Conditions: Anaemia
Keywords: Anemia Daprodustat Blood pressure ESA CKD
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 105
Healthy volunteers: no

Brief summary:
This will be an open-label, randomized, parallel-group study in hemodialysis-dependent (HD) participants with anemia associated with chronic kidney disease (CKD), designed to compare the effects of daprodustat to epoetin alfa on blood pressure (BP). Participants will be screened for eligibility within 7 and 30 days prior to erythropoesis-stimulating agent (ESA) washout. Following a 2-week ESA washout period, on Day 1 participants will be randomized 1:1 and stratified by prior ESA dose before they 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 milligrams \[mg\]) to the highest starting dose of epoetin alfa (100 units/kilogram \[U/kg\]). This will be followed by an 8-week hemoglobin (Hgb)-maintenance period, where doses of either daprodustat or epoetin alfa will be administered and adjusted. At the end of Hgb maintenance period, on Day 57 an Acute Challenge 2 will be repeated utilizing the same treatment dose administered in Acute Challenge 1; there will be a follow-up visit within 14+/-3 days after completing treatment.

Detailed description:

Arms:
arm 1: On Day 1, participants will undergo 24-hour Acute Challenge 1, in which participants will receive a single dose of 100 U/kg epoetin alfa IV. After completing Acute Challenge 1, participants will enter in an 8-week Hgb maintenance period. At the end of Hgb maintenance period, on Day 57, Acute Challenge 2 will be performed utilizing the same treatment dose administered in Acute Challenge 1. arm 2: On Day 1, participants will undergo 24-hour Acute Challenge 1, in which participants will receive 24 mg daprodustat. After completing Acute Challenge 1, participants will enter an 8-week Hgb maintenance period. At the end of Hgb maintenance period, on Day 57, Acute Challenge 2 will be performed utilizing the same treatment dose administered in Acute Challenge 1.

Interventions: intervention 1: Daprodustat intervention 2: Epoetin alfa
Intervention descriptions: intervention 1: Daprodustat will be available as oral tablets at unit dose strength of 1, 2, 4, 6, 8 and 10 mg. intervention 2: 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)

Protocol document:
Prot_000.pdf: 
2015N267693_04
CONFIDENTIAL
The GlaxoSmithKline group of companies
205665
1
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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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.
REFERENCES
Abraham PA, Macres MG. Blood pressure in hemodialysis patients during amelioration 
of anemia with erythropoietin. J Am Soc Nephrol 1991; 2: 927-936.
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.
GlaxoSmithKline Document Number 2015N266524_00 Supplement to GSK1278863 
Investigator’s Brochure, 17-DEC-2015.
GlaxoSmithKline Document Number 2015N266524_01 Supplement to GSK1278863 
Investigator’s Brochure, 08-APR-2016.
GlaxoSmithKline Document Number RM2008/00267/07 Investigator’s Brochure, 14-
OCT-2015.
Haase VH. Mechanisms of Hypoxia Responses in Renal Tissue. JASN 2013; 24: 537-
541.
Hofherr, A., et al, HIF-1α drives cyst growth in advanced stages of autosomal dominant 
polycystic kidney disease; Kidney International (2018) 94, 849–851.


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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 
hydroxylase inhibitor GSK1278863 for treatment of anemia. JASN 2016; 27:1234-1244
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 
Nephrol 1988; 66:114-122.
Smith TG, Brooks JT, Balanos GM, Lappin TR, Layton DM, Leedham DL, Liu C, 
Maxwell PH, McMullin MF, McNamara CJ, Percy MJ, Pugh CW, Ratcliffe PJ, Talbot 


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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
Westra J, Molema G, Kallenberg CG. Hypoxia-inducible factor-1 as regulator of 
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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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 
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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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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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Summary of Data/Rationale for Risk
Mitigation Strategy
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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Summary of Data/Rationale for Risk
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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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 


2015N267693_04
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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.
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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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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 (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

Instream mMonitoring of emerging safety data 
by an internal GSK sSafety rReview Tteam


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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
Instream mMonitoring of emerging safety data 
by an internal GSK sSafety rReview Tteam


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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 
by an internal GSK Safety Review safety review
team


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Mitigation Strategy
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 
Instream mMonitoring of emerging safety data 
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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 
Instream mMonitoring of emerging safety data 
by an internal GSK sSafety rReview tTeam


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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 
by an internal GSK sSafety rReview tTeam


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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 


2015N267693_04
CONFIDENTIAL
205665
203
Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
history of pure red cell aplasia are outlined in 
Section 5.3

SAP_001.pdf: 
 
CONFIDENTIAL 
 
The GlaxoSmithKline group of companies 
 
205665 
 
1 
 
Division 
: Worldwide Development 
Information Type 
: Reporting and Analysis Plan (RAP) 
 
Title 
: Reporting and Analysis Plan for a randomized, open-label 
study to evaluate the effect of daprodustat on blood pressure 
in participants with anemia associated with chronic kidney 
disease on hemodialysis switched from a stable dose of an 
erythropoiesis-stimulating agent 
Compound Number  : Daprodustat (GSK1278863) 
Effective Date  
: Refer to document date 
 
Description: 
• 
The purpose of this RAP is to describe the planned analyses and output to be 
included in the Clinical Study Report for Protocol 205665. 
• 
This RAP is intended to describe the final analyses required for the study.  
• 
This RAP will be provided to the study team members to convey the content of 
the Statistical Analysis Complete (SAC) deliverable. 
 
Author(s) 
Approver 
Date 
Lead 
 
Refer to document date 
Statistician (FPD Clinical Statistics) 
Co-Author 
 
Refer to document date 
Manager (Clinical Pharmacology, Modelling 
and Simulation) 
 
 
Copyright 2020 the GlaxoSmithKline group of companies. All rights reserved.  
Unauthorised copying or use of this information is prohibited. 
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CONFIDENTIAL 
 
The GlaxoSmithKline group of companies 
 
205665 
 
2 
 
RAP Team Review Confirmations  
 (Method: E-mail) 
 
Reviewer 
Date 
 
16-JUN-2020 
Senior Programmer (FPD Clinical 
Programming) 
 
Programming Manager (FPD Clinical 
Programming) 
17-JUN-2020 
 
09-JUN-2020 
Director Clinical Development (Clinical 
Science Specialty) 
 
15-JUN-2020 
Clinical Development Manager (GCSD Clinical 
Pharmacology) 
 
Director Clinical Development (Clinical 
Science Nephrology) 
16-JUN-2020 
 
Principal Clinical Data Manager (FPD PCPS) 
09-JUN-2020 
Clinical Statistics and Clinical Programming Line Approvals: 
(Method: Pharma TMF eSignature) 
 
Approver 
Date 
 
Refer to document date 
Statistics Director (FPD Clinical Statistics) 
 
Refer to document date 
Programming Manager (FPD Clinical 
Programming) 
 
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PPD
PPD
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CONFIDENTIAL 
 
 
 
 
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TABLE OF CONTENTS 
PAGE 
1. 
INTRODUCTION ...................................................................................................... 6 
2. 
SUMMARY OF KEY PROTOCOL INFORMATION .................................................. 7 
2.1. 
Changes to the Protocol Defined Statistical Analysis Plan ............................ 7 
2.2. 
Study Objective(s) and Endpoint(s)............................................................... 8 
2.3. 
Study Design .............................................................................................. 10 
2.4. 
Statistical Hypotheses................................................................................. 11 
3. 
PLANNED ANALYSES .......................................................................................... 12 
3.1. 
Interim Analyses ......................................................................................... 12 
3.2. 
Final Analyses ............................................................................................ 12 
4. 
ANALYSIS POPULATIONS ................................................................................... 12 
4.1. 
Protocol Deviations ..................................................................................... 13 
5. 
CONSIDERATIONS FOR DATA ANALYSES AND DATA HANDLING 
CONVENTIONS ..................................................................................................... 14 
5.1. 
Study Treatment & Sub-group Display Descriptors ..................................... 14 
5.2. 
Baseline Definitions and Derivations ........................................................... 15 
5.2.1. 
Baseline Definitions ..................................................................... 15 
5.2.2. 
Derivations and Handling of Missing Baseline Data ..................... 15 
5.3. 
Multicentre Studies ..................................................................................... 17 
5.4. 
Examination of Covariates, Other Strata and Subgroups ............................ 17 
5.4.1. 
Covariates and Other Strata ........................................................ 17 
5.4.2. 
Examination of Subgroups ........................................................... 18 
5.5. 
Multiple Comparisons and Multiplicity ......................................................... 18 
5.6. 
Other Considerations for Data Analyses and Data Handling 
Conventions ................................................................................................ 18 
6. 
STUDY POPULATION ANALYSES ....................................................................... 19 
6.1. 
Overview of Planned Study Population Analyses ........................................ 19 
6.2. 
Display Details ............................................................................................ 19 
6.2.1. 
Participant Disposition ................................................................. 19 
6.2.2. 
Protocol Deviations ...................................................................... 20 
6.2.3. 
Population Analysed .................................................................... 21 
6.2.4. 
Demographic and Baseline Characteristics .................................. 21 
6.2.5. 
Medical Conditions, Prior and Concomitant Medications .............. 22 
6.2.6. 
Exposure and Treatment Compliance .......................................... 22 
7. 
EFFICACY ANALYSES .......................................................................................... 24 
7.1. 
Primary Efficacy Analyses .......................................................................... 24 
8. 
SAFETY ANALYSES ............................................................................................. 25 
8.1. 
Adverse Events Analyses ........................................................................... 25 
8.2. 
Adverse Events of Special Interest Analyses .............................................. 26 
8.3. 
Clinical Laboratory Analyses ....................................................................... 27 
8.4. 
Other Safety Analyses ................................................................................ 28 
9. 
PHARMACOKINETIC ANALYSES ......................................................................... 30 
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9.1. 
Primary Pharmacokinetic Analyses ............................................................. 30 
9.2. 
Secondary Pharmacokinetic Analyses ........................................................ 30 
9.2.1. 
Endpoint / Variables ..................................................................... 30 
9.2.1.1. 
Drug Concentration Measures .................................... 30 
9.2.1.2. 
Derived Pharmacokinetic Parameters......................... 30 
9.2.2. 
Summary Measure ...................................................................... 31 
9.2.3. 
Population of Interest ................................................................... 31 
9.2.4. 
Strategy for Intercurrent (Post-Randomization) Events ................ 31 
9.2.5. 
Statistical Analyses / Methods ..................................................... 31 
10. POPULATION PHARMACOKINETIC (POPPK) ANALYSES .................................. 32 
10.1. 
Statistical Analyses / Methods .................................................................... 32 
11. PHARMACODYNAMIC AND BIOMARKER ANALYSES ........................................ 33 
11.1. 
Primary Pharmacodynamic Analyses .......................................................... 33 
11.1.1. 
Endpoint / Variables ..................................................................... 33 
11.1.2. 
Summary Measure ...................................................................... 33 
11.1.3. 
Population of Interest ................................................................... 33 
11.1.4. 
Strategy for Intercurrent (Post-Randomization) Events ................ 33 
11.1.5. 
Statistical Analyses / Methods ..................................................... 34 
11.1.5.1. Interim Analysis .......................................................... 34 
11.1.5.2. Statistical Methodology Specification .......................... 34 
11.2. 
Secondary Pharmacodynamic Analyses ..................................................... 35 
11.2.1. 
Endpoint / Variables ..................................................................... 35 
11.2.2. 
Summary Measure ...................................................................... 35 
11.2.3. 
Population of Interest ................................................................... 36 
11.2.4. 
Strategy for Intercurrent (Post-Randomization) Events ................ 36 
11.2.5. 
Statistical Analyses / Methods ..................................................... 36 
11.2.5.1. Statistical Methodology Specification .......................... 36 
11.3. 
Exploratory Pharmacodynamic and Biomarker Analyses ............................ 37 
11.3.1. 
Endpoint / Variables ..................................................................... 37 
11.3.1.1. Statistical Methodology Specification .......................... 38 
12. PHARMACOKINETIC / PHARMACODYNAMIC ANALYSES ................................. 40 
12.1. 
Primary Pharmacokinetic / Pharmacodynamic Analyses ............................. 40 
12.2. 
Secondary Pharmacokinetic / Pharmacodynamic Analyses ........................ 40 
12.3. 
Exploratory Pharmacokinetic / Pharmacodynamic Analyses ....................... 40 
12.3.1. 
Endpoint / Variables ..................................................................... 40 
12.3.2. 
Summary Measure ...................................................................... 40 
12.3.3. 
Population of Interest ................................................................... 40 
12.3.4. 
Strategy for Intercurrent (Post-Randomization) Events ................ 41 
12.3.5. 
Statistical Analyses / Methods ..................................................... 41 
13. REFERENCES ....................................................................................................... 42 
14. APPENDICES ........................................................................................................ 43 
14.1. 
Appendix 1: Protocol Deviation Management and Definitions for Per 
Protocol Population ..................................................................................... 43 
14.1.1. 
Exclusions from Per Protocol Population ..................................... 43 
14.2. 
Appendix 2: Schedule of Activities .............................................................. 44 
14.2.1. 
Protocol Defined Schedule of Events ........................................... 44 
14.3. 
Appendix 3: Assessment Windows ............................................................. 46 
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14.3.1. 
Definitions of Assessment Windows for Analyses ........................ 46 
14.4. 
Appendix 4: Study Phases and Treatment Emergent Adverse 
Events ........................................................................................................ 47 
14.4.1. 
Study Phases .............................................................................. 47 
14.4.1.1. Study Phases for Concomitant Medication ................. 47 
14.4.2. 
Treatment Emergent Flag for Adverse Events ............................. 49 
14.5. 
Appendix 5: Data Display Standards & Handling Conventions .................... 51 
14.5.1. 
Reporting Process ....................................................................... 51 
14.5.2. 
Reporting Standards .................................................................... 51 
14.5.3. 
Reporting Standards for Pharmacokinetic .................................... 52 
14.6. 
Appendix 6: Derived and Transformed Data ............................................... 53 
14.6.1. 
General ........................................................................................ 53 
14.6.2. 
Study Population .......................................................................... 55 
14.6.3. 
Efficacy ........................................................................................ 56 
14.6.4. 
Safety .......................................................................................... 57 
14.6.5. 
Pharmacokinetic .......................................................................... 59 
14.6.6. 
Pharmacodynamic and Biomarker ............................................... 60 
14.7. 
Appendix 7: Reporting Standards for Missing Data ..................................... 66 
14.7.1. 
Premature Withdrawals ................................................................ 66 
14.7.2. 
Handling of Missing Data ............................................................. 66 
14.7.2.1. Handling of Missing and Partial Dates ........................ 66 
14.8. 
Appendix 8: Values of Potential Clinical Importance ................................... 68 
14.8.1. 
Laboratory Values ........................................................................ 68 
14.8.2. 
Vital Signs .................................................................................... 68 
14.9. 
Appendix 9: Population Pharmacokinetic (PopPK) Analyses ...................... 69 
14.10. Appendix 10: Pharmacokinetic / Pharmacodynamic Analyses .................... 70 
14.11. Appendix 11: Abbreviations & Trade Marks ................................................ 71 
14.11.1. Abbreviations ............................................................................... 71 
14.11.2. Trademarks ................................................................................. 72 
14.12. Appendix 12: List of Data Displays.............................................................. 73 
14.12.1. Data Display Numbering .............................................................. 73 
14.12.2. Mock Example Shell Referencing ................................................ 73 
14.12.3. Deliverables ................................................................................. 73 
14.12.4. Study Population Tables .............................................................. 74 
14.12.5. Safety Tables ............................................................................... 77 
14.12.6. Pharmacokinetic Tables ............................................................... 84 
14.12.7. Pharmacokinetic Figures ............................................................. 85 
14.12.8. Pharmacodynamic and Biomarker Tables .................................... 89 
14.12.9. Pharmacodynamic and Biomarker Figures .................................. 93 
14.12.10. Pharmacokinetic / Pharmacodynamic Figures ............................. 95 
14.12.11. ICH Listings ................................................................................. 96 
14.12.12. Non-ICH Listings .......................................................................... 99 
14.13. Appendix 13: Example Mock Shells for Data Displays .............................. 100 
 
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1. 
INTRODUCTION 
The purpose of this reporting and analysis plan (RAP) is to describe the analyses to be 
included in the Clinical Study Report for GSK Document Number 2015N267693_04. 
Revision Chronology: 
Protocol number: 
Date: 
Version: 
2015N267693_00 
02/Aug/2016 
Original Protocol 
2015N267693_01 
21/Nov/2016 
Protocol Amendment 1 
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 was added. 
2015N267693_02 
31/Jul/2017 
Protocol Amendment 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 
21/May/2018 
Protocol Amendment 3 
This protocol amendment was written to streamline recruitment of participants 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 
23/Oct/2019 
Protocol Amendment 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. 
 
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2. 
SUMMARY OF KEY PROTOCOL INFORMATION 
2.1. 
Changes to the Protocol Defined Statistical Analysis Plan 
Changes from the originally planned statistical analysis specified in the protocol are 
outlined in Table 1. 
Table 1 
Changes to Protocol Defined Analysis Plan 
Protocol 
Reporting & Analysis Plan 
Statistical Analysis Plan 
Statistical Analysis Plan 
Rationale for Changes 
• 
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) 
• 
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) 
• 
The derivation of t½ was 
removed since this 
parameter would be difficult 
to determine with or without 
treatment. 
• 
Change from pre-dose in SBP, 
DBP, HR, and MAP at each 
timepoint at Day 1 
• 
Change from pre-dose in 
SBP, DBP, HR, and MAP at 
each timepoint at Day 1 
and Day 57 
• 
Day 57 and for both 
treatments inadvertently left 
out of protocol 
• 
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 
• 
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), area under 
concentration-time curve 
from time zero to 24 hours 
(AUC[0-24]), and area 
under concentration-time 
curve from time zero to 
infinity (AUC[0-inf]) as 
appropriate 
• 
Added AUC (0-inf) as this 
was inadvertently left out of 
protocol 
 
• 
The daprodustat exposure 
(AUC) compared to the 
AUEC of SBP, DBP, MAP, 
and HR at Day 1 and Day 
57 
• 
To investigate if a 
relationship exists between 
daprodustat exposure and 
BP  
 
• 
The daprodustat exposure 
(AUC) compared to the 
biomarker AUEC at Day 1 
• 
To investigate if a 
relationship exists between 
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Protocol 
Reporting & Analysis Plan 
Statistical Analysis Plan 
Statistical Analysis Plan 
Rationale for Changes 
and Day 57. Biomarkers 
included erythropoietin, 
endothelin-1, nitric oxide, 
asymmetric 
dimethylarginine, renin, 
angiotensin-II (and 
metabolites), and 
noradrenalin.  
daprodustat exposure and 
biomarkers of interest 
 
 
2.2. 
Study Objective(s) and Endpoint(s) 
Objectives 
Endpoints 
Primary Objectives 
Primary Endpoints 
• 
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 Objectives 
Secondary Endpoints 
• 
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 and epoetin alfa on SBP, 
DBP, HR and MAP after Acute 
Challenge 1 and 2 
• 
Change from pre-dose in SBP, DBP, HR, and MAP at 
each timepoint at Day 1 and Day 57 
• 
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 Objectives 
Safety Endpoints 
• 
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 
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Objectives 
Endpoints 
• 
Absolute values and changes from baseline over time in 
laboratory parameters, electrocardiograms (ECGs) and 
vital signs 
Exploratory Objectives 
Exploratory Endpoints 
• 
To investigate the effect of 
daprodustat and epoetin alfa on 
vasoactive mediators of blood 
pressure 
• 
Plasma concentrations and derived parameters including 
Cmax, tmax, 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 the 
study treatment 
• 
Change in SBP from pre-dose on Day 1 to Cmax of the 
study treatment on Day 1, as measured by ABPM 
• 
Change in SBP from pre-dose on Day 1 to Cmax of the 
study treatment on Day 57, as measured by ABPM 
• 
Change in SBP from pre-dose on Day 57 to Cmax of the 
study treatment on Day 57, as measured by ABPM 
• 
To compare the effect of daprodustat 
to epoetin alfa on SBP at Cmax of the 
erythropoietin level 
• 
Change in SBP from pre-dose on Day 1 to Cmax of 
erythropoietin on Day 1, as measured by ABPM 
• 
Change in SBP from pre-dose on Day 1 to Cmax of 
erythropoietin on Day 57, as measured by ABPM 
• 
Change in SBP from pre-dose on Day 57 to Cmax of 
erythropoietin  on Day 57, as measured by ABPM 
• 
To investigate if an exposure-
response relationship exists between 
daprodustat and BP 
• 
The daprodustat exposure (AUC) compared to the 
AUEC of SBP, DBP, MAP, and HR at Day 1 and Day 57 
• 
To investigate if an exposure-
response relationship exists between 
daprodustat and biomarkers of 
interest 
• 
The daprodustat exposure (AUC) compared to the 
biomarker AUEC at Day 1 and Day 57. Biomarkers 
included erythropoietin, endothelin-1, nitric oxide, 
asymmetric dimethylarginine, renin, angiotensin-II (and 
metabolites), and noradrenalin.  
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2.3. 
Study Design 
Overview of Study Design and Key Features 
Pre protocol amendment 3: 
 
 
Post protocol amendment 3: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Design 
Features 
• 
This study will be an open-label, randomized, parallel-group design in HD 
participants with anemia associated with CKD. 
• 
This study will randomise approximately 31 participants per treatment arm 
assuming that 25 participants per treatment arm will complete the study and 
therefore, undertake and pass QC for acute challenge 2. 
• 
There will be a 7-30 day screening period, a 2-week ESA washout period, an 8-
week Hgb-maintenance period, two 24-hr acute challenges on Day 1 and Day 57 
and a follow-up visit at 14±3 days after completing treatment. 
• 
ABPM blood pressure monitoring will be performed for the 24 hours following each 
acute challenge. If the ABPM data at acute challenge 2 do not meet the required 
quality standards, an additional acute challenge 2 will be performed 
• 
Blood samples will be collected for PK and biomarkers as detailed in the Time & 
Events table. 
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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Overview of Study Design and Key Features 
Dosing 
• 
The details of the study treatments are given below and the daprodustat dose will 
be adjusted based on the Hgb value using a pre-defined algorithm (Protocol Section 
6.4.1). 
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 (Protocol Section 
6.4.1) 
24 mg 
daprodustat 
Time & 
Events 
• 
[Refer to Appendix 2: Schedule of Activities] 
Treatment 
Assignment 
• 
Randomization & Acute Challenge 1 (Day 1): Participants 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 participant’s dialysis session. 
• 
Hgb Maintenance Period: Participants randomized to daprodustat will start an 8-
week Hgb maintenance period based on a starting dose and dose adjustment 
algorithm. Participants 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 (Day 57) 
participants 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 participant’s dialysis session. 
Interim 
Analysis 
• 
No interim analyses are currently planned for this study. 
 
