confirm; take average of 2 values.  If confirmed, permanently 
discontinue study treatment and withdraw subject from the study.
11.50
Repeat HemoCue assessment on the same sample at same study visit to confirm; take average of 2 
values.  If confirmed, HOLD the dose for 1 week and progress with Acute Challenge 2 one week 
later.permanently discontinue study treatment and withdraw subject from the study.  If Hgb remains 
above 11.5 one week later, then withdraw subject from the study.
Section 6.1 
Investigational Product and Other Study Treatment
REVISED TEXT, where text in strikethrough has been removed and bolded text has been 
added.  
The term ‘study treatment’ is used throughout the protocol to describe any combination 
of products received by the subject as per the protocol design.  Study treatment may 
therefore refer to the individual study treatments or the combination of those study 
treatments.
Product name:
Daprodustat
Dosage form:
Tablet
Unit dose strength(s)/Dosage level(s):
1 mg, 2 mg, 4 mg, 6 mg, 8 mg, 10 mg tablet strengths/1 mg, 2 mg, 4 mg, 
6 mg, 10 mg, 12 mg & 24 mg dosage levels
Route of Administration
Oral
Physical description:
1 mg, 2 mg & 4 mg tablets: 7.0 mm round, compound radius, white film 
coated tablets
6 mg, 8 mg & 10 mg tablets: 9.0 mm round, compound radius, white film 
coated tablets
Method for individualizing dosage:
See Section 6.4.1

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For a description of epoetin alfa, please consult the local label.
All eligible subjects will discontinue their current ESA therapy and will undergo a 4 2-
week ESA washout period.  Following washout, subjects will be randomized to receive 
either daprodustat or epoetin alfa, on a dialysis day.  For subjects with a three-time 
weekly dialysis schedule, randomization must not occur on the first dialysis session of the 
week (e.g., if Monday-Wednesday-Friday schedule, the study visit cannot be on 
Monday).  For subjects with a four to five times weekly dialysis schedule, randomization 
can be on any hemodialysis session of the week.
Subjects can take their tablets without regard to food.  For all study visits, it is 
recommended for subjects not to eat a heavy meal before coming to the clinic in order to 
avoid lipemia of the blood sample collected for the analysis of transferrin, iron and total 
iron binding capacity (TIBC).
Section 6.4.1 Subjects Randomized to Daprodustat
REVISED TEXT, where text in strikethrough has been removed and bolded text has been 
added.  
Subjects randomized to daprodustat will have doses adjusted, as required, to target Hgb 
within the range of 10.0-11.0 g/dL.  Dose adjustments will be assigned automatically via 
the IVWRS based on the subject’s Hgb value via onsite HemoCue assessment according 
to the following algorithms:
Day 1 (HemoCue Prior to Acute Challenge 1)
Hgb (g/dL)
Action or Dose
<7.5
Repeat HemoCue assessment on the same sample at same study visit to confirm; take 
average of 2 values.  If confirmed, withdraw subject from the study.
7.5 and <9.0
8 mg daprodustat
7.5 9 and <10.0
6 mg daprodustat
10.0 and <11.5
4 mg daprodustat
11.5
Repeat HemoCue assessment on the same sample at same study visit to confirm; take 
average of 2 values.  If confirmed, withdraw subject from the study. avoid dosing and 
continue washout for one additional week.  If Hgb remains above 11.5 then withdraw 
subject from study.
The 8 week Hgb maintenance dosing will begin on Day 2, following Acute Challenge 1.
Acute Challenge dosing is the same for all subjects on the daprodustat arm: 24 mg.
Days 15, 29, and 43
The available dose steps for daprodustat are outlined below (highlighted boxes indicate 
starting doses).  Dose adjustments will result in the daprodustat dose being increased or 
decreased by one dose step.

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PREVIOUS IMAGE
REVISED IMAGE
Hgb (g/dL)
Hgb change since
Day 1 previous study
visit
Dose Adjustment
<7.5
Any change
Repeat HemoCue assessment on the same sample at same study 
visit to confirm; take average of 2 values.  If confirmed, permanently 
discontinue study drug and withdraw subject from the study.
7.5 to <9.5
Decreasing or No change1
Increase to the next higher dose step
7.5 to <9.5
Increasing2
Maintain dose
9.5 to ≤11.5
Any change
Maintain dose
>11.5 to <12.0
Increasing or No change
Decrease to the next lower dose step
Decreasing
Maintain dose
≥12.0
Any change
Repeat HemoCue assessment on the same sample at same study 
visit to confirm; take average of 2 values.  If confirmed, permanently 
discontinue study treatment and withdraw subject from the study.
HOLD dosing for 2 weeks until next study visit.3
1No change is defined as an increase < 0.5 g/dL
2Increase is defined as an increase ≥ 0.5 g/dL
3 If Hgb remains ≥12.0 at next visit, the subject should be withdrawn from the study.  If the Hgb drops below 
12.0, the subject should be restarted on the next lowest dose.
Section 6.10.1 
Meals and Dietary Restrictions
REVISED TEXT, where text in strikethrough has been removed.
Daprodustat can be taken without regard to meals.
All subjects will be instructed to limit caffeine- or xanthine- containing products (e.g., 
coffee, tea, cola drinks, chocolate) for 24h prior to both Acute Challenge 1 and Acute 
Challenge 2.  Should the Additional Acute Challenge 2 be necessary, the subject does not 
need to limit the products listed above.
Section 6.11.1 Estimated Dry Weight and Antihypertensive Medication Changes
REVISED TEXT, where text in strikethrough has been removed and bolded text has been 
added.  
It is preferred that changes to EDW and antihypertensive medication(s) are not made 
while the subject is part of this study, however, Subjects subjects should remain in the 

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study regardless of any changes.  All medication and dose changes should be recorded 
in the eCRF.
Section 6.11.3    Prohibited Medications and Non-Drug Therapies
REVISED TEXT, where text in strikethrough has been removed and bolded text has been 
added. 
Use of any of the following prescription drugs from screening (Week -8) until 7 days 
after the last dose of randomized treatment is prohibited and will constitute a protocol 
violation.

The sStrong inhibitors of CYP2C8 (e.g., gemfibrozil, high dose clopidogrel [300 
mg])

Strong inducers of CYP2C8 (e.g., rifampin/rifampicin)
Section 7.1 Time and Events Table
Table 3 Study Procedures and Assessments
REVISED TEXT, where text in strikethrough has been removed and bolded text has been 
added. 

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Procedure1
Screening
ESA Washout
Treatment Period2
Follow-up2
Week -8
Week -6
Week -4
Week -2
Day 1
Day 15
Day 29
Day 43
Day 57
Early WD
Week 10
Informed Consent
X
Entry Criteria
X
Physical, Medical History, Demography
X
HemoCue Hgb
X
X
X
X
X4
X
X
X
X4
X
X
Enrollment
X
IVWRS 
X
X
X
X
Randomization
X
Acute Challenge
X4
X4
ABPM Assessment
X4
X4
Dose Adjustment
X
X
X
Females Only: Serum Pregnancy Test
X
X
X
X
X
X
X
Females Only: Estradiol & FSH (if required)3
X
X
ECG
X
X4
X4
X
X
Vital signs & weight (Pre- & Post-dialysis)
X
X
X
X
X4
X
X4
X
X
Clinical Chemistry
X
X
X
X
X
X
X
Hematology
X
X
X
X
X
X
X
Folate and Vitamin B12
X
Ferritin, transferrin, total iron,, TSAT, UIBC
X
X
Pharmacokinetic/Biomarker Assessments
X4
X4
Hgb Maintenance Period5
=======================================
Adverse Events Assessment
X6
X6
X
X
X4
X
X
X
X4
X
X
Review Concomitant Medications
X
X
X
X4
X
X
X
X4
X
X
1 All assessments should be done predialysis/predose except as noted.
2 Allowable time window 2 days EXCEPT Follow-up Visit which is 3 days.
3 As detailed in Inclusion Criteria.
4 Detailed timings for assessments on Acute Challenge Days are given in Table 4.
5 From the end of Acute Challenge 1 to the beginning of Acute Challenge 2.
6 Only SAEs assessed as related to study participation are collected at this visit. See Section 12.4 for additional details.

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Section 7.2 
Screening and Critical Baseline Assessments
REVISED TEXT, where text in strikethrough has been removed.  
Medical history, including cardiovascular disease and associated risk factors, (as detailed 
in the eCRF) will be assessed at screening.
The following demographic parameters will be captured: year of birth, sex, race and 
ethnicity.
Medical/medication/family history will be assessed as related to the inclusion/exclusion 
criteria listed in Section 5.
Procedures conducted as part of the subject’s routine clinical management [e.g., Hgb 
monitoring] and obtained prior to signing of informed consent may be utilized for 
Screening or baseline purposes provided the procedure meets the protocol-defined criteria 
and have been performed in the timeframe of the study.
Section 7.3.1.1 Time Period and Frequency for Collecting AE and SAE Information
REVISED TEXT, where text in strikethrough has been removed.  

Any SAEs assessed as related to study participation (e.g., protocol-mandated 
procedures, invasive tests, or change in existing therapy) or related to a GSK 
product will be recorded from the time a subject consents to participate in the 
study up to and including any follow-up contact.

AEs will be collected from the start of washout (Week – 4) until the follow-up 
contact (see Section 7.3.1.3), at the timepoints specified in the Time and Events 
Table (Section 7.1).

Medical occurrences that begin prior to the start of washout but after obtaining 
informed consent may be recorded on the Medical History/Current Medical 
Conditions section of the CRF.

All SAEs will be recorded and reported to GSK within 24 hours, as indicated in 
Section 12.4.

Investigators are not obligated to actively seek AEs or SAEs in former study 
subjects.  However, if the investigator learns of any SAE, including a death, at any 
time after a subject has been discharged from the study, and he/she considers the 
event reasonably related to the study treatment or study participation, the 
investigator must promptly notify GSK.
NOTE: The method of recording, evaluating and assessing causality of AEs and SAEs 
plus procedures for completing and transmitting SAE reports to GSK are provided in 
Section 12.4.
Section 7.3.5 Electrocardiogram (ECG)
REVISED TEXT, where text in strikethrough has been removed.  

