An Integrated Pharmacokinetic and Safety Open-label Basket Trial of Daprodustat for the Treatment of Anemia Associated With Chronic Kidney Disease in Male and Female Children and Adolescents Aged 3 Months to Under 18 Years Requiring or Not Requiring Dialysis
Phase: PHASE3
Conditions: Anaemia
Sponsor: GlaxoSmithKline

PROTOCOL AND PROTOCOL AMENDMENTS 
Protocol 214066 Amendment 02 dated 18-November-2022 
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GSK group of companies 
214066 
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TITLE PAGE 
Protocol Title: An Integrated Pharmacokinetic and Safety Open-label Basket Trial of 
Daprodustat for the Treatment of Anemia Associated with Chronic Kidney Disease in 
Male and Female Children and Adolescents Aged 3 Months to Under 18 Years Requiring 
or Not Requiring Dialysis. 
Protocol Number: 214066/Amendment 02 
Compound Number: GSK1278863 
Brief Title: Anemia Studies in CKD: Erythropoiesis via a Novel PHI Daprodustat - 
Pediatric (ASCEND-P) 
Study Phase: Phase 3a 
Acronym: ASCEND-P 
Sponsor Name and Legal Registered Address: 
GSK Research & Development Limited 
980 Great West Road 
Brentford 
Middlesex, TW8 9GS 
UK 
Regulatory Agency Identifying Number(s): 
IND 
101291 
EudraCT 
2021-002013-34 
Medical Monitor Name and Contact Information can be found in the Study 
Reference Manual 
Sponsor Signature: 
Dr Juliet Roberts 
Senior Clinical Development Director - Renal 
Approval Date: 18 Nov 2022 
©2022 GSK group of companies or its licensor. All rights reserved. 
Unauthorized copying or use of this information is prohibited. 
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PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE 
DOCUMENT HISTORY 
Document 
Date 
Document Identifier 
Amendment 02 
18 Nov 2022 
TMF-15144431 
Amendment 01 
22 June 2022 
TMF-14729908 
Original Protocol 
09 December 2021 
TMF-13909650 
Amendment 02 / 18 Nov 2022 
This amendment is considered to be substantial based on the criteria set forth in Article 
10(a) of Directive 2001/20/EC of the European Parliament and the Council of the 
European Union. 
Overall Rationale for the Amendment: 
The primary rationale for Amendment 02 is to include heart failure (HF) and 
esophageal/gastric erosions as adverse events of special interest (AESIs) following recent 
review of the clinical trial data in the adult daprodustat global development program. The 
description of the changes to the protocol by adding HF and esophageal/gastric erosions 
as an AESI are provided in the table below. Additional changes are to provide further 
clarity. A description and brief rationale for each change is provided in the table below. 
Section # and Name 
Description of Change 
Brief Rationale 
Section 2.3.1. Table 3 Risk 
Assessment 
Addition of HF and 
esophageal/gastric erosions as 
potential risk of clinical 
significance in Table 3, with a 
summary of the data/rational 
for risk and mitigation strategy. 
To add in HF and 
esophageal/gastric erosions 
as AESIs following recent 
review of the clinical trial data 
in the adult daprodustat global 
development program. 
Section 8.3.6. Adverse 
Events of Special Interest 
Addition of 2 new AESIs 
defined for this protocol 
To add in HF and 
esophageal/gastric erosions 
as AESIs following recent 
review of the clinical trial data 
in the adult daprodustat global 
development program 
Section 5.1. Inclusion Criteria Revision of wording of 
inclusion criterion 4, from 
acceptable method of 
contraception, to a highly 
effective method of 
contraception. 
To align with the wording in 
Appendix 10.4, as requested 
by a Regulatory Agency. 
Section 4.6. Hemoglobin 
Target Range and 
Frequency of Checks 
Revision to Table 11 for 
participants requiring 
temporary stop but already on 
the lowest dose step. 
To provide guidance on dose 
level for restart in these 
scenarios.  
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Section 8.4.1. Integrated PK 
Phase 
Addition of new reference. 
To refer to updated guidance 
on blood volume sampling in 
minors. 
Throughout protocol 
Minor editorial updates 
To correct spelling and 
formatting. 
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TABLE OF CONTENTS 
PAGE 
1.
PROTOCOL SUMMARY .......................................................................................... 7
1.1.
Synopsis ....................................................................................................... 7
1.2.
Schema ...................................................................................................... 11
1.3.
Schedule of Activities .................................................................................. 11
2.
INTRODUCTION .................................................................................................... 17
2.1.
Study Rationale .......................................................................................... 17
2.2.
Background ................................................................................................ 18
2.3.
Benefit/Risk Assessment ............................................................................ 19
2.3.1. 
Risk Assessment ......................................................................... 20
2.3.2. 
Benefit Assessment ..................................................................... 25
2.3.3. 
Overall Benefit: Risk Conclusion .................................................. 25
3.
OBJECTIVES, ENDPOINTS AND ESTIMANDS .................................................... 26
3.1.
Pharmacokinetic Estimand ......................................................................... 27
3.2.
Main Study Estimands ................................................................................ 28
4.
STUDY DESIGN .................................................................................................... 31
4.1.
Overall Design ............................................................................................ 31
4.2.
Scientific Rationale for Study Design .......................................................... 32
4.2.1.
Participant Input into Design ........................................................ 34
4.3.
Justification for Dose .................................................................................. 34
4.4.
Starting Dose .............................................................................................. 35
4.4.1.
Starting Dose in the 12 to <18 years Age Group: ......................... 35
4.4.2.
Starting Dose in the Younger Age Groups: .................................. 35
4.5.
Dose Adjustment Algorithm......................................................................... 37
4.5.1.
Dose Adjustment Algorithm in the 12 to <18 Years Age 
Group .......................................................................................... 37
4.5.2.
Dose Adjustment Algorithm in the Younger Age Groups .............. 37
4.6.
Hemoglobin Target Range and Frequency of Checks ................................. 40
4.7.
Role of the IDMC in Confirming the Dosing Strategy .................................. 42
4.8.
End of Study Definition ............................................................................... 43
5.
STUDY POPULATION ........................................................................................... 45
5.1.
Inclusion Criteria ......................................................................................... 45
5.2.
Exclusion Criteria ........................................................................................ 47
5.3.
Lifestyle Considerations .............................................................................. 49
5.4.
Screen Failures........................................................................................... 50
5.5.
Criteria for Temporarily Delaying Enrollment /Administration of 
Study Intervention ....................................................................................... 50
6.
STUDY INTERVENTION AND CONCOMITANT THERAPY .................................. 51
6.1.
Study Intervention Administered ................................................................. 51
6.2.
Preparation, Handling, Storage and Accountability ..................................... 54
6.3.
Measures to Minimize Bias: Randomization and Blinding ........................... 54
6.4.
Study Intervention Compliance ................................................................... 54
6.5.
Dose Modification ....................................................................................... 55
6.6.
Continued Access to Study Intervention after the End of the Study ............ 55
6.7.
Treatment of Overdose ............................................................................... 55
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6.8. 
Concomitant Therapy.................................................................................. 56
6.8.1.
Prohibited Medications ................................................................. 56
6.8.2.
Standard of Care, including Iron Management ............................. 57
6.8.3.
Rescue Therapy .......................................................................... 57
7.
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT
DISCONTINUATION/WITHDRAWAL ..................................................................... 59
7.1. 
Discontinuation of Study Intervention .......................................................... 59
7.1.1.
Liver Chemistry Stopping Criteria ................................................ 59
7.1.2.
QTc Stopping Criteria .................................................................. 61
7.1.3.
Temporary Discontinuation .......................................................... 61
7.1.4.
Rechallenge ................................................................................. 62
7.2.
Participant Discontinuation/Withdrawal from the Study ............................... 62
7.3.
Lost to Follow-Up ........................................................................................ 62
8.
STUDY ASSESSMENTS AND PROCEDURES ..................................................... 64
8.1.
Efficacy Assessments ................................................................................. 64
8.2.