2.4. 
Statistical Hypotheses 
The primary objective of this study is to compare the effect of daprodustat to epoetin alfa 
on BP after Acute Challenge 2 (8 weeks of Hgb maintenance therapy). Specifically, the 
primary endpoint is the average of SBP as measured by ABPM over 6-hr post-dosing 
after 8 weeks of Hgb maintenance therapy. The estimand of interest is the effect of 8 
weeks of randomized treatment on the primary endpoint. 
• Null Hypothesis: The difference between 24 mg daprodustat versus 100 U/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 U/kg 
epoetin alfa on 6-hr average SBP under a background of treatment (i.e. during Acute 
Challenge 2) is not zero. 
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3. 
PLANNED ANALYSES 
3.1. 
Interim Analyses 
No interim analyses are currently planned for this study. 
 
3.2. 
Final Analyses 
The final planned primary analyses will be performed after the completion of the 
following sequential steps: 
1. All participants (N=50) have completed the study as defined in the protocol and have 
passed QC for acute challenges 1 and 2. 
2. All required database cleaning activities have been completed and final database 
release and database freeze has been declared by Data Management. 
 
4. 
ANALYSIS POPULATIONS 
Population 
Definition / Criteria 
Analyses Evaluated 
Screened  
• 
All participants who were screened for eligibility 
• 
Screen Failures 
 
Enrolled 
• 
All participants who enter washout. 
• 
Participants will be analyzed according to the treatment 
to which they were randomized, if randomized. 
• 
Study Population, 
Safety 
Safety 
• 
All randomized participants who received at least one 
dose of study treatment. 
• 
This population will be based on the treatment the 
participant actually received.1 
• 
Note: Participants who were not randomized but 
received at least one dose of study treatment should be 
listed. 
• 
Safety 
Intent-To-Treat 
(ITT) 
• 
All randomized participants [who received at least one 
dose of study treatment]. 
• 
This population will be based on the treatment the 
participant was randomized to. 
• 
Any participants who receives a treatment 
randomization number will be considered to have been 
randomized. 
• 
Primary, 
secondary, and 
exploratory 
endpoints 
excluding PK 
endpoints 
 
Per-Protocol  
(PP) 
• 
All participants in the ITT population who comply with 
the protocol. 
• 
Protocol deviations that would exclude participants from 
the PP population are defined in Section 4.1 (Protocol 
Deviations) and Appendix 1: Protocol Deviation 
Management and Definitions for Per Protocol 
Population). 
• 
Sensitivity analysis 
of primary 
endpoint 
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Population 
Definition / Criteria 
Analyses Evaluated 
• 
The PP set will not be analysed if this population 
comprises more than 90% of the ITT population. 
Pharmacokinetic 
(PK) 
• 
All participants in the Safety population who had at least 
1 non-missing PK assessment (Non-quantifiable [NQ] 
values will be considered as non-missing values). 
• 
All PK endpoints 
Refer to  Appendix 12: List of Data Displays which details the population used for each display. 
[1]: Only participants receiving incorrect randomized treatment for the duration of their study participation will be 
analyzed according to the treatment received. If participant received both treatments then analysis will be based 
on treatment received for the greatest number of days. Otherwise, participants will be analyzed according to the 
treatment to which they were randomized. 
 
4.1. 
Protocol Deviations 
Important protocol deviations (including deviations related to study inclusion/exclusion 
criteria, conduct of the trial, patient management or patient assessment) will be 
summarised and listed. 
Protocol deviations will be tracked by the study team throughout the conduct of the study 
in accordance with the Protocol Deviation Management Plan [13Apr2020 V5.0]. 
o Data will be reviewed prior to freezing the database to ensure all important 
deviations and deviations which may lead to exclusion from the analysis are 
captured and categorised on the protocol deviations dataset.  
o This dataset will be the basis for the summaries and listings of protocol 
deviations. 
A separate summary and listing of all inclusion/exclusion criteria deviations will also be 
provided. This summary will be based on data as recorded on the inclusion/exclusion 
page of the eCRF. 
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5. 
CONSIDERATIONS FOR DATA ANALYSES AND DATA 
HANDLING CONVENTIONS 
5.1. 
Study Treatment & Sub-group Display Descriptors 
Treatment Group Descriptions 
[RandAll NG / FSO Randomization System] 
Data Displays for Reporting  
Code 
Description 
Description 
Order in TLF  
A 
IV epoetin alfa 
rhEPO 
2 
B 
Daprodustat 
Dapro  
1 
- 
- 
Total 
3 
 
Treatment comparisons will be displayed as follows using the descriptors as specified: 
Dapro vs rhEPO 
Within each treatment group/arm, the display descriptors for the study periods/visits will 
be as follows: 
Pre-Protocol Amendment 3 
Post-Protocol Amendment 3 
Study Period 
(Visit) 
Study Period 
(Visit) 
Screening* 
(Week -8 to Week -4) 
Screening* 
(7-30 days prior to Week -2) 
ESA Washout* 
(Week -4 to Day 1) 
ESA Washout* 
(Week -2 to Day 1) 
Acute Challenge 1 
(Day 1) 
Acute Challenge 1 
(Day 1) 
Hgb Maintenance Phase 
(Day 2 to Day 56) 
Hgb Maintenance Phase 
(Day 2 to Day 56) 
Acute Challenge 2 
(Day 57) 
Acute Challenge 2 
(Day 57) 
Hgb Maintenance Phase 
(Day 58 to day before repeated 
AC2) 
Hgb Maintenance Phase 
(Day 58 to day before repeated 
AC2) 
Repeat Acute Challenge 2** 
Repeat Acute Challenge 2** 
Early Withdrawal 
Early Withdrawal 
Follow-up 
(Day 58 to Week 10) 
Follow-up 
(Day 58 to Week 10) 
 
*For these visits, the period will include the first visit up to but not including the last 
reference visit. For example, screening period for pre-protocol amendment 3 will 
defined as week -8 up to but not including the week -4 visit. 
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**For subjects with a repeat acute challenge 2, the follow-up period will be the day 
following this visit 
5.2. 
Baseline Definitions and Derivations 
5.2.1. 
Baseline Definitions 
For all endpoints the baseline value will be the latest non-missing pre-dose assessment 
before Acute Challenge 1 as detailed in the following table. Pre-dose values following 
Acute Challenge 1 following the maintenance therapy will not be used as baseline. 
Parameter 
Study Assessments Considered As Baseline 
Baseline Used in 
Data Display 
Screening 
Week -2 
Day 1 (Pre-Dose) 
Pre-Acute Challenge 1 
ABPM Parameters 
 
 
X 
Post-HD/Pre-Acute 
Challenge 1 
Vital signs (SBP, 
DBP and pulse rate) 
X 
X 
X (post-HD) 
Post-HD and Pre-
Acute Challenge 1 
Laboratory data  
X 
 
X 
Day 1(Pre-dose) 
ECG 
X 
 
X 
Day 1(Pre-dose) 
Biomarkers 
 
 
X 
Day 1(Pre-dose) 
NOTES: 
Unless otherwise stated, the mean of replicate assessments at any given time point will be used as 
the value for that time point. 
 
5.2.2. 
Derivations and Handling of Missing Baseline Data 
Unless otherwise stated, if baseline data is missing no derivation will be performed and 
baseline will be set to missing. 
Change from Baseline 
Definition 
Reporting Details 
Change from Baseline 
= Post-Dose Visit Value – Baseline 
NOTES: 
• 
Unless otherwise specified, the baseline definitions specified in Section 5.2.1 Baseline Definitions will be used 
for derivations for endpoints / parameters and indicated on summaries and listings. 
• 
Unless otherwise stated, if baseline data is missing no derivation will be performed and the change from 
baseline value will be set to missing. 
• 
The baseline definition will be footnoted on all change from baseline displays. 
Percent Change from Baseline 
Ferritin and serum iron will be log-transformed. Instead of reporting change from 
baseline and mean, percent change from baseline and geometric mean will be reported. 
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To calculate a geometric mean for baseline measurement or at a specified timepoint, the 
following steps are used: 
1. Log-transform the data points 
2. Calculate the mean and standard error (SE) of the log-transformed data 
3. Exponentiate the mean, (if required, the mean – SE, mean + SE) and the endpoints of 
the confidence interval back to the original scale in order to obtain the geometric 
mean, (the geometric mean – SE, the geometric mean + SE) and the confidence 
interval for the geometric mean. 
4. Coefficient of variation will be calculated as  
1
)
exp(
log
−
=
scale
Var
CV
 100% 
To calculate a geometric mean for the ratio of a specific timepoint to baseline (expressed 
as a percent change from baseline), the following steps are used: 
1. Log-transform the data at both the baseline and the specified timepoint  
2. For each participant, calculate a change from baseline using the log-transformed data 
3. Calculate the mean and standard error (SE) of the log-transformed data 
4. Exponentiate the mean, (if required, the mean – SE, the mean + SE) and the 
endpoints of the confidence interval, back to the original scale and then subtract 1, 
then multiply everything by 100% in order to express the geometric mean, (the 
geometric mean – SE, the geometric mean + SE) and the confidence interval (CI) as 
the percent change from baseline. 
Geometric mean for percent change from baseline = 
   [ Exp(∑ {log(value at specified time point_i) – log(baseline value_i) }/n) – 1 ] x 100, 
Where i = participant, n= total number of participants, and ∑ represents the sum over all 
participants. 
To calculate the minimum, median and maximum for the ratio of a specific timepoint to 
baseline (expressed as a percent change from baseline), the following steps are used: 
1. Log-transform the data at both the baseline and the specified timepoint  
2. For each participant, calculate a change from baseline using the log-transformed data 
3. Calculate the minimum (median and maximum) of change from baseline using the 
log transformed data. 
4. Exponentiate the minimum (median and maximum), back to the original scale and 
then subtract 1, then multiply everything by 100% in order to express the minimum 
(median and maximum) as the percent change from baseline.  
Minimum percent change from baseline = 
   [ Exp(min {log(value at specified time point_i) – log(baseline value_i) }) – 1 ] x 100, 
Where i = participant. 
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Unless otherwise specified, the baseline definitions specified in Section 5.2.1 will be used 
for derivations for endpoints/parameters and indicated on summaries and listings. Unless 
otherwise specified, if baseline data is missing, no derivation will be performed and the 
% change from baseline value will be set to missing. 
5.3. 
Multicentre Studies 
In this multicentre study, enrolment will be presented by investigative site. 
5.4. 
Examination of Covariates, Other Strata and Subgroups 
5.4.1. 
Covariates and Other Strata 
The list of covariates and other strata may be used in descriptive summaries and 
statistical analyses, some of which may also be used for subgroup analyses. Additional 
covariates and other strata of clinical interest may also be considered. 
Category 
Details 
Strata 
Prior treatment by ESA Dose (low ESA/high ESA) 
Covariates 
Treatment (daprodustat/epoetin alfa) 
 
Post_HD/pre-Acute Challenge 1 BP (SBP, DBP, MAP, HR) 
 
Difference in SBP between post-HD/pre-Acute Challenge 2 BP (SBP, DBP, MAP, 
HR)and post-HD/pre-Acute Challenge 1. 
 
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.  Therefore, pre-Acute Challenge 
2 SBP will not be used as a covariate. Instead, any impact on the SBP due to the covariate 
between Challenge 1 to Challenge 2 will be adjusted for using the covariate ‘Difference 
in SBP between post-HD/pre-Acute Challenge 2 SBP and post-HD/pre-Acute Challenge 
1’. 
The primary model will include the interaction between treatment and ‘difference in post-
HD SBP between Acute Challenge 1 and 2’. 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, post-HD/pre-Acute 
Challenge 1 SBP, and prior ESA dose (low/high). 
Stratification factor (previous ESA dose) will be used as a fixed factor in the model 
where indicated in Section 11. See details below: 
Classification Name (Description) 
Value 
Code/Range 
Treatment by ESA Dose  
(Treatment by Previous ESA Dose) 
Low ESA Dose 
1 
High ESA Dose 
2 
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5.4.2. 
Examination of Subgroups 
No subgroups will be examined. 
5.5. 
Multiple Comparisons and Multiplicity 
No multiplicity adjustments will be made for the final analysis of the secondary 
endpoints. Although the secondary and exploratory analyses will include statistical 
testing, these will be considered as exploratory and no Type I error adjustments will be 
made. 
5.6. 
Other Considerations for Data Analyses and Data Handling 
Conventions 
Other considerations for data analyses and data handling conventions are outlined in the 
appendices: 
Section 
Component 
14.3 
Appendix 3: Assessment Windows 
14.4 
Appendix 4: Study Phases and Treatment Emergent Adverse Events 
14.5 
Appendix 5: Data Display Standards & Handling Conventions 
14.6 
Appendix 6: Derived and Transformed Data 
14.7 
Appendix 7: Reporting Standards for Missing Data 
14.8 
Appendix 8: Values of Potential Clinical Importance 
 
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6. 
STUDY POPULATION ANALYSES 
6.1. 
Overview of Planned Study Population Analyses 
The study population analyses will be based on the ITT population unless otherwise 
specified. 
Study population analyses including analyses of participant’s disposition, protocol 
deviations, demographic and baseline characteristics, prior and concomitant medications, 
and exposure will be based on GSK Core Data Standards.  Details of the planned displays 
are presented in Appendix 12: List of Data Displays. 
6.2. 
Display Details 
6.2.1. 
Participant Disposition 
Participant Status and Reason for Study Withdrawal 
The number and percentage of participants who completed the study as well as 
participants who withdrew from the study will be summarized by participant status and 
reason for withdrawal. The number of participants who completed the study for purpose 
of the disposition table will consist of all randomized participants who, as documented in 
the eCRF, Study Conclusion form, have completed all study periods through the Day 57 
visit. This table will also include those subjects who entered washout but were never 
randomized. 
 
A listing of reasons for study withdrawal will be provided for all participants who were 
withdrawn from the study. This listing will include treatment, site ID, unique subject ID, 
date of withdrawal, study day of withdrawal, primary reason for withdrawal from study, 
was a follow-up phone contact attempted 3 times, and was a follow-up certified letter 
mailed. 
 
Treatment Status and Reasons for Discontinuation of Study Treatment 
A summary of the number and percentage of participants who completed the study 
treatment as planned, as well as participants who stopped study treatment prematurely 
will be produced.  
 
A listing of the randomized treatment discontinuation record will be provided for all 
participants who prematurely discontinued randomized treatment. This listing will 
include treatment, site ID, unique subject ID, date of last dose, study day of 
discontinuation, primary reason for discontinuation, and sub reasons for discontinuation, 
and related to study treatment.  
 
Participant Disposition at Each Study Period 
The number and percentage of participants who entered, withdrew from and completed 
screening, washout, HGB maintenance Period, and follow-up of the study will be 
summarized by treatment group and overall. 
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Pre-Protocol Amendment 3 
Post-Protocol Amendment 3 
Study Period 
(Visit) 
Study Period 
(Visit) 
Screening* 
(Week -8 to Week -4) 
Screening* 
(7-30 days prior to Week -2) 
ESA Washout* 
(Week -4 to Day 1) 
ESA Washout* 
(Week -2 to Day 1) 
Hgb Maintenance Phase 
(Day 1 to Day 57) 
Hgb Maintenance Phase 
(Day 1 to Day 57) 
Follow-up 
(Day 58 to Week 10) 
Follow-up 
(Day 58 to Week 10) 
 
*For these visits, the period will include the first visit up to but not including the last 
reference visit. For example, screening period for pre-protocol amendment 3 will 
defined as week -8 up to but not including the week -4 visit. 
 
Screening Status and Reasons for Screen Failure 
The number and percentage of participants who passed screening (i.e. enrolled) and who 
failed screening and therefore were not entered into the study will be summarized along 
with the reasons for failure will be summarized for those participants who failed 
screening. If a subject has been screened multiple times, the subject’s latest screening 
information will be displayed. (Note that the reasons for rescreen participants who 
initially failed but subsequently enrolled are not included in the display.) 
 
A listing of the screen failure record for all participants who failed screening and were 
not enrolled in the study will be produced. This listing will include site ID, unique subject 
ID, date of screen failure, reason term(s) for screen failure (including the specify text, if 
any).  
 
Number of Participants by Site ID 
The number and percentage of participants by Site ID will be summarized by treatment 
group and overall for the Enrolled population.  
A listing of planned and actual treatments will be provided. This listing will include site 
ID, unique subject ID, randomization number, randomization date, randomized treatment, 
actual treatment and deviation. 
 
6.2.2. 
Protocol Deviations 
Important Protocol Deviations 
The number and percentage of participants who had important protocol deviations 
(defined in protocol deviation management plan) will be summarized by category and by 
treatment group and overall. 
 
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A listing of important protocol deviations will be provided. The listing will include 
treatment, site ID, unique subject ID, date of deviation, study day of deviation, protocol 
deviation category, protocol deviation coded term, and protocol deviation description. 
 
Participants with Inclusion/Exclusion Criteria Deviations 
The number and percentage of participants who had inclusion/exclusion criteria 
deviations will be summarized by inclusion/exclusion type, criteria description and by 
treatment group and overall. 
 
A listing of participants with inclusion/exclusion criteria deviations will be provided. The 
listing will include treatment, site ID, unique subject ID, inclusion/exclusion type, and 
criteria description. 
 
6.2.3. 
Population Analysed  
Study Populations 
The number and percentage of screened participants in the Screened, Enrolled, Safety, 
ITT, PP, PK will be summarized by treatment group and overall. 
 
Exclusion from Safety Population 
The number and percentage of participants excluded from the Safety population will be 
summarized by reason, treatment group and overall in individual displays for each study 
population. 
 
A listing of participants excluded from the Safety population will be provided. The listing 
will include the treatment arm, site ID, unique subject ID, date of deviation, study day of 
deviation, category, coded term and criteria which lead to exclusion. 
 
6.2.4. 
Demographic and Baseline Characteristics 
Demographic Characteristics 
Demographic and baseline data will be summarized by treatment group and overall for 
ITT, Safety, and PP populations. PP only to be produced if used in sensitivity analysis. 
 