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ECG measurements will be taken at the time points specified in the Time and Events 
Table (Section 7.1).  Full 12-lead ECGs will be recorded with the subject in a supine 
position.  Heart rate (HR), PR interval, QRS duration, and QT (uncorrected) interval will 
be measured.  QTcB will be calculated (machine-read or manually).
At the Screening visit (Week -8)  two additional ECGs are required if the initial ECG 
indicates prolonged QTc (see Section 5.3) using the automated or manually calculated 
QTcB value.  The average QTcB value of all three ECGs will be used to determine 
eligibility.  Additional details are provided in the SRM.
ECG data will be read locally.
All ECGs will be performed before measurement of vital signs and collection of blood 
samples for laboratory testing.
Section 7.3.6 Clinical safety Laboratory Assessments
A spelling error was corrected in the notes of Table 5.
Section 7.4.1 Blood Sample Collection
REVISED TEXT, where bolded text has been added.
Blood samples for pharmacokinetic (PK) analysis of daprodustat and its metabolites 
(GSK2391220 [M2], GSK2531403 [M3], GSK2487818 [M4], GSK2506102 [M5], 
GSK2531398 [M6], and GSK2531401 [M13]) will be collected at the time points 
indicated in Section 7.1, Time and Events Table.  The actual date and time of each blood 
sample collection will be recorded.  The timing of PK samples may be altered and/or PK 
samples may be obtained at additional time points to ensure thorough PK monitoring.
Details of PK blood sample collection (including volume to be collected), processing, 
storage and shipping procedures are provided in the SRM.
If the subject is unable to provide a sufficient blood quantity per time point or there 
is significant concern for this by the subject or investigator, these serial blood draws 
may be omitted.
Section 7.5.1.1 
ABPM Delay Due to High Hgb
REVISED TEXT, where bolded text has been added.
Day 1:  If the HemoCue Hgb is confirmed to be ≥11.5 g/dL then avoid dosing and 
continue washout for one additional week.  No other assessments should be 
performed for that subject during the visit.  When the subject returns 7 days later, 
re-draw the Hgb for HemoCue and assess.  If confirmed to be <11.5 g/dL, then 
progress with the remainder of assessments and perform Acute Challenge 1.  If the 
Hgb remains high, the subject must be withdrawn. 
Day 57:  If the HemoCue Hgb is confirmed to be ≥11.5 g/dL then hold the dose(s) of 
IP for 1 week. No other assessments should be performed for that subject during 
the visit.  When the subject returns 7 days later, re-draw the Hgb for HemoCue and 
assess.  If confirmed to be <11.5 g/dL, then progress with the remainder of 

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assessments and perform Acute Challenge 2.  If the Hgb remains high, the subject 
must be withdrawn.
Section 7.5.2 Blood pressure Regulation Biomarkers
REVISED TEXT, where bolded text has been added.
Blood samples will be collected during this study to investigate the mechanism of the 
effect of daprodustat on blood pressure.  Biomarkers selected will explore the renin-
angiotensin-aldosterone axis, the nitric oxide and endothelin axes, sodium retention and 
HIF signalling.
Biomarkers may include erythropoietin, nitric oxide (NO), asymmetric dimethyarginine 
(ADMA), renin, angiotensin-II (1-8) and metabolites (1-7 and 1-5), endothelin-1 (ET-1), 
and noradrenalin. Samples will be collected as specified in the Time and Events Table 
(Section 7.1).  The timing of the collections may be adjusted on the basis of emerging 
pharmacokinetic or pharmacodynamic (PD) data from this study or other new 
information in order to ensure optimal evaluation of the PD endpoints.
If the subject is unable to provide a sufficient blood quantity per time point or there 
is significant concern for this by the subject or investigator, these serial blood draws 
may be omitted.
Section 11 
References
The following reference was added:
Holdstock L, Meadowcroft AM, Maier R, Johnson BM, Jones D, Rastogi A, Zeig S, 
Lepore JJ, Cobitz AR. Four-week studies of oral hypoxia-inducible factor-prolyl 
hydroxylase inhibitor GSK1278863 for treatment of anemia. JASN 2016; 27:1234-1244
Section 12.1 Appendix 1 – Abbreviations and Trademarks
REVISED TEXT, where text in strikethrough has been removed and bolded text has been 
added
ABPM
Ambulatory blood pressure monitoring
ADMA
Asymmetric dimethyarginine
AE
Adverse event
ALT
Alanine transaminase
AMD
Age-Related Macular Degeneration
ANCOVA
Analysis of Covariance
AST
Aspartate transaminase
AUEC
Area under the effect curve
AUC (0-24)
Area under concentration-time curve from time zero to 24 hours
BP
Blood pressure
CHr
Reticulocyte haemoglobin content
CI
Confidence interval
CKD
Chronic kidney disease
Cmax
Maximum observed concentration

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CPK
Creatine phosphokinase
CV
Cardiovascular
DBP
Diastolic blood pressure
dL
Deciliter
DNA
Deoxyribonucleic acid
ECG
Electrocardiogram
eCRF
Electronic Case Report Form
EDW
Estimated Dry Weight
EPO
Erythropoietin
ESA
Erythropoiesis-stimulating agent
ET-1
Endothelin-1
FDA
Food and Drug Administration
FRP
Females of Reproductive Potential
FSH
Follicle Sstimulating Hhormone
GCP
Good Clinical Practice
G
Gram
GI
Gastrointestinal
GSK
GlaxoSmithKline
hCG
Human chorionic gonadotrophin
HD
Hemodialysis dependent
HDPE
High Density Polyethylene
HF
Heart Failure
Hgb
Hemoglobin
HIF
Hypoxia-inducible factor
HPLC
High Performance Liquid Chromatography
HR
Hour/heart rate
IB
Investigator’s Brochure
ICH
International Conference on Harmonization
IEC
Independent Ethics Committee
INR
International Nnormalized Rratio
IRB
Institutional Review Board
ITT
Intent-to-treat
IU
International Unit
IV
Intravenous
IVWRS
Interactive Voice/Web Response System
KDIGO
Kidney Disease Improving Global Outcomes
KG
Kilogram
LDH
Lactate dehydrogenase 
MAP
Mean Arterial Blood Pressure
MCH
Mean corpuscular hemoglobin
MCHC
Mean corpuscular hemoglobin concentration
MCV
Mean corpuscular volume
MedDRA
Medical Dictionary for Regulatory Activities
MG
Milligram
MI
Myocardial infarction
ML
Milliliter 

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mmHG
Millimeter of mercury
MSDS
Material Safety Data Sheet
ND
Non-dialysis dependent
NO
Nitric Oxide
NOAEL
No Observed Adverse Effect Level
NYHA
New York Heart Association
PD
Pharmacodynamic
PEG
Polyethylene glycol
PGI2
Prostaglandin I2
PHD
Prolyl hydroxylase domain
PHI
Prolyl hydroxylase inhibitor
PK
Pharmacokinetic
proADM
Proadrenomedullin
PRS
Project Requirement Specification
PRVP
Peak Right Ventricular Pressure
PSRAE
Possible suicidality related adverse event
QC
Quality Control
QTc
QT interval corrected for heart rate
QTcB
QT interval corrected for heart rate using Bazett’s formula
RAP
Reporting and Analysis Plan
RBC
Red blood cell
RDW
Red blood cell distribution width
rhEPO
Recombinant human erythropoietin 
RNA
Ribonucleic acid
SAE
Serious adverse event
SBP
Systolic blood pressure
SC
Subcutaneous
SD
Standard deviation
SGOT
Serum glutamic oxaloacetic transaminase
SGPT
Serum glutamic-pyruvic transaminase
sPAP
Systolic Pulmonary Artery Pressure
SRM
Study Reference Manual
T1/2
Terminal phase half-life
TIBC
Total iron binding capacity
Tmax
Time of occurrence of Cmax
TSAT
Transferrin saturation
UG
Microgram
UIBC
Unsaturated iron binding capacity
ULN
Upper limit of normal
URR
Urea reduction ratio
WBC
White blood cells

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12.7.4.
Amendment 4
Summary of Amendment Changes with Rationale
This protocol amendment applies to all centers where this study may be performed.
This protocol amendment was written to remove the interim analysis from the statistical 
section due to more rapid recruitment than anticipated.  During the update, the objectives 
and endpoints were streamlined, the stratification variable of previous ESA dose was 
added to the models as it was inadvertently left out, the daprodustat dosing algorithm was 
updated, and exploratory endpoints were added to further clarify results. 
During this time the safety language was updated as well as clarification of 
inclusion/exclusion criteria in response to an internal audit.
List of Specific Changes
Title Page
REVISED TEXT, where text in strikethrough has been removed and bolded text has been 
added:
Author (s):
 
 
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 can be found in the Study 
Reference Manual (SRM).
Regulatory Agency Identifying Number(s): IND Number: 101,291
Medical Monitor Page
REVISED TEXT, where text in strikethrough has been removed:
Medical Monitor/SAE Contact Information:
Role
Name
Day Time Phone 
Number and email 
address
After-hours (Cell) 
Number
Fax Number
PPD

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Primary 
Medical 
Monitor
, MD, 
PhD
Tel:
Secondary 
Medical 
Monitor
, MD, 
FACC
Tel:
 
Tertiary 
Medical 
Monitor
, MD
Tel:
Site and 
SAE 
Contact 
Address:
GlaxoSmithKline
1250 S. Collegeville Road, UP4400
Collegeville, PA 19426
Sponsor Legal Registered Address:
GlaxoSmithKline Research & Development Limited
980 Great West Road
Brentford
Middlesex, TW8 9GS
UK
In some countries, the clinical trial sponsor may be the local GlaxoSmithKline Affiliate 
Company (or designee).  If applicable, the details of the alternative Sponsor and contact 
person in the territory will be provided to the relevant regulatory authority as part of the 
clinical trial application.
Regulatory Agency Identifying Number(s): IND Number: 101,291
Section 1 PROTOCOL SYNOPSIS FOR STUDY 205665 
(Objective(s)/Endpoints(s))
REVISED TEXT, where text in strikethrough has been removed and bolded text has been 
added. 
Objectives
Endpoints
Primary

To compare the effect of daprodustat to epoetin 
alfa on blood pressure (BP) after Acute 
Challenge 2 (8 weeks of hemoglobin [Hgb] 
maintenance therapy)

Average of systolic blood pressure (SBP) as 
measured by ambulatory blood pressure 
monitoring (ABPM) over 6-hr post-dosing after 
8 weeks of Hgb maintenance therapy
Secondary

To compare the initial effect of daprodustat to 
epoetin alfa on BP after Acute Challenge 1 (2 
weeks of erythropoiesis-stimulating agent [ESA]
washout)

Average of SBP, diastolic blood pressure 
(DBP), mean arterial blood pressure (MAP), 
and heart rate (HR) as measured by ABPM 
over 6-hr post-dosing at Day 1
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD

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Objectives
Endpoints

Area under the effect curve (AUEC) of SBP, 
DBP, MAP, and HR as measured by ABPM 
over 24-hr post-dosing at Day 1

To compare the effect of daprodustat to epoetin 
alfa on BP after Acute Challenge 2

Average of DBP, MAP, and HR as measured 
by ABPM over 6 hr post-dosing at Day 57.

AUEC of SBP, DBP, MAP, and HR as 
measured by ABPM over 24-hr post-dosing at 
Day 57.

To estimate the initial effect of daprodustat on 
SBP, DBP, HR and MAP after Acute Challenge 
1

Change from pre-dose in SBP, DBP, HR, and 
MAP at each timepoint at Day 1

To characterize the pharmacokinetics of 
daprodustat

Plasma concentrations of daprodustat and 
metabolites and derived pharmacokinetic 
parameters including maximum observed 
concentration (Cmax), time of occurrence of 
Cmax (tmax), terminal phase half-life (t½) and 
area under concentration-time curve from time 
zero to 24 hours (AUC[0-24]) as appropriate
Safety

To assess the safety and tolerability of 
daprodustat

Incidence and severity of adverse events (AEs)
and serious adverse events (SAEs)

Reasons for discontinuation of study treatment

Absolute values and changes from baseline 
over time in laboratory parameters, 
electrocardiograms (ECGs) and vital signs
Exploratory

To investigate the effect of daprodustat and 
epoetin alfa on vasoactive mediators of blood 
pressure

Plasma concentrations and derived 
parameters including Cmax, tmax, t½ and 
AUC(0-24) as appropriate (to include 
erythropoietin, endothelin-1, nitric oxide, 
asymmetric dimethylarginine, renin, 
angiotensin-II and metabolites, and 
noradrenalin) 

Evaluate exposure-response relationships for 
daprodustat and: erythropoietin, endothelin-1, 
nitric oxide, asymmetric dimethylarginine, renin, 
angiotensin-II (and metabolites), and 
noradrenalin 

Further models (as appropriate) to describe the 
daprodustat exposure-response relationship 
with: erythropoietin, endothelin-1, nitric oxide, 
asymmetric dimethylarginine, renin, 
angiotensin-II (and metabolites), and 
noradrenalin. 