Safety Assessments ................................................................................... 65
8.2.1.
Physical Examinations ................................................................. 65
8.2.2.
Vital Signs .................................................................................... 65
8.2.3.
Electrocardiogram ........................................................................ 65
8.2.4.
Clinical Safety Laboratory Tests .................................................. 66
8.2.5.
Pregnancy Testing ....................................................................... 66
8.3. 
Adverse Events (AEs), Serious Adverse Events (SAEs) and Other 
Safety Reporting ......................................................................................... 67
8.3.1.
Time Period and Frequency for Collecting AE and SAE 
Information ................................................................................... 67
8.3.2.
Method of Detecting AEs and SAEs ............................................. 67
8.3.3.
Follow-up of AEs and SAEs ......................................................... 68
8.3.4.
Regulatory Reporting Requirements for SAEs ............................. 68
8.3.5.
Pregnancy ................................................................................... 68
8.3.6.
Adverse Events of Special Interest .............................................. 69
8.3.7.
Tertiary Endpoints ........................................................................ 69
8.4.
Pharmacokinetics ....................................................................................... 70
8.4.1.
Integrated PK Phase .................................................................... 70
8.4.2.
Optional PK Sampling .................................................................. 71
8.5.
Genetics ..................................................................................................... 71
8.6.
Biomarkers ................................................................................................. 71
8.7.
Immunogenicity Assessments ..................................................................... 72
8.8.
Medical Resource Utilization and Health Economics .................................. 72
9.
STATISTICAL CONSIDERATIONS ........................................................................ 73
9.1.
Statistical Hypotheses................................................................................. 73
9.2.
Analysis Sets .............................................................................................. 73
9.3.
Statistical Analyses ..................................................................................... 74
9.3.1.
PK Analyses ................................................................................ 74
9.3.2.
Main Study Analyses ................................................................... 75
9.4.
Interim Analysis .......................................................................................... 77
9.4.1.
Integrated PK Phase .................................................................... 77
9.4.2.
Main Study ................................................................................... 78
9.5.
Sample Size Determination ........................................................................ 78
9.5.1.
Integrated PK Phase .................................................................... 78
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9.5.2. 
Main Study ................................................................................... 79
10. SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS ............................................................................................... 80
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations ............................................................................................ 80
10.1.1.
Regulatory and Ethical Considerations ........................................ 80
10.1.2.
Financial Disclosure ..................................................................... 81
10.1.3.
Informed Consent and Assent Process ........................................ 81
10.1.4.
Data Protection ............................................................................ 82
10.1.5.
Committees Structure .................................................................. 82
10.1.6.
Dissemination of Clinical Study Data ........................................... 82
10.1.7.
Data Quality Assurance ............................................................... 83
10.1.8.
Source Documents ...................................................................... 84
10.1.9.
Study and Site Start and Closure ................................................. 84
10.1.10. Publication Policy ......................................................................... 85
10.2. 
Appendix 2: Clinical Laboratory Tests ......................................................... 86
10.3. 
Appendix 3: AEs and SAEs: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting ....................................... 87
10.3.1.
Definition of AE ............................................................................ 87
10.3.2.
Definition of SAE .......................................................................... 88
10.3.3.
Recording and Follow-Up of AE and SAE .................................... 89
10.3.4.
Reporting of SAE to GSK ............................................................. 91
10.4.
Appendix 4: Contraceptive and Barrier Guidance ....................................... 93
10.4.1.
Definitions .................................................................................... 93
10.4.2.
Contraception Guidance .............................................................. 93
10.5.
Appendix 5: Liver Safety: Required Actions and Follow-up 
Assessments .............................................................................................. 95
10.6.
Appendix 6: Country-specific Requirements ............................................... 99
10.6.1. 
Country-Specific Requirements for Japan .................................... 99
10.7.
Appendix 7: Protocol amendment history .................................................. 101
10.8.
Appendix 8: Abbreviations and Trademarks .............................................. 107
11. REFERENCES ..................................................................................................... 112
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1.
PROTOCOL SUMMARY
1.1. 
Synopsis
Protocol Title:  
An Integrated Pharmacokinetic and Safety Open-label Basket Trial of Daprodustat for the 
Treatment of Anemia Associated with Chronic Kidney Disease in Male and Female 
Children and Adolescents Aged 3 Months to Under 18 Years Requiring or Not Requiring 
Dialysis. 
Brief Title:  
Anemia Studies in CKD: Erythropoiesis via a Novel PHI Daprodustat - Pediatric 
(ASCEND-P) 
Rationale: 
Anemia associated with chronic kidney disease (CKD) affects most children with 
moderate to advanced CKD, occurring in 58% of patients with CKD stage 2 and 
increasing to 93% in patients with CKD stage 5. As in adults, anemia results primarily 
from impaired erythropoietin production by the failing kidneys and can be treated by 
interventions that restore erythropoietin deficiency. 
Daprodustat has been extensively studied in adults for the treatment of anemia associated 
with CKD, demonstrating dose-dependent increases in hemoglobin (Hgb) in CKD 
patients who were not receiving erythropoiesis stimulating agent (ESA) therapy for their 
anemia, or the ability to effectively replace existing ESA therapy in CKD patients on 
prior stable therapy. Daprodustat has not been investigated in a pediatric population of 
renal anemia, where, despite available treatments of injectable ESA therapy and standard 
of care (SoC) iron supplementation, there remains an unmet medical need for alternative 
treatments. 
The purpose of this study is to investigate the pharmacokinetics (PK), safety and efficacy 
(Hgb response) of daprodustat in children (aged 3 months to 11 years) and adolescents 
(aged 12 to 17 years) with anemia of CKD in both ESA users and non-users.* 
Overall Design: 
This protocol describes 2 independent, prospective, interventional, open-label, single arm 
trials, evaluating PK (4 weeks), safety (52 weeks) and efficacy (Hgb response over 
52 weeks) of oral daprodustat in pediatric patients with CKD: 
•
not yet requiring dialysis (non-dialysis [ND]),
•
requiring dialysis (D).
* ESA users are defined as patients who received at least 1 dose of ESA in the 3 months (90 days) prior to
enrollment for the treatment of anemia associated with CKD. This includes patients on a “dose hold”
(zero dose) at the time of enrollment.
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Conducting separate trials in these 2 populations is a regulatory commitment. However, 
given that the 2 trials differ only in the degree of kidney function at entry and their 
dialysis status, the ND and D trials are presented as sub-trials (hereafter the ND and D 
sub-trial) in a master protocol. Trial stages, procedures, analyses and reporting will 
remain separate for the ND and D sub-trials unless otherwise specified. Operational 
aspects will be unified within the master protocol to promote efficiency, as shown in the 
figure below. 
Two Independent Sub-trials within a Master Protocol 
 Abbreviations: IDMC = independent data monitoring committee. 
Brief Summary: 
The purpose of this study is to investigate the PK, safety and efficacy (Hgb response) of 
daprodustat in pediatric participants aged 3 months to less than 18 years with anemia 
associated with CKD (who will be studied sequentially in 4 decreasing age groups: 12 to 
<18 years, 6 to <12 years, 2 to <6 years and 3 months to <2 years). 
All eligible participants will receive daprodustat for 52 weeks. PK assessments in the first 
4 weeks of dosing are required in the initially recruited subset of participants in each age 
group (Integrated PK Phase) for each sub-trial (ND/D). These participants, who undergo 
the Integrated PK Phase, continue seamlessly with further dosing in the sub-trial, but 
further recruitment of their age group and the opening up of recruitment in the next 
sequential younger age group is prohibited until the data (PK, safety and Hgb response) 
from each Integrated PK Phase is analyzed, and no concerns for continuing the study as 
planned are detected. 
Concomitant SoC therapy is permitted (with the exception of erythropoietin and its 
analogues), including iron supplementation at the discretion of the investigator to ensure 
iron replete status. 
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All participants who are approached for this study will already be participating in the 
prospective observational Cohort Study 212914, also running at the same trial sites. 