A by-subject listing of demographic and baseline characteristics will also be produced. 
This listing will include treatment, site ID, unique subject ID, year of birth, age, sex, 
ethnicity, height, weight, and other demographic and baseline characteristics. 
 
Age Ranges 
A summary of age ranges will be produced based on the Enrolled population. 
 
 
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Race and Racial Combinations 
Summaries of race and racial combinations will be produced for each treatment group 
and overall.  
 
A listing of race details by participant will also be produced, which will include 
treatment, site ID, unique subject ID, race, and race detail.  
 
6.2.5. 
Medical Conditions, Prior and Concomitant Medications 
Medical Conditions 
A summary of baseline medical conditions will be provided by treatment group and 
overall. 
A listing of medical conditions will be produced, which will capture both pre-specified 
medical conditions and other medical conditions collected on the eCRF.  
Concomitant Medications 
For reporting purposes, medications will be classified as prior (pre-treatment), 
concomitant (on-treatment), and post-treatment using the associated start and stop dates 
recorded in the eCRF and relative to the first and last dose dates of IP (see Section 
14.4.1). Medications will be coded using the GSK Drug coding dictionary (current 
version at the time of DBR). 
 
The number and percentage of participants reporting the use of each concomitant 
medication will be summarized by GSK-Drug Anatomical Therapeutic Chemical (ATC) 
classification level 1, 2, 3 (body system) and ingredient. Drugs that are composed of a 
combination of ingredients will be displayed according to the ATC classifications of the 
ingredients, not of the combination. Summaries of pre-treatment, on-treatment, and post-
treatment medication will be provided separately. See Section 14.4.1.1 for a summary of 
study phases for concomitant medications. 
 
A listing of all medications taken by participants, including any of which are only prior or 
post-treatment, will be produced. The relationship between ATC level 1, 2, 3, and 
ingredients and verbatim text for all medications in the study will be listed. 
6.2.6. 
Exposure and Treatment Compliance 
Months (or days) of exposure (see Section 14.6.2) will be summarized using mean, 
standard deviation, minimum, P25, median, P75, and maximum by treatment group and 
overall. 
A listing of exposure data will be provided. This listing will include treatment, site ID, 
unique subject ID, dose start date, dose stop date, duration of time on dose, dose, dose 
units, dose form, route of administration, and dosing frequency. 
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Summary of percent compliance will be summarized using mean, standard deviation, 
minimum, P25, median, P75, and maximum. 
A listing of compliance data will be provided. This listing will include treatment, site ID, 
unique subject ID, and percent compliance. 
Compliance is only calculated for Daprodustat because rhEPO subjects are dosed at site. 
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7. 
EFFICACY ANALYSES 
7.1. 
Primary Efficacy Analyses 
Efficacy is not evaluated for this study. The primary objective is Pharmacodynamic, the 
average systolic blood pressure (SBP) over 6-hr post-dosing after 8 weeks, this is 
described in Section 11. 
 
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8. 
SAFETY ANALYSES 
The safety analyses will be based on the Safety population, unless otherwise specified. 
Objectives 
Endpoints 
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 
 
8.1. 
Adverse Events Analyses 
Adverse events analyses including the analysis of AEs of special interest (AESI), adverse 
events (AEs), Serious (SAEs) and other significant AEs will be based on GSK Core Data 
Standards. The details of the planned displays are provided in Appendix 12: List of Data 
Displays. 
Adverse Events 
The number and percentage of participants reporting at least one AE will be provided for 
each treatment group. These events will be summarized by treatment group, primary 
system organ class, and preferred term. Pre-treatment, post-randomization, treatment 
emergent and follow-up AEs will be summarized separately, specifically the on treatment 
AEs will be separated by acute challenge 1, HGB maintenance, and acute challenge 2. 
HGB maintenance is defined as the dates between acute challenge 1 and 2.  
Summaries of all AEs will be produced for the safety population. 
A listing of AE records for all participants who reported AEs will be produced. 
The number and percentage of participants reporting the most common treatment 
emergent AEs (those occurring in  2% of participants in any treatment group) will be 
summarized by preferred term and treatment group. Rounding is not applied, e.g. with a 
threshold of 2% then a preferred term occurring in 1.99% of subjects would not be 
included. 
The number and percentage of participants reporting treatment emergent AEs assessed by 
the investigator to be related to the study drug will be summarized by treatment group, 
primary system organ class, and preferred term and separately by overall frequency.  
The number and percentage of participants and the number of occurrences of common 
non-serious treatment emergent adverse events will be summarized by primary system 
organ class, preferred term, and treatment group and separately by overall frequency. 
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A listing of which participants reported specific adverse events will be produced. 
The hierarchical relationship between MedDRA SOCs, PTs and verbatim text will be 
listed for all adverse events. 
Adverse events occurring during the 24-hour acute challenge will be grouped in the 
appropriate acute challenge phase. Any AE occurring after AC2 but before repeat-AC2 
will be grouped in the HGB maintenance phase. 
Adverse events occurring after the last on treatment date will be grouped either in early 
withdrawal or follow-up depending on the final status of the subject, 
Serious and Other Significant Adverse Events 
The number and percentage of participants and the number of occurrences of SAEs will 
be provided for each treatment group. These events will be summarized by treatment 
group, primary system organ class, and preferred term. Pre-treatment, post-
randomization, treatment emergent and follow-up SAEs will be summarized separately. 
Treatment emergent SAE preferred terms will also be summarized by treatment group 
and overall frequency. 
A listing of reasons for considering as a SAE will be produced for all treatment emergent 
SAEs. 
The number and percentage of participants and the number of occurrences of treatment 
emergent drug-related SAEs, and drug-related fatal SAEs will be summarized by 
treatment group. 
A listing of treatment emergent fatal SAE records and a listing of treatment emergent 
non-fatal SAE records will be provided. 
The number and percentage of participants reporting treatment emergent AEs leading to 
discontinuation of randomized treatment will be summarized by treatment group, primary 
system organ class, and preferred term. 
A listing of treatment emergent AEs leading to discontinuation of randomized treatment 
will be provided. 
8.2. 
Adverse Events of Special Interest Analyses 
A comprehensive list of MedDRA terms based on clinical review will be used to identify 
each type of event. [Changes to the MedDRA dictionary may occur between the start of 
the study and the time of reporting and/or emerging data from on-going studies may 
highlight additional adverse events of special interest, therefore the list of terms to be 
used for each event of interest and the specific events of interest will be based on the 
safety review team (SRT) agreements in place at the time of reporting.] The details of the 
planned displays are provided in Appendix 12: List of Data Displays. See Section 14.6.4 
for complete list of AESIs 
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Summaries of AESIs will include the number, percentage and rate per 100 person-years 
of participants having at least one occurrence, the number of events, the number of 
participants by number of occurrence, the characteristics of the AE (serious, drug-related, 
etc.), outcome, maximum intensity, time to first onset/worsening, the duration of first, 
second, and third occurrence of the AE, and action taken summarized by treatment group. 
For each count, a participant will be summarized as follows: 
• Serious/drug-related/severe/fatal: If any specific AE falls in the respective 
category, the participant will be counted in that category. 
• Outcome: The participant will be counted within a category if there is at least one 
specific AE in that category. 
• Maximum intensity: The specific AE with the maximum intensity will be counted 
for this purpose. For example, a participant will be counted in the ‘severe’ 
category if there is at least one specific AE with severe intensity. A participant 
will be counted in the ‘moderate’ category if there is at least one specific AE with 
moderate intensity and there is no specific AE with severe intensity. 
• Time to first onset/worsening (days): The earliest of onset dates for the specific 
AE – treatment start + 1 
• Duration of the occurrence (days): AE resolution date – AE onset date/AE 
worsening date + 1 for the occurrence 
If the AE onset date/AE worsening and/or resolution date is missing or incomplete in the 
database for any occurrence of the specific AE, time to first onset/worsening and/or 
duration of the first, second, and third occurrence will be left missing for the participant. 
These summaries of special interest AEs will be provided for those AEs classified as 
treatment emergent, follow-up and post-randomization. 
Kaplan-Meier plots may be produced for each special interest AE summarizing the time 
to first occurrence of the special interest AE by treatment group. 
 
8.3. 
Clinical Laboratory Analyses 
Laboratory evaluations including the analyses of Chemistry laboratory tests, Hematology 
laboratory tests, Urinalysis, and liver function tests will be based on GSK Core Data 
Standards. The details of the planned displays are in Appendix 12: List of Data Displays 
and include the following tests: 
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The clinical chemistry tests performed in this study include ALT, AST and bilirubin. In 
addition to being summarized with the clinical chemistry values, these laboratory values 
will be included in some of the Hepatobiliary (liver) displays. 
In addition to the visits listed for the laboratory assessments in the Schedule of Activities 
(see Section 14.2.1), any of these assessments can be performed at an unscheduled/retest 
visit or at the follow-up visit at the discretion of the investigator. See Section 14.5.2 for 
handling of unscheduled values. The laboratory’s normal range values will be provided 
by the central laboratory and potential clinical importance thresholds are defined in 
Section 14.8.1. 
In addition to the other screening tests, serum iron will also be collected and summarized 
similar to the parameters listed in the table above. Both ferritin and serum iron will be log 
transformed. 
HGB will be summarized with both the central lab and local lab (Hemocue). 
All of the tabular summaries described below will include summaries in SI units and 
conventional units for the following laboratory tests: hemoglobin, MCHC, albumin-
adjusted calcium, phosphate, and albumin. Conversions from SI units to conventional 
units are included in Section 14.6.4. 
The clinical laboratory safety analyses will be based on the Safety population and GSK 
Core Data Standards, unless otherwise specified. The details of the planned displays are 
in Appendix 12: List of Data Displays. 
8.4. 
Other Safety Analyses 
The analyses of non-laboratory safety test results including ECGs and vital signs will be 
based on GSK Core Data Standards, unless otherwise specified. The details of the 
planned displays are presented in Appendix 12: List of Data Displays. 
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The analyses of non-laboratory safety test results including vital signs, concomitant 
medications and meeting protocol defined stopping criteria (e.g., liver chemistry) will be 
based on GSK Core Data Standards, unless otherwise specified. The details of the 
planned displays are presented in Appendix 12: List of Data Displays. 
Vital signs and weight are assessed in this study according to the schedule outlined in the 
Time and Events table (see Section 14.2.1) and include the following assessments: 
• Temperature 
• SBP 
• DBP 
• HR 
• MAP 
• Weight (pre- and post-dialysis) 
The vital signs analyses will be based on the Safety population, unless otherwise 
specified. 
Vital signs will be summarized for both pre and post dialysis recordings. 
Vital sign values will be summarized using mean, standard deviation, minimum, P25, 
median, P75, and maximum for each scheduled visit and for baseline and end of 
treatment by treatment group. 
Vital sign change from baseline values will be summarized using mean, standard 
deviation, minimum, P25, median, P75, and maximum for each scheduled visit. 
A listing of all vital signs with PCI criteria for participants with on-treatment vital signs 
values outside of PCI criteria will be provided for the parameters listed in Section 14.8. 
Reasons for early study withdrawal and for stopping randomized treatment will also be 
summarized by treatment group with Table 1.1 and Table 1.2 respectively under study 
population tables using the enrolled and ITT populations respectively. 
Summaries of subjects affected by COVID-19 will be provided. These will include a 
summary of all treatment emergent adverse events. See Appendix 12: List of Data 
Displays for list of summary tables. 
 
 
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9. 
PHARMACOKINETIC ANALYSES 
9.1. 
Primary Pharmacokinetic Analyses 
There are no primary Pharmacokinetic analyses, only secondary. The primary objective is 
Pharmacodynamic, the average systolic blood pressure (SBP) over 6-hr post-dosing after 
8 weeks, this is described in Section 11. 
9.2. 
Secondary Pharmacokinetic Analyses 
9.2.1. 
Endpoint / Variables 
• 
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), 
area under concentration-time curve from time zero to 24 
hours (AUC[0-24]), and area under concentration-time 
curve from time zero to infinity (AUC[0-inf]) as appropriate 
 
9.2.1.1. 
Drug Concentration Measures  
Refer to Appendix 5: Data Display Standards & Handling Conventions (Standards for 
Pharmacokinetic) 
9.2.1.2. 
Derived Pharmacokinetic Parameters 
Pharmacokinetic parameters will be calculated by standard non-compartmental analysis 
according to current working practices and using the currently supported version of 
WinNonlin. All calculations of non-compartmental parameters will be based on actual 
sampling times. Pharmacokinetic parameters listed will be determined from the plasma 
concentration-time data, as data permits. 
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 14.2.1, 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 participant is 
unable to provide a sufficient blood quantity per time point or there is 
significant concern for this by the participant or investigator, these serial blood draws 
may be omitted. 
 
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 
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[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). 
 
9.2.2. 
Summary Measure 
All pharmacokinetic endpoints will be summarized in tabular form.  Descriptive statistics 
(n, arithmetic mean, standard deviation, minimum, median, maximum) will be calculated 
for all pharmacokinetic endpoints by regimen. In addition, for AUC(0-24, AUC(0-inf), 
Cmax, t1/2, geometric means and geometric CVs (CVb(%)) will be calculated for each 
regimen. Geometric mean and geometric CV% will not be calculated for tmax.   
A participant listing of individual PK parameters for each treatment group will be 
provided.  Pharmacokinetic parameters will be summarized by treatment group using 
descriptive statistics. 
9.2.3. 
Population of Interest  
The secondary pharmacokinetic analyses will be based on the PK population, unless 
otherwise specified. 
9.2.4. 
Strategy for Intercurrent (Post-Randomization) Events 
Not required. 
9.2.5. 
Statistical Analyses / Methods 
Details of the planned displays are provided in Appendix 12: List of Data Displays and 
will be based on GSK Data Standards and statistical principles. 
Unless otherwise specified, endpoints / variables defined in Section 9.2.1 will be 
summarised using descriptive statistics, graphically presented (where appropriate) and 
listed. 
Geometric mean=exp (mean on loge scale)  
CVb (%)=SQRT(exp(SD**2)-1)x100, where SD is the standard deviation of the loge-
transformed data. 
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10. 
POPULATION PHARMACOKINETIC (POPPK) 
ANALYSES 
10.1. 
Statistical Analyses / Methods 
POPPK is not evaluated for this study. The primary objective is Pharmacodynamic, the 
average systolic blood pressure (SBP) over 6-hr post-dosing after 8 weeks, this is 
described in Section 11. 
 
 
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11. 
PHARMACODYNAMIC AND BIOMARKER ANALYSES 
11.1. 
Primary Pharmacodynamic Analyses 
11.1.1. 
Endpoint / Variables 
Primary Objectives 
Primary Endpoints 
• 
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 
The primary endpoint is average systolic blood pressure (SBP) over 6-hr post-dosing 
after 8 weeks. Other variables used in the primary endpoint model include: 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. 
11.1.2. 
Summary Measure 
Average of systolic blood pressure (SBP) as measured by ambulatory blood pressure 
monitoring (ABPM) over 6-hr post-dosing after 8 weeks (i.e. Day 57) of Hgb 
maintenance therapy. 
11.1.3. 
Population of Interest 
The primary pharmacodynamics analyses will be based on the Intent-To-Treat 
population, unless otherwise specified. 
If there are protocol deviations that are thought to potentially impact the primary 
endpoints (defined as at least 10% of the ITT population being excluded from the PP 
population), an exploratory sensitivity analysis may be considered using the PP 
population.   
Any such important protocol deviations will be identified before DBR and the subsequent 
sensitivity analysis on the PP population will be documented in the CSR. 
11.1.4. 
Strategy for Intercurrent (Post-Randomization) Events 
ABPM data is collected every 15 minutes for the first 6-hrs and then every 20 minutes 
thereafter until 24-hrs post dose. In order to reduce the extent of missing ABPM data due 
to device issues, the device is designed to retry measuring blood pressure if it fails to 
record a BP during the scheduled timepoint. In addition, 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 participant agrees. This repeat Acute Challenge 2 would 
replace the failed QC Acute Challenge 2. 
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For these participants who have a failed QC of the ABPM for a given acute challenge 
day, the data that is available from the ABPM device will be used during a sensitivity 
analysis on the primary endpoint. For those participants that fail QC both Acute 
Challenge 2, and a repeat Acute Challenge 2, the repeat Acute Challenge 2 data will be 
utilized. 
Since participants who discontinue randomized study medication are withdrawn from the 
study and would have already performed their Day 1 acute challenge, multiple imputation 
will be used to attempt to impute what the missing data would have been had the 
participant not stopped randomized study medication. These participants who are early 
withdrawn will have their missing Day 57 ABPM data imputed to be included in a 
sensitivity analysis on the primary endpoint. This sensitivity analysis will include those 
participants who both early withdrawal and have their ABPM data imputed as well as 
those participants whose ABPM data did not pass QC for a given day. Details of the 
multiple imputation can be found in Section 14.6.6. 
11.1.5. 
Statistical Analyses / Methods 
Details of the planned displays are provided in Appendix 12: List of Data Displays and 
will be based on GSK Data Standards and statistical principles. 
Unless otherwise specified, endpoints / variables defined in Section 11.1.1 will be 
summarised using descriptive statistics, graphically presented (where appropriate) and 
listed. 
11.1.5.1. 
Interim Analysis 
No interim analyses are currently planned for this study. 
11.1.5.2. 
Statistical Methodology Specification 
Endpoint / Variables 
• 
Average of systolic blood pressure (SBP) as measured by ambulatory blood pressure monitoring 
(ABPM) over 6-hr post-dosing after 8 weeks (i.e. Day 57) of Hgb maintenance therapy 
Model Specification 
• 
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. 
Model Checking & Diagnostics 
• 
Distributional assumptions underlying the statistical analyses will be assessed by visual inspection of 
residual plots. Normality will be examined by normal probability plots, while homogeneity of variance 
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will be assessed by plotting the residuals against the predicted values for the model. If assumptions 
are grossly violated, alternative analyses will be considered. 
Model Results Presentation 
• 
The point estimate, two-sided 95% CI and p-value for the difference between treatment groups will 
be presented from the selected final model for the superiority assessment. Superiority will be 
established if the p-value is <0.05. 
Sensitivity and Supportive Analyses 
• 
If there are protocol deviations that are thought to potentially impact the primary endpoints (defined 
as at least 10% of the ITT population being excluded from the PP population), an exploratory 
sensitivity analysis will be completed. The analysis used for the primary endpoint will be repeated 
and similar results will be presented. 
• 
Participants who discontinue randomized study medication early will have their missing Day 57 AC2 
ABPM data imputed; a sensitivity analysis will be run on the primary endpoint including these 
participants. 
• 
The primary endpoint will analyse using a 6-hour average of BP from ABPM device, sensitivity 
analyses using 8, 12, and 24-hour averages will be analysed using the primary model explained 
above in the model specification section.  
 