To summarize the effect of daprodustat and 
epoetin alfa on SBP after Acute Challenge 1 
and Acute Challenge 2

AUEC of SBP as measured by ABPM over 24-
hr post-dosing

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Objectives
Endpoints

To compare the effect of daprodustat to epoetin 
alfa on SBP after 8 weeks of Hgb maintenance 
therapy

Change from Day 1 pre-dose SBP to Day 57
pre-dose

To compare the effect of daprodustat to 
epoetin alfa on SBP at Cmax of each study 
treatment, as measured by ABPM

Change in SBP from pre-dose on Day 1 to 
Cmax of the study treatment on Day 1

Change in SBP from pre-dose on Day 1 to 
Cmax of the study treatment on Day 57

Change in SBP from pre-dose on Day 57 to 
Cmax of the study treatment on Day 57

To compare the effect of daprodustat to 
epoetin alfa on SBP at Cmax of the 
erythropoietin level, as measured by ABPM

Change in SBP from pre-dose on Day 1 to 
Cmax of erythropoietin on Day 1

Change in SBP from pre-dose on Day 1 to 
Cmax of erythropoietin on Day 57

Change in SBP from pre-dose on Day 57 to 
Cmax of erythropoietin  on Day 57
Study Design
PREVIOUS IMAGE
Week -2: ESA 
Washout
Day 1: Randomize & 
Acute Challenge 1
Day 29: Dose Adjustment 
(as needed)
Day 57: Acute Challenge 2
Hgb Maintenance Period 
Week 10: Follow-up
Screening: Between 7 and 30  
days prior to ESA Washout
REVISED IMAGE
Week -2: ESA 
Washout
Day 1: Randomize & 
Acute Challenge 1
Day 15, 29 & 43: Dose 
Adjustment (as needed)
Day 57: Acute Challenge 2
Hgb Maintenance Period 
Week 10: Follow-up
Screening: Between 7 and 30 
days prior to ESA Washout

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REVISED TEXT, where text in strikethrough has been removed:
Following the 2-week ESA washout, subjects will be randomized 1:1 and stratified by 
prior ESA dose, based on the average weekly (for epoetins or darbepoetin) or monthly 
(for methoxy polyethylene glycol (PEG)-epoetin beta) dosing during the 12 weeks prior 
to ESA washout as follows:

Low ESA dose: <100 IU/kg/week epoetin alfa OR <0.5 µg/kg/week darbepoetin 
OR <0.6 µg/kg/week methoxy PEG-epoetin beta

High ESA dose: ≥100 IU/kg/week epoetin alfa OR ≥0.5 µg/kg/week darbepoetin 
OR 0.6 µg/kg/week methoxy PEG-epoetin beta
On Day 1, subjects will be randomized and undergo Acute Challenge 1, a single dose 
challenge to compare the acute effects on BP of the highest planned once-daily 
maintenance dose of daprodustat (24 mg) to the highest starting dose of epoetin alfa 
(100 IU/kg).  Subjects will have BP monitored for 24 hr using ABPM, and will have 
serial blood sampling to assess the pharmacokinetics of daprodustat and the time-course 
of various biomarkers.  Acute Challenge 1 will be started promptly following completion 
of a mid-week dialysis session.
Analysis
REVISED TEXT, where text in strikethrough has been removed and bolded text has been 
added. 

The primary endpoint for this study is average systolic blood pressure (SBP) over 
6 hours of measurements taken at 15-minute intervals after the administration of 
study treatment for the Acute Challenge 2.  The primary comparison of interest is 
daprodustat versus epoetin alfa for this challenge.

The primary analysis of average SBP over 6 hr post-dose during Acute Challenge 
2 will be an analysis of covariance (ANCOVA) with terms for treatment, prior 
ESA dose (low/high), and post-HD/pre-Acute Challenge 1 SBP, difference 
between post-HD/pre-Acute Challenge 2 SBP and post-HD/pre-Acute Challenge 
1 SBP, and treatment by (difference in post-HD SBP between Acute Challenge 1 
and 2) interaction.  Note that the pre-challenge SBP may change over time 
between Acute Challenge 1 and Acute Challenge 2 as a result of the maintenance 
therapy, and thus the pre-challenge SBP at Acute Challenge 2 is not a true pre-
treatment covariate.  As a result, the interpretation of the effect of the Acute 
Challenge 2 may be confounded by the impact of treatment phase on the 
covariate. Therefore, if the interaction term in this model is significant at the 0.10 
level, then the primary model will be ANCOVA with terms for treatment, prior 
ESA dose (low/high), and post-HD/pre-Acute Challenge 1 SBP.  The primary 
model will provide a point estimate and two-sided 95% CI for the treatment effect 
and a p-value for the superiority assessment.  Superiority will be established if the 
p-value is <0.05.

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
The comparison of daprodustat versus epoetin alfa on 6 hr average SBP during 
Acute Challenge 1 is a secondary endpoint.  Average SBP over 6 hr post-dose in 
Acute Challenge 1 will be analyzed using ANCOVA with terms for treatment, 
prior ESA dose (low/high), and post-HD/pre-Acute Challenge 1 SBP.  Similar 
analyses will be performed for DBP, MAP, and HR.

ANCOVA using the primary model will be used for the analysis of average DBP, 
MAP, and HR over 6 hr post-dose in Acute Challenge 2 replacing the baseline 
SBP term with the analogous baseline measurement for DBP, MAP, and HR, 
respectively.

AUECs of SBP, DBP, MAP, and HR post Acute Challenge 2 and 1 will be 
analyzed using ANCOVA with terms for treatment and prior ESA dose 
(low/high) with 95% CIs and p-values provided for the treatment effect.

Null Hypothesis: The difference between 24 mg daprodustat versus 100 IU/kg 
epoetin alfa on 6 hr average SBP under a background of treatment (i.e., during 
Acute Challenge 2) is zero.

Alternative Hypothesis: The difference between 24 mg daprodustat versus 100 
IU/kg epoetin alfa on 6 hr average SBP under a background of treatment (i.e. 
during Acute Challenge 2) is not zero.

An interim analysis will be conducted after approximately 24 subjects have 
completed Acute Challenge 2.

If the mean change in SBP from pre-Acute Challenge 1 to the 6-hour mean
following both Acute Challenge 1 and Acute Challenge 2 is less than 5 mmHg in 
the epoetin alfa group, then the study will be stopped.  However, if a clinically 
meaningful difference between the two treatment groups in mean change in SBP 
from pre-Acute Challenge 1 to the 6-hour mean following Acute Challenge 1 (i.e., 
>5 mmHg) is observed, then the study will be continued in order to further 
characterize the effects of daprodustat on blood pressure.

Simulations show that under assumptions of a true mean change in SBP of 0 
mmHg and SD of 18 mmHg for both treatment groups at Acute Challenge 1 and 
the epoetin alfa group at Acute Challenge 2, this stopping guideline will result in 
stopping the trial >99% of the time.  Under the assumptions of a true mean change 
in SBP of 8 mmHg and SD of 18 mmHg for both treatment groups at Acute 
Challenge 1 and the epoetin alfa group at Acute Challenge 2, this rule will result 
in stopping the trial <1% of the time.
While the above is a guideline for stopping the trial due to futility, the totality of the data 
will be considered when making the decision at the time of the interim analysis.
Section 2  INTRODUCTION
REVISED TEXT, where text in strikethrough has been removed and bolded text has been 
added. 
Daprodustat (GSK1278863) is a small molecule, oral inhibiter of the HIF-PHD enzymes 
which may present several important advantages over other ESAs.  It is an oral 
medication and does not require cold-chain storage as do some ESAs, thus increasing 
ease of use for patients.  Moreover, data indicate that daprodustat can effectively raise 

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Hgb concentrations with lower EPO levels than those observed after administration of 
ESAs [Provenzano, 2011].  Because of the increased CV risk associated with raising Hgb 
concentrations through large increases in EPO levels [Pfeffer, 2009], daprodustat has the 
potential to raise Hgb with less CV risk than other ESAs. 
 
.
Section 3 OBJECTIVES AND ENDPOINTS
REVISED TEXT, where text in strikethrough has been removed and bolded text has been 
added. 
Objectives
Endpoints
Primary

To compare the effect of daprodustat to epoetin 
alfa on blood pressure (BP) after Acute 
Challenge 2 (8 weeks of hemoglobin [Hgb] 
maintenance therapy)

Average of systolic blood pressure (SBP) as 
measured by ambulatory blood pressure 
monitoring (ABPM) over 6-hr post-dosing after 
8 weeks of Hgb maintenance therapy
Secondary

To compare the initial effect of daprodustat to 
epoetin alfa on BP after Acute Challenge 1 (2 
weeks of erythropoiesis-stimulating agent [ESA]
washout)

Average of SBP, diastolic blood pressure 
(DBP), mean arterial blood pressure (MAP), 
and heart rate (HR) as measured by ABPM 
over 6-hr post-dosing at Day 1

Area under the effect curve (AUEC) of SBP, 
DBP, MAP, and HR as measured by ABPM 
over 24-hr post-dosing at Day 1

To compare the effect of daprodustat to epoetin 
alfa on BP after Acute Challenge 2

Average of DBP, MAP, and HR as measured 
by ABPM over 6 hr post-dosing at Day 57.

AUEC of SBP, DBP, MAP, and HR as 
measured by ABPM over 24-hr post-dosing at 
Day 57.

To estimate the initial effect of daprodustat on 
SBP, DBP, HR and MAP after Acute Challenge 
1

Change from pre-dose in SBP, DBP, HR, and 
MAP at each timepoint at Day 1

To characterize the pharmacokinetics of 
daprodustat

Plasma concentrations of daprodustat and 
metabolites and derived pharmacokinetic 
parameters including maximum observed 
concentration (Cmax), time of occurrence of 
Cmax (tmax), terminal phase half-life (t½) and 
area under concentration-time curve from time 
zero to 24 hours (AUC[0-24]) as appropriate
Safety

To assess the safety and tolerability of 
daprodustat

Incidence and severity of adverse events (AEs)
and serious adverse events (SAEs)

Reasons for discontinuation of study treatment

Absolute values and changes from baseline 
over time in laboratory parameters, 
CCI
CCI
CCI

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Objectives
Endpoints
electrocardiograms (ECGs) and vital signs
Exploratory

To investigate the effect of daprodustat and 
epoetin alfa on vasoactive mediators of blood 
pressure

Plasma concentrations and derived 
parameters including Cmax, tmax, t½ and 
AUC(0-24) as appropriate (to include 
erythropoietin, endothelin-1, nitric oxide, 
asymmetric dimethylarginine, renin, 
angiotensin-II and metabolites, and 
noradrenalin) 

Evaluate exposure-response relationships for 
daprodustat and: erythropoietin, endothelin-1, 
nitric oxide, asymmetric dimethylarginine, renin, 
angiotensin-II (and metabolites), and 
noradrenalin 

Further models (as appropriate) to describe the 
daprodustat exposure-response relationship 
with: erythropoietin, endothelin-1, nitric oxide, 
asymmetric dimethylarginine, renin, 
angiotensin-II (and metabolites), and 
noradrenalin. 