Participants will attend a study site visit at Screening and Day 1 (Baseline) before starting 
daprodustat (study intervention) at the end of Day 1 assessments. To allow flexibility, 
Screening and Day 1 Visits can be conducted up to 4 weeks apart but may also be 
performed on the same day. Blood tests for eligibility checked at Screening do not need 
to be repeated if the Day 1 Visit is performed within 7 days of the Screening Visit. After 
commencement of daprodustat, participants will be seen at Week 2 and Week 4 Visits to 
assess the initial safety and Hgb response to daprodustat. Further visits while participants 
remain on daprodustat are scheduled at 4-weekly intervals up to Week 28, then every 8 
weeks up to Week 52. There is a Follow-up Visit at Week 56, 4 weeks after the last dose 
of daprodustat. Between Weeks 28 to 52, an extra Hgb check visit should be undertaken 
if a dose change has been made and the next scheduled visit is not within 4 weeks. An 
unscheduled (UNS) visit (at any time during the study) may be conducted if, in the 
opinion of the investigator, the participant would benefit from additional monitoring of 
Hgb sooner than the next scheduled visit (within 4 weeks) and/or for other parameters or 
if there is a safety concern. 
Number of Participants: 
Overall, the study will enroll approximately 120 participants, aged 3 months to <18 years 
with anemia associated with CKD, divided equally across the 2 sub-trials (ND/D). Each 
of the 2 sub-trials will include 24 participants in their respective Integrated PK Phase, 
with a minimum of at least 4 participants required from each of the 4 age groups (12 to 
<18 years, 6 to <12 years, 2 to <6 years, 3 months to <2 years). 
Intervention Groups and Duration: 
All participants will receive oral daprodustat for a total of 52 weeks and will be followed 
for an additional 4 weeks after completing treatment. The lowest dose level defined 
(0.125 mg once daily [QD]) will be achieved by dosing 0.25 mg three times a week 
(TIW). All other dose steps involve QD dosing frequency. 
The initial starting dose is dependent on the participant’s Hgb at baseline, ESA and 
dialysis status. Dose adjustment, according to an age specific algorithm within the range 
0.125 mg to 24 mg QD equivalent, will be performed to achieve and maintain the Hgb 
within a target range. 
Data Monitoring Committee:  
An Independent Data Monitoring Committee (IDMC) will be utilized in this study. In this 
study, the IDMC is responsible for oversight of safety and specifically for: 
1.
confirming the dosing strategy in the younger age groups (based on comparison of
the actual PK data generated in the Integrated PK Phase of each sub-trial in each age
group versus that predicted by a physiological based pharmacokinetic [PBPK]
model, as well as review of available safety and Hgb data within this Phase and the
sub-trial at that time),
2.
permitting further recruitment in an age group once their Integrated PK Phase is
completed, and,
3.
allowing sequential recruitment to the younger age groups.
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Objectives and Endpoints: 
Objectives 
Endpoints 
Primary (Safety) 
•
Describe the safety of
daprodustat, overall (all
ages) and in each age
group.
•
Incidence of Adverse Events (AEs), Serious
Adverse Events (SAEs), Adverse Events of
Special Interest (AESIs), and AEs leading to
study intervention discontinuation.
Secondary Safety 
•
Describe changes in other
parameters relevant to
safety, overall and in each
age group.
•
Changes from baseline in laboratory safety
parameters, blood pressure (BP), heart rate (HR),
height and weight at each time point.
Secondary Efficacy 
•
Describe the effect of
daprodustat on Hgb, overall
and in each age group (and
additionally overall in all
ages by ESA use [yes/no]
at study enrollment).
At each study time point: 
•
Hgb value.
•
Hgb change from baseline.
•
Hgb above, below and within the target range (10
to 12 g/dL).
•
Describe the change in
required dose over time, in
each age group.
At each study time point: 
•
Daprodustat dose.
•
Daprodustat dose change from starting dose.
During the course of the study: 
•
Number of dose changes.
Secondary Pharmacokinetic 
•
Characterize the PK of
daprodustat in each age
group.
•
PK parameters: maximum plasma concentration
(Cmax) and Area Under the Curve (AUC) at
steady state.
•
Describe the systemic
exposure to daprodustat
metabolites M2, M3, M4,
M5, M6 and M13 in each
age group.
•
Plasma concentrations of each daprodustat
metabolite at pre-dose (trough) between Week 2
to Week 4, and corresponding Cmax if data permit.
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1.2. 
Schema 
Figure 1 
Schema of Study Design 
Abbreviations: m = months 
Figure 1A). Two parallel sub-trials are conducted, in the ND and D populations respectively. For each sub-trial, 
24 participants contribute to an integrated 4-week PK study which overlaps with the first 4 weeks of a 52-week, 
60-participant safety study. Thus, 60 participants are recruited overall to each sub-trial, of which 24 contribute to the
Integrated PK Phase.
Figure 1B). For each sub-trial, 4 age groups will be studied sequentially in the Integrated PK Phase: 12 to <18 years, 
6 to <12 years, 2 to <6 years and 3 months to <2 years. Twenty-four participants (with a minimum of at least 4 
participants from each age group) must complete this Integrated PK Phase. Further recruitment to that age group will 
pause until the IDMC agrees that further participants from that age group can be recruited and participants from the 
next younger age group can in turn commence enrollment to their Integrated PK Phase. Participants in the Integrated 
PK Phase continue dosing after Week 4 in the main study without interruption. 
1.3. 
Schedule of Activities 
The Schedule of Activities (SoA) is presented in Table 1. 
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Table 1 
Schedule of Activities 
Procedure 
Screening  
(-4 weeks 
to Day 1) 
Treatment Period 
Extra Hgb Check 
Visit 
Early 
Discontinuation 
from Study 
Intervention / 
Withdrawal Visit 
Follow
-up
Day 1 
Week  
2 
(± 3 
days) 
Week  
4 
(-7 to 
+2 
days)
Week  
8 
(-7 to 
+2 
days)
Week 
12 
(-7 to 
+2 
days)
Week 
16 
(-7 to 
+2 
days)
Week 
20 
(-7 to 
+2 
days)
Week 
24 
(-7 to 
+2 
days)
Week 
28 
(-7 to 
+2 
days)
Week 
36 
(-7 to 
+2 
days)
Week 
44 
(-7 to 
+2 
days)
Week 
52 
(-7 to 
+2 
days)
UNS at 
Any 
Time 
Day 1 to 
Week  
56 a 
4-weekly 
if needed
(Weeks
32, 40 & 
48) b 
Week 
56 
(-7 to 
+2 
days)
Informed consent 
X 
ELIGIBILITY ASSESSMENTS 
Inclusion and 
exclusion criteria 
X 
X 
Demography 
X 
Medical and 
treatment history 
X 
12-lead ECG c
X 
SAFETY ASSESSMENTS 
AE/SAE 
assessment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signs  
(BP, HR) d 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Height, weight e 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical exam 
X 
X 
X 
X 
X 
X 
X g 
X 
X 
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Procedure 
Screening  
(-4 weeks 
to Day 1) 
Treatment Period 
Extra Hgb Check 
Visit 
Early 
Discontinuation 
from Study 
Intervention / 
Withdrawal Visit 
Follow
-up
Day 1 
Week  
2 
(± 3 
days) 
Week  
4 
(-7 to 
+2 
days)
Week  
8 
(-7 to 
+2 
days)
Week 
12 
(-7 to 
+2 
days)
Week 
16 
(-7 to 
+2 
days)
Week 
20 
(-7 to 
+2 
days)
Week 
24 
(-7 to 
+2 
days)
Week 
28 
(-7 to 
+2 
days)
Week 
36 
(-7 to 
+2 
days)
Week 
44 
(-7 to 
+2 
days)
Week 
52 
(-7 to 
+2 
days)
UNS at 
Any 
Time 
Day 1 to 
Week  
56 a 
4-weekly 
if needed
(Weeks
32, 40 & 
48) b 
Week 
56 
(-7 to 
+2 
days)
Tanner staging 
X 
X 
X f 
LABORATORY ASSESSMENTS 
Hgb 
(full blood count) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X g 
X 
X 
X 
Iron parameters 
(TSAT, ferritin) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X g 
X g 
X 
X 
Creatinine, 
urea/BUN, 
potassium, 