11.2. 
Secondary Pharmacodynamic Analyses 
11.2.1. 
Endpoint / Variables 
Secondary Objectives 
Secondary Endpoints 
• 
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 and epoetin alfa on SBP, 
DBP, HR and MAP after Acute 
Challenge 1 and 2 
• 
Change from pre-dose in SBP, DBP, HR, and MAP at 
each timepoint at Day 1 and Day 57 
11.2.2. 
Summary Measure 
Secondary Endpoints 
Summary Measure 
• 
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 SBP, DBP, MAP, and HR over 6 
hours post-dosing on Day 1 
• 
AUEC for SBP, DBP, MAP, and HR over 24 
hours post-dosing on Day 1 
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Secondary Endpoints 
Summary Measure 
• 
Area under the effect curve (AUEC) of SBP, 
DBP, MAP, and HR as measured by ABPM over 
24-hr post-dosing at Day 1 
• 
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. 
• 
Average DBP, MAP, and HR over 6 hours 
post-dosing on Day 57 
• 
AUEC for SBP, DBP, MAP, and HR over 24 
hours post-dosing on Day 57 
• 
Change from pre-dose in SBP, DBP, HR, and 
MAP at each timepoint at Day 1 and Day 57 
• 
Mean change in SBP, DBP, HR, and MAP at 
each timepoint on Day 1 and Day 57 
11.2.3. 
Population of Interest  
The secondary pharmacodynamics analyses will be based on the ITT population, unless 
otherwise specified. 
11.2.4. 
Strategy for Intercurrent (Post-Randomization) Events 
If the primary sensitivity analysis for missing data differs with the primary endpoint, 
further sensitivity analyses on the secondary endpoints will be analysed. These potential, 
additional sensitivity analyses will follow how the primary endpoint sensitivity analysis 
was analysed, see Section 11.1.4 and Section 14.6.6 for details. 
11.2.5. 
Statistical Analyses / Methods 
Details of the planned displays are provided in Appendix 12: List of Data Displays and 
will be based on GSK Data Standards and statistical principles. 
Unless otherwise specified, endpoints / variables defined in Section 11.2.1 will be 
summarised using descriptive statistics, graphically presented (where appropriate) and 
listed. 
11.2.5.1. 
Statistical Methodology Specification 
Endpoint / Variables 
• 
Average of SBP, DBP, HR, and MAP 
• 
AUEC of SBP, DBP, HR, and MAP 
• 
Change from pre-dose in SBP, DBP, HR, and MAP at each timepoint at Day 1 and Day 57 
Model Specification 
• 
For the first 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 SBP terms with the analogous  measurement for DBP, 
MAP, and HR respectively. 
o ANCOVA with terms for treatment, prior ESA dose (low/high), and post-HD/pre-Acute 
Challenge 1 ABPM (DBP/MAP/HR), difference between post-HD/pre-Acute Challenge 
2 ABPM (DBP/MAP/HR) and post-HD/pre-Acute Challenge 1 ABPM (DBP/MAP/HR), 
and treatment by (difference in post-HD ABPM (DBP/MAP/HR) between Acute 
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Challenge 1 and 2) interaction.  Note that the pre-challenge ABPM (DBP/MAP/HR) 
may change over time between Acute Challenge 1 and Acute Challenge 2 as a result 
of the maintenance therapy, and thus the pre-challenge ABPM (DBP/MAP/HR) 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 ABPM (DBP/MAP/HR). 
• 
For the second secondary endpoint, AUEC of SBP, DBP, HR, and MAP post-acute challenge 1 and 
2 will be analyzed using an ANCOVA model with terms for treatment and prior ESA dose (low/high). 
• 
The AUEC for ABPM will only be analysed if a subject has ABPM data up to hour 24. 
o For example if the subject has ABPM data up to hour 23, the subject will be excluded 
from the ABPM AUEC analysis. 
o If more than 25% of subjects are excluded from the ABPM AUEC analysis because the 
subject is missing any of the 3 possible hour 24 ABPM measurements, then an 
extrapolation technique of average hour 23 measurement carried forward to hour 24 
may be utilized as a sensitivity analysis for AUEC ABPM. 
Model Checking & Diagnostics 
• 
Distributional assumptions underlying the statistical analyses will be assessed by visual inspection of 
residual plots. Normality will be examined by normal probability plots, while homogeneity of variance 
will be assessed by plotting the residuals against the predicted values for the model. If assumptions 
are grossly violated, alternative analyses will be considered. 
• 
Section 14.6.6 outlines any transformation of data as needed. 
Model Results Presentation 
• 
The point estimate, two-sided 95% CI and p-value for the difference between treatment groups will 
be presented from all ANCOVA models for the superiority assessment. Superiority will be 
established if the p-value is <0.05. 
• 
Plot of hourly average ABPM will be created for SBP, DBP, MAP, and HR for both AC1 and AC2. 
• 
Change from pre-dose in SBP, DBP, HR, and MAP at each timepoint at Day 1 and Day 57will be 
summarized in a table. 
Sensitivity and Supportive Analyses 
• 
If more than 25% of subjects are excluded from the ABPM AUEC analysis because the subject is 
missing any of the 3 possible hour 24 ABPM measurements, then an extrapolation technique of 
average hour 23 measurement carried forward to hour 24 may be utilized as a sensitivity analysis for 
AUEC ABPM. 
o This will be only for the AC2 SBP, other sensitivity analyses may be considered. 
 
11.3. 
Exploratory Pharmacodynamic and Biomarker Analyses 
11.3.1. 
Endpoint / Variables 
Exploratory Objectives 
Exploratory Endpoints 
• 
To investigate the effect of 
daprodustat and epoetin alfa on 
vasoactive mediators of blood 
pressure 
• 
Plasma concentrations and derived parameters including 
Cmax, tmax, and AUC(0-24) as appropriate (to include 
erythropoietin, endothelin-1, nitric oxide, asymmetric 
dimethylarginine, renin, angiotensin-II and metabolites, 
and noradrenalin)  
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Exploratory Objectives 
Exploratory 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 Day 57 pre-dose 
• 
To compare the effect of daprodustat 
to epoetin alfa on SBP at Cmax of the 
study treatment 
• 
Change in SBP from pre-dose on Day 1 to Cmax of the 
study treatment on Day 1, as measured by ABPM 
• 
Change in SBP from pre-dose on Day 1 to Cmax of the 
study treatment on Day 57, as measured by ABPM 
• 
Change in SBP from pre-dose on Day 57 to Cmax of the 
study treatment on Day 57, as measured by ABPM 
• 
To compare the effect of daprodustat 
to epoetin alfa on SBP at Cmax of the 
erythropoietin level 
• 
Change in SBP from pre-dose on Day 1 to Cmax of 
erythropoietin on Day 1, as measured by ABPM 
• 
Change in SBP from pre-dose on Day 1 to Cmax of 
erythropoietin on Day 57, as measured by ABPM 
• 
Change in SBP from pre-dose on Day 57 to Cmax of 
erythropoietin on Day 57, as measured by ABPM 
11.3.1.1. 
Statistical Methodology Specification 
Endpoint / Variables 
• 
Cmax, tmax, and AUC(0-24) for erythropoietin, endothelin-1, nitric oxide, asymmetric 
dimethylarginine, renin, angiotensin-II and metabolites, and noradrenalin 
• 
AUEC of SBP, comparing Day 57 vs Day 1 
• 
Change in pre-dose SBP from Day 1 to Day 57 
• 
Change in SBP from pre-dose on Day 1 to Cmax of the study treatment on Day 1, as measured by 
ABPM 
• 
Change in SBP from pre-dose on Day 57 to Cmax of the study treatment on Day 1, as measured by 
ABPM 
• 
Change in SBP from pre-dose on Day 57 to Cmax of the study treatment on Day 57, as measured by 
ABPM 
• 
Change in SBP from pre-dose on Day 1 to Cmax of erythropoietin on Day 1, as measured by ABPM 
• 
Change in SBP from pre-dose on Day 57 to Cmax of erythropoietin on Day 1, as measured by 
ABPM 
• 
Change in SBP from pre-dose on Day 57 to Cmax of erythropoietin on Day 57, as measured by 
ABPM 
Overview of exploratory endpoints 
• 
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. Descriptive statistics (n, arithmetic mean, standard deviation, 
minimum, median, maximum) will be calculated for all biomarkers endpoints by regimen. In addition, 
for AUC, Cmax, tmax, baseline adjusted AUC and baseline adjusted Cmax; geometric means and 
geometric CVs (CVb(%)) will be calculated for each regimen. Geometric mean and geometric CV% 
will not be calculated for tmax. Line graphs of this information will be provided by treatment group for 
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each acute challenge. Cmax, tmax, AUC(0-24), baseline adjusted AUC and baseline adjusted Cmax 
will all be summarized by treatment arm and for each acute challenge day. 
• 
Change in AUEC of SBP from Day 57 to Day 1 for each treatment arm will be summarized in a table. 
• 
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. 
• 
For the following endpoints, an ANCOVA model will be used with terms for baseline SBP, treatment, 
and prior ESA dose (low/high): 
o 
Change in SBP from pre-dose on Day 1 to Cmax of the study treatment on Day 1, as measured 
by ABPM 
o 
Change in SBP from pre-dose on Day 57 to Cmax of the study treatment on Day 1, as 
measured by ABPM 
o 
Change in SBP from pre-dose on Day 57 to Cmax of the study treatment on Day 57, as 
measured by ABPM 
o 
Change in SBP from pre-dose on Day 1 to Cmax of erythropoietin on Day 1, as measured by 
ABPM 
o 
Change in SBP from pre-dose on Day 57 to Cmax of erythropoietin on Day 1, as measured by 
ABPM 
o 
Change in SBP from pre-dose on Day 57 to Cmax of erythropoietin on Day 57, as measured by 
ABPM 
Model Checking & Diagnostics 
• 
Distributional assumptions underlying the statistical analyses will be assessed by visual inspection of 
residual plots. Normality will be examined by normal probability plots, while homogeneity of variance 
will be assessed by plotting the residuals against the predicted values for the model. If assumptions 
are grossly violated, alternative analyses will be considered. 
Presentation of Exploratory Endpoints 
• 
Line graphs for each acute challenge and each biomarker by treatment group 
• 
Table summaries for AUEC of SBP, comparing Day 57 vs Day 1, and change in pre-dose SBP from 
Day 1 to Day 57 
• 
Plot of hourly average ABPM will be created for SBP, over-lay for both AC1 and AC2. 
• 
The point estimate, two-sided 95% CI and p-value for the difference between treatment groups will 
be presented from all ANCOVA models. 
 
 
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12. 
PHARMACOKINETIC / PHARMACODYNAMIC 
ANALYSES 
12.1. 
Primary Pharmacokinetic / Pharmacodynamic Analyses 
There are no primary Pharmacokinetic / Pharmacodynamic Analyses, only exploratory. 
The primary objective is Pharmacodynamic, the average systolic blood pressure (SBP) 
over 6-hr post-dosing after 8 weeks, this is described in Section 11. 
12.2. 
Secondary Pharmacokinetic / Pharmacodynamic Analyses 
There are no secondary Pharmacokinetic / Pharmacodynamic Analyses, only exploratory. 
The primary objective is Pharmacodynamic, the average systolic blood pressure (SBP) 
over 6-hr post-dosing after 8 weeks, this is described in Section 11. 
12.3. 
Exploratory Pharmacokinetic / Pharmacodynamic Analyses 
12.3.1. 
Endpoint / Variables 
• 
To investigate if an exposure-
response relationship exists between 
daprodustat and BP 
• 
The daprodustat exposure (AUC) compared to the AUEC 
of SBP, DBP, MAP, and HR at Day 1 and Day 57 
• 
To investigate if an exposure-
response relationship exists between 
daprodustat and biomarkers of 
interest 
• 
The daprodustat exposure (AUC) compared to the 
biomarker AUEC at Day 1 and Day 57. Biomarkers 
included erythropoietin, endothelin-1, nitric oxide, 
asymmetric dimethylarginine, renin, angiotensin-II (and 
metabolites), and noradrenalin.  
 
12.3.2. 
Summary Measure 
To investigate if an exposure-response relationship exists between daprodustat and 
average systolic blood pressure (SBP), the daprodustat exposure (AUC) and SBP, DBP, 
MAP and HR AUEC from Days 1 and 57 will be plotted to determine if further 
modelling is required. Similar plot analyses (daprodustat AUC vs. biomarker AUEC on 
Days 1 and 57) will be explored to determine if a daprodustat exposure-response 
relationships exist with: erythropoietin, endothelin-1, nitric oxide, asymmetric 
dimethylarginine, renin, angiotensin-II (and metabolites), and noradrenalin to determine 
if further modelling is deemed necessary. 
These figures will be created for Day 1 and Day 57 visits. The x-axis will be the AUC of 
Daprodustat for each subject and the y-axis will be the AUEC of either BP or biomarkers 
for that subject. The figures will be scatter plots. 
12.3.3. 
Population of Interest  
The exploratory Pharmacokinetic / Pharmacodynamic Analyses will be based on the PK 
population, unless otherwise specified. 
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12.3.4. 
Strategy for Intercurrent (Post-Randomization) Events 
Not required. 
12.3.5. 
Statistical Analyses / Methods 
Details of the planned displays are provided in Appendix 12: List of Data Displays and 
will be based on GSK Data Standards and statistical principles. 
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13. 
REFERENCES 
GlaxoSmithKline Document Number 2015N267693_04, GSK1278864, 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 (ASCEND-BP). 23-OCT-2019 
Iverson C, Christiansen S, Flanagin A, et al. AMA Manual of Style: A Guide for Authors 
and Editors. 10th ed. New York, NY: Oxford University Press; 2007. 
Rubin DB. Multiple Imputation for Nonresponse in Surveys.  John Wiley & Sons, 1987. 
 
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14. 
APPENDICES 
14.1. Appendix 1: Protocol Deviation Management and Definitions 
for Per Protocol Population 
14.1.1. 
Exclusions from Per Protocol Population 
A participant meeting any of the following criteria will be excluded from the Per Protocol 
population as detailed in the PDMP V5.0: 
Number 
Exclusion Description 
01 
Signed informed consent/assent not available on site 
02 
Wrong informed consent/assent version signed  
03 
Informed consent/assent not signed and/or dated by participant (parent/Legally Acceptable 
representative, if applicable)  
04 
Informed consent/assent not signed and/or dated by appropriate site staff.  
05 
Informed consent/assent not signed prior to any study procedure 
06 
Other informed consent/assent deviations 
07 
Meets Hgb stopping criteria 
08 
Receives a blood transfusion 
09 
Receives a kidney transplant 
10 
Becomes pregnant 
11 
Misses 2 consecutive dialysis sessions 
12 
Need for chronic use of prohibited medication 
13 
Myocardial infarction or acute coronary syndrome 
14 
Stroke or transient ischemic attack 
15 
New diagnosis of heart failure 
16 
Active chronic inflammatory disease that could impact erythropoiesis 
17 
Any new diagnosis of hematological disease 
18 
Active GI bleeding 
19 
Medication, excluded by the protocol, was administered* 
20 
Wrong study treatment or assignment administered 
21 
Assessment not properly performed* 
22 
Missed visit/phone contact* 
NOTES: 
• * Case by case basis. 
• The list may be updated to reflect any amendments to the PDMP 
 
 
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14.2. 
Appendix 2: Schedule of Activities 
14.2.1. 
Protocol Defined Schedule of Events 
 
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 of the 
protocol for additional details. 
 
 
 
 
 
 
 
 
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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 participants only 
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14.3. 
Appendix 3: Assessment Windows 
14.3.1. 
Definitions of Assessment Windows for Analyses 
Data for continuous variables will be summarized according to the scheduled visit time 
period for which they were recorded in the eCRF. Unscheduled assessments will not be 
slotted to a particular time point, but will remain as unscheduled if they are either 
summarized or listed unless otherwise specified. 
 
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14.4. 
Appendix 4: Study Phases and Treatment Emergent 
Adverse Events 
14.4.1. 
Study Phases 
Assessments and events will be classified according to time of occurrence relative to the 
treatment start and stop dates. 
Treatment 
States 
Treatment State 
Definition 
Pre-Treatment 
Date < Treatment Start Date 
On-Treatment 
Treatment Start Date <= Date ≤ Treatment Stop Date + 1 day 
Post-Treatment 
Date > Treatment Stop Date + 1 day 
NOTES:  
• 
If the treatment stop date is missing and the treatment start date is non-missing, then the assessment will be 
considered to be On-Treatment 
 
14.4.1.1. 
Study Phases for Concomitant Medication 
Pre-treatment medications are those taken (i.e., started) before the start date of 
randomized treatment. On-treatment medications are those taken (i.e., started or 
continued) at any time between the randomized treatment start date and the last non-zero 
dose date + 1 day, inclusive. Pre-treatment medications that were continued during this 
on-treatment period are also considered to be on-treatment medications. Post-treatment 
medications are those taken (i.e., started or continued) at any time after the last non-zero 
dose date + 1 day. On-treatment medications that were continued during this post-
treatment period are also considered to be post-treatment medications. 
It will be assumed that the medication has been taken on the date in which it is reported 
as started or stopped. Also, for any medication starting on the same date as randomized 
treatment, it will be assumed that the medication was taken after the participant started 
taking randomized treatment. 
Illustrations of the pre-treatment, on-treatment, and post-treatment treatment states are 
included below: 
 
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Pre-
treatment 
On-treatment 
Post-
treatment 
Pre-
treatment 
medicatio
n 
On-
treatment 
medicatio
n 
Post-
treatment 
medicatio
n 
(a) 
x⎯⎯x 
Randomized Treatment Start Date 
 
Last Non-zero Dose Date + 1 Day 
Last Non-zero Dose Date + 2 Days 
 
Y 
N 
N 
(b) 
x⎯⎯ 
⎯⎯x 
 
Y 
Y 
N 
(c) 
x⎯⎯ 
⎯⎯⎯ 
⎯⎯⎯x 
Y 
Y 
Y 
(d) 
 
x⎯⎯x 
 
N 
Y 
N 
(e) 
 
x⎯⎯ 
⎯⎯⎯x 
N 
Y 
Y 
(f) 
 
 
x⎯⎯x 
N 
N 
Y 
(g) 
?⎯⎯ x 
 
 
Y 
N 
N 
(h) 
?⎯⎯⎯ 
⎯⎯x 
 
Y* 
Y 
N 
(i) 
?⎯⎯⎯ 
⎯⎯⎯ 
⎯⎯⎯x 
Y* 
Y* 
Y 
(j) 
x⎯⎯⎯ 
⎯⎯⎯ 
⎯⎯⎯? 
Y 
Y** 
Y** 
(k) 
 
x⎯⎯ 
⎯⎯⎯? 
N 
Y 
Y** 
(l) 
 
 
x⎯⎯? 
N 
N 
Y 
(m) ?⎯ ⎯⎯ 
 
⎯⎯⎯  
 
⎯⎯⎯? 
Y*** 
Y*** 
Y*** 
(n) 
x⎯⎯⎯ 
x 
 
 
 
 
Y 
Y 
N 
(o) 
?⎯ ⎯⎯ 
x 
 
 
 
 
Y* 
Y 
N 
(p) 
 
x 
⎯⎯x 
 
 
 
N 
Y 
N 
(q) 
 
x 
⎯⎯⎯ 
x 
 
 
N 
Y 
N 
(r) 
 
 
 
x 
⎯ ⎯⎯⎯x 
N 
Y 
Y 
(s) 
 
 
 
x 
⎯ ⎯⎯⎯? 
N 
Y 
Y** 
(t) 
 
 
 
 
x 
⎯⎯⎯x 
N 
N 
Y 
(u) 
 
 
 
 
x 
⎯⎯⎯? 
N 
N 
Y 
(v) 
 
 
x⎯⎯ 
⎯ 
x 
 
N 
Y 
Y 
x = start/stop date of medication 
? = missing start/stop date of medication 
* If a medication is stopped On-treatment or Post-treatment and no start date is recorded it will be 
assumed that the medication was ongoing from the Pre-treatment phase 
** If a medication is started Pre-treatment or On-treatment and no stop date is recorded then 
usage will be assumed to be ongoing for the remainder of the study 
*** If a medication has no start or stop date it will be assumed that the medication was ongoing 
from the Pre-treatment phase to the Post-treatment phase 
 
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14.4.2. 
Treatment Emergent Flag for Adverse Events 
All AEs (non-serious AEs and serious AEs) will be collected and recorded on the eCRF 
from the start of treatment, including washout period, until the follow-up visit at the time 
points specified in the SoA from Appendix 2. Serious AEs assessed as related to study 
participation (e.g., study treatment, protocol-mandated procedures, invasive tests, or 
change in existing therapy) or related to a GSK product will be recorded on the eCRF 
from the time a participant consents to participate in the study up to and including any 
follow-up contact. 
Treatment State 
Definition 
Pre-treatment 
• 
For participants with a non-missing screen failure date, if AE onset is on or 
before the screen failure date: AE Start Date  Screen Failure Date 
• 
For randomized participants with a missing treatment start date, all AEs are 
considered pre-treatment 
• 
For randomized subjects with a non-missing treatment start date, if AE onset 
date is before treatment start date: AE Start Date < Treatment Start Date 
Post-
randomization 
If AE onset date or AE worsening date is on or after the randomization date 
Randomization date  AE Start Date 
Randomization date  AE Worsening Date 
Treatment 
emergent 
If AE onset date or AE worsening date is on or after treatment start date & on or 
before the last non-zero dose date plus 1 day. 
Treatment Start Date ≤ AE Start Date ≤ Last Non-Zero Dose Date + 1 day 
Treatment Start Date ≤ AE Worsening Date ≤ Last Non-Zero Dose Date + 1 day 
Follow-up 
If AE onset date or AE worsening date is after the last non-zero dose date plus 1 
day. 
AE Start Date > Last Non-Zero Dose Date + 1 day 
AE Worsening Date > Last Non-Zero Dose Date + 1 day 
Onset 
/Worsening Time 
Since 1st Dose 
(Days) 
If Treatment Start Date ˃ AE Onset Date = AE Onset Date - Treatment Start Date 
If Treatment Start Date ≤ AE Onset Date = AE Onset Date - Treatment Start Date 
+1 
If Treatment Start Date ˃ AE Worsening Date = AE Worsening Date - Treatment 
Start Date 
If Treatment Start Date ≤ AE Worsening Date = AE Worsening Date - Treatment 
Start Date +1 
Missing otherwise. 
Onset/Worsening 
Time Since Last 
Dose (Days) 
If Last Non-Zero Dose Date < AE onset date: AE onset date – last non-zero dose 
date 
If Last Non-Zero Dose Date  AE onset date: AE onset date – last non-zero dose 
date 
If Last Non-Zero Dose Date < AE worsening date: AE worsening date – last non-
zero dose date 
If Last Non-Zero Dose Date  AE worsening date: AE worsening date – last non-
zero dose date 
 
Missing otherwise. 
Duration (Days)  
AE Resolution Date – AE Onset Date/AE Worsening Date + 1 
Drug-related 
If relationship is marked ‘YES’ on eCRF or if the value is missing. 
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NOTES:  
• 
AEs that occur or worsen during interruptions of randomized study treatment will be classified as treatment 
emergent and post-randomization. 
• 
If the treatment stop date is missing and the treatment start date is non-missing and the AE onset date or AE 
worsening date is on or after the treatment start date, then the AE will be considered to be treatment emergent. 
• 
If AE onset date or AE worsening date is missing and AE resolution date is before the treatment start date, 
then the AE will be classified as Pre-treatment. 
• 
If AE onset date or AE worsening date is missing and AE resolution date is either missing or on or after 
treatment start date, then the AE will be classified as treatment emergent and post-randomization. 
 