To summarize the effect of daprodustat and 
epoetin alfa on SBP after Acute Challenge 1 
and Acute Challenge 2

AUEC of SBP as measured by ABPM over 24-
hr post-dosing

To compare the effect of daprodustat to epoetin 
alfa on SBP after 8 weeks of Hgb maintenance 
therapy

Change from Day 1 pre-dose SBP to Day 57
pre-dose

To compare the effect of daprodustat to 
epoetin alfa on SBP at Cmax of each study 
treatment, as measured by ABPM

Change in SBP from pre-dose on Day 1 to 
Cmax of the study treatment on Day 1

Change in SBP from pre-dose on Day 1 to 
Cmax of the study treatment on Day 57

Change in SBP from pre-dose on Day 57 to 
Cmax of the study treatment on Day 57

To compare the effect of daprodustat to 
epoetin alfa on SBP at Cmax of the 
erythropoietin level, as measured by ABPM

Change in SBP from pre-dose on Day 1 to 
Cmax of erythropoietin on Day 1

Change in SBP from pre-dose on Day 1 to 
Cmax of erythropoietin on Day 57

Change in SBP from pre-dose on Day 57 to 
Cmax of erythropoietin on Day 57
Section 4.1 Overall Design
Figure 1 Study Design
PREVIOUS IMAGES

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Week -2: ESA 
Washout
Day 1: Randomize & 
Acute Challenge 1
Day 29: Dose Adjustment 
(as needed)
Day 57: Acute Challenge 2
Hgb Maintenance Period 
Week 10: Follow-up
Screening: Between 7 and 30  
days prior to ESA Washout
REVISED IMAGE
REVISED TEXT, where text in strikethrough has been removed:
Following the 2-week ESA washout, subjects will be randomized 1:1 and stratified by 
prior ESA dose, based on the average weekly (for epoetins or darbepoetin) or monthly 
(for methoxy polyethylene glycol (PEG)-epoetin beta) dosing during the 12 weeks prior
to ESA washout as follows:

Low ESA dose: <100 IU/kg/week epoetin alfa OR <0.5 µg/kg/week darbepoetin 
OR <0.6 µg/kg/week methoxy PEG-epoetin beta

High ESA dose: ≥100 IU/kg/week epoetin alfa OR ≥0.5 µg/kg/week darbepoetin 
OR 0.6 µg/kg/week methoxy PEG-epoetin beta
On Day 1, subjects will be randomized and undergo Acute Challenge 1, a single dose 
challenge to compare the acute effects on BP of the highest planned once-daily 
maintenance dose of daprodustat (24 mg) to the highest starting dose of epoetin alfa 
(100 IU/kg).  Subjects will have BP monitored for 24 hr using ABPM, and will have 
serial blood sampling to assess the pharmacokinetics of daprodustat and the time-course 
Week -2: ESA 
Washout
Day 1: Randomize 
& Acute Challenge 
1
Day 15, 29 & 43: Dose 
Adjustment (as 
needed)
Day 57: Acute Challenge 2
Hgb Maintenance 
Period 
Week 10: Follow-up
Screening: Between 7 and 
30 days prior to ESA 
Washout

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of various biomarkers.  Acute Challenge 1 will be started promptly following completion 
of a mid-week dialysis session.
Section 4.4 Design Justification
REVISED TEXT, where text in strikethrough has been removed and bolded text has been 
added:

This will be an open-label study since the primary endpoint (SBP by ABPM) is an 
objective measure and unlikely to be influenced by knowledge of the treatment 
received.  Additionally, an open label design will facilitate the conduct of the 
interim analysis.  Lastly, Additionally, blinding of an injectable comparator and 
oral study drug is impractical in this case.
Section 4.6 Benefit: Risk Assessment
REVISED TEXT, where text in strikethrough has been removed and bolded text has been 
added:
Summaries of findings from both clinical and non-clinical studies conducted with 
daprodustat can be found in the Daprodustat Investigator’s Brochure (IB) and IB 
Supplements, if applicable. [GlaxoSmithKline Document Number RM2008/00267/07; 
GlaxoSmithKline Document Number 2015N266524_00; GlaxoSmithKline Document 
Number 2015N266524_01].
Section 5 SELECTION OF STUDY POPULATION AND WITHDRAWAL 
CRITERIA
REVISED TEXT, where text in strikethrough has been removed and bolded text has been 
added:
Specific information regarding warnings, precautions, contraindications, adverse events, 
and other pertinent information on daprodustat that may impact subject eligibility is 
provided in the Daprodustat Investigator’s Brochure [GlaxoSmithKline Document 
Number RM2008/00267/07] and IB Supplements, if applicable. [GlaxoSmithKline 
Document Number 2015N266524_00; GlaxoSmithKline Document Number 
2015N266524_01].
Deviations from inclusion and exclusion criteria are not allowed because they can 
potentially jeopardize subject safety, the scientific integrity of the study, or regulatory 
acceptability.  Adherence to the criteria as specified in the protocol is essential.
Section 5.2 Inclusion Criteria
REVISED TEXT, where text in strikethrough has been removed and bolded text has been 
added:

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A subject will be eligible for inclusion in this study only if all of the following criteria 
apply:
AGE
1. ≥40 years of age, at the time of signing the informed consent.
TYPE OF SUBJECT AND DIAGNOSIS INCLUDING DISEASE SEVERITY
2. Hemoglobin: Stable Hgb 8.5 to 11.5 g/dL inclusive (See Section 5.1).
3. Dialysis frequency: On hemodialysis (HD, hemofiltration or hemodiafiltration) 
three-to five-times weekly for at least 4 weeks prior to screening.
4. Dialysis adequacy: A single pool Kt/Vurea 1.2 based on a historical value obtained 
within the 3 months prior to screening in order to ensure the adequacy of dialysis.  If 
Kt/Vurea is not available, then an average of the last 2 values of urea reduction ratio 
(URR) is at least 65%.  NOTE: Only needs confirming at screening.
5. ESA treatment: Treated with an ESA (epoetins or their biosimilars, darbepoetin, or 
methoxy PEG-epoetin beta) for at least 4 weeks prior to screening.
6. Iron replacement therapy: Subjects may be on stable (<50% change in overall 
dose and compliance of 80% of prescribed doses in the 4 weeks prior to and 
including the screening period) maintenance oral or IV (≤100 mg/week) iron 
supplementation.  If subjects are on oral or IV iron, then doses must be stable for the 
4 weeks prior to Washout.
7. Estimated Dry Weight (EDW):  Mid-week average weight gain change between 
dialysis treatments <5% as assessed pre- and post-dialysis from at the sScreening to
and Washout visits.
8. Antihypertensive Medication: Meets the following criteria:

On at least 1 antihypertensive medication [excluding diuretics]
AND

On that same medication and the same dose for at least 1 week prior to Washout
INFORMED CONSENT
9. Capable of giving signed informed consent as described in Section 10.2 which 
includes compliance with the requirements and restrictions listed in the consent form 
and in this protocol.
10. Willing and able to wear ABPM device for at least 25 hours on two separate 
sessions.
Section 5.3 Exclusion Criteria
REVISED TEXT, where text in strikethrough has been removed and bolded text has been 
added:
A subject will not be eligible for inclusion in this study if any of the following criteria 
apply:

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CKD-RELATED CRITERIA
1. Dialysis modality: Planned change from HD to peritoneal dialysis within the study 
time period, or on home dialysis.
2. Renal transplant: Planned kidney transplant within the 16 weeks following the 
Screening visit.
3. High ESA dose: An epoetin alfa dose of ≥360 IU/kg/week IV or ≥250 IU/kg/week 
subcutaneous (SC), or darbepoetin dose of ≥1.8 µg/kg/week IV or SC, or methoxy 
PEG-epoetin beta dose of 2.2 µg/kg/week within the 8 weeks prior to screening 
through Week -4.
4. Mircera: Planned or recorded administration of Mircera (methoxy PEG-epoetin beta) 
within the 4 weeks prior to the Washout visit.
CARDIOVASCULAR DISEASE-RELATED CRITERIA
5. Myocardial infarction or acute coronary syndrome: Within the 3 months prior to 
Washout.
6. Stroke or transient ischemic attack: Within the 3 months prior to Washout.
7. Heart failure: Chronic Class IV heart failure (HF), as defined by the New York 
Heart Association (NYHA) functional classification system diagnosed prior to 
Washout.
8. QT interval corrected for heart rate using Bazett’s formula (QTcB): QTcB >500 
msec, or QTcB >530 msec in subjects with Bundle Branch Block.  There is no QTc 
exclusion for subjects with a predominantly paced rhythm.
9. Current uncontrolled hypertension: Resting post dialysis systolic blood pressure 
>160 mmHg; or diastolic blood pressure >100 mmHg at screening or uncontrolled 
hypertension as determined by the investigator.
10. Atrial Fibrillation: Presence of atrial fibrillation.
OTHER DISEASE-RELATED CRITERIA
11. Inflammatory disease: Active chronic inflammatory disease that could impact 
erythropoiesis (e.g., scleroderma, systemic lupus erythematosus, rheumatoid arthritis, 
celiac disease) diagnosed prior to Washout.
12. Aplasias: History of bone marrow aplasia or pure red cell aplasia.
13. Other causes of anemia: Pernicious anemia, thalassemia major, sickle cell disease or 
myelodysplastic syndrome.
14. Liver disease (any one of the following):

Alanine transaminase (ALT) >2x upper limit of normal (ULN) (screening only)

Bilirubin >1.5xULN (screening only)
NOTE: Isolated bilirubin >1.5xULN is acceptable to keep in the study 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 

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hepatitis B or C, or Gilbert’s syndrome) are acceptable if subject otherwise meets 
entry criteria.
15. Major surgery: Major surgery (excluding vascular access surgery) within the 3 
months prior to Washout, or planned during the study.
16. Transfusion: Blood transfusion within the 8 weeks prior to Washout, or an 
anticipated need for blood transfusion during the study.
17. Gastrointestinal (GI) bleeding: Evidence of actively bleeding gastric, duodenal, or 
esophageal ulcer disease OR clinically significant GI bleeding within the 8 weeks
prior to Washout.
18. Acute Infection: Clinical evidence of acute infection or history of infection requiring 
intravenous (IV) antibiotic therapy within the 8 weeks prior to Washout.
NOTE: IV antibiotics as prophylaxis are allowed.
19. Malignancy: History of malignancy within the two years prior to screening through 
Day 1 or currently receiving treatment for cancer, or has a known complex kidney 
cyst (e.g., Bosniak Category IIF, III or IV) 3 cm.
NOTE: ONLY exception is localized squamous cell or basal cell carcinoma of the 
skin that has been definitively treated more than 4 weeks prior to screening.
20. Blood Pressure Measurement: Subjects with an upper arm diameter which cannot 
be measured by oscillometer/ sphygmomanometer cuff OR for whom blood pressure 
cannot be measured in the opposite arm of current vascular access.