sodium, calcium 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X g 
X g 
X 
X 
LFTs (+INR h) 
X 
X 
X 
X 
X 
X 
X 
X 
X g 
X g 
X 
X 
Pregnancy test 
(FOCBP only) i, l 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X g 
X g 
X 
X 
PK Sampling 
(Optional unless 
in the Integrated 
PK Phase) 
X j 
X k 
X k 
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Procedure 
Screening  
(-4 weeks 
to Day 1) 
Treatment Period 
Extra Hgb Check 
Visit 
Early 
Discontinuation 
from Study 
Intervention / 
Withdrawal Visit 
Follow
-up
Day 1 
Week  
2 
(± 3 
days) 
Week  
4 
(-7 to 
+2 
days)
Week  
8 
(-7 to 
+2 
days)
Week 
12 
(-7 to 
+2 
days)
Week 
16 
(-7 to 
+2 
days)
Week 
20 
(-7 to 
+2 
days)
Week 
24 
(-7 to 
+2 
days)
Week 
28 
(-7 to 
+2 
days)
Week 
36 
(-7 to 
+2 
days)
Week 
44 
(-7 to 
+2 
days)
Week 
52 
(-7 to 
+2 
days)
UNS at 
Any 
Time 
Day 1 to 
Week  
56 a 
4-weekly 
if needed
(Weeks
32, 40 & 
48) b 
Week 
56 
(-7 to 
+2 
days)
STUDY INTERVENTION 
IRT 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X g 
X 
X 
X 
Daprodustat 
dispensing 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X g 
X 
OTHER 
Blood transfusion/ 
iron supplement 
status 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Dialysis modality 
/transplant status 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant 
medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Acceptability and 
Palatability 
Questionnaire 
X 
Complete eCRF 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Abbreviations: AE = adverse events; BP = blood pressure; BUN = blood urea nitrogen; eCRF = electronic case report form; ECG = electrocardiogram; FOCBP = females of 
childbearing potential; Hgb = hemoglobin; HR = heart rate; INR = international normalized ratio; IRT = interactive response technology; LFT(s) = liver function test(s); PK = 
pharmacokinetics; rhEPO = recombinant human erythropoietin; SAE = serious adverse event; TSAT = transferrin saturation; UNS = Unscheduled Visit. 
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NOTE: 
•
All visit timings are relative to Day 1. Daprodustat will be dispensed to cover the visit period (plus permitted time window) at each dispensing visit. An IRT transaction will be
required to dispense daprodustat. Additional IRT transactions may occur to dispense additional daprodustat in case replacement is needed.
•
Blood tests for eligibility checked at Screening do not need to be repeated if the Day 1 Visit is performed within 7 days of the Screening Visit.
•
All Day 1 procedures will be before the first of dose of daprodustat, except for post dose PK sampling on Day 1 (which occurs at the end of Day 1 once a participant is confirmed
as eligible and is enrolled into the study). PK sampling is required for those participants in the Integrated PK Phase, otherwise PK sampling is optional.
a.
An unscheduled (UNS) /extra check Hgb Visit may be conducted at any time during the study if, in the opinion of the investigator, the participant would benefit from additional
monitoring of Hgb and/or other parameters if clinically indicated.
b.
From Week 28, an extra Hgb check Visit should be arranged 4 weeks after the last dose visit if:
•
At the last study visit:
o
there was a dose change
o
if dosing was temporarily withheld as Hgb >12.5 g/dL
o
a dose reduction was needed but the participant was on lowest dose already
•
Since the last study visit the following occurred:
o
a moderate CYP2C8 was prescribed
o
a rhEPO or analogue was given in error
o
a Hgb check performed outside of the study indicates a dose change is needed
•
In the opinion of the investigator the participant would benefit from continued 4-weekly Hgb checks:
o
as the Hgb is at the upper end of the target range
o
waiting 8 weeks for the next Hgb check is considered too long.
c. If prolonged QT/QTcF is noted, 2 additional ECG measurements should be obtained and the average QT/QTcF of the triplicate assessment used for eligibility determination. No
further ECG monitoring is required, unless as indicated as part of routine care of a participant, see Section 8.2.3.
d. BP and HR will be assessed with using an appropriate size cuff. BP and HR should be preceded by at least 5 minutes of rest for the participant in a quiet setting without
distractions. Three consecutive BP measurements will be obtained, of which the median will be recorded.
e. Height (or supine length in the very young) and weight will be measured as appropriate for the participant’s age and plotted on age and gender appropriate charts as per SoC at
the site, see Section 8.2.1.
f. Tanner Staging is not needed if early discontinuation from study intervention, only if an early study withdrawal visit.
g. If clinically indicated or required (IRT drug dispensing) at the extra UNS Visit (at any time during the study).
h. If liver monitoring is required after Day 1, INR should also be performed, see Section 7.1.1 and Section 10.5
i. Pregnancy tests will be conducted using urine, unless estimated Glomerular Filtration Rate (eGFR) ≤15 mL/min/1.73m2 when a serum human chorionic gonadotrophin (hCG) is
required.
j. A total of 3 samples to be collected at 0.5 to 1.5 hour, >1.5 to 3 hour, and ≥4 (maximum 8) hour time intervals after taking the first dose of daprodustat, which should be taken in
the clinic on Day 1, once the participant is confirmed as enrolled in the study having passed screening.
k. A total of 4 samples to be collected pre-dose, then at 3 time intervals post administration of the daprodustat dose (which should be taken in the clinic on that day) as follows: 0.5 to
1.5 hour, >1.5 to 3 hour, and ≥4 hour time (maximum 8 hour) intervals. It is recommended that the PK samples are taken at Week 2, but flexibility in collecting these 4 PK samples
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is allowed over the first 2 to 4 weeks provided each sample is collected at a different specified time interval]). If a participant has PK sampling deferred to Week 4, but is put on a 
dose hold at Week 2 (as the Hgb>12.5 g/dL), then the PK sampling should be delayed until the visit after daprodustat is restarted.
l. For Argentina ONLY: Pregnancy testing will be performed every 4 weeks for FOCBP as required by local law..
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2.
INTRODUCTION
2.1. 
Study Rationale
Anemia associated with chronic kidney disease (CKD) affects most children with 
moderate to advanced CKD, occurring in 58% of patients with CKD stage 2 and 
increasing to 93% in CKD stage 5 [Atkinson, 2010]. Data from the Chronic Kidney 
Disease in Children (CKiD) consortium indicate that once CKD stage 3b is reached 
(estimated glomerular filtration rate [eGFR] below 45 mL/min/1.73m2), hemoglobin 
(Hgb) declines by 0.3 g/dL for every further 5 mL/min/1.73m2 decline in glomerular 
filtration rate (GFR) [Fadrowski, 2008]. As in adults, anemia results primarily from 
impaired erythropoietin (EPO) production by the failing kidneys [Atkinson, 2018], 
although other factors associated with the uremic milieu such as iron deficiency and 
inflammation may be contributing factors. During fetal development, EPO synthesis 
occurs in both the liver and kidneys. Hepatic synthesis declines during the first trimester 
and ceases during the first few months of life [Dame, 2000], such that infants and 
children are dependent on renal EPO synthesis to maintain erythropoiesis. Anemia 
associated with CKD in children can be successfully treated by interventions that restore 
EPO deficiency [Fischbach, 2018]. 
Daprodustat: 
Daprodustat, a hypoxia-inducible factor (HIF) prolyl hydroxylase inhibitor (PHI), holds 
promise as a novel treatment to correct Hgb in the treatment of anemia associated with 
CKD. Daprodustat stimulates erythropoiesis through the inhibition of HIF-prolyl-4-
hydroxylases, PHD1, PHD2 and PHD3, resulting in nuclear accumulation of HIFα and 
increased transcription of HIF-responsive genes including EPO. 