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14.5. 
Appendix 5: Data Display Standards & Handling 
Conventions 
14.5.1. 
Reporting Process 
Software 
• 
The currently supported versions of SAS software, Version 9.2 (or higher) will be used for all 
analyses unless otherwise specified. Additionally, R Version 3.1.0 or higher may be used for analysis 
and the production of graphics. 
Reporting Area 
HARP Server 
: us1salx00259 
HARP Compound 
: gsk1278863/mid205665 
Analysis Datasets  
• 
Analysis datasets will be created according to clinical data interchange standards consortium 
(CDISC) standards: study data tabulation model (SDTM) implementation guide (IG) Version 3.1.3 
with some updates from Version 3.2, Analysis data model (ADaM) IG Version 1.1, and GSK ADaM 
specification template. 
• 
For creation of ADaM datasets (ADCM/ADAE), the same version of dictionary datasets will be 
implemented for conversion from system independent (SI) to SDTM. 
Generation of RTF Files 
• 
Rich text format (RTF) files will be generated for Tables. 
14.5.2. 
Reporting Standards 
General 
• 
The current GSK Integrated Data Standards Library (IDSL) will be applied for reporting, unless 
otherwise stated (IDSL Standards Location: 
https://spope.gsk.com/sites/IDSLLibrary/SitePages/Home.aspx): 
• 
4.03 to 4.23: General Principles 
• 
5.01 to 5.08: Principles Related to Data Listings 
• 
6.01 to 6.11: Principles Related to Summary Tables 
• 
7.01 to 7.13: Principles Related to Graphics  
• 
Do not include subject level listings in the main body of the GSK Clinical Study Report. All subject 
level listings should be located in the modular appendices as ICH or non-ICH listings 
• 
In all displays (TFLs) the term “Subjects” will be used to refer to the “Participants”. 
Formats 
• 
GSK IDSL Statistical Principles (5.03 & 6.06.3) for decimal places (DP’s) will be adopted for 
reporting of data based on the raw data collected, unless otherwise stated. 
• 
Numeric data will be reported at the precision collected on the eCRF. 
• 
The reported precision from non eCRF sources will follow the IDSL statistical principles but may be 
adjusted to a clinically interpretable number of DP’s. 
Planned and Actual Time 
• 
Reporting for tables, figures and formal statistical analyses: 
• 
Planned time relative to dosing will be used in figures, summaries, statistical analyses and 
calculation of any derived parameters, unless otherwise stated. 
• 
The impact of any major deviation from the planned assessment times and/or scheduled visit 
days on the analyses and interpretation of the results will be assessed as appropriate. 
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• 
Reporting for Data Listings:  
• 
Planned and actual time relative to study drug dosing will be shown in listings (Refer to IDSL 
Statistical Principle 5.05.1). 
• 
Unscheduled or unplanned readings will be presented within the subject’s listings.  
Unscheduled Visits 
• 
Unscheduled visits will not be included in summary tables, with the following exceptions: 
o If the table includes a row for all post-baseline assessments, unscheduled visits will be 
included in this row. All unscheduled visits will be included in listings. 
Descriptive Summary Statistics 
Continuous Data 
Refer to IDSL Statistical Principle 6.06.1 
Categorical Data 
N, n, frequency, % 
Graphical Displays 
• 
Refer to IDSL Statistical Principals 7.01 to 7.13. 
14.5.3. 
Reporting Standards for Pharmacokinetic 
Pharmacokinetic Concentration Data 
Descriptive Summary 
Statistics, Graphical 
Displays and Listings 
Refer to IDSL PK Display Standards. 
Refer to IDSL Statistical Principle 6.06.1. 
Note: Concentration values will be imputed as per GUI_51487 for descriptive 
summary statistics/analysis and summarized graphical displays only.  
Pharmacokinetic Parameter Derivation 
Descriptive Summary 
Statistics.                        
(Loge Transformed)   
N, n, geometric mean, 95% CI of geometric mean, standard deviation 
(SD) of log transformed data and %CVb will be reported. 
CVb (%) = √ (exp(SD2) - 1) * 100 
[NOTE: SD = SD of loge transformed data] 
Parameters Not Being 
Loge Transformed   
%AUCex and Tmax  
Summary Tables 
Cmax, Tmax, AUC(0-t), AUC (0-∞), t1/2, and %AUCex as data permit. 
The following PK parameters will not be summarised: first point, last 
point, and number of points used in the determination of λz. 
Listings 
Include PK Parameters Cmax, Tmax, AUC(0-t), AUC (0-∞), and t1/2 as 
data permit. Include the first point, last point and number of points used in 
the determination of λz. 
 
 
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14.6. 
Appendix 6: Derived and Transformed Data 
14.6.1. 
General 
Multiple Measurements at One Analysis Time Point 
• 
Mean of the measurements will be calculated and used in any derivation of summary statistics but if 
listed, all data will be presented. 
• 
If there are two values within a time window (as per Section 14.3.1) the value closest to the target 
day for that window will be used. If values are the same distance from the target, then the mean will 
be taken. 
• 
Participants having both High and Low values for Normal Ranges at any post-baseline visit for safety 
parameters will be counted in both the High and Low categories of “Any visit post-baseline” row of 
related summary tables. This will also be applicable to relevant Potential Clinical Importance 
summary tables. 
Treatment Day 
• 
Calculated as the number of days from treatment start date: 
• 
Treatment Start Date = Missing        → Treatment Day = Missing  
• 
Ref Date < Treatment Start Date      → Treatment Day = Ref Date – Treatment Start Date     
• 
Ref Data ≥ Treatment Start Date      → Treatment Day = Ref Date – (Treatment Start Date) + 1    
Randomization Date 
• 
Date subject was randomized 
Study Day 
• 
Calculated as the number of days from First Dose Date: 
• 
Ref Date = Missing                      → Study Day = Missing  
• 
Ref Date < Randomization Date → Study Day = Ref Date – Randomization Date 
• 
Ref Date ≥ Randomization Date → Study Day = Ref Date – (Randomization Date) + 1     
Study Completion/Withdrawal Date 
• 
Date of withdrawal for subjects withdrawing (i.e., subjects who actively withdraw or are deemed lost 
to follow-up) from study or date of completion of study for subjects who complete the study. 
• 
Early withdrawal subjects during washout will be calculated if the subject has a withdrawal date but 
no randomization date 
First Study Contact Date 
• 
First study contact with the subject while on the study is defined as consent date 
o If subject has been re-screened, latest consent date will be used 
Last Study Contact Date 
• 
Last study contact with subject (clinic, telephone or other contact with subject) with the subject while 
on the study 
 
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Time Definitions (per GSK standard principles) 
• 
1 week = 7 days 
• 
1 month = 30.4375 days 
• 
1 year = 365.25 days 
Last Non-Zero Dose Date 
• 
Date of last actual dose of randomized study treatment from the IP Discontinuation eCRF form. 
o The dose steps used by the dosing algorithm described in the protocol include a dose hold 
or a zero dose. If participants are assigned by the algorithm to a zero dose, they do not 
receive randomized treatment for that period. Hence, it would be possible for a participant 
to complete the study, while still following the dosing algorithm, but not actually taking any 
actual randomized treatment. The last non-zero dose date then captures the latest date in 
the study that a participant physically took a dose of randomized treatment. 
• 
The eCRF allows for the possibility of partial or missing dates to be recorded for the last actual dose 
of randomized study treatment on the IP Discontinuation form (i.e., missing day, or day and month, 
or day and month and year). In such a case, or in case of a missing IP Discontinuation form, the 
following conventions will be applied in order to impute a last non-zero dose date: 
o Missing day: 
▪ 
The last day of the month will be used, unless the treatment stop date also occurs 
in the same month; in this case, the treatment stop date will be used. 
o Missing day and month; 
▪ 
‘31’ will be used for the day and ‘Dec’ will be used for the month, unless the 
treatment stop date also occurs in the same year; in this case the treatment stop 
date will be used. 
o Missing day, month, and year: 
• 
Treatment stop date will be used only for participants who have a non-missing treatment start date. 
 
Screening and Washout visits 
Screening 
• 
Screening is an average of all screening values. For subject’s pre-protocol amendment 3, this is the 
average of the week -8 up to but not including the week -4 visits. For subject’s post-protocol amendment 
3, this is the average of the 7-30 days prior to week -2 visit but not including the week -2 visits. 
• 
Rescreened subjects data will only be counted once, the latest visit will only be summarized. 
Washout 
• 
Washout is the average of all washout visit values. For subject’s pre-protocol amendment 3, this is the 
average of the week -4 up to but not including the Day 1 visits. For subject’s post-protocol amendment 
3, this is the average of the week -2 up to but not including Day 1 visits 
 
Day 57 Repeat visits 
How to summarize data 
• 
For subjects with a repeat Day 57 visit, data such as vital signs and ECG will be summarized under the 
Day 57 table heading. 
o Day 57 data will be replaced with day 57 repeat visit data 
 
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14.6.2. 
Study Population 
Demographics 
Body Mass Index (BMI) 
• 
Calculated as Weight (kg) / [Height (m)]2 
Race Groups 
• 
Geographic ancestry data will be combined into categories as provided by the United States (US) Food 
and Drug Administration (FDA) and summarized as FDA race group: 
o American Indian or Alaskan Native 
o Asian (Asian-East Asian Heritage, Asian-Japanese Heritage, Asian-Central/South Asian 
Heritage, Asian-South East Asian Heritage, Asian-Mixed Race) 
o Black (African American/African Heritage) 
o Native Hawaiian or Other Pacific Islander 
o White (White-Arabic/North African Heritage, White-White/Caucasian/European Heritage, White 
– Mixed Race) 
o Mixed Race (Multiple races are selected, but excludes Asian – Mixed Race and White – Mixed 
Race) 
Note: Asian – Mixed Race includes subjects who have more than one Asian category selected, but no other 
categories. White – Mixed Race includes subjects who have more than one White category selected, but no 
other categories. 
 
Study Withdrawal 
• 
Time to Study Withdrawal (days) = Study withdrawal date – Randomization date +1 
• 
Time To Study Withdrawal (days), subjects withdrawn during washout = Study withdrawal date – Week -
2 Visit date +1, if subject was consented after protocol amendment 3 
• 
Time To Study Withdrawal (days), subjects withdrawn during washout = Study withdrawal date – Week -
4 Visit date +1, if subject was consented before protocol amendment 3 
 
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Treatment Compliance 
• 
Treatment compliance will be calculated based on the formula:   
o Daprodustat: 
▪ 
Compliance (%) = [(Total # of tablets actual taken) / (Total # of tablets planned 
taken)] * 100 
• 
Where: 
o Total # of tablets actual taken = Sum of (Numbers of Tablets Taken 
at Each Visit) 
o Total # of tablets planned taken = Sum of [(Treatment Stop Date – 
Treatment Start Date + 1 day) x Planned # of tablet / day in Each 
Visit] 
▪ 
Exclude any dose hold days from sum if able to calculate 
dose hold days. 
o rhEPO: 
▪ 
For rhEPO subjects, compliance will not be calculated since the data is not 
being collected. These subjects are dosed within the clinic during their visit. 
• 
Planned Treatment Duration is defined as day 1 to day 57 ( day 57 repeat if applicable) 
Extent of Exposure 
• 
Number of days of exposure to study drug will be calculated based on the formula: 
o Duration of Exposure in Days = Treatment Stop Date – (Treatment Start Date) + 1 
• 
Participants who were randomized but did not report a treatment start date will be categorised as having 
zero days of exposure. 
• 
The cumulative dose will be based on the formula: 
o Cumulative Dose = Sum of (Each dose taken recorded in the eCRF) 
 
14.6.3. 
Efficacy 
No Efficacy analyses being performed 
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14.6.4. 
Safety 
Adverse Events 
AEs of Special Interest 
Adverse events of special interest are classified as follows: 
• 
Death, MI, stroke, heart failure, PE, DVT, thromboembolic events, thrombosis of vascular access 
• 
Thrombosis and/or tissue ischemia secondary to excessive erythropoiesis 
• 
Cardiomyopathy   
• 
Pulmonary artery hypertension 
• 
Cancer-related mortality and tumor progression and recurrence  
• 
Esophageal and gastric erosions 
• 
Proliferative retinopathy, macular edema, choroidal neovascularization  
• 
Exacerbation of rheumatoid arthritis 
• 
Worsening of hypertension 
 
The above list text can be shortened for displays as follows: 
• 
Fatal, CV, and thromboembolic events 
• 
Excessive erythropoiesis sequelae 
• 
Cardiomyopathy   
• 
Pulmonary artery hypertension 
• 
Cancer progression or recurrence 
• 
Esophageal and gastric erosions 
• 
Retinal and choroidal neovascularization 
• 
Exacerbation of rheumatoid arthritis 
• 
Worsening of hypertension 
 
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Thrombosis and tissue ischemia events will be considered to be secondary to excessive 
erythropoiesis if during the window of [AE start date – 30 days, AE start date +15 days] any one of 
the following 3 events occurs: 
• 
Any Hgb value >= 13 g/dL (measured pre-dialysis) 
• 
Hgb increase > 2 g/dL over 2 weeks 
• 
Hgb increase > 4 g/dL over 4 weeks 
 
Note: Scheduled central laboratory Hgb values will be used, unless a scheduled central laboratory 
Hgb value is missing, in which case, a corresponding non-missing scheduled HemoCue Hgb value 
will be used. Unscheduled Hgb values will also be used in the assessment of secondary to 
excessive erythropoiesis as follows: 
• 
If an unscheduled central laboratory Hgb value and an unscheduled HemoCue Hgb value are on 
the same date, only the central laboratory Hgb value will be used. 
• 
If there is only one unscheduled Hgb value available on an individual date, then that value will 
be used regardless of the data source (i.e., either central laboratory or HemoCue). 
 
Potential AESIs will be identified through a pre-defined terms of interest process in which predefined 
lists of AE preferred terms corresponding with each AESI will be used to identify events 
considered to be potential AESIs. Sites will be prompted via query to complete any necessary 
additional information for these AESIs in the eCRF. 
 
For the category of thrombosis and/or tissue ischemia secondary to excessive erythropoiesis, after 
the terms of interest list has been applied, the additional Hgb criteria described above will be 
applied to identify only those events that are considered to be secondary to excessive 
erythropoiesis as meeting the AESI definition for thrombosis and/or tissue ischemia secondary to 
excessive erythropoiesis. 
General Definitions 
• 
For the analysis of the time to AE onset/worsening, if the AE onset/worsening date is missing then 
the time to AE onset/worsening will be counted as 1 day. 
 
Laboratory Parameters 
• 
If a laboratory value which is expected to have a numeric value for summary purposes, has a non-
detectable level reported in the database, where the numeric value is missing, but typically a character 
value starting with ‘<x’ or ‘>x’ (or indicated as less than x or greater than x in the comment field) is 
present, the number of significant digits in the observed values will be used to determine how much to 
add or subtract in order to impute the corresponding numeric value.  
o Example 1: 2 Significant Digits = ‘< x’ becomes x – 0.01 
o Example 2: 1 Significant Digit = ‘> x’ becomes x + 0.1 
o Example 3: 0 Significant Digits = ‘< x’ becomes x – 1     
• 
If a laboratory value which is expected to have a numeric value for summary purposes, has a non-
detectable level reported in the database, where the numeric value is missing, but typically a character 
value starting with ‘x’ or ‘x’ is present, then the corresponding numeric value will be set equal to x. 
• 
If there is more than one laboratory value on the same date for the same laboratory test, then the 
laboratory values associated with scheduled visits will be used. 
• 
The following will be used to convert laboratory values from SI units to conventional units if the 
specific lab value is not already in this format. [Iverson, 2007]: 
• 
Hemoglobin, MCHC and Albumin: Divide the g/L value by 10 to get the g/dL value. 
• 
Albumin-adjusted calcium: Divide the mmol/L value by 0.25 to get the mg/dL value. 
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• 
Phosphate: Divide the mmol/L value by 0.323 to get the mg/dL value. 
• 
Lab values that are converted will be reported in place of original value 
• 
Heart rate and pulse rate can be used interchangeably 
• 
Total calcium and calcium can be used interchangeably 
• 
Total protein and protein can be used interchangeably 
• 
Total bilirubin and bilirubin can be used interchangeably 
• 
TSAT and transferrin saturation can be used interchangeably 
• 
Baseline HGB will be based either on the pre-dose value on Day 1 or screening value. Any 
unscheduled HGB values taken after the pre-dose value on Day 1 will not be used. 
Normal Range Categories, PCI Criteria Categories and Worst Case Values 
• 
Normal range categories are: To Low, To Normal or No Change, To High 
• 
PCI criteria categories are: To Low, To w/in Range or No Change, To High 
• 
Subjects with a missing baseline value are to be assumed to have a normal/within range baseline 
value. 
• 
The determination of the worst-case post baseline value takes into account both planned and 
unscheduled assessments. 
• 
Worst case can be either High or Low.  
o If a subject has both a decrease ‘To Low’ and an increase ‘To High’, then the subject is 
counted in both the ‘To Low’ and ‘To High’ categories.  
o If a subject was High at baseline and decreases to Low during the time interval, then the 
subject is counted in the ‘To Low’ category. Likewise, if a subject was low at baseline and 
increases to high during the time interval, then the subject is counted in the ‘To High’ 
category. 
o Subjects are only counted in the ‘To Normal or No Change’ or ‘To w/in Range or No Change’ 
category if their values are: 
▪ 
When using normal ranges: Normal at baseline and have no high and no low values; 
When using PCI ranges: Within range at baseline and have no high and no low 
values 
▪ 
High at baseline and do not change to low 
▪ 
Low at baseline and do not change to high 
 
 
14.6.5. 
Pharmacokinetic 
 
Parameter 
Parameter Description 
AUC(0-) 
Area under the concentration-time curve from time zero to the end of the dosing 
interval , where =24 h will be calculated using the linear trapezoidal rule for 
each incremental trapezoid and the log trapezoidal rule for each decremental 
trapezoid. 
AUC(0-∞) 
Area under the concentration-time curve extrapolated to infinity will be calculated 
as:  
AUC = AUC(0-t) + C(t) / lambda_z (Day 1 only) 
Cmax 
Maximum observed concentration, determined directly from the concentration-
time data. 
tmax 
Time to reach Cmax, determined directly from the concentration-time data. 
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Parameter 
Parameter Description 
t½ 
Apparent terminal half-life will be calculated as:  
t½ = ln2 / lambda_z (Day 1 only) 
Percent drug related 
material (%DRM) 
For parent as well as each metabolite, where the denominator is the sum of the 
exposures of all analytes. The AUCs will be corrected for the molecular weight 
(MW) of each compound. 
Example: 
%DRMdaprodustat = 100* (AUCdaprodustat / MWdaprodustat) / ((AUCdaprodustat / 
MWdaprodustat) +(AUCM2 / MWM2) + (AUCM3 / MWM3) + (AUCM4 / MWM4) + (AUCM5 / 
MWM5) + (AUCM6 / MWM6) + (AUCM13 / MWM13)) 
 
Parameters to be used in this calculation are: 
Day 1: AUC(0-), AUC(0-∞) 
Day 57 AUC(0-) 
 
NOTES: 
• 
Additional parameters may be included as required. 
• 
Lambda_z is the terminal phase rate constant. 
 