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CONCOMITANT MEDICATIONS
21. Severe allergic reactions: History of severe allergic or anaphylactic reactions or 
hypersensitivity to excipients in the investigational product (see Daprodustat IB for 
list of excipients [GlaxoSmithKline Document Number RM2008/00267/07]).
22. Drugs and supplements: Use of any prescription or non-prescription drugs or 
dietary supplements that are prohibited (See Section 6.11.3), from screening until 
Washout.
23. Prior investigational product exposure: The subject has participated in a clinical 
trial and has received an experimental investigational product within the 30 days prior 
to Day 1 or within 5 half lives of the investigational product prior to screening, 
whichever is longer.
GENERAL HEALTH RELATED CRITERIA
24. Other conditions: Any other condition, clinical or laboratory abnormality, or 
examination finding that the investigator considers would put the subject at 
unacceptable risk, which may affect study compliance or prevent understanding of the 
aims or investigational procedures or possible consequences of the study.
25. Females ONLY: Subject is pregnant [as confirmed by a positive serum human 
chorionic gonadotrophin (hCG) test for females of reproductive potential (FRP) 
only], subject is breastfeeding, or subject is of reproductive potential and does not 
agree to follow one of the contraceptive options listed in the List of Highly Effective 
Methods for Avoiding Pregnancy in Section 12.4.7.
DIAGNOSTIC ASSESSMENTS AND OTHER CRITERIA
26. Vitamin B12: At or below the lower limit of the reference range (may rescreen in a 
minimum of 8 weeks, following treatment).
27. Folate: <2.0 ng/mL (4.5 nmol/L) (may rescreen in a minimum of 4 weeks, following 
treatment).
28. Ferritin: <100 ng/mL
29. Transferrin saturation (TSAT): <20%.
Section 5.5.1 Criteria for Permanent Discontinuation from Study Treatment and 
Early Withdrawal
REVISED TEXT, where text in strikethrough has been removed and bolded text has been 
added:
Subjects must permanently discontinue study treatment and be withdrawn from the 
study for the following reasons:

Meets Hgb stopping criteria (See Section 5.5.1.1)

Receives a blood transfusion

Receives a kidney transplant

Becomes pregnant or intends to become pregnant during the study

Active GI bleeding

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
Diagnosis of cancer, with the exception of squamous cell or basal cell carcinoma

Liver chemistry abnormalities exceeding the threshold criteria (See Section 5.5.3)

Misses 2 consecutive dialysis sessions

Need for chronic (more than 14 days) use Use of prohibited medication (See 
Section 6.11.3)

Myocardial infarction or acute coronary syndrome

Stroke or transient ischemic attack

New diagnosis of Class IV heart failure, as defined by the New York Heart 
Association (NYHA) functional classification system

Active chronic inflammatory disease that could impact erythropoiesis

Any new diagnosis of hematological disease including those affecting platelets, 
white or red blood cells, coagulation disorders, or any other cause of anemia of
chronic disease other than renal disease
Section 5.5.1.1 Hemoglobin Stopping Criteria
Table 2 Hgb Stopping Criteria
REVISED TEXT, where text in strikethrough has been removed:
Day 1 (Prior to Acute Challenge 1)
Hgb at Visit
Action
<7.5
Repeat HemoCue assessment on the same sample at same study visit to confirm; take average of 2 
values.  If confirmed, withdraw subject from the study.
7.5-<11.5
decrease of 2.0 in Hgb 
over 2 weeks
Repeat HemoCue assessment on the same sample at same study visit 
to confirm; take average of 2 values.  If confirmed, permanently 
withdraw subject from the study.
increase of 1.3 in Hgb 
over 2 weeks
Repeat HemoCue assessment on the same sample at same study visit 
to confirm; take average of 2 values.  If confirmed, withdraw subject 
from the study.
11.5
Repeat HemoCue assessment on the same sample at same study visit to confirm; take average of 2 
values.  If confirmed, avoid dosing and continue washout for one additional week.  Progress with 
Acute Challenge 1 one week later if Hgb has decreased below 11.5; if not then withdraw subject from 
study.

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Days 15, 29, & 43
Hgb at Visit
Action
<7.5
Repeat HemoCue assessment on the same sample at same study visit to confirm; take average of 2 
values.  If confirmed, permanently discontinue study treatment and withdraw subject from the study.
7.5-<12.0
decrease of 2.0 in Hgb 
over 2 weeks
Repeat HemoCue assessment on the same sample at same study visit 
to confirm; take average of 2 values.  If confirmed, permanently 
discontinue study treatment and withdraw subject from the study.
increase of 1.3 in Hgb 
over 2 weeks
Repeat HemoCue assessment on the same sample at same study visit 
to confirm; take average of 2 values.  If confirmed, permanently 
discontinue study treatment and withdraw subject from the study.
Day 57 (Prior to Acute Challenge 2)
Hgb at Visit
Action
<7.5
Repeat HemoCue assessment on the same sample at same study visit to confirm; take average of 2 
values.  If confirmed, permanently discontinue study treatment and withdraw subject from the study.
7.5-<11.5
decrease of 2.0 in Hgb 
over 2 weeks
Repeat HemoCue assessment on the same sample at same study visit 
to confirm; take average of 2 values.  If confirmed, permanently 
discontinue study treatment and withdraw subject from the study.
increase of 1.3 in Hgb 
over 2 weeks
Repeat HemoCue assessment on the same sample at same study visit 
to confirm; take average of 2 values.  If confirmed, permanently 
discontinue study treatment and withdraw subject from the study.
11.5
Repeat HemoCue assessment on the same sample at same study visit to confirm; take average of 2 
values.  If confirmed, HOLD the dose for 1 week and progress with Acute Challenge 2 one week 
later.  If Hgb remains above 11.5 one week later, then withdraw subject from the study.
Section 5.5.3 Liver Chemistry Stopping Criteria
REVISED TEXT, where text in strikethrough has been removed and bolded text has been 
added:
Liver chemistry stopping and increased monitoring criteria have been designed to 
assure subject safety and evaluate liver event etiology (in alignment with the Food and 
Drug Administration [FDA] premarketing clinical liver safety guidance). 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM174090.pdf
Discontinuation of study intervention for abnormal liver tests is required when:

a participant meets one of the conditions outlined in the algorithm below.

when in the presence of abnormal liver chemistries not meeting protocol-
specified stopping rules, the investigator believes study intervention 
discontinuation is in the best interest of the participant. 
Section 6.2 Treatment Assignment

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REVISED TEXT, where text in strikethrough has been removed and bolded text has been 
added:
Subjects will be stratified by prior ESA dose (as outlined in Section 4.1) and randomized 
1:1 to receive open-label oral daprodustat or IV epoetin alfa.  A central randomization 
approach will be used due to the small sample size and to protect against potential 
selection bias due to the open-label design.  Once a randomization number has been 
assigned by the an Interactive Voice/Web Response System (IVWRS) at time of 
Randomization, it must not be re-assigned.
Subjects will be assigned to study medication in accordance with the randomization 
schedule generated by Clinical Statistics, prior to the start of the study, using validated 
internal software.
Section 6.3 Blinding
REVISED TEXT, where text in strikethrough has been removed:
This will be an open-label study.  However, there are no plans to generate any aggregated 
unblinded summaries during the conduct of the study except the summaries necessary for 
the planned interim analysis as defined in Section 9.3.2.
Section 6.4.1 Subjects Randomized to Daprodustat
REVISED TEXT, where text in strikethrough has been removed and bolded text has been 
added:
Subjects randomized to daprodustat will have doses adjusted, as required, to target Hgb 
within the range of 10.0-11.0 g/dL.  Dose adjustments will be assigned automatically via 
the IVWRS based on the subject’s Hgb value via onsite HemoCue assessment according 
to the following algorithms:
Day 1 (HemoCue Prior to Acute Challenge 1)
Hgb (g/dL)
Action or Dose
<7.5
Repeat HemoCue assessment on the same sample at same study visit to confirm; take 
average of 2 values.  If confirmed, withdraw subject from the study.
7.5 and <10.0
6 mg daprodustat
10.0 and <11.5
4 mg daprodustat
11.5
Repeat HemoCue assessment on the same sample at same study visit to confirm; take 
average of 2 values.  If confirmed, avoid dosing and continue washout for one additional week.  
If Hgb remains above 11.5 then withdraw subject from study.
The 8 week Hgb maintenance dosing will begin on Day 2, following Acute Challenge 1. 
Acute Challenge dosing is the same for all subjects on the daprodustat arm: 24 mg.
Days 15, 29, & 43, & 57

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The available dose steps for daprodustat are outlined below (highlighted boxes indicate 
starting doses).  Dose adjustments will result in the daprodustat dose being increased or 
decreased by one dose step.
Hgb (g/dL)
Hgb change since
previous study visit
Dose Adjustment
<7.5
Any change
Repeat HemoCue assessment on the same sample at same study 
visit to confirm; take average of 2 values.  If confirmed, permanently 
discontinue study drug and withdraw subject from the study.
7.5 to <9.5
Decreasing or No change1
Increase to the next higher dose step
7.5 to <9.5
Increasing2
Maintain dose
9.5 to ≤11.5
Any change
Maintain dose
>11.5 to <12.0
Increasing or No change
Decrease to the next lower dose step
Decreasing
Maintain dose
≥12.0
Any change
Repeat HemoCue assessment on the same sample at same study 
visit to confirm; take average of 2 values.  If confirmed, HOLD dosing 
for 2 weeks until next study visit.3
7.5 to <12.0
increase of 1.3 in Hgb 
over 2 weeks4
Repeat HemoCue assessment on the same sample at same 
study visit to confirm; take average of 2 values. If confirmed, 
decrease to next lower dose step,
7.5 to <12.0
Increase of > 2.0 in Hgb 
over previous 4 weeks 
(Days 29, 43, 574 only)
Repeat HemoCue assessment on the same sample at same 
study visit to confirm; take average of 2 values. If confirmed, 
decrease to next lower dose step,
1No change is defined as an increase < 0.5 g/dL
2Increase is defined as an increase ≥ 0.5 g/dL
3 If Hgb remains ≥12.0 at next visit, the subject should be withdrawn from the study.  If the Hgb drops below 12.0, the 
subject should be restarted on the next lowest dose.
4 Only applies at Day 57 if a repeat AC2 is necessary.  The dose should be decreased for the 1 week between AC2 
and Additional AC2.
Section 6.11.1 Estimated Dry Weight and Antihypertensive Medication Changes
REVISED TEXT, where text in strikethrough has been removed and bolded text has been 
added (including the section title):
It is preferred that changes to EDW subject weight and antihypertensive medication(s) 
are not made while the subject is part of this study, however, subjects should remain in 
the study regardless of any changes.  All medication and dose changes should be 
recorded in the eCRF.
Section 6.11.3 Prohibited Medications and Non-Drug Therapies

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REVISED TEXT, where text in strikethrough has been removed and bolded text has been 
added:
Use of any of the following prescription drugs from sScreening 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, high dose clopidogrel [300 mg])

Strong inducers of CYP2C8 (e.g., rifampin/rifampicin)
Section 6.11.5 Iron Protocol
REVISED TEXT, where bolded text has been added:
Subjects must remain iron replete throughout the study.  If ferritin and TSAT are 
collected per local clinical practice while enrolled, the following is recommended.
Iron therapy will be administered if ferritin is ≤100 ng/mL and/or TSAT is ≤20%.  The 
investigator should choose the route of administration and dose of iron based on subject’s 
iron status and local clinical practice.  
All iron (excluding multivitamins) must be stopped and cannot be administered if:

Ferritin >800 ng/mL AND TSAT >20% OR

TSAT >40%
Section 7.1 Time and Events Table
Table 4 Study Procedures and Assessments on Acute Challenge Days (Treatment Period 
Day 1 and Day 57)
No changes made to the table itself.
Revised text in the footnotes only; text in bold has been added:
1 Procedures to be repeated if Acute Challenge 2 fails quality control criteria (For more detail refer to Section 7.5.1)
2 Applies to Acute Challenge 1 only
3 Timing of ABPM measurements does not correlate with specified time points in Table 4.
4 PK to be drawn from daprodustat subjects only.
Section 7.3.1.1 Time Period and Frequency for Collecting AE and SAE Information
REVISED TEXT, where bolded text has been added:

Any SAEs assessed as related to study participation (e.g., protocol-mandated 
procedures, invasive tests, or change in existing therapy) or related to a GSK 
product will be recorded from the time a subject consents to participate in the 
study up to and including any follow-up contact.

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
AEs will be collected from the start of washout until the follow-up contact (see 
Section 7.3.1.3), at the timepoints specified in the Time and Events Table (Section 
7.1).

Medical occurrences that begin prior to the start of washout but after obtaining 
informed consent may be recorded on the Medical History/Current Medical 
Conditions section of the CRF.

All SAEs will be recorded and reported to GSK within 24 hours, as indicated in 
Section 12.4. The investigator will submit any updated SAE data to the 
sponsor within 24 hours of it being available.  