Daprodustat has been extensively studied in 5338 adults in clinical trials to date for the 
treatment of anemia associated with CKD, including a comprehensive Phase 3 program 
and additionally has been licensed (June 2020) and commercially available since August 
2020 in Japan for the treatment of anemia in adult patients with CKD, both on dialysis 
and not on dialysis. 
In the adult CKD studies conducted to date, daprodustat has produced either dose-
dependent increases in Hgb in patients who were not receiving recombinant human 
erythropoietin (rhEPO), an erythropoiesis stimulating agent (ESA) therapy for their 
anemia, or has demonstrated the ability to effectively replace existing ESA in patients 
who were on prior stable rhEPO therapy. Overall, treatment with daprodustat has been 
well tolerated. The most frequent (≥10%) adverse events (AEs) reported in completed 
adult trials with daprodustat were hypertension, urinary tract infection, and peripheral 
odema in participants not on dialysis; and hypertension, diarrhea and dialysis hypotension 
in participants on dialysis. 
Whilst daprodustat has been extensively evaluated in an adult population with anemia of 
CKD, both requiring and not requiring dialysis, no studies have been conducted in 
patients <18 years of age. Therefore, there is a need to generate data in children and 
adolescents to confirm the safety of daprodustat and determine an appropriate dose 
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strategy (starting and maintenance dose) based on the results of pediatric 
pharmacokinetic (PK) data and exposure-response knowledge and modelling from the 
adult program. In this study a lower age boundary of 3 months will be used. 
2.2. 
Background 
The definition of anemia in children is not straightforward. In contrast to adults with 
CKD, where a fixed cut-off value for Hgb level of <11.0 g/dL has been used to define 
anemia, the Hgb concentration values that define anemia in children are dependent on age 
and sex. The Kidney Disease: Improving Global Outcomes (KDIGO) clinical practice 
guidelines [KDOQI, 2006] for anemia uses World Health Organization (WHO) age 
specific Hgb values to define anemia in children with CKD. An alternative source for 
normative Hgb values is the National Health and Nutrition Examination Survey 
(NHANES) III data [Hollowell, 2005], which reports age and sex specific fifth percentile 
values; these levels are used by the National Kidney Foundation Kidney Disease 
Outcomes Quality Initiative (NKF-KDOQI) to define anemia, see Table 2. 
Table 2 
KDIGO and NKF-KDOQI Guidelines Age Definition of Renal Anemia 
KDIGO guidelines  
(based on WHO normative values) 
NKF-KDOQI guidelines  
(based on NHANES III normative values 
– 5th percentile)
Age (years) 
Hgb value (g/dL) 
Age (years) 
Hgb value (g/dL) 
Males 
Females 
Males 
Females 
0.5 to <5 
<11.0 
<11.0 
1-2
10.7 
10.8 
5 to <12 
<11.5 
<11.5 
3-5
11.2 
11.1 
12 to <15 
<12.0 
<12.0 
6-8
11.5 
11.5 
>15
<13.0 
<12.0 
9-11
12.0 
11.9 
12-14
12.4 
11.7 
15-19
13.5 
11.5 
While KDIGO guidelines for treatment of anemia in children with CKD specifically 
avoid recommending a target Hgb level at which to initiate an ESA, KDOQI guidelines 
suggest initiating treatment at a Hgb concentration <11.0 g/dL. This level is also 
recommended by the European Pediatric Peritoneal Dialysis Working Group (EPPWG) 
with the rationale of improved quality of life and survival. 
Observational studies relate Hgb levels to mortality, where an elevated risk of mortality is 
present when Hgb levels are <9.9 g/dL compared with levels >9.9 g/dL (adjusted 
Relative Risk [RR] 1.52; 95% Confidence Interval [CI] 1.03 to 2.26 p<0.05) [Warady, 
2003]. Additionally, ESA therapy to maintain Hgb level >10 g/dL was associated with 
improved cardiac index, reduction in left ventricular hypertrophy and improved exercise 
tolerance [Morris, 1994]. The EPPWG does not recommend an upper limit for Hgb level, 
while NKF-KDOQI has most recently suggested that Hgb level should be 11 to 12 g/dL 
[Keithi-Reddy, 2009].  
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Current treatment and unmet medical need: 
To date, treatment of CKD associated anemia has relied on iron supplementation, blood 
transfusion and rhEPO, all of which have important limitations in childhood. Iron 
administration is often necessary to optimize rhEPO therapy [Atkinson, 2011], but oral 
supplements are associated with gastrointestinal (GI) side effects and intravenous (IV) 
infusions are time and resource intensive and may result in infusion reactions [Auerbach, 
2010]. Blood transfusion increases the risk of transplant sensitization and may limit 
access to transplantation. Furthermore, rhEPO requires frequent injections that are 
traumatic to the young [McLenon, 2019] and results in circulating EPO concentrations 
above the physiological range. Therefore, there is an unmet need for alternative 
treatments for renal anemia. 
Daprodustat may confer advantages over rhEPO or its analogues. It is an oral medication, 
hence, avoids the need for regular injections that is inherent to rhEPO therapy, and unlike 
rhEPO, does not require cold-chain storage, which can pose a logistical challenge in 
some healthcare regions.  
2.3. 
Benefit/Risk Assessment 
Summaries of findings from both clinical and non-clinical studies conducted with 
GSK1278863 (daprodustat) can be found in the Investigator’s Brochure (IB). Table 3 and 
the following section outlines the risk assessment and mitigation strategy for this 
protocol. 
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2.3.1. 
Risk Assessment 
Table 3 
Risk Assessment 
Potential Risk 
of Clinical 
Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
Study Intervention (Daprodustat) 
Excessive 
erythropoiesis 
leading to 
thrombosis and/or 
tissue ischemia 
In animal studies, excessive erythropoiesis (Hgb/hematocrit > upper limit normal) attributed to daprodustat 
was associated with vascular congestion, microthrombi, and tissue ischemia in a number of organs. 
In the Phase 2 proof of concept study, a high incidence of discontinuation due to Hgb stopping criteria 
(Hgb >13.5 g/dL or Hgb increased >1 g/dL over any 2-week period) was observed. In non-dialysis (ND) 
participants administered 10 mg, 25 mg, 50 mg or 100 mg of daprodustat daily, a total of 21 of 61 participants 
(34%) met these criteria. In hemodialysis (HD) dependent participants administered either 10 mg or 25 mg of 
daprodustat daily, a total of 8 of 31 participants (26%) met these criteria. 
Phase 2 dose-ranging studies and associated statistical and dose response modelling has informed Phase 3 
dose rationale, starting doses, dose steps, and dose adjustment scheme to optimize Hgb management. 
Integrated AE data including 2 global Phase 3 cardiovascular outcomes studies (200807/ASCEND-D and 
200808/ASCEND-ND): Few participants experienced a possible thrombosis-related AE in the setting of 
excessive erythropoiesis (25/3419 [0.7%] participants on daprodustat vs. 14/3407 [0.4%] on rhEPO; relative 
risk [RR] 1.78 [0.93,3.42])a. 
Following review of clinical data received to date, erythropoiesis has not been identified as a safety concern 
for daprodustat when dose is managed appropriately according to target Hgb.  
•
Specific eligibility criteria related to
Hgb requirements for entry are
detailed in Section 5.
•
Hgb will be closely monitored
throughout the dosing period as
outlined in Section 4.6.
•
Specific guidance for dose adjustment
or temporary discontinuation of
daprodustat based on measured Hgb
is provided in Section 4.6 and
Section 7.1.3 respectively.
•
Monitoring of emerging safety data by
an internal GSK Safety Review Team
and an IDMC. The IDMC will be
provided with safety data at the IDMC
decision time points described in
Section 9.4.1.
Worsening 
hypertension 
In a dog cardiovascular study, single oral doses of daprodustat (up to 90 mg/kg) did not produce effects on 
blood pressure (BP). 
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 
•
Specific eligibility criteria related to
BP, including exclusion of participants
with uncontrolled hypertension, see
Section 5.2.