Compound 
Molecular Weight (MW) (g/mol) 
daprodustat 
393.442 
M2 
425.442 
M3 
425.442 
M4 
425.442 
M5 
425.442 
M6 
425.442 
M13 
441.442 
 
 
 
 
14.6.6. 
Pharmacodynamic and Biomarker 
Pharmacodynamic and Biomarker 
ABPM Data 
• 
Only subjects whose ABPM data QC passes will be included in the PD TLFs 
• 
ABPM data will be recorded during the challenge agents on Day 1, Day 57, and repeat Day 57 if 
applicable. 
• 
The pre-acute challenge measurement will come from ABPM data if the first included ABPM 
measurement is within  10 min of the adjusted start time of the ABPM device. 
o Else, the pre-acute challenge measurement will be taken from the vitals dataset, post-
dialysis measurement only. This is for Day 1, Day 57, repeat Day 57. If day 1 is missing 
from the vitals dataset, then week-2 or screening can be used.  
▪ 
The time used for replacing excluded ABPM measurement with a vitals 
measurement will remain the adjusted start time of the ABPM device. 
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• 
If there is an additional ABPM data for Day 57, this means the subjects original Day 57 ABPM data 
failed QC and this data will not be included for any analysis 
• 
6, 8, 12, and 24-hour averages will be calculated using the following method: 
o Each hour will be averaged (up to 4 measurements per hour for the first 6 hours) 
o Then average the 6, 8, 12, and 24 hour measurements 
o This applies for ABPM data (SBP, DP, MAP, HR) 
o Missing or data that has been deemed not of good quality based on QC criteria, will be 
flagged with an excluded flag. These data will not be used when averaging ABPM. 
o This will be calculated for 6, 8, 12 and 24 hours 
o Example: 
• 
X represents missing data 
Hour 
ABPM 
 
 
1st 
Measurement 
2nd 
Measurement 
3rd 
Measurement 
4th Measurement 
Average 
0-1 
***, not used for 
average ABPM, 
being used as 
baseline BP 
value unless 
baseline comes 
from vitals 
112 
116 
115 
= 
(112+116+115)/3 
= 114.33 
1-2 
120 
118 
121 
X, missing 
= 
(120+118+121)/3 
= 119.67 
2-3 
120 
118 
121 
125 
= (120+118+121 
+ 125)/4 = 121 
3-4 
120 
118 
121 
125 
121 
4-5 
120 
118 
121 
125 
121 
5-6 
120 
118 
121 
125 
121 
6 Hour Average 
(114.33 
+119.67+121+121 
+121+121)/6 = 
119.67 
Post HD Pre Acute Challenge Variable 
• 
The Post HD Pre Acute Challenge Variable data point will come from the SBP/DBP/HR/MAP reading 
recorded from the ABPM data. The zero time, first recorded measurement from the ABPM device, 
will be used as the post HD pre acute challenge variable 
o If the data is missing from the ABPM data, the eCRF vital signs data will be used 
▪ 
Post-dialysis measurement will be used 
o If MAP variable is needed from eCRF, MAP will be calculated the following way: 
▪ 
MAP = (SBP + 2(DBP)) / 3 
Difference between post-HD/pre-Acute Challenge 2 and post-HD/pre-Acute Challenge 1 
Difference between post-HD/pre-Acute Challenge 2 and post-HD/pre-Acute Challenge 1  
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Pharmacodynamic and Biomarker 
= post-HD/pre- Acute challenge 2– post-HD/pre-Acute challenge 1  
• 
This applies for SBP, DBP, HR, and MAP 
AUEC Secondary Endpoints 
• 
Baseline, or time zero, for AUEC of ABPM data will be defined as the first ABPM measurement. If 
the first ABPM measurement is missing or excluded, then BP data from vitals will be used. 
o For these subjects, if the recorded time of vitals measurement is > 24 hours before the last 
ABPM measurement, then last ABPM measurement time is used in place of baseline time. 
• 
AUEC will be calculated using the linear trapezoidal rule for each incremental trapezoid and the log 
trapezoidal rule for each decremental trapezoid. 
• 
AUEC timepoints will be converted to be on the hourly scale 
o For example, if the second measurement is listed as 00:15, then this will be converted to 
the hourly scale of 0.25 
• 
The AUEC for ABPM will only be analysed if a subject has ABPM data up to hour 24. 
o For example if the subject has ABPM data up to hour 23, the subject will be excluded from 
the ABPM AUEC analysis. 
o If more than 25% of subjects are excluded from the ABPM AUEC analysis because the 
subject is missing any of the 3 possible hour 24 ABPM measurements, then an 
extrapolation technique of average hour 23 measurement carried forward to hour 24 may 
be utilized as a sensitivity analysis for AUEC ABPM. 
• 
If the AUEC data appears to be skewed, then the data will be log-transformed. Instead of reporting 
mean and standard deviation, the geometric mean and CV will be reported 
Change from pre-dose in SBP, DBP, HR, and MAP at each timepoint at Day 1 
• 
Each timepoint is defined as every 15 minutes for the first 6 hours, then every 20 minutes after. 
• 
The first measurement will be defined as pre-acute challenge and will not be used when calculating 
the averages. 
• 
The calculation will look like the following: 
o Change = Measurement – Pre-acute challenge measurement 
Hou
r 
Measuremen
t 1 Chg 
Measuremen
t 2 Chg 
Measuremen
t 3 Chg 
Measuremen
t 4 Chg 
Average 
0-1 
***, not used 
for average 
ABPM, being 
used as 
baseline BP 
value 
121-115=6 
122-115=7 
120-115=5 
(6+7+5)/3=6 
… 
 
 
 
 
 
5-6 
120-115=5 
121-115=6 
122-115=7 
missing 
(5+6+7)/3=6 
6-7 
120-115=5 
121-115=6 
122-115=7 
No data 
possible 
(5+6+7)/3=6 
… 
 
 
 
 
 
23-
24 
120-115=5 
121-115=6 
missing 
No data 
possible 
(5+6)/2=5.5 
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Pharmacodynamic and Biomarker 
Change from pre-dose at Day 1 
(6+…+6+6+…+5.5)/24=5.8
75 
 
• 
This will be calculated only for the Daprodustat treated arm and will be done for SBP, DBP, HR, and 
MAP on Day 1 
 
Pharmacodynamic and Biomarker 
Multiple Imputation 
• 
A sensitivity analysis will be performed on the primary endpoint to include those subjects who stop 
randomized treatment and those participants who fail any QC for their acute challenge. 
o The first group are those participants who stop randomized treatment. These participants 
will have their Day 57 6hr average SBP ABPM data imputed to assess what would have 
happened had the participant not stopped IP. Since these participants would have been 
randomized, there will be data for acute challenge 1, however acute challenge 2 data will 
need to be imputed. 
▪ 
Post-HD/pre-Acute Challenge 2 SBP will also be imputed. 
o The second group are those participants who have QC failed either their Day 1 or Day 57 
acute challenge, or QC failed both acute challenges. For this group no data imputation will 
be performed, instead the data that is available from the ABPM device will be used to 
calculate what the 6hr average is. 
▪ 
Like for the primary endpoint, post-HD/pre-Acute Challenge SBP will be taken from 
the first measurement on the ABPM device. If missing, then the vital signs BP will 
be used instead. 
 
• 
Multiple imputation for the first group, those participants who stop randomized treatment, will be 
done under the assumption of a multivariate normal distribution using the Markov Chain Monte Carlo 
(MCMC) procedure assuming missing at random. 
o Both the pre AC2 SBP and Day 57 6hr average SBP will be imputed 
o The first step will be to calculate the number of missing data points to see what the missing 
pattern is 
o Next the imputation phase will fill in values for the missing data points 
▪ 
Seed code of 205665 will be used 
▪ 
Burn in iterations and maximum iterations are set to default, 200 
▪ 
This will result in 1,000 imputations being calculated 
▪ 
Trace plots and autocorrelation figures will be used to assess the imputations 
▪ 
Variables to be included for imputation: 
• 
Day 1 6 hr average SBP from ABPM 
• 
Day 1 baseline SBP 
• 
Day 57 baseline SBP 
• 
Day 57 6 hr average SBP from ABPM 
• 
Add treatment and prior esa dose as by variables in proc mi 
o If there are error and or warning messages related to the by 
statement, try by randomized treatment only until no 
error/warning messages. 
• 
Next the imputed dataset will be used to calculate the difference between 
the pre AC1 and pre AC2 SBP, now using the imputed pre AC2 SBP. 
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Pharmacodynamic and Biomarker 
o The analysis phase will then calculate what the parameter estimates are using the same 
model as the primary endpoint, ANCOVA model with terms for treatment, prior ESA dose 
(low/high), pre AC1 SBP, difference between pre AC1 and pre AC2 SBP, and interaction of 
treatment and difference between pre AC1 and pre AC2 SBP. 
▪ 
if the interaction term in this model is significant at the 0.10 level, then the model 
will be an ANCOVA with terms for treatment, prior ESA dose (low/high), and pre 
AC1 SBP, just like the primary endpoint 
o The pooling phase will then pool all 1,000 model’s parameter estimates. 
• 
After the sensitivity analysis pooled parameter estimates are calculated, output will be compared with 
original non-imputed model (primary endpoint). 
o Day 57 6hr average SBP values will be computed and compared across treatment groups 
using the primary ANCOVA model described above. Rubin’s rules [Rubin, 1987] will be 
used to combine results of the imputed datasets using SAS PROC MIANALYZE procedure. 
As a result, a single estimated treatment difference and its standard error will be produced, 
with which a 95% CI will be calculated. 
o For each parameter, the estimate, 95% CI, and p-value will be compared 
o If the results of the primary endpoint differs when compared with this sensitivity analysis, 
then further secondary endpoint sensitivity analyses will be analysed in a similar fashion. 
Biomarker Derivations 
• 
Nitrate umol/L = Nitrite Total - Nitrite Endogenous 
o The Nitrate concentration is an indirect method to estimate Nitric Oxide. 
o Nitric Oxide label will be used in place of nitrate concentration 
 
• 
Geometric mean=exp (mean on loge scale) 
 
• 
CVb (%)=SQRT(exp(SD**2)-1)x100, where SD is the standard deviation of the loge-transformed 
data. 
• 
Natural Log-transformation, (Ln), of biomarker data will not be done for Tmax 
• 
AUC(baseline corrected) = Calculated AUC - (baseline level*time) 
o Where baseline level is defined as the pre-dose measurement for each visit 
o Where time is the last time measurement, for most subjects this would be 24 hours. 
o To be done on a by subject level then summarized by treatment for each visit 
• 
Cmax(baseline corrected) = Cmax - baseline level 
o Where baseline level is defined as the pre-dose measurement for each visit 
o To be done on a by subject level then summarized by treatment for each visit 
Parameter 
Parameter Description 
AUC(0-24) 
Area under the concentration-time curve from time zero to the time of the last 
quantifiable concentration (C(t)) will be calculated using the linear trapezoidal 
rule for each incremental trapezoid and the log trapezoidal rule for each 
decremental trapezoid. 
o If subject is missing pre-dose or 24-hour data, then exclude 
from AUC calculation. 
Cmax 
Maximum observed plasma concentration, determined directly from the 
concentration-time data. 
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Tmax 
Time to reach Cmax, determined directly from the concentration-time data. 
Exploratory endpoints 
• 
For exploratory endpoints utilizing ANCOVA models: 
o Baseline SBP data point will come from the SBP/DBP/HR/MAP reading recorded from the 
ABPM data. The zero time, first recorded measurement from the ABPM device, will be used 
as the post HD pre acute challenge variable as per the guidelines under ABPM data. 
▪ 
If the data is missing from the ABPM data, the eCRF vital signs data will be used 
• 
Post-dialysis measurement will be used 
▪ 
If MAP variable is needed from eCRF, MAP will be calculated the following way: 
▪ 
MAP = (SBP + 2(DBP)) / 3 
o Change from baseline will be defined as average of the BP from ABPM device, within  20 
min from tmax, minus the baseline SBP data point. 
▪ 
Discrete timepoints will be used 
▪ 
If no ABPM data is available with the  20 min window, then the calculated 
average will be marked as “.” to indicate missing since no ABPM data is available 
within that window. 
o If repeat day 57 data is available, then the Cmax data will be based on the non-repeat visit 
and the ABPM data will be based on the repeated visit. 
o If more than one tmax is listed for a given cmax, only the first tmax will be used. 
• 
For Daprodustat subjects, the tmax from treatment and the tmax from epoetin alfa data will be used 
• 
For rhEPO subjects, the tmax from epoetin alfa will be used for both endpoints analysing tmax of 
ABPM data. 
Plot of ABPM Data 
• 
Hourly average of each of the four ABPM measurements (SBP, DBP, MAP, and HR) for AC1 and 
AC2 will be generated for each subject 
o Hourly averages defined as follows: 
Hour 
Measurement 
1 
Measurement 
2 
Measurement 
3 
Measurement 
4 
Average 
0-1 
121 
115 
122 
120 
(121+115+122+120)/4 
=119.5 
… 
 
 
 
 
 
5-6 
121 
115 
122 
Missing 
(121+115+122)/3 
=119.3 
6-7 
121 
115 
122 
No data 
possible 
(121+115+122)/3 
=119.3 
… 
 
 
 
 
 
23-24 
120 
121 
missing 
No data 
possible 
(120+121)/2=120.5 
 
• 
The treatment arm averages of these hourly averaged subject values will then be plotted 
 
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14.7. 
Appendix 7: Reporting Standards for Missing Data 
14.7.1. 
Premature Withdrawals 
Element 
Reporting Detail 
General 
• 
Participant study completion (i.e. as specified in the protocol) was defined as a 
participant who has completed all phases of the study including the follow-up visit.  
• 
Participants that withdraw prior to the Acute Challenge 2 assessment or subjects who 
do not pass QC for Acute Challenge 2 will be replaced so that 25 participants per 
treatment arm complete and pass QC for Acute Challenge 2. 
• 
All available data from participants who were withdrawn from the study will be listed 
and all available planned data will be included in summary tables and figures, unless 
otherwise specified.  
• 
Withdrawal visits will be slotted as per Appendix 3: Assessment Windows or will be 
summarised as withdrawal visits. 
14.7.2. 
Handling of Missing Data 
Element 
Reporting Detail 
General 
• 
Missing data occurs when any requested data is not provided, leading to blank fields 
on the collection instrument: 
o These data will be indicated by the use of a “blank” in participant listing displays. 
Unless all data for a specific visit are missing in which case the data is excluded 
from the table.  
o Answers such as “Not applicable” and “Not evaluable” are not considered to be 
missing data and should be displayed as such. 
Outliers 
• 
Any participants excluded from the summaries and/or statistical analyses will be 
documented along with the reason for exclusion in the clinical study report. 
14.7.2.1. 
Handling of Missing and Partial Dates 
Element 
Reporting Detail 
General 
• 
Partial dates will be displayed as captured in participant listing displays. 
Adverse 
Events 
• 
The eCRF allows for the possibility of partial dates (i.e., only month and year) to be 
recorded for AE start and end dates; that is, the day of the month may be missing. In 
such a case, the following conventions will be applied for calculating the time to onset 
and the duration of the event: 
o Missing Start Day: First of the month will be used unless this is before the start 
date of study treatment; in this case the study treatment start date will be used and 
hence the event is considered On-treatment as per Appendix 4: Study Phases 
and Treatment Emergent Adverse Events. 
o Missing Stop Day: Last day of the month will be used, unless this is after the stop 
date of study treatment; in this case the study treatment stop date will be used. 
• 
Completely missing start or end dates will remain missing, with no imputation applied. 
Consequently, time to onset and duration of such events will be missing. 
Concomitant 
Medications/
Medical 
History 
• 
Partial dates for any concomitant medications recorded in the CRF will be imputed 
using the following convention: 
o If the partial date is a start date, a '01' will be used for the day and 'Jan' will be 
used for the month 
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Element 
Reporting Detail 
o If the partial date is a stop date, a '28/29/30/31' will be used for the day (dependent 
on the month and year) and 'Dec' will be used for the month. 
• 
The recorded partial date will be displayed in listings. 
 
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14.8. 
Appendix 8: Values of Potential Clinical Importance 
14.8.1. 
Laboratory Values 
Haematology 
Laboratory Parameter 
 
Units 
Category 
Clinical Concern Range 
Low Flag (< x) 
High Flag (>x) 
Hemoglobin 
G/DL 
 
<8.5 G/DL 
>11 G/DL 
Platelet Count 
GI/L 
 
< 80 GI/L 
> 500 GI/L 
Neutrophils 
GI/L 
 
< 0.5x LLRR 
  
Lymphocytes 
GI/L 
 
< 0.5x LLRR 
  
 
Clinical Chemistry 
Laboratory Parameter 
Units 
Category 
Clinical Concern Range 
Low Flag (< x) 
High Flag (>x) 
Potassium 
mmol/L 
 
> 0.5 mmol/L 
below LLRR 
> 1.0 mmol/L 
above ULRR 
Albumin 
g/dL 
 
< 3.0 g/dL 
> 5.5 g/dL 
AST (SGOT) 
IU/L 
 
  
>= 3x ULRR 
ALT (SGPT) 
IU/L 
 
  
>= 3x ULRR 
Calcium (Albumin adjusted) 
mg/dL 
 
< 7.48 mg/dL 
> 10.24 mg/dL 
Phosphate 
mg/dL 
 
< 2.50 mg/dL 
> 5.47 mg/dL 
Total bilirubin 
mol/L 
 
  
>= 2x ULRR 
Serum ferritin 
ng/mL 
 
< 100 ng/mL 
> 800 ng/mL 
TSAT 
% 
 
<15% 
> 40% 
Sodium 
mmol/L 
 
< 130 mmol/L 
> 150 mmol/L 
Glucose  
mmol/L 
 
<3.9 mmol/L 
>22 mmol/L 
 
14.8.2. 
Vital Signs 
Vital Sign Parameter 
(Absolute) 
Units 
Clinical Concern Range 
Lower 
Upper 
Systolic Blood Pressure 
mmHg 
<= 80 mmHg 
>= 160 mmHg 
Diastolic Blood Pressure 
mmHg 
<= 50 mmHg 
>= 100 mmHg 
Pulse Rate 
bpm 
<= 40 bpm 
>= 110 bpm 
Notes: 
• 
At visits where BP and HR are assessed more than once, the average of the values will be used to 
assess PCI criteria. 
• 
For participants who undergo in-clinic dialysis, the post-dialysis BP and HR values will be used to 
assess PCI criteria, unless otherwise specified. 
 
 
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14.9. 
Appendix 9: Population Pharmacokinetic (PopPK) Analyses 
PopPK is not evaluated for this study. The primary objective is Pharmacodynamic, the 
average systolic blood pressure (SBP) over 6-hr post-dosing after 8 weeks, this is 
described in Section 11. 
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14.10. 
Appendix 10: Pharmacokinetic / Pharmacodynamic 
Analyses 
PK/PD is not evaluated for this study. The primary objective is Pharmacodynamic, the 
average systolic blood pressure (SBP) over 6-hr post-dosing after 8 weeks, this is 
described in Section 11.  
 