Investigators are not obligated to actively seek AEs or SAEs in former study 
subjects.  However, if the investigator learns of any SAE, including a death, at any 
time after a subject has been discharged from the study, and he/she considers the 
event reasonably related to the study treatment or study participation, the 
investigator must promptly notify GSK.
NOTE: The method of recording, evaluating and assessing causality of AEs and SAEs 
plus procedures for completing and transmitting SAE reports to GSK are provided in 
Section 12.4.
Section 7.3.1.4 Adverse Events of Special Interest
REVISED TEXT, where bolded text has been added:
The investigator or site staff will be responsible for detecting, documenting and reporting 
any AEs of special interest or any event that may potentially be one of the categories 
listed below (using preferred terms):

Death, myocardial infarction (MI), stroke, heart failure, thromboembolic events,
thrombosis of vascular access

Thrombosis and/or tissue ischemia secondary to excessive erythropoiesis

Cardiomyopathy

Pulmonary artery hypertension (see also Section 7.3.1.5)

Cancer-related mortality and tumor progression and recurrence

Esophageal and gastric erosions

Proliferative retinopathy, macular edema, choroidal neovascularization

Exacerbation of rheumatoid arthritis

Worsening of hypertension
The results of any investigation should be recorded in the relevant sections of the 
subject’s eCRF.
Section 7.3.2 Pregnancy

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REVISED TEXT, where text in strikethrough has been removed and bolded text has been 
added:
Details of all pregnancies in female subjects and the outcome for the neonate, if 
applicable, will be collected after the start of dosing and until 14 7 days post-last dose.  
If a pregnancy is reported, then the investigator should inform GSK within 2 weeks of 
learning of the pregnancy and should follow the procedures outlined in Section 12.4.8.
Section 7.3.6 Clinical Safety Laboratory Assessments
Table 5 Protocol Required Safety Laboratory Assessments
REVISED TEXT, where text in strikethrough has been removed and bolded text has been 
added:
All protocol required laboratory assessments, as defined in Table 5 must be conducted in 
accordance with the Laboratory Manual, and Protocol Time and Events Schedule.  
Laboratory requisition forms must be completed and samples must be clearly labelled 
with the subject number, protocol number, site/center number, and visit date.  Details for 
the preparation and shipment of samples will be provided by the laboratory and are 
detailed in the SRM.  Reference ranges for all safety parameters will be provided to the 
site by the laboratory responsible for the assessments.
If additional non-protocol specified laboratory assessments are performed at the 
institution’s local laboratory and result in a change in subject management or are 
considered clinically significant by the investigator (e.g., SAE or AE or dose 
modification) the results must be recorded in the eCRF.
Refer to the SRM for appropriate processing and handling of samples to avoid duplicate 
and/or additional blood draws.
All study-required laboratory assessments will be performed by a central laboratory, apart 
from HemoCue Hgb. The results of each HemoCue test must be entered into the eCRF.
NOTE:  Local laboratory results are only required in the event that the central laboratory 
results are not available in time for either a treatment and/or response evaluation to be 
performed.  If a local sample is required, it is important that the sample for central 
analysis is obtained at the same time. Additionally if the local laboratory results are used 
to make either a treatment or response evaluation, the results must be entered into the 
eCRF.

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Hematology, clinical chemistry, and additional parameters to be tested are listed in Table 
5.
Laboratory 
Assessments
Parameters
Hematology
Platelet Count
RBC Indices:
WBC Count with 
Differential:
RBC Count
MCV
Neutrophils
Hemoglobin
MCH
Lymphocytes
Hematocrit
MCHC
Monocytes
WBC Count (absolute)
RDW
Eosinophils
Reticulocyte Count
CHr
Basophils
Clinical 
Chemistry
Potassium
AST (SGOT)
Total and direct/indirect 
bilirubin
Sodium
ALT (SGPT)
Total Protein
Glucose
Calcium (Albumin adjusted)
Alkaline Phosphatase
Albumin
Phosphate
Other Screening 
Tests
Serum hCG pregnancy test
Serum ferritin
Folate
Estradiol1
Serum iron
Vitamin B12
FSH1
Serum transferrin
UIBC
TSAT
NOTE: Details of Liver Chemistry Stopping Criteria and Required Actions and Follow-Up Assessments after liver 
stopping or monitoring event are given in Section 12.2.
1 As needed in women of non-child bearing potential only.
Abbreviations: ALT= Alanine transaminase; AST= Aspartate transaminase; CHr=Reticulocyte haemoglobin content; 
FSH=follicle stimulating hormone; MCH= Mean corpuscular haemoglobin; MCHC= Mean corpuscular hemoglobin 
concentration; MCV= Mean corpuscular volume; RBC= Red blood cell; RDW= Red blood cell distribution width; 
SGOT=Serum glutamic oxaloacetic transaminase; SGPT=Serum glutamic-pyruvic transaminase; TSAT = transferrin 
saturation; UIBC= unsaturated iron binding capacity; WBC= White blood cells;
Section 9.2.1 Sample Size Assumptions
REVISED TEXT, where bolded text has been added:
It is expected that 31 subjects will be randomized into each treatment arm.  Assuming a 
20% withdrawal rate during the Hgb Maintenance Period, there will be 25 subjects per 
treatment arm that will undertake Acute Challenge 2.  The study will continue to recruit 
subjects until it is projected that 25 subjects per treatment arm complete and pass QC for
Acute Challenge 2.
Assuming a 5% significance level and a true standard deviation (SD) of 16 mmHg for 
average SBP over 6 hours, a sample size of 25 subjects per treatment group will provide 
greater than 90% power to detect a -15 mmHg difference between treatment groups.  
Under these assumptions, statistical significance will be obtained if there is more than a 
9.1 mmHg mean difference observed in favor of daprodustat.
Section 9.3.2 Interim Analysis
REVISED TEXT, where text in strikethrough has been removed and bolded text has been 
added:

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No interim analyses are currently planned for this study.
An interim analysis will be conducted after approximately 24 subjects have completed 
Acute Challenge 2.
If the mean change in SBP from pre-Acute Challenge 1 to the 6-hour mean following 
both Acute Challenge 1 and Acute Challenge 2 is less than 5 mmHg in the epoetin alfa 
group, then the study will be stopped.  However, if a clinically meaningful difference 
between the two treatment groups in mean change in SBP from pre-Acute Challenge 1 to 
the 6-hour mean following Acute Challenge 1 (i.e., >5 mmHg) is observed, then the 
study will be continued in order to further characterize the effects of daprodustat on blood 
pressure.
Simulations show that under assumptions of a true mean change in SBP of 0 mmHg and 
SD of 18 mmHg for both treatment groups at Acute Challenge 1 and the epoetin alfa 
group at Acute Challenge 2, this stopping guideline will result in stopping the trial >99% 
of the time.  Under the assumptions of a true mean change in SBP of 8 mmHg and SD of 
18 mmHg for both treatment groups at Acute Challenge 1 and the epoetin alfa group at 
Acute Challenge 2, this rule will result in stopping the trial <1% of the time.
While the above is a guideline for stopping the trial due to futility, the totality of the data 
will be considered when making the decision at the time of the interim analysis.
Section 9.4.1 Primary Analyses
REVISED TEXT, where bolded text has been added:
The primary analysis of average SBP over 6 hr post-dose during Acute Challenge 2 will 
be an analysis of covariance (ANCOVA) with terms for treatment, prior ESA dose 
(low/high), and post-HD/pre-Acute Challenge 1 SBP, difference between post-HD/pre-
Acute Challenge 2 SBP and post-HD/pre-Acute Challenge 1 SBP, and treatment by 
(difference in post-HD SBP between Acute Challenge 1 and 2) interaction.  Note that the 
pre-challenge SBP may change over time between Acute Challenge 1 and Acute 
Challenge 2 as a result of the maintenance therapy, and thus the pre-challenge SBP at 
Acute Challenge 2 is not a true pre-treatment covariate.  As a result, the interpretation of 
the effect of the Acute Challenge 2 may be confounded by the impact of treatment phase 
on the covariate. Therefore, if the interaction term in this model is significant at the 0.10 
level, then the primary model will be ANCOVA with terms for treatment, prior ESA 
dose (low/high), and post-HD/pre-Acute Challenge 1 SBP.  The primary model will 
provide a point estimate and two-sided 95% CI for the treatment effect and a p-value for 
the superiority assessment.  Superiority will be established if the p-value is <0.05.
Section 9.4.2 Secondary Analyses
REVISED TEXT, where bolded text has been added:
Average SBP over 6 hr post-dose in Acute Challenge 1 will be analyzed using ANCOVA 
with terms for treatment, prior ESA dose (low/high), and post-HD/pre-Acute Challenge 
1 SBP.  Similar analyses will be performed for DBP, MAP, and HR.

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ANCOVA using the primary model will be used for the analysis of average DBP, MAP, 
and HR over 6 hr post-dose in Acute Challenge 2 replacing the baseline SBP term with 
the analogous baseline measurement for DBP, MAP, and HR respectively.
AUECs of SBP, DBP, MAP, and HR post Acute Challenge 2 and 1 will be analyzed 
using ANCOVA with terms for treatment and prior ESA dose (low/high) with 95% CIs 
and p-values provided for the treatment effect.
Section 11 References 
REVISED TEXT, where bolded text has been added:
Campochiaro PA and the first ARVO/Pfizer Institute Working Group et al. Ocular 
versus extraocular neovascularization: Mirror images or vague resemblances. Invest 
Ophthalmol & Vis Sci. 2006; 47:462-474.
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.
Navaneethan SD, for CRIC investigators: Prevalence, Predictors, and Outcomes of 
Pulmonary Hypertension in CKD. J Am Soc Nephrol 2016, 27:877–886.
Section 12.1 Appendix 1 – Abbreviations and Trademarks
REVISED TEXT, where bolded text has been added:
ABPM
Ambulatory blood pressure monitoring
ADMA
Asymmetric dimethyarginine
AE
Adverse event
ALT
Alanine transaminase
AMD
Age-Related Macular Degeneration
ANCOVA
Analysis of Covariance
AST
Aspartate transaminase
AUEC
Area under the effect curve
AUC (0-24)
Area under concentration-time curve from time zero to 24 hours
BP
Blood pressure
CHr
Reticulocyte hemoglobin content
CI
Confidence interval
CKD
Chronic kidney disease
Cmax
Maximum observed concentration
CPK
Creatine phosphokinase
CV
Cardiovascular
DBP
Diastolic blood pressure
dL
Deciliter

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DNA
Deoxyribonucleic acid
ECG
Electrocardiogram
ECHO
Echocardiogram
eCRF
Electronic Case Report Form
EDW
Estimated Dry Weight
EPO
Erythropoietin
ESA
Erythropoiesis-stimulating agent
ET-1
Endothelin-1
FDA
Food and Drug Administration
FRP
Females of Reproductive Potential
FSH
Follicle Stimulating Hormone
GCP
Good Clinical Practice
G
Gram
GI
Gastrointestinal
GSK
GlaxoSmithKline
hCG
Human chorionic gonadotrophin
HD
Hemodialysis dependent
HDPE
High Density Polyethylene
HF
Heart Failure
Hgb
Hemoglobin
HIF
Hypoxia-inducible factor
HR
Hour/heart rate
IB
Investigator’s Brochure
ICH
International Conference on Harmonization
IEC
Independent Ethics Committee
INR
International Normalized Ratio
IRB
Institutional Review Board
ITT
Intent-to-treat
IU
International Unit
IV
Intravenous
IVWRS
Interactive Voice/Web Response System
KDIGO
Kidney Disease Improving Global Outcomes
KG
Kilogram
LDH
Lactate dehydrogenase 
MAP
Mean Arterial Blood Pressure
MCH
Mean corpuscular hemoglobin
MCHC
Mean corpuscular hemoglobin concentration
MCV
Mean corpuscular volume
MedDRA
Medical Dictionary for Regulatory Activities
MG
Milligram
MI
Myocardial infarction
ML
Milliliter 
mmHG
Millimeter of mercury
MSDS
Material Safety Data Sheet
ND
Non-dialysis dependent
NO
Nitric Oxide