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Potential Risk 
of Clinical 
Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
initiation or increase in their antihypertensive medications; hypertensive encephalopathy and seizures have 
been reported. The contribution of rhEPO-associated hypertension 
 to the unfavorable effects on cardiovascular outcomes remains uncertain). 
Integrated AE data from clinical trials with daprodustat, including 2 global Phase 3 cardiovascular outcomes 
studies (200807/ASCEND-D and 200808/ASCEND-ND):  
•
The majority (>90%) of participants had baseline history of hypertension.
•
No meaningful difference was seen between treatment groups in this AESI (637/3419 [18.6%]
daprodustat vs. 676/3407 [19.8%]; RR 0.94 [0.85,1.03])a.
•
Although no clinically meaningful changes in BP were observed, a similar proportion of patients treated
with daprodustat required an increase in anti-hypertensive medications as compared to rhEPOs in both
the D (23% daprodustat vs 21% rhEPO) and the ND (33% daprodustat vs 30% darbepoetin alfa)
populations.
Following review of clinical data received to date, no increased risk for hypertension relative to rhEPO has 
been identified for daprodustat. 
•
BP will be closely monitored
throughout the dosing period as
outlined in the SoA in Section 1.3.
•
Monitoring of emerging safety data by
an internal GSK Safety Review Team
and an IDMC.
Drug-drug 
interactions 
Daprodustat is a substrate of CYP2C8. Co-administration of daprodustat with the strong CYP2C8 inhibitor, 
gemfibrozil increased the maximum plasma concentration (Cmax ) and area under the curve (AUC) of 
daprodustat, 4- and 19-fold, respectively, while co-administration of the weak inhibitor, trimethoprim increased 
the Cmax and AUC of daprodustat by 1.3- and 1.5-fold, respectively.  
Population PK analysis from completed Phase 2 studies suggests that co-administration of daprodustat with a 
moderate CYP2C8 inhibitor (clopidogrel) leads to a ~2-fold increase in AUC, with no clinically significant 
increase in the measured Hgb response. Although CYP2C8 induction studies were not performed, co-
administration of daprodustat with an inducer of CYP2C8 (e.g., rifampin/rifampicin) may decrease the 
exposure of daprodustat. 
•
Co-administration of daprodustat with
strong CYP2C8 inhibitors, (e.g.,
gemfibrozil) and inducers, (e.g.,
rifampin/rifampicin) is not permitted as
outlined in Section 5.2 and
Section 6.8.1.
•
Specific guidance on the management
of potential drug-drug interactions and
concomitant medications is provided
in Section 6.8 and Section 7.1.
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Potential Risk 
of Clinical 
Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
•
Hgb will be closely monitored
throughout the dosing period as
outlined in the SoA in Section 1.3.
•
Specific guidance for (permanent or
temporary) discontinuation of
daprodustat based on achieved Hgb is
provided in Section 7.1.
•
Monitoring of emerging safety data by
an internal GSK Safety Review Team
and an IDMC.
Death, myocardial 
infarction (MI), 
stroke, heart failure 
(HF), thrombo-
embolic events, 
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. Clinical studies with marketed rhEPO/analogues have 
suggested “higher” target Hgb, rate of Hgb rise of greater than 1 g/dL in any 2-week period, and/or higher 
doses may contribute to these risks. 
Daprodustat has been shown to be non-inferior to ESAs in terms of first occurrence of major adverse 
cardiovascular events (MACE) defined as all-cause mortality, non-fatal MI and non-fatal stroke in both D 
patients (374/1487 [25.2%]) daprodustat vs 394/1477 [26.7%] rhEPO; hazard ratio [HR] 0.93 [0.81, 1.07]) and 
ND patients (378/1937 [19.5%] daprodustat vs 371/1935 [19.2%] darbepoetin; HR 1.03 [0.89, 1.19])b. 
Analysis of time to first occurrence of fatal or non-fatal thromboembolic events (deep venous thrombosis, 
pulmonary embolism, vascular access thrombosis) in each of the cardiovascular outcomes studies showed 
daprodustat did not significantly reduce the risk of fatal or non-fatal thromboembolic events compared with 
rhEPO in D patients (185/1487 [12.4%] daprodustat vs 215/1477 [14.6%] rhEPO; HR 0.84 [0.69, 1.02]) or ND 
patients (64/1937 [3.3%] daprodustat vs 51/1935 [2.6%] darbepoetin; HR 1.27 [0.88, 1.84])b. 
Analysis of time to first occurrence of fatal or non-fatal hospitalization for HF in each of the cardiovascular 
outcomes studies showed daprodustat did not significantly reduce the risk of hospitalization for HF (fatal or 
non-fatal) compared with rhEPO in D patients (112/1487 [7.5%] daprodustat vs 101/1477 [6.8%] rhEPO;  
•
Specific eligibility criteria related to
cardiovascular risk are outlined in
Section 5.2.
•
Hgb will be closely monitored
throughout the dosing period as
outlined Section 4.6.
•
Monitoring of emerging safety data by
an internal GSK Safety Review Team
and an IDMC.
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Potential Risk 
of Clinical 
Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
HR 1.10 [0.84, 1.45]) or ND patients (140/1937 [7.2%] daprodustat vs 115/1935 [5.9%] darbepoetin; HR 1.22 
[0.95, 1.56])b. 
Following review of clinical data received to date, no increased risk for serious cardiovascular events relative 
to rhEPO has been identified for daprodustat. 
Cancer-related 
mortality and tumor 
progression and 
recurrence 
Marketed rhEPOs have been associated with increased risk of cancer related morbidity and mortality when 
used in patients with cancer. 
Administration of 60 mg/kg daprodustat to mice caused minimal increases in circulating vascular endothelial 
growth factor (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 from clinical trials with daprodustat, including 2 global Phase 3 cardiovascular outcomes 
studies (200807/ASCEND-D and 200808/ASCEND-ND): No meaningful difference was seen between 
treatment groups in the occurrence of this AESI (119/3419 [3.5%] daprodustat vs. 121/3407 [3.6%] rhEPO; 
RR 0.98 [0.76,1.26])a. 
Clinical experience to date is not yet sufficient to substantiate or refute this as a safety concern for 
daprodustat. 
•
Specific eligibility criteria related to
personal history of malignancy are
outlined in Section 5.2.
•
Stopping criteria for participants with
treatment emergent malignancy are
outlined in Section 7.1.
•
Monitoring of emerging safety data by
an internal GSK Safety Review Team
and an IDMC.
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 observed with IV and oral administration of daprodustat. 
Gender-averaged systemic exposure (AUC) at the no observed adverse effect levels (NOAEL) are 3.3-fold 
(monkeys) and 737-fold (rats) above human exposure (25 mg daprodustat). 
•
Suspected GI bleeding or significant
symptoms consistent with erosion
should be investigated clinically and
diagnostically as per SoC and as
clinically warranted.
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Potential Risk 
of Clinical 
Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
In clinical trials to date with daprodustat, mild-moderate GI signs and symptoms represent the most frequently 
reported AE, however causal association has not been established. 
Integrated AE data from clinical trials with daprodustat, including 2 global Phase 3 cardiovascular outcomes 
studies (200807/ASCEND-D and 200808/ASCEND-ND): no meaningful difference was seen between 
treatment groups in reports of this AESI (130/3419 [3.8%] daprodustat vs. 130/3407 [3.8%] rhEPO; RR 1.00 
[0.79,1.26]) a. However, treatment group differences occurred in opposite directions in the two trials: 
200807/ASCEND-D: daprodustat: 60 (4%), rhEPO: 82 (6%) and 200808/ASCEND-ND: daprodustat: 70 (4%), 
darbepoetin: 48 (2%)a. 
Following review of clinical data received to date, GI erosions have not been identified as a safety concern for 
daprodustat. 