 
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14.11. 
Appendix 11: Abbreviations & Trade Marks 
14.11.1. 
Abbreviations 
Abbreviation 
Description 
ABPM 
Ambulatory blood pressure monitoring 
AC 
Acute challenge 
ADaM 
Analysis Data Model 
AE 
Adverse Event 
AESI 
Adverse event of special interest 
AIC 
Akaike's Information Criteria 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
ANCOVA 
Analysis of covariance 
AST 
Aspartate aminotransferase 
AUC 
Area under curve 
AUEC 
Area under effect curve 
A&R 
Analysis and Reporting  
BP 
Blood pressure 
CDISC 
Clinical Data Interchange Standards Consortium 
CHF 
Chronic heart failure 
CHR 
Reticulocyte hemoglobin content 
CI 
Confidence Interval 
CKD 
Chronic kidney disease 
CPMS 
Clinical Pharmacology Modelling & Simulation 
CS 
Clinical Statistics 
CSR 
Clinical Study Report 
CTR 
Clinical Trial Register 
CVb / CVw 
Coefficient of Variation (Between) / Coefficient of Variation (Within) 
DBF 
Database Freeze 
DBP 
Diastolic blood pressure 
DBR 
Database Release 
DOB 
Date of Birth 
DP 
Decimal Places 
DR 
Dry run 
eCRF 
Electronic Case Record Form 
EMA 
European Medicines Agency 
ESA 
Erythropoiesis-stimulating agent 
FDA 
Food and Drug Administration 
FDAAA 
Food and Drug Administration Clinical Results Disclosure Requirements 
GSK 
GlaxoSmithKline 
HD 
Hemodialysis-dependent 
HR 
Heart rate 
IA 
Interim Analysis 
ICH 
International Conference on Harmonization 
IDMC 
Independent Data Monitoring Committee  
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Abbreviation 
Description 
IDSL 
Integrated Data Standards Library 
IMMS 
International Modules Management System 
IP 
Investigational Product 
ITT 
Intent-To-Treat 
MAP 
Mean arterial blood pressure 
MCH 
Mean corpuscular hgb 
MCHC 
Mean corpuscular hgb concentration 
MCV 
Mean corpuscular volume 
MI 
Myocardial Infarction 
MMRM 
Mixed Model Repeated Measures 
PCI 
Potential Clinical Importance  
PD 
Pharmacodynamic 
PDMP 
Protocol Deviation Management Plan 
PK 
Pharmacokinetic 
PP 
Per Protocol 
PopPK 
Population PK 
QC 
Quality Control 
QTcF 
Frederica’s QT Interval Corrected for Heart Rate 
QTcB 
Bazett’s QT Interval Corrected for Heart Rate 
RAP 
Reporting & Analysis Plan 
RAMOS 
Randomization & Medication Ordering System  
RC 
Reticulocyte count 
RDW 
Red blood cell distribution width 
SAC 
Statistical Analysis Complete 
SAE 
Serious adverse event 
SBP 
Systolic blood pressure 
SDSP 
Study Data Standardization Plan 
SDTM 
Study Data Tabulation Model 
SOP 
Standard Operation Procedure 
TA 
Therapeutic Area 
TFL 
Tables, Figures & Listings  
WBC 
White blood cell count 
14.11.2. 
Trademarks 
Trademarks of the GlaxoSmithKline 
Group of Companies 
 
Trademarks not owned by the 
GlaxoSmithKline Group of Companies 
None 
 
HemoCue 
 
 
SAS 
 
 
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14.12. 
Appendix 12: List of Data Displays 
14.12.1. 
Data Display Numbering 
The following numbering will be applied for RAP generated displays: 
Section 
Tables 
Figures 
Study Population 
1.01 to 1.19 
- 
Safety 
2.01 to 2.35 
- 
Pharmacokinetic 
3.01 to 3.2 
3.01 to 3.21 
Pharmacodynamic and Biomarker 
4.01 to 4.42 
4.01 to 4.12 
Pharmacokinetic / Pharmacodynamic 
- 
5.01-5.02 
Section 
Listings 
ICH Listings 
1 to 30 
Other Listings 
 
31 to 35 
 
All tables and figures will start with numbering scheme like “X.01, X.02, etc”. 
14.12.2. 
Mock Example Shell Referencing 
Non IDSL specifications will be referenced as indicated and if required example mock-up 
displays provided in Appendix 13: Example Mock Shells for Data Displays. 
 
Section 
Figure 
Table 
Listing 
Pharmacodynamic and Biomarker 
PDF1 
PDT1 - PDT10 
PDL1 
Pharmacokinetic / Pharmacodynamic 
PKPDF1 
- 
- 
NOTES:  
• 
Non-Standard displays are indicated in the ‘IDSL /  Example Shell’ or ‘Programming Notes’ column as ‘[Non-
Standard] + Reference.’ 
 
14.12.3. 
Deliverables 
Delivery 
Description 
DR 
Dry Run 
SAC 
Final Statistical Analysis Complete 
 
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14.12.4. 
Study Population Tables 
Study Population Tables 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
Subject Disposition 
1.1. 
Enrolled 
ES1 
Summary of Subject Status and Reason for Study Withdrawal 
ICH E3, FDAAA, EudraCT 
No sub reason 
DR, SAC 
1.2. 
ITT 
SD1  
Summary of Treatment Status and Reasons for Discontinuation 
of Study Treatment 
ICH E3 
No sub reason 
 
DR, SAC 
1.3. 
Screened 
PDT10 
Summary of Participant Disposition at Each Study Period 
ICH E3 
 
Add footnote: 
Withdrawn subjects may be greater 
than entered for no treatment due to 
subject’s first follow-up visit occurring 
after second screen failure. 
DR, SAC 
1.4. 
Screened 
ES6 
Summary of Screening Status and Reasons for Screen Failure 
Journal Requirements 
 
DR, SAC 
1.5. 
Enrolled 
NS1 
Summary of Number of Participant by Country and Site ID 
EudraCT/Clinical Operations 
DR, SAC 
Protocol Deviation 
1.6. 
ITT 
DV1 
Summary of Important Protocol Deviations 
ICH E3 
DR, SAC 
1.7. 
ITT 
IE1 
Summary of Inclusion/Exclusion Criteria Deviations 
ICH E3 
DR, SAC 
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Study Population Tables 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
Population Analysed 
1.8. 
Screened 
SP1 
Summary of Study Populations  
IDSL, all populations to be used 
(Screened, enrolled, safety, ITT, 
PP, PK) 
 
DR, SAC 
1.9. 
ITT 
SP2 
Summary of Exclusions from the Safety Population 
IDSL 
 
DR, SAC 
1.10. 
ITT 
SP2 
Summary of Exclusions from the Per Protocol Population 
IDSL 
 
DR, SAC 
Demographic and Baseline Characteristics 
1.11. 
ITT 
DM1 
Summary of Demographic Characteristics - ITT 
ICH E3, GSK CTR, FDAAA, EudraCT 
Footnote: Age is imputed from year and 
month of birth 
DR, SAC 
1.12. 
Safety 
DM1 
Summary of Demographic Characteristics - Safety 
ICH E3, GSK CTR, FDAAA, EudraCT 
Footnote: Age is imputed from year and 
month of birth 
DR, SAC 
1.13. 
Enrolled 
DM11 
Summary of Age Ranges 
EudraCT 
Footnote: Age is imputed from year and 
month of birth 
DR, SAC 
1.14. 
ITT 
DM5 
Summary of Race and Racial Combinations 
ICH E3, FDA, GSK CTR, FDAAA, 
EudraCT 
DR, SAC 
Prior and Concomitant Medications 
1.15. 
ITT 
MH1 
Summary of Medical Conditions 
ICH E3  
 
DR, SAC 
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Study Population Tables 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
1.16. 
ITT 
CM1 
Summary of Concomitant Medications (Pre-treatment) 
ICH E3 
 
DR, SAC 
1.17. 
ITT 
CM1 
Summary of Concomitant Medications (On-treatment) 
ICH E3 
 
DR, SAC 
1.18. 
ITT 
CM1 
Summary of Concomitant Medications (Post-treatment) 
ICH E3 
 
DR, SAC 
Exposure and Treatment Compliance 
1.19. 
Safety 
EX1 
Summary of Exposure and Compliance to Study Treatment 
ICH E3, add line for average percent 
compliant for each treatment group. 
Total column not needed. 
 
Add the following footnote if unable to 
calculate dose hold days: Compliance 
calculation assumed dose hold days 
and missed doses to be the same. 
 
Add footnote, daprodustat only, rhEPO 
done at site so no compliance to 
calculate 
 
DR, SAC 
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Study Population Tables 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
Additional Study Population Tables 
1.20. 
PP 
DM1 
Summary of Demographic Characteristics - PP 
ICH E3, GSK CTR, FDAAA, EudraCT 
Footnote: Age is imputed from year and 
month of birth 
 
Only produce if PP used in sensitivity 
analyses 
SAC 
 
14.12.5. 
Safety Tables 
Safety: Tables 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
Adverse Events (AEs) 
2.1.  
Safety 
AE1 
Summary of All Adverse Events by System Organ Class and 
Preferred Term 
 
ICH E3, by treatment, then summarized 
by pre-treatment, post-randomization, 
treatment emergent, and follow-up.  
 
DR, SAC 
2.2.  
Safety 
AE1 
Summary of All Adverse Events by System Organ Class and 
Preferred Term by Phase 
 
Treatment AEs will be separated by 
AC1, HGB maintenance, and AC2. 
 
DR, SAC 
2.3.  
Safety 
AE3 
Summary of Common (>=2%) Adverse Events by Overall 
Frequency 
ICH E3, by preferred term and 
treatment group, includes treatment 
emergent AEs 
 
DR, SAC 
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Safety: Tables 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
2.4.  
Safety 
AE5A 
Summary of Common (>=2%) Adverse Events by Maximum 
Intensity 
ICH E3, by treatment, includes 
treatment emergent AEs 
 
DR, SAC 
2.5.  
Safety 
AE1 
Summary of All Drug-Related Adverse Events by System Organ 
Class and Preferred Term 
 
ICH E3, by treatment, includes 
treatment emergent AEs 
 
DR, SAC 
2.6.  
Safety 
AE1 
Summary of All Serious Drug-Related Adverse Events by 
System Organ Class and Preferred Term 
 
By treatment, includes treatment 
emergent AEs  
DR, SAC 
2.7.  
Safety 
AE1 
Summary of All Non-Serious Drug-Related Adverse Events by 
System Organ Class and Preferred Term 
 
By treatment, includes treatment 
emergent AEs  
DR, SAC 
2.8.  
Safety 
AE15 
Summary of Common (>=2%) Non-serious Adverse Events by 
System Organ Class and Preferred Term (Number of Participant 
and Occurrences) 
FDAAA, EudraCT, by treatment group, 
includes treatment emergent AEs 
 
DR, SAC 
2.9.  
Safety 
AE5A 
Summary of Common (>=2%) Drug Related Adverse Events by 
Maximum Intensity 
ICH E3, by treatment group, includes 
treatment emergent AEs 
 
DR, SAC 
2.10. 
Safety 
AE5A 
Summary of All Adverse Events by System Organ Class and 
Preferred Term and Maximum Intensity 
ICH E3, by treatment, then summarized 
by pre-treatment, post-randomization, 
treatment emergent, and follow-up.  
 
SAC 
2.11. 
Safety 
AE1 
Summary of AEs of Special Interest 
By treatment 
SAC 
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Safety: Tables 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
Serious and Other Significant Adverse Events 
2.12. 
Safety 
AE16 
Summary of Serious Adverse Events by System Organ Class 
and Preferred Term (Number of Participants and Occurrences) 
FDAAA, EudraCT, by treatment, then 
summarized by pre-treatment, post-
randomization, treatment emergent, 
and follow-up. 
 
DR, SAC 
2.13. 
Safety 
AE1 
Summary of Adverse Events Leading to Permanent 
Discontinuation of Study Treatment or Withdrawal from Study by 
System Organ Class and Preferred Term 
IDSL, by treatment 
 
DR, SAC 
Laboratory: Chemistry  
2.14. 
Safety 
PDT9 
Summary of chemistry lab values 
ICH E3 
Includes: sodium, glucose, potassium, 
phosphate, calcium, ALT, AST, ALP, 
albumin, total protein, and total and 
indirect/direct bilirubin 
 
DR, SAC 
2.15. 
Safety 
LB1 
Summary of change from baseline in chemistry lab values  
ICH E3 
Includes: sodium, glucose, potassium, 
phosphate, calcium, ALT, AST, ALP, 
albumin, total protein, and total and 
indirect/direct bilirubin 
 
 
DR, SAC 
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Safety: Tables 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
Laboratory: Hematology 
2.16. 
Safety 
PDT9 
Summary of hematology lab values 
ICH E3 
Includes: platelets, WBC count, 
basophils, eosinophils, lymphocytes, 
monocytes, neutrophils, haematocrit, 
RDW, CHr, HGB, Mean Hemocue 
HGB, MCHC, RBC, Reticulocyte, MCH, 
MCV, neutrophils segmented 
 
Basophils/leukocytes (%), eosinophils/ 
leukocytes (%), lymphocytes/leukocytes 
(%), monocytes/ leukocytes (%), 
neutrophils/leukocytes (%), neutrophils 
segmented/ leukocytes (%) 
DR, SAC 
2.17. 
Safety 
LB1 
Summary of change from baseline in hematology lab values  
ICH E3 
Includes: platelets, WBC count, 
basophils, eosinophils, lymphocytes, 
monocytes, neutrophils, haematocrit, 
RDW, CHr, HGB, Mean Hemocue 
HGB, MCHC, RBC, Reticulocyte, MCH, 
MCV, neutrophils segmented 
 
Basophils/leukocytes (%), eosinophils/ 
leukocytes (%), lymphocytes/leukocytes 
(%), monocytes/ leukocytes (%), 
neutrophils/leukocytes (%), neutrophils 
segmented/ leukocytes (%) 
DR, SAC 
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Safety: Tables 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
Laboratory: Other Screening Tests 
2.18. 
Safety 
PDT9 
Summary of other screen test lab values 
ICH E3 
Includes: Serum hCG pregnancy test, 
Serum ferritin, Folate, Estradiol, Serum 
iron, Vitamin B12, FSH, Serum 
transferrin, UIBC, TSAT 
 
Display only screening visits, query DM 
if other parameters are found at 
screening 
DR, SAC 
2.19. 
Safety 
PDT9 
Summary of other screen test lab values, log transformed 
ICH E3 
Includes: Log transformed Serum 
ferritin and Serum iron 
 
Display only screening visits 
DR, SAC 
ECG 
2.20. 
Safety 
EG2 
Summary of ECG values 
IDSL 
Includes: QTc, QTcB, QRS duration, 
and PR interval 
 
ECG mean heart rate, QT interval, 
QTcF 
DR, SAC 
2.21. 
Safety 
EG2 
Summary of change from baseline in ECG values  
IDSL 
Includes: QTc, QTcB, QRS duration, 
and PR interval 
 
ECG mean heart rate, QT interval, 
QTcF 
DR, SAC 
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Safety: Tables 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
Vital Signs 
2.22. 
Safety 
PDT9 
Summary of vital signs values 
ICH E3 
Includes: temperature, heart rate, SBP, 
and DBP 
 
DR, SAC 
2.23. 
Safety 
VS1 
Summary of change from baseline in vital signs 
ICH E3 
Includes: temperature, heart rate, SBP, 
and DBP 
 
DR, SAC 
Additional Safety Tables 
2.24. 
Safety 
AE5A 
Summary of Adverse Events by System Organ Class and 
Preferred Term and Maximum Intensity 
ICH E3, by treatment, then summarized 
by pre-treatment, post-randomization, 
treatment emergent, and follow-up.  
 
SAC 
2.25. 
Safety 
LB17 
Summary of Worst Case Chemistry Results by PCI Criteria 
Post-Baseline Relative to Baseline 
 
SAC 
2.26. 
Safety 
LB17 
Summary of Worst Case Hematology Results by PCI Criteria 
Post-Baseline Relative to Baseline 
 
SAC 
2.27. 
Safety 
VS7 
Summary of Worst Case Vital Signs Results by PCI Criteria 
Post-Baseline Relative to Baseline 
 
SAC 
2.28. 
Safety 
EG1 
Summary of ECG Findings 
 
SAC 
2.29. 
Safety 
PAN1 
Summary of COVID-19 Assessment 
 
SAC 
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Safety: Tables 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
2.30. 
Safety 
PAN10 
Summary of Exposure Adjusted Incidence Rates Over Time 
 
SAC 
2.31. 
Safety 
PAN10 
Summary of Exposure Adjusted Incidence Rates Over Time by 
Region 
 
SAC 
2.32. 
Safety 
PAN10 
Summary of Exposure Adjusted Incidence Rates Over Time by 
Age 
 
SAC 
2.33. 
Safety 
PAN10 
Summary of Exposure Adjusted Incidence Rates Over Time by 
Gender 
 
SAC 
2.34. 
Safety 
PAN11 
Summary of Exposure Adjusted Incidence Rate for Common 
(>=5%) Adverse Events 
 
SAC 
 
 
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14.12.6. 
Pharmacokinetic Tables 
Pharmacokinetic: Tables 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
3.1.  
PK 
PK01 
Summary of  Daprodustat and Metabolite Plasma 
Concentrations (ng/mL) by Scheduled Time for Each Acute 
Challenge Day 
Have column for analyte (daprodustat, 
M2, M3, M4, M5, M6, M13) 
 
N, mean, sd, 95% CI, median, min, 
max 
DR, SAC 
3.2.  
PK 
PK04 
Summary of  Daprodustat and Metabolite Plasma 
Pharmacokinetic Parameters for Each Acute Challenge Day 
Paginate by analyte (daprodustat, M2, 
M3, M4, M5, M6, M13) 
 
N, mean, 95% CI, sd, median, min, 
max, geometric mean, 95% CI based 
on geometric mean, sd (ln), CV 
 
Include log transformed descriptive 
statistics 
 
 
DR, SAC 
 
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14.12.7. 
Pharmacokinetic Figures 
Pharmacokinetic: Figures 
No. 
Population 
IDSL / 
Example Shell Title  
Programming Notes 
Deliverable 
Individual Plots 
3.1.  
PK 
PK16A 
Individual Plasma Daprodustat Concentration-Time Plots – 
by Subjects and Acute Challenge Day (Linear and Semi-
Log) 
1. x-axis should display actual 
relative time  
2. Include line for LLQ with 
footnote defining LLQ value. 
3. Include values below LLQ. 
4. Can do both challenge days on 
one page by adding legends. 
 
Overlay of Day 1 and day 57 
DR, SAC 
3.2.  
PK 
PK16A 
Individual Plasma GSK2391220 (M2) Concentration-Time 
Plots – by Subjects and Acute Challenge Day (Linear and 
Semi-Log) 
Overlay of Day 1 and day 57 
DR, SAC 
3.3.  
PK 
PK16A 
Individual Plasma GSK2531403 (M3) Concentration-Time 
Plots – by Subjects and Acute Challenge Day (Linear and 
Semi-Log) 
Overlay of Day 1 and day 57 
DR, SAC 
3.4.  
PK 
PK16A 
Individual Plasma GSK2487818 (M4) Concentration-Time 
Plots – by Subjects and Acute Challenge Day (Linear and 
Semi-Log) 
Overlay of Day 1 and day 57 
DR, SAC 
3.5.  
PK 
PK16A 
Individual Plasma GSK2506102 (M5) Concentration-Time 
Plots – by Subjects and Acute Challenge Day (Linear and 
Semi-Log) 
Overlay of Day 1 and day 57 
DR, SAC 
3.6.  
PK 
PK16A 
Individual Plasma GSK2531398 (M6) Concentration-Time 
Plots – by Subjects and Acute Challenge Day (Linear and 
Semi-Log) 
Overlay of Day 1 and day 57 
DR, SAC 
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Pharmacokinetic: Figures 
No. 
Population 
IDSL / 
Example Shell Title  
Programming Notes 
Deliverable 
3.7.  
PK 
PK16A 
Individual Plasma GSK2531401 (M13) Concentration-
Time Plots – by Subjects and Acute Challenge Day 
(Linear and Semi-Log) 
Overlay of Day 1 and day 57 
DR, SAC 
Mean Plots 
3.8.  
PK 
PK17 
Mean ( SD) Plasma daprodustat Concentration-Time Plots 
(Linear and Semi-log) by Acute Challenge Day (Linear and 
Semi-Log) 
1. Include bars for SD. 
2. x-axis displays planned 
relative time. 
3. Include line for LLQ with 
footnote defining LLQ value. 
4. Can do both challenge days on 
one page by adding legends. 
 