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NOAEL
No Observed Adverse Effect Level
NYHA
New York Heart Association
PASP
Pulmonary Artery Systolic Pressure
PCI
Percutaneous Coronary Intervention
PD
Pharmacodynamic
PEG
Polyethylene glycol
PGI2
Prostaglandin I2
PHD
Prolyl hydroxylase domain
PHI
Prolyl hydroxylase inhibitor
PK
Pharmacokinetic
proADM
Proadrenomedullin
PRS
Project Requirement Specification
PRVP
Peak Right Ventricular Pressure
PSRAE
Possible suicidality related adverse event
QC
Quality Control
QTc
QT interval corrected for heart rate
QTcB
QT interval corrected for heart rate using Bazett’s formula
RAP
Reporting and Analysis Plan
RBC
Red blood cell
RDW
Red blood cell distribution width
rhEPO
Recombinant human erythropoietin 
RNA
Ribonucleic acid
SAE
Serious adverse event
SBP
Systolic blood pressure
SC
Subcutaneous
SD
Standard deviation
SGOT
Serum glutamic oxaloacetic transaminase
SGPT
Serum glutamic-pyruvic transaminase
sPAP
Systolic Pulmonary Artery Pressure
SRM
Study Reference Manual
T1/2
Terminal phase half-life
TIBC
Total iron binding capacity
Tmax
Time of occurrence of Cmax
TSAT
Transferrin saturation
UG
Microgram
UIBC
Unsaturated iron binding capacity
ULN
Upper limit of normal
URR
Urea reduction ratio
WBC
White blood cells

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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Excessive erythropoiesis (polycythemia) 
leading to thrombosis and/or tissue ischemia
In animal studies, excessive erythropoiesis (Hgb/Hct > upper limit normal)
attributed to daprodustat was associated with vascular 
congestion/inflammation, microthrombi, and tissue ischemia in a number of 
organs.
In the phase 2 proof of concept study, a high incidence of 
discontinuation due to hemoglobin stopping criteria (Hgb > 13.5 g/dL or 
Hgb increased > 1 g/dL over any 2-week period) was observed.  In non-
dialysis subjects administered 10 mg, 25 mg, 50 mg or 100 mg of 
daprodustat daily, a total of 21 of 61 subjects (34%) met these criteria.  In 
hemodialysis-dependent subjects administered either 10 mg or 25 mg of 
daprodustat daily, a total of 8 of 31 subjects (26%) met these criteria.
Following review of clinical data received to date, this has not been identified 
as a safety concern for daprodustat.
Phase 2 dose-ranging studies, and associated statistical and exposure 
response modelling has informed Phase 3 dose rationale, starting doses, 
dose levels, and dose adjustment scheme to optimize Hgb management.
Integrated AE data [including 2 global phase 2b studies (24-week 
treatment duration) and 2 Japanese phase 3 studies (52-week treatment 
duration)]: Few subjects experienced a possible thrombosis related 
adverse event in the setting of excessive erythropoiesis [3/688 (0.5%) 
subjects on daprodustat vs. 0/404 on rhEPO].
Following review of clinical data received to date, this has not been 
identified as a safety concern for daprodustat when dose is managed 

Specific eligibility criteria related to requirements 
for entry Hgb are detailed in Section 5

Hgb will be closely monitored throughout the 
dosing period as outlined in the Time and Events 
Table (Section 7.1)

Specific guidance for dose adjustment, dose 
interruption, or discontinuation of daprodustat 
based on achieved Hgb (including rate of 
change) is provided in Section 5.5.1.1

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appropriately according to target Hgb. However, experience with 
daprodustat is currently insufficient to fully characterize this risk.
Worsening hypertension
In a dog cardiovascular study, single oral doses of daprodustat (up to 90 
mg/kg) did not produce effects on blood pressure.
Marketed rhEPO and its analogues have been associated with risks 
related to uncontrolled hypertension, including the need for initiation of 
or increases in antihypertensive therapy when used in patients with 
anemia of CKD (i.e. 25% Epogen, 27% Mircera, and 40% Aranesp treated 
patients with renal anemia required initiation or increase in their anti-
hypertensive medications; hypertensive encephalopathy and seizures 
have been reported. The contribution of rhEPO-associated hypertension 
to the unfavourable effects on cardiovascular outcomes remains 
uncertain).
Integrated AE data from clinical trials with daprodustat [including 2 
global phase 2b studies (24-week treatment duration) and 2 Japanese 
phase 3 studies (52-week treatment duration)]: 
o
The majority (>90%) of subjects had baseline history of 
hypertension.
o
No meaningful difference was seen between treatment groups in 
AEs (preferred term) of “hypertension” [29/688 (4%) daprodustat vs. 
19/404 (4%) rhEPO; 0.91 relative risk (RR) (95% confidence interval: 
0.5, 1.67)] or “blood pressure increased” [16 (2%) daprodustat vs. 7 
(2%) rhEPO; RR 1.22 (0.48,3.11)]. Results were not substantively 
different between non-dialysis and haemodialysis subjects.
o
Although no clinically meaningful changes in blood pressure were 
observed, subjects in both treatment groups required increases in 
anti-HTN medications:

Specific eligibility criteria related to blood 
pressure, including exclusion of subjects 
with uncontrolled hypertension, are 
detailed in Section 6.2

Blood pressure will be closely monitored 
throughout the dosing period as outlined in 
the Time and Events Table Section 7.1.

Monitoring of emerging safety data by an 
internal GSK Safety Review Team.

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o
In the 24-week global phase 2b studies, 25/170 (15%) of ND 
subjects receiving daprodustat vs. 18/80 (14%) control and 
22/177 (12%) of HD subjects receiving daprodustat vs. 2/39 
(5%) control.
o
In the 52-week Japan phase 3 studies, 57/149 (38%) of ND 
subjects receiving daprodustat vs. 68/150 (45%)  rhEPO 
and 51/136 (38%) of HD subjects receiving daprodustat vs. 
66/135 (49%) for rhEPO.
The data received to date from completed clinical trials with daprodustat 
are insufficient to refute this risk.
Death, MI, stroke, heart failure, 
thromboembolic events, thrombosis of 
vascular access at Hgb levels which are within 
the normal range (i.e. not polycythemic 
conditions)
Marketed rhEPO/ESAs and its analogs have been associated with an 
increased risk for death and serious cardiovascular events when used in 
patients with anemia of CKD.  Clinical studies with marketed 
rhEPO/analogs have suggested “higher” target hemoglobin, rate of 
hemoglobin rise of greater than 1 g/dL in any 2-week period, and/or 
higher doses may contribute to these risks.
In non-clinical studies conducted to date, not observed at tolerated 
doses when hemoglobin/hematocrit within normal range for species.
Integrated AE data from clinical trials with daprodustat [including 2 
global phase 2b studies (24-week treatment duration) and 2 Japanese 
phase 3 studies (52-week treatment duration)]: No meaningful difference 
was seen between treatment groups in the overall incidence of this 
AESI: [39/688 (5.5%) daprodustat vs. 25/404 (6%) rhEPO; 0.92 relative 
risk (95% confidence interval: 0.55, 1.53)]. Within this composite AESI, 
the most frequent event types were heart failure (at least 12 events 
daprodustat vs. at least 13 events rhEPO) and thrombosis (at least 14 
events daprodustat vs. at least 8 event rhEPO); and a numerical 
imbalance was noted in events of myocardial ischemia (at least 7 events 
daprodustat vs. at least 1 event rhEPO). The small number of events 
Specific eligibility criteria related to CV risk are 
outlined in Section 5.3
Hgb will be closely monitored throughout the 
dosing period as outlined in the Time and Events 
Table Section 7.1
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makes it difficult to draw any firm conclusions.
Not observed at tolerated doses when hemoglobin/hematocrit within normal 
range for species.
The clinical data received to date from completed clinical trials with 
daprodustat are insufficient to conclude substantiate or refute this risk.
Esophageal and gastric erosions
In animal studies, undesirable GI effects including emesis, abnormal feces 
and/or decreased food consumption/body weight loss and stomach erosions/ 
ulcers with hemorrhage were observed with daprodustat.
In rats rodents, stomach erosions were observed with intravenous and oral 
administration of daprodustat.
Stomach erosions/ulcers also reported in rats with marketed rhEPOs/ESAs.
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.
Suspected GI bleeding or significant symptoms 
consistent with erosion should be investigated 
diagnostically (i.e. endoscopic examination) as 
clinically warranted
Instream mMonitoring of emerging safety data 
by an internal GSK Safety Review safety review
team
Cancer-related mortality and tumor 
progression and recurrence
Marketed rheEPO and its analogs have been associated with increased risk 
of cancer related morbidity and mortality when used in patients with cancer.
Administration of 60mg/kg daprodustat to mice caused minimal increases in 
Specific eligibility criteria related to personal 
history of malignancy or subjects with complex 
kidney cyst are outlined in Section 5.3.

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circulating VEGF while significant EPO increases were observed.
In clinical studies with daprodustat up to 4 weeks duration, a dose-
ordered increase in VEGF plasma concentrations, an angiogenic factor 
that has been implicated in tumor growth, was observed at doses 
ranging from 10 to 150 mg.  In clinical studies up to 24 weeks duration at 
doses up to 25 mg, changes in VEGF plasma concentrations were 
variable but similar relative to control.
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.
There were no daprodustat-related neoplastic findings in a 2-year rat oral 
carcinogenicity study (lifetime study).
In clinical studies conducted to date, administration of daprodustat has been 
associated with:
Once daily administration:

In studies up to 4 weeks duration, a dose-ordered increase in VEGF 
plasma concentrations at doses ranging from 10 to 150 mg.

In studies up to 24 weeks duration at doses up to 25 mg, changes in 
VEGF plasma concentration were variable but similar relative to control.

Systemic EPO concentrations within the physiologic range.
Stopping criteria for subjects with treatment 
emergent malignancy are outlined in Section 
5.5.1.
Instream mMonitoring of emerging safety data 
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team

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Three times weekly administration:

In studies up to 4 weeks duration at doses of 10 to 30 mg:
o
Dose dependent increases in plasma VEGF and EPO 
concentrations were observed.
o
Pre-dose concentrations of EPO and VEGF were near or 
below baseline indicating no accumulation of EPO or 
VEGF after three times weekly dosing.
Following review of clinical data received to date, this has not been identified 
as a safety concern for daprodustat.
Pulmonary artery hypertension (PAH)
A role for HIF-regulated pathways in the pathophysiology of PAH has been 
suggested based on well established effects of acute and chronic hypoxia in 
man on the pulmonary vasculature (vasoconstriction), and by findings in 
patients with naturally occurring mutations that result in decreased HIF 
degradation [Smith, 2006; Formenti, 2011].
There have been no histopathologic findings suggestive of PAH in pre-clinical 
safety studies (up to 13-weeks duration in mice and dogs, up to 26-weeks 2 
years in rats and mice, and up to 39-weeks in monkeys.
Acute hypoxic challenge (rats): Daprodustat produced increases in peak right 
ventricular pressure (PRVP) during acute hypoxia that were slightly higher 
than the vehicle control group.  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 hads no clinically significant effect on transthoracic
echocardiographically (ECHO) estimatesd of systolic pulmonary artery 
systolic pressure (sPASP) under either normoxic or hypoxic conditions.
ECHO assessments performed in Phase 2b studies (24 weeks treatment 
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team

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duration) did not identify any clinically meaningful changes in sPAP PASP
in subjects participants not on dialysis for daprodustat. In hemodialysis 
subjects participants, mean absolute change from baseline in sPAP PASP
was similar for both treatment groups; however, there was a numeric 
imbalance (Daprodustat Total: 8 [7%]; Control 0) in subjects participants
reaching the sPAP PASP PCI (>20 mmHg increase from baseline). 
Regarding this imbalance, there were a number of confounding factors in 
the study, most notably a 4.5:1 randomization scheme and inconsistency in 
timing of ECHOs relative to dialysis day.  Additionally, 2 of 3 subjects
participants with resolution of sPAP PASP on safety follow-up ECHOs had 
confounding conditions that could contribute to resolution other than 
discontinuation of study treatment drug; and there was no dose relationship 
for subjects participants meeting the sPAP PASP percutaneous 
coronary intervention(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 commonly cited in 
the literature [Navaneethan, 2016]. Subjects with sPAP >35 mmHg 
and/or tricuspid regurgitation maximum jet velocity (TRV) >2.5 m/s 
were considered as having PAH.  Regardless of baseline status of 
PAH, there was no clinically meaningful difference in the proportion of 
subjects with on-treatment PAH between the two treatment groups:
o
Subjects with PAH at baseline: 35/113 (31%) vs. 21/54 
(39%) (ND) and 37/115 (32%) vs. 7/21 (33%) (HD), 
daprodustat vs. control, respectively.
o
Subjects without PAH at baseline: 25/113 (22%) vs. 12/54 
(22%) (ND) and 22/115 (19%) vs. 6/21 (29%) (HD), 
daprodustat vs. control, respectively.
Integrated AE data [including 2 global phase 2b studies (24-week 
treatment duration) and 2 Japanese phase 3 studies (52-week treatment 
duration)]: Four (0.5%) non-serious AEs in the daprodustat group vs 0 in 
rhEPO. 