•
Monitoring of emerging safety data by
an internal GSK Safety Review Team
and an IDMC.
a. Dosing frequency adjusted
b. Full intention to treat follow-up
Abbreviations: AE = adverse event; AESI = adverse event of special interest; AUC = area under the curve; BP = blood pressure; CI = confidence interval; CKD = chronic kidney
disease; Cmax = maximum plasma concentration; D = dialysis; ESA = erythropoiesis stimulating agent; GI = gastrointestinal; HD = hemodialysis; Hgb = hemoglobin; HF = heart failure;
HR = Hazard Ratio; IDMC = independent data monitoring committee; IV = intravenous; MACE = major adverse cardiovascular events; ND = non-dialysis; NOAEL = no observed
adverse effect level; rhEPO = recombinant human erythropoietin; RR = relative risk; SD = standard deviation; SoC = standard of care; VEGF = vascular endothelial growth factor; vs. =
versus
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2.3.2. 
Benefit Assessment 
Study 214066 is a 52-week, open-label, basket, single arm, international, multicenter 
study to investigate the PK, safety and efficacy (Hgb response) of oral daprodustat in the 
treatment of anemia associated with CKD in participants aged 3 months to 17 years. 
Benefit has not been established with daprodustat in participants less than 18 years of 
age. However, in clinical trials of 52 weeks or longer in duration in adult participants 
with anemia associated with CKD, it has been shown that daprodustat increased Hgb to 
target range with an acceptable safety profile. 
It is planned to use the study results as the basis for regulatory submissions for 
daprodustat for the treatment of pediatric renal anemia. 
2.3.3. 
Overall Benefit: Risk Conclusion 
Data from daprodustat preclinical and clinical development support the ability of 
daprodustat to stimulate erythropoiesis through inhibition of the HIF-PHI pathway and 
consequently treat anemia associated with CKD.  
There are no known evident safety concerns with daprodustat to date that would preclude 
investigation in pediatric participants with anemia associated with CKD stage 3 to 5 not 
yet requiring dialysis (non-dialysis [ND]) and those with CKD stage 5d, undergoing 
dialysis (D); either peritoneal dialysis (PD) or hemodialysis (HD). Furthermore, this 
protocol employs precautions to mitigate known and potential risks to study participants. 
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 of care 
(SoC), the overall benefit-risk balance is considered to be positive. 
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3.
OBJECTIVES, ENDPOINTS AND ESTIMANDS
Objectives and endpoints (see Table 4) and estimands (see Section 3.1 and Section 3.2) 
are identical for the ND and D sub-trials, but will be separately assessed in each sub-trial, 
overall (all ages) and within each age group (except for PK and dose change, which is 
within each age group only). 
Table 4 
Objectives and Endpoints 
Objectives 
Endpoints 
Primary (Safety) 
•
Describe the safety of
daprodustat, overall (all ages)
and in each age group.
•
Incidence of AEs, Serious Adverse Events (SAEs),
AESIs, and AEs leading to study intervention
discontinuation.
Secondary Safety 
•
Describe changes in other
parameters relevant to safety,
overall and in each age group.
•
Changes from baseline in laboratory safety
parameters, blood pressure (BP), heart rate (HR),
height and weight at each time point.
Secondary Efficacy 
•
Describe the effect of
daprodustat on Hgb, overall and
in each age group (and
additionally overall in all ages by
ESA use [yes/no] at study
enrollment).
At each study time point: 
•
Hgb value.
•
Hgb change from baseline.
•
Hgb above, below and within the target range (10 to
12 g/dL).
•
Describe the change in required
dose over time, in each age
group.
At each study time point: 
•
Daprodustat dose.
•
Daprodustat dose change from starting dose.
During the course of the study: 
•
Number of dose changes.
Secondary Pharmacokinetic 
•
Characterize the PK of
daprodustat in each age group.
•
PK parameters: maximum plasma concentration
(Cmax) and area under the curve (AUC) at steady
state.
•
Describe the systemic exposure
to daprodustat metabolites, M2,
M3, M4, M5, M6 and M13 in each
age group.
•
Plasma concentrations of each daprodustat
metabolite at pre-dose (trough) between Week 2 to
Week 4, and corresponding Cmax if data permit.
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Objectives 
Endpoints 
Tertiary 
•
Evaluate the incidence of health
outcomes of interest in a CKD
population, overall and in each
age group.
During the study, the incidence of other health 
outcomes of interest related to the following:  
•
Hgb and rescue therapy:
o
Use of iron supplements (oral/IV/both).
o
Blood transfusion.
o
Use of rhEPO and analogues.
•
Changes in kidney function/intervention:
o
Transplantation.
o
End stage kidney disease (ESKD) (ND
only).*a
o
Switch between dialysis modalities (D only).
•
Other:
o
Death.
o
All-cause hospitalization.
o
Thrombosis.
o
All-cause loss of vascular access patency.
•
To assess the acceptability and
palatability of the immediate
release (IR) tablets and tablets
for oral suspension (TfOS).
Participant related Palatability and Acceptability 
Questionnaire to include but limited to: 
•
Palatability rating (good; acceptable; neither good
nor bad; bad; very bad).
•
Ease of swallowing (very easy; easy; neither easy
nor difficult; difficult; very difficult).
a.
* ESKD in the ND sub-trial population defined as at least one of the following: 
•
an estimated eGFR, based on the Schwartz equation of < 15mL/min/1.73 m2
•
new kidney transplantation 
•
the requirement for maintenance dialysis for ≥30 days
3.1. 
Pharmacokinetic Estimand 
The PK target estimand aims to assess the geometric mean of PK parameters Cmax and 
AUC at steady state following administration of daprodustat up to 4 weeks in children 
and adolescents with anemia of CKD in 2 sub-trials (ND/D) while on treatment and 
regardless of disruptions or delays in treatment. 
The primary estimand is described by the following attributes: 
Population 
Children and adolescent participants with anemia associated with 
CKD in the ND/D sub-trials. 
Treatment 
Daprodustat immediate release (IR) tablets or tablets for oral 
suspension (TfOS).  
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Intercurrent 
Events (ICEs) 
•
Permanent treatment discontinuation due to any reason
addressed with while on treatment strategy. Treatment effect is
only considered before the ICE occurs.
•
Disruptions in treatment and treatment delays addressed with
treatment policy strategy.
•
Unplanned use of strong CYP2C8 inhibitors and inducers
(which are prohibited during the study) are addressed with
treatment policy strategy.
Endpoints 
PK parameters: Cmax and AUC at steady state. 
Summary 
Measure 
Geometric mean of Cmax and AUC at steady state. 
Rationale for estimand: 
The motivation for the while on treatment strategy to deal with permanent treatment 
discontinuation is to estimate the PK parameters when participants have actually taken 
the dose/treatment. However, treatment policy strategy will be used in case of disruptions 
in treatment, treatment delays and unplanned use of strong CYP2C8 inhibitors and 
inducers (which are prohibited during the study, see Section 6.8.1). This is because PK 
data collected under these circumstances is still relevant and the model used to derive the 
PK parameters of interest (Cmax and AUC) can account for these ICEs and produce 
meaningful values of Cmax and AUC for participants affected by these ICEs. 
3.2. 
Main Study Estimands 
Primary and Key Secondary Main Study Estimands: 
The primary target estimand for the Main Study is the proportion of participants with 
AEs, SAEs, AESIs, and AEs leading to treatment discontinuation of daprodustat in 
children and adolescents with anemia of CKD in the 52-week ND/D sub-trials, regardless 
of permanent treatment discontinuation, disruptions or delays in treatment, intermittent 
use of rescue therapy or unplanned ESA use. 
The secondary efficacy target estimand for the Main Study is the Hgb endpoints at each 
study time point in children and adolescents with anemia of CKD in the 52-week ND/D 
sub-trials, regardless of disruptions or delays in treatment and transition to dialysis (ND 
sub-population only) whilst still continuing study intervention (daprodustat) and before 
any unplanned ESA therapy or rescue therapy. 
The primary and key secondary estimands are described by the following attributes: 
Population 
Children and adolescent participants with anemia associated with 
CKD in the ND/D sub-trials. 
Treatment 
Daprodustat IR tablets or TfOS. 