Overlay of Day 1 and day 57 
DR, SAC 
3.9.  
PK 
PK17 
Mean ( SD) Plasma GSK2391220 (M2) Concentration-Time 
Plots (Linear and Semi-log) by Acute Challenge Day (Linear 
and Semi-Log) 
Overlay of Day 1 and day 57 
DR, SAC 
3.10.  
PK 
PK17 
Mean ( SD) Plasma GSK2531403 (M3) Concentration-Time 
Plots (Linear and Semi-log) by Acute Challenge Day (Linear 
and Semi-Log) 
Overlay of Day 1 and day 57 
DR, SAC 
3.11.  
PK 
PK17 
Mean ( SD) Plasma GSK2487818 (M4) Concentration-Time 
Plots (Linear and Semi-log) by Acute Challenge Day (Linear 
and Semi-Log) 
Overlay of Day 1 and day 57 
DR, SAC 
3.12.  
PK 
PK17 
Mean ( SD) Plasma GSK2506102 (M5) Concentration-Time 
Plots (Linear and Semi-log) by Acute Challenge Day (Linear 
and Semi-Log) 
Overlay of Day 1 and day 57 
DR, SAC 
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Pharmacokinetic: Figures 
No. 
Population 
IDSL / 
Example Shell Title  
Programming Notes 
Deliverable 
3.13.  
PK 
PK17 
Mean ( SD) Plasma GSK2531398 (M6) Concentration-Time 
Plots (Linear and Semi-log) by Acute Challenge Day (Linear 
and Semi-Log) 
Overlay of Day 1 and day 57 
DR, SAC 
3.14.  
PK 
PK17 
Mean ( SD) Plasma GSK2531401 (M13) Concentration-
Time Plots (Linear and Semi-log) by Acute Challenge Day 
(Linear and Semi-Log) 
Overlay of Day 1 and day 57 
DR, SAC 
Median Plots 
3.15.  
PK 
PK18 
Median (range) Plasma daprodustat Concentration-Time Plots 
(Linear and Semi-log) by Acute Challenge Day (Linear and 
Semi-Log) 
1. Include bars for range. 
2. x-axis displays planned 
relative time. 
3. Include line for LLQ with 
footnote defining LLQ value. 
4. Can do both challenge days on 
one page by adding legends. 
 
Overlay of Day 1 and day 57 
DR, SAC 
3.16.  
PK 
PK18 
Median (range) Plasma GSK2391220 (M2) Concentration-
Time Plots (Linear and Semi-log) by Acute Challenge Day 
(Linear and Semi-Log) 
Overlay of Day 1 and day 57 
DR, SAC 
3.17.  
PK 
PK18 
Median (range) Plasma GSK2531403 (M3) Concentration-
Time Plots (Linear and Semi-log) by Acute Challenge Day 
(Linear and Semi-Log) 
Overlay of Day 1 and day 57 
DR, SAC 
3.18.  
PK 
PK18 
Median (range) Plasma GSK2487818 (M4) Concentration-
Time Plots (Linear and Semi-log) by Acute Challenge Day 
(Linear and Semi-Log) 
Overlay of Day 1 and day 57 
DR, SAC 
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Pharmacokinetic: Figures 
No. 
Population 
IDSL / 
Example Shell Title  
Programming Notes 
Deliverable 
3.19.  
PK 
PK18 
Median (range) Plasma GSK2506102 (M5) Concentration-
Time Plots (Linear and Semi-log) by Acute Challenge Day 
(Linear and Semi-Log) 
Overlay of Day 1 and day 57 
DR, SAC 
3.20.  
PK 
PK18 
Median (range) Plasma GSK2531398 (M6) Concentration-
Time Plots (Linear and Semi-log) by Acute Challenge Day 
(Linear and Semi-Log) 
Overlay of Day 1 and day 57 
DR, SAC 
3.21.  
PK 
PK18 
Median (range) Plasma GSK2531401 (M13) Concentration-
Time Plots (Linear and Semi-log) by Acute Challenge Day 
(Linear and Semi-Log) 
Overlay of Day 1 and day 57 
DR, SAC 
 
 
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14.12.8. 
Pharmacodynamic and Biomarker Tables 
Pharmacodynamic and Biomarker: Tables 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
ABPM Summary Tables 
4.1.  
ITT 
PDT1 
Summary of ABPM SBP by Treatment Group and Visit 
 
DR, SAC 
4.2.  
ITT 
PDT1 
Summary of ABPM DBP by Treatment Group and Visit 
 
DR, SAC 
4.3.  
ITT 
PDT1 
Summary of ABPM HR by Treatment Group and Visit 
 
DR, SAC 
4.4.  
ITT 
PDT1 
Summary of ABPM MAP by Treatment Group and Visit 
 
DR, SAC 
Primary Endpoint 
4.5.  
ITT 
PDT3 
Summary of Analysis of Average 6hr ABPM SBP post-AC2 
Primary ANCOVA model output 
DR, SAC 
Secondary Endpoints 
4.6.  
ITT 
PDT3 
Summary of Analysis of Average 6hr ABPM SBP post-AC1 
Secondary ANCOVA model output 
DR, SAC 
4.7.  
ITT 
PDT3 
Summary of Analysis of Average 6hr ABPM DBP post-AC1 
Secondary ANCOVA model output 
DR, SAC 
4.8.  
ITT 
PDT3 
Summary of Analysis of Average 6hr ABPM MAP post-AC1 
Secondary ANCOVA model output 
DR, SAC 
4.9.  
ITT 
PDT3 
Summary of Analysis of Average 6hr ABPM HR post-AC1 
Secondary ANCOVA model output 
DR, SAC 
4.10. 
ITT 
PDT3 
Summary of Analysis of Average 6hr ABPM DBP post-AC2 
Secondary ANCOVA model output 
DR, SAC 
4.11. 
ITT 
PDT3 
Summary of Analysis of Average 6hr ABPM MAP post-AC2 
Secondary ANCOVA model output 
DR, SAC 
4.12. 
ITT 
PDT3 
Summary of Analysis of Average 6hr ABPM HR post-AC2 
Secondary ANCOVA model output 
DR, SAC 
4.13. 
ITT 
PDT4 
Summary of Analysis of AUEC SBP over 24hr post-AC1 
 
DR, SAC 
4.14. 
ITT 
PDT4 
Summary of Analysis of AUEC DBP over 24hr post-AC1 
 
DR, SAC 
4.15. 
ITT 
PDT4 
Summary of Analysis of AUEC MAP over 24hr post-AC1 
 
DR, SAC 
4.16. 
ITT 
PDT4 
Summary of Analysis of AUEC HR over 24hr post-AC1 
 
DR, SAC 
4.17. 
ITT 
PDT4 
Summary of Analysis of AUEC SBP over 24hr post-AC2 
 
DR, SAC 
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Pharmacodynamic and Biomarker: Tables 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
4.18. 
ITT 
PDT4 
Summary of Analysis of AUEC DBP over 24hr post-AC2 
 
DR, SAC 
4.19. 
ITT 
PDT4 
Summary of Analysis of AUEC MAP over 24hr post-AC2 
 
DR, SAC 
4.20. 
ITT 
PDT4 
Summary of Analysis of AUEC HR over 24hr post-AC2 
 
DR, SAC 
4.21. 
ITT 
PDT5 
Summary of change from pre-dose SBP 
At each timepoint on day 1 and day 57 
by treatment 
DR, SAC 
4.22. 
ITT 
PDT5 
Summary of change from pre-dose DBP 
At each timepoint on day 1 and day 57 
by treatment 
DR, SAC 
4.23. 
ITT 
PDT5 
Summary of change from pre-dose MAP 
At each timepoint on day 1 and day 57 
by treatment 
DR, SAC 
4.24. 
ITT 
PDT5 
Summary of change from pre-dose HR 
At each timepoint on day 1 and day 57 
by treatment 
DR, SAC 
Exploratory Endpoints 
4.25. 
ITT 
PDT6 
Summary of Change from Day 1 AUEC of 24hr SBP to Day 57 
AUEC of 24hr SBP 
 
DR, SAC 
4.26. 
ITT 
PDT7 
Summary of change from Day 1 pre-dose SBP to Day 57 pre-
dose 
 
DR, SAC 
4.27. 
ITT 
PDT3 
Summary of Analysis of change in SBP from pre-dose on Day 
1 to Cmax of the study treatment on Day 1, as measured by 
ABPM 
 
DR, SAC 
4.28. 
ITT 
PDT3 
Summary of Analysis of change in SBP from pre-dose on Day 
57 to Cmax of the study treatment on Day 1, as measured by 
ABPM 
 
DR, SAC 
4.29. 
ITT 
PDT3 
Summary of Analysis of change in SBP from pre-dose on Day 
57 to Cmax of the study treatment on Day 57, as measured by 
ABPM 
 
DR, SAC 
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Pharmacodynamic and Biomarker: Tables 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
4.30. 
ITT 
PDT3 
Summary of Analysis of change in SBP from pre-dose on Day 
1 to Cmax of erythropoietin on Day 1, as measured by ABPM 
 
DR, SAC 
4.31. 
ITT 
PDT3 
Summary of Analysis of change in SBP from pre-dose on Day 
57 to Cmax of erythropoietin on Day 1, as measured by ABPM 
 
DR, SAC 
4.32. 
ITT 
PDT3 
Summary of Analysis of change in SBP from pre-dose on Day 
57 to Cmax of erythropoietin on Day 57, as measured by 
ABPM 
 
DR, SAC 
Biomarker Concentration Table, Exploratory Endpoints 
4.33. 
ITT 
PK01 
Summary of Biomarker Plasma Concentration-Time Data 
 
DR, SAC 
Biomarker Derived Parameters, Exploratory Endpoints 
4.34. 
ITT 
PK06 
Summary of Derived Biomarker Plasma Parameters (Non-
Transformed)  
Parameters with units 
Include baseline adjusted AUC and 
CMAX 
DR, SAC 
4.35. 
ITT 
PK06 
Summary of Derived Biomarker Plasma Parameters (Ln-
Transformed)  
Parameters with units 
Include baseline adjusted AUC and 
CMAX 
DR, SAC 
Sensitivity Analyses 
4.36. 
PP 
PDT3 
Summary of Analysis of Average 6hr ABPM SBP post-AC2, 
Per Protocol 
Use PP population if at least 10% of 
the ITT population is excluded from PP 
population 
DR, SAC 
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Pharmacodynamic and Biomarker: Tables 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
4.37. 
ITT 
PDT8 
Summary of Analysis of Average 6hr ABPM SBP post-AC2, 
Imputed Data 
Use imputed missing values for AC2 
for early withdrawal subjects, calculate 
6hr averages for those subjects who 
failed QC for any AC. 
 
For subjects who AC2 failed QC, 6hr 
average SBP will be calculated without 
imputation 
DR, SAC 
4.38. 
ITT 
PDT3 
Summary of Analysis of Average 8hr ABPM SBP post-AC2 
 
DR, SAC 
4.39. 
ITT 
PDT3 
Summary of Analysis of Average 12hr ABPM SBP post-AC2 
 
DR, SAC 
4.40. 
ITT 
PDT3 
Summary of Analysis of Average 24hr ABPM SBP post-AC2 
 
DR, SAC 
4.41. 
ITT 
PDT4 
Summary of Analysis of AUEC SBP over 24hr post-AC2, 
Imputed Data 
• If more than 25% of subjects are 
excluded from the ABPM AUEC 
analysis then this sensitivity analysis 
will be performed for the AC2 SBP 
AUEC model 
• 
If during dry-run less than 25% 
of subjects are excluded, then 
table is not needed for dry-run 
SAC 
Additional PD tables 
4.42. 
ITT 
PDT10 
Summary of Subjects who QC Pass Acute Challenges 
Column by treatment, row by Day 1 
and Day 57, where Day 57 includes 
repeat AC2 
SAC 
 
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14.12.9. 
Pharmacodynamic and Biomarker Figures 
Pharmacodynamic and Biomarker: Figures 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
Secondary Endpoints 
4.1.  
ITT 
PDF1   
Mean (95% CI) Hourly ABPM SBP over 24hr post-AC1 
1. Include bars for 95% CI. 
2. x-axis displays planned relative 
time. 
3. Separate by treatment group 
DR, SAC 
4.2.  
ITT 
PDF1   
Mean (95% CI) Hourly ABPM DBP over 24hr post-AC1 
Same comments as Figure 4.1 
DR, SAC 
4.3.  
ITT 
PDF1   
Mean (95% CI) Hourly ABPM MAP over 24hr post-AC1 
Same comments as Figure 4.1 
DR, SAC 
4.4.  
ITT 
PDF1   
Mean (95% CI) Hourly ABPM HR over 24hr post-AC1 
Same comments as Figure 4.1 
DR, SAC 
4.5.  
ITT 
PDF1   
Mean (95% CI) Hourly ABPM SBP over 24hr post-AC2 
Same comments as Figure 4.1 
DR, SAC 
4.6.  
ITT 
PDF1   
Mean (95% CI) Hourly ABPM DBP over 24hr post-AC2 
Same comments as Figure 4.1 
DR, SAC 
4.7.  
ITT 
PDF1   
Mean (95% CI) Hourly ABPM MAP over 24hr post-AC2 
Same comments as Figure 4.1 
DR, SAC 
4.8.  
ITT 
PDF1   
Mean (95% CI) Hourly ABPM HR over 24hr post-AC2 
Same comments as Figure 4.1 
DR, SAC 
Exploratory Endpoints 
4.9.  
ITT 
PDF1   
Mean (95% CI) Hourly ABPM SBP over 24hr post-AC2 post-
AC1 comparison 
Same comments as Figure 4.1 
 
Overlay AC1 and AC2 on the same 
figure 
 
Page by treatment 
DR, SAC 
Individual Concentration Plots 
4.10. 
ITT 
PK16A 
Individual Biomarker Plasma Concentration-Time Plots (Linear 
and Semi-Logarithmic) 
Paginate by analyte 
DR, SAC 
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Pharmacodynamic and Biomarker: Figures 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
Mean / Median Concentration Plots 
4.11. 
ITT 
PK17 
Mean ( SD) Biomarker Plasma Concentration-Time Plots 
(Linear and Semi-Logarithmic) 
1. Include bars for SD. 
2. x-axis displays planned 
relative time. 
3. Include line for LLQ with 
footnote defining LLQ value. 
4. Paginate by analyte 
DR, SAC 
4.12. 
ITT 
PK18 
Median (range) Biomarker Plasma Concentration-Time Plots 
(Linear and Semi-Logarithmic) 
 
DR, SAC 
 
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14.12.10. Pharmacokinetic / Pharmacodynamic Figures 
Pharmacokinetic / Pharmacodynamic Figures 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
Secondary Endpoints 
5.1 
PK 
PKPDF1 
Scatterplot of Daprodustat AUC and BP AUEC 
Page by visit (Day 1, Day 57) and by 
BP (SBP, DBP, MAP, and HR) 
 
For Daprodustat subjects only 
 
SAC 
5.2 
PK 
PKPDF1 
Scatterplot of Daprodustat AUC and Biomarker AUEC 
Page by visit (Day 1, Day 57) and by 
Biomarker (erythropoietin, 
endothelin-1, nitric oxide, 
asymmetric dimethylarginine, renin, 
angiotensin-II (and metabolites), 
and noradrenalin.) 
 
For Daprodustat subjects only 
 
SAC 
 
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14.12.11. ICH Listings 
ICH: Listings 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
Subject Disposition 
1.  
Screened 
ES7 
Listing of Reasons for Screen Failure 
Journal Guidelines 
DR, SAC 
2.  
Enrolled 
ES2 
Listing of Reasons for Study Withdrawal 
ICH E3 
DR, SAC 
3.  
ITT 
SD2 
Listing of Reasons for Study Treatment Discontinuation 
ICH E3 
 
DR, SAC 
4.  
ITT 
TA1 
Listing of Planned and Actual Treatments 
IDSL 
 
DR, SAC 
Protocol Deviations 
5.  
ITT 
DV2 
Listing of Important Protocol Deviations  
ICH E3 
 
DR, SAC 
6.  
ITT 
IE3 
Listing of Participants with Inclusion/Exclusion Criteria 
Deviations 
ICH E3 
DR, SAC 
Populations Analysed 
7.  
Screened 
SP3 
Listing of Participants Excluded from Any Population 
ICH E3 
 
DR, SAC 
Demographic and Baseline Characteristics 
8.  
ITT 
DM2 
Listing of Demographic Characteristics 
ICH E3 
Footnote: Age is imputed from year 
and month of birth 
DR, SAC 
9.  
ITT 
DM9 
Listing of Race 
ICH E3 
DR, SAC 
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ICH: Listings 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
Prior and Concomitant Medications 
10.  
ITT 
CM10 
Listing of Concomitant Medications 
IDSL 
 
DR, SAC 
11.  
ITT 
CM6 
Relationship between ATC Level 1, 2, 3, Ingredient and 
Verbatim Text 
IDSL 
 
DR, SAC 
Exposure and Treatment Compliance 
12.  
Safety 
EX3 
Listing of Exposure and Treatment Compliance Data 
ICH E3, include % treatment 
compliance for each subject 
DR, SAC 
Adverse Events 
13.  
Safety 
AE8 
Listing of All Adverse Events - Safety 
ICH E3 
DR, SAC 
14.  
Enrolled 
AE8 
Listing of All Adverse Events - Enrolled 
ICH E3 
DR, SAC 
15.  
Safety 
AE7 
Listing of Subject Numbers for Individual Adverse Events 
ICH E3 
DR, SAC 
16.  
Safety 
AE2 
Listing of Relationship Between Adverse Event System Organ 
Classes, Preferred Terms, and Verbatim Text 
IDSL 
DR, SAC 
Serious and Other Significant Adverse Events 
17.  
Safety 
AE8 
Listing of Fatal Serious Adverse Events 
ICH E3 
 
DR, SAC 
18.  
Safety 
AE8 
Listing of Non-Fatal Serious Adverse Events 
ICH E3 
 
DR, SAC 
19.  
Safety 
AE14 
Listing of Reasons for Considering as a Serious Adverse Event 
ICH E3 
DR, SAC 
20.  
Safety 
AE8 
Listing of Adverse Events Leading to Withdrawal from Study / 
Permanent Discontinuation of Study Treatment 
ICH E3 
DR, SAC 
Hepatobiliary (Liver) 
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ICH: Listings 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
21.  
Safety 
MH2 
Listing of Medical Conditions for Participants with Liver 
Stopping Events 
IDSL 
DR, SAC 
22.  
Safety 
SU2 
Listing of Substance Use for Participants with Liver Stopping 
Events 
IDSL 
DR, SAC 
All Laboratory 
23.  
Safety 
LB5 
Listing of All Laboratory Data for Participants with Any Value of 
Potential Clinical Importance 
ICH E3 
Include abnormal ranges 
DR, SAC 
24.  
Safety 
LB5 
Listing of Laboratory Values of Potential Clinical Importance 
Include abnormal ranges 
DR, SAC 
25.  
Safety 
LB14 
Listing of Laboratory Data with Character Results 
ICH E3 
DR, SAC 
ECG 
26.  
Safety 
EG3 
Listing of All ECG Values for Participants 
IDSL 
 
DR, SAC 
27.  
Safety 
EG5 
Listing of All ECG Findings for Participants with an Abnormal 
ECG Finding 
IDSL 
 
DR, SAC 
28.  
Safety 
EG5 
Listing of Abnormal ECG Findings 
IDSL 
DR, SAC 
Vital Signs 
29.  
Safety 
VS4 
Listing of All Vital Signs Data for Participants with Any Value of 
Potential Clinical Importance 
IDSL 
 
DR, SAC 
30.  
Safety 
VS4 
Listing of Vital Signs of Potential Clinical Importance 
IDSL 
 
DR, SAC 
 
 
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14.12.12. Non-ICH Listings 
Non-ICH: Listings 
No. Population 
IDSL / Example 
Shell 
Title  
Programming Notes 
Deliverable 
 
31.  
ITT 
MH2 
Listing of Medical Conditions 
 
DR, SAC 
32.  
PK 
PK07 
Listing of Daprodustat and Metabolites Plasma 
Pharmacokinetic Concentration-Time Data  
Please list all the concentration 
data including unscheduled 
 
Have column for analyte 
(daprodustat, M2, M3, M4, M5, 
M6, M13) 
DR, SAC 
33.  
PK 
PK07 
Listing of Derived Daprodustat and Metabolites Plasma 
Pharmacokinetic Parameters  
Parameters with units 
 
Have column for analyte 
(daprodustat, M2, M3, M4, M5, 
M6, M13) 
DR, SAC 
Pharmacodynamic and Biomarkers 
34.  
ITT 
PDL1 
Listing of ABPM data 
 
DR, SAC 
35.  
ITT 
PK07 
Listing of Biomarker data 
 
DR, SAC 
 
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14.13. 
Appendix 13: Example Mock Shells for Data Displays 
Example mock shells for data displays are developed as separate documents. 
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