Review of subject level information did not suggest adverse 
treatment effect: 2 subjects from phase2b that met protocol 

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specified stopping criteria on scheduled ECHO had non-serious 
AEs of ‘pulmonary arterial pressure increased’ and 2 subjects from 
Japan Phase 3 had non-serious AE ‘pulmonary hypertension’ in 
setting of concurrent serious AEs of acute pulmonary embolus and 
mitral regurgitation 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.
Small increases in cardiac troponin in 6 month rat study with 
daprodustat were consistent with the background finding of 
spontaneous rodent cardiomyopathy.  There were no elevations 
observed in cardiac troponin in 9 month monkey study with 
daprodustat.
With lifetime exposure to daprodustat in a 2-year rat oral carcinogenicity 
study, an exacerbation of rat spontaneous, progressive cardiomyopathy 
(PCM)(focal myofiber degeneration/necrosis with inflammatory infiltrates) was 
observed at doses of 0.8 mg/kg/day and above, although total incidence and 
severity distribution within any daprodustat-group were within historical control 
ranges.  This is consistent with an equivocal threshold for exacerbation of 
spontaneous, progressive cardiomyopathy at 0.8 mg/kg/day which is also the 
threshold dose for observing increased Hct values in individual rats.
Cardiomyopathy has not been associated with naturally 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 
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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.
Aside from congestion of retinal vessels and optic disc hyperemia secondary 
to markedly increased red cell mass, there were no ocular abnormalities 
observed in non-clinical studies.
No ocular abnormalities with daprodustat were seen in non-clinical 
studies of up to 13 weeks duration in mice and dogs, 26 weeks in rats, 
and 39 weeks in monkeys.
In clinical studies up to 4 weeks duration, a dose-ordered increase in VEGF 
plasma concentrations was observed at doses ranging from 10 to 150 mg 
administered once daily and from 10 to 30 mg administered three times 
weekly. In studies up to 24 weeks duration at doses up to 25 mg, changes in 
VEGF plasma concentrations were variable but similar relative to control.
Ophthalmologic assessments performed in phase 2b studies (24 weeks 
treatment duration) did not identify any clinically meaningful changes in 
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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 received to date, this has not been identified 
as a safety concern for daprodustat.
Exacerbation of rheumatoid arthritis
In inflamed rheumatic joints, activation of HIF- related genes secondary to 
decreased oxygen and pro-inflammatory cytokines has been postulated to 
contribute to the neo-angiogenesis, proliferation and infiltration of rheumatoid 
synovial fibroblasts [Westra, 2010; Muz, 2009].
No abnormalities seen in non-clinical studies conducted to date for 
daprodustat.
Integrated AE data [including 2 global phase 2b studies (24-week 
treatment duration) and 2 Japanese phase 3 studies (52-week treatment 
duration)]: No meaningful difference was seen between treatment 
groups in reports of this AESI [2 (0.3%) daprodustat vs. 1 (0.2%) rhEPO; 
1.20 relative risk; (95% confidence interval: 0.07, 20.87) and the 
incidence of musculoskeletal AEs was generally lower in the 
daprodustat treatment group].
Following review of clinical data received to date, this has not been identified 
as a safety concern for daprodustat.
Instream mMonitoring of emerging safety data 
by an internal GSK sSafety rReview tTeam
Drug-drug interactions
Daprodustat is a substrate of CYP2C8: Co-administration of daprodustat 
with a strong CYP2C8 inhibitor increased the maximum plasma 
concentration (Cmax) and area under curve (AUC) of daprodustat, 4- and 
19-fold, respectively, while co-administration of a weak inhibitor (i.e., 
Co-administration of daprodustat with strong 
CYP2C8 inhibitors (e.g., gemfibrozil) and 
inducers (e.g., rifampin/rifampicin) is not 

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trimethoprim) increased the Cmax and AUC of daprodustat by 1.3- and 1.5-
fold, respectively. Population PK analysis from completed Phase 2 
studies suggests that co-administration of daprodustat with a moderate 
CYP2C8 inhibitor (i.e., clopidogrel) leads to a ~ 2-fold increase in AUC, 
with no clinically-significant increase in the measured Hb response.
Although CYP2C8 induction studies were not performed, co-administration of 
daprodustat with an inducer of CYP2C8 (e.g., rifampin/rifampicin) may
decrease the exposure of daprodustat.
Although co-administration of daprodustat with strong inhibitors and inducers 
of CYP2C8 is prohibited, inadvertent co-administration may occur. Due to the 
known time delay in enhancing erythropoiesis by daprodustat, co-
administration with strong CYP2C8 inhibitors for up to 14 days is not 
anticipated to lead to immediate marked increases in hemoglobin levels. 
Therefore, there is adequate time to change to alternate therapy that does not 
inhibit CYP2C8.
Additionally, as the time for maximum induction of CYP2C8 occurs 
approximately 10-14 days of dosing with rifampin (Brodie, 2013; Ohnhaus, 
1989), daprodustat systemic exposure will decrease over time which will result 
in a lag period before an effect on Hgb is recognized and is of clinical concern.
Daprodustat is an inhibitor of CYP2C8: A clinical drug interaction study 
between 25mg and 100mg daprodustat with a CYP2C8 substrate (i.e., 
pioglitazone) showed that there is no PK interaction at these doses of 
daprodustat.  
Daprodustat is a substrate of Breast cancer resistance protein (BCRP):  
Population PK analysis from Phase 2 studies suggested that while
BCRP inhibitors were a covariate for daprodustat apparent total body 
clearance (CL/F) (8.6% lower clearance) the predicted change in 
exposure was not considered to be of clinical relevance.
Daprodustat is an inhibitor of organic anion transporter polypedtides
(OATP)1B1/1B3:  A clinical drug interaction study between 25mg and 
permitted as outlined in Section 6.11.3.
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. Specific 
guidance on the management of potential drug-
drug interactions and concomitant medications is 
provided in Section 6.11.
Hgb will be closely monitored throughout the 
dosing period as outlined in the Time and Events 
Table (Section 7.1)
Specific guidance for dose adjustment, dose 
interruption, or discontinuation of daprodustat 
based on achieved Hgb is provided in Section 
5.5.1.1.
Instream mMonitoring of emerging safety data 
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100mg daprodustat with an OATP1B1/1B3 substrate (i.e., rosuvastatin) 
showed no PK interaction at these doses of daprodustat.
Population PK analysis from completed Phase 2 studies suggests that co-
administration of daprodustat with a moderate CYP2C8 inhibitor, 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 completed Phase 2 studies suggests that co-
administration of daprodustat with clopidogrel (a moderate CYP2C8 inhibitor) 
leads to a ~ 2-fold increase in AUC, with no clinically-significant increase in 
the measured Hgb response
Co-administration of daprodustat with potent BCRP inhibitors has the potential 
to increase exposure of daprodustat.  Use of BCRP inhibitors (mostly weak) 
was found to result in a small change in metabolite exposure (20% increase in 
AUC).
Daprodustat is an inhibitor of OATP1B1/1B3 in vitro, with IC50 values of 6 µM 
and 11 µM, respectively. A clinical drug interaction study between 25 mg 
daprodustat with either a CYP2C8 substrate or an OATP1B1/1B3 substrate 
showed that there is no PK interaction at this dose of daprodustat.
Cyst progression in patients with 
autosomal dominant polycystic kidney 
disease (ADPKD)
Published data provide in vivo evidence for a potential role of HIF-1a in 
the growth of polycystic kidneys; Hif-1a deletion was sufficient to 
significantly mitigate a progressive polycystic phenotype in an ADPKD 
mouse model, while conversely pharmacologic HIF-1a stabilization was 
sufficient to convert a mild polycystic disease into a severely 
aggravated phenotype with marked loss of renal function. However, the 
dose of FG-2216 (a PHI) used resulted in a significant erythropoietic 
response as reflected by ≥10% relative increases in hematocrit over the 
course of the study (Kraus, 2018; Hofherr, 2018). (Kraus, 2018; Hofherr, 

Kidney function  will be monitored 
throughout the dosing period as outlined in 
the Time and Events Table (Section7.1).

Monitoring of emerging safety data by an 
internal GSK Safety Review Team.

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2018).
A review of the non-clinical data from toxicity studies conducted with 
daprodustat does not indicate an exacerbation in incidence or severity 
of kidney cysts in daprodustat-treated animals in comparison to 
controls.  However, the wild type animals used in these toxicity studies 
have a very low background incidence of renal cysts and are not 
comparable to the mice used in the Kraus article (Kraus, 2018) which are 
an inducible kidney epithelium-specific Pkd1-deletion model.
There is limited experience with daprodustat in subjects with ADPKD in 
completed clinical trials. In the Japan phase 3 study in non-dialysis 
subjects, there were 5 subjects with ADPKD (all CKD stage 5) in each 
treatment group.  Mean baseline eGFR was 10 mL/min/1.73m2 in the 
daprodustat subjects vs. 16 mL/min/1.73m2 in the rhEPO subjects.  The 
mean (SD) percent change from baseline at Week 52 in eGFR was: -18% 
(8) vs. -21% (14) in daprodustat vs. rhEPO, respectively.
Following review of clinical data received to date, this has not been 
identified as a safety concern for daprodustat.
Other
rhEPO risks (Control)
See risks outlined in table for daprodustat for excessive erythropoiesis 
(polycythemia) leading to thrombosis and/or tissue ischemia, death, MI, 
stroke, heart failure, thromboembolic events, thrombosis of vascular access, 
and for cancer-related mortality and tumor progression.
Uncontrolled hypertension
Pure red cell aplasia
See mitigation strategies outlined in table for 
daprodustat for excessive erythropoiesis 
(polycythemia) leading to thrombosis and/or 
tissue ischemia; risk of death, MI, stroke, heart 
failure, thromboembolic events, thrombosis of 
vascular access; and for increased cancer-
related mortality and tumor progression.
Specific eligibility criteria related to blood 
pressure management are outlined in Section 5.
Specific eligibility criteria related to personal 

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history of pure red cell aplasia are outlined in 
Section 5.3