ICEs 
•
Permanent treatment discontinuation due to any reason,
addressed with treatment policy strategy, i.e., the treatment
effect of interest is determined regardless of the occurrence of
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the ICE, except for Hgb endpoints, which are addressed with 
while-on-treatment strategy. 
•
Disruptions in treatment or treatment delays addressed with
treatment policy strategy, i.e., the treatment effect of interest is
determined regardless of the occurrence of the ICE.
•
Unplanned use of ESA therapy addressed with treatment policy
strategy, i.e., the treatment effect of interest is determined
regardless of the occurrence of the ICE, except for Hgb
endpoints which are addressed with while-on-treatment strategy,
i.e., the Hgb values are excluded for the period of 8 weeks
following the occurrence of the ICE.
•
Intermittent use of rescue therapy within the trial is addressed
with treatment policy strategy, i.e., the treatment effect of
interest is determined regardless of the occurrence of the ICE,
except for Hgb endpoints, which are addressed with  while-on-
treatment strategy i.e., the Hgb values are excluded from the
date of unplanned ESA use until 8 weeks after the last dose of
unplanned ESA.
•
Transition to dialysis (ND sub-trial only) addressed with a
treatment policy strategy.
•
Kidney transplantation and death addressed with, while-on-
treatment strategy.
Primary Safety 
Endpoints 
Incidence of AEs, SAEs and AESI from Day 1 to 56 weeks of 
treatment. 
AEs leading to study intervention discontinuation from Day 1 to 
52 weeks of treatment. 
Summary 
Measure 
Proportion of participants with AEs, SAEs, AESI and AEs leading 
to study intervention discontinuation. 
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Secondary Efficacy 
Endpoints 
At each study time point: 
•
Hgb value.
•
Change in Hgb from baseline.
•
Hgb above, below and within the target range (10 to 12 g/dL).
Summary 
Measure 
At each study time point: 
•
Summary statistics of Hgb value (number, mean, SD, median,
25th percentile [P25], 75th percentile [P75], minimum,
maximum).
•
Mean change in Hgb from baseline (number, mean, SD, median,
P25, P75, minimum, maximum).
•
Proportion of participants with Hgb above, below and within the
target range (10 to 12 g/dL).
Rationale for estimand:  
The primary interest lies in the safety of daprodustat for the treatment of anemia 
associated with CKD for the entire study duration; therefore, the treatment policy strategy 
is used regardless of disruptions in treatment, treatment delays, intermittent use of rescue 
therapy and/or unplanned use of ESA therapy, which reflect clinical practice. All safety 
data will be included up to the end of the period or up to the end of the follow-up period 
in the analysis irrespective of the occurrence of this ICE. Transition to dialysis (ND sub-
trial only) is also addressed with treatment policy strategy. 
The secondary efficacy interest lies in the Hgb response to oral daprodustat for the 
treatment of anemia associated with CKD for the entire study duration; therefore, the 
treatment policy strategy is used regardless of disruptions in treatment or treatment 
delays, which reflect clinical practice. However, while-on-treatment strategy is used for 
the ICEs of intermittent use of rescue therapy and/or unplanned use of ESA therapy for 
the period of 8 weeks following the occurrence of the ICE, since these ICE may confound 
interpretation of Hgb response to daprodustat. Permanent treatment discontinuation for 
any reason is also addressed with while-on-treatment strategy.  
Transition to dialysis (ND sub-trial only) is addressed with treatment policy strategy. 
For participants who undergo a kidney transplantation, data will be considered up to the 
time of transplantation; therefore, this ICE is addressed with, while-on-treatment strategy. 
Such participants stop study intervention (daprodustat) and discontinue the study (see 
Section 7.2). Participants who die during the trial will be addressed with, while-on-
treatment strategy. 
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4.
STUDY DESIGN
4.1. 
Overall Design
This is an open-label, basket, single arm, international, multicenter trial, evaluating PK 
(4 weeks), safety (52 weeks) and Hgb response (52 weeks) to oral daprodustat in children 
and adolescent participants with anemia associated with CKD incorporating 2 
independent sub-trials (ND and D). 
These 2 sub-trial populations (ND and D) differ only in the degree of CKD, hence the 
requirement for dialysis, and are cared for by the same teams and centers. The design and 
conduct of these 2 sub-trials are therefore described in a single master protocol: they will 
share operational aspects but represent independent populations, recruited, conducted and 
analyzed separately. A graphical representation of the study design is shown in Figure 1. 
The points at which Independent Data Monitoring Committee (IDMC) reviews occur, 
when trial conduct decisions are required, is shown in Figure 2. 
Figure 2 
Pauses to Recruitment After Each Integrated PK Phase 
For all study participants, the study will consist of the following: 
•
Screening period of up to 4 weeks, although the Screening and Day 1 (Baseline)
Visits can be performed on the same day. Blood tests for eligibility checked at
Screening do not need to be repeated if the Day 1 Visit is performed within 7 days of
the Screening Visit.
•
Fifty-two-week treatment period with daprodustat. For the 24 participants in each
sub-trial (ND/D) contributing to the Integrated PK Phase, the first 4 weeks of the 52-
week treatment period will include sampling for PK. Optional PK sampling is offered
to non-Integrated PK Phase participants.
•
Follow-up period of 4 weeks off treatment.
All participants (who meet the eligibility criteria) will receive the first dose of 
daprodustat at the Day 1 Visit and will continue on treatment for a planned total of 
52 weeks. 
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As this is an open-label single arm trial, where all participants are on active treatment 
with daprodustat, clinical and laboratory parameters will not be blinded during the study. 
Investigators may adjust daprodustat dose from the Week 2 Visit based on Hgb response 
(see Section 4.6) using an age specific dose adjustment algorithm (see Section 4.5).  
Participants in the ND sub-trial reaching the requirement for dialysis will remain in the 
study and will continue to receive daprodustat, remaining in that (ND) sub-trial unless 
they withdraw consent. Participants who undergo kidney transplantation will be 
withdrawn from the study (see Section 7.2). 
Trial centers are required to also undertake an observational Comprehensive Cohort 
Study 212914, from which all participants in this study (214066) must be recruited. 
4.2. 
Scientific Rationale for Study Design 
Study Population: 
The study will enroll male and female participants aged 3 months to 17 years with 
anemia associated with CKD, in 2 distinct sub-populations differing only by their CKD 
stage and dialysis requirement (ND: CKD stage 3 to 5 not yet receiving dialysis and D: 
CKD stage 5d undergoing PD or HD). This study population describes a broad group of 
participants considered likely to benefit from daprodustat therapy for their renal anemia. 
In addition, the population replicates that studied in adults, allowing extrapolation of 
dosing strategy, efficacy and safety to the pediatric population. 
Basket Trial: 
The operational efficiency is enhanced by running the 2 distinct ND/D populations within 
one master protocol. The integrity of the sub-trial populations is preserved by its separate 
recruitment, study conduct, IDMC decision making, analysis and reporting. 
Single Arm Design: 
Daprodustat has been shown to be efficacious, well tolerated and with a favorable risk-
benefit profile in adults with anemia associated with CKD. Therefore, it is appropriate to 
provide an active treatment to all pediatric participants. Since this is a rare disease 
population, where clinical trials have historically struggled to recruit, a single arm design 
rather than a larger active controlled clinical trial is considered a more feasible approach. 
Comparator data are possible to derive from the literature or retrospectively and 
prospectively from the Cohort Study 212914, which acts as a feeder pool for this 
interventional study. The single arm design adequately allows for PK, safety and Hgb 
response to daprodustat to be evaluated. 
Study Intervention Duration: 
The total study intervention duration is 52 weeks. To achieve the study objective, which 
is to evaluate the safety (primary) and Hgb response (secondary) in the study population, 
a 52-week treatment period with daprodustat is deemed appropriate. The initial 4-week 
dosing period enables PK data at steady state to be collected for within trial decision 
making (Integrated PK Phase in the initially recruited [minimum 4] participants per age 
group) and to be used for the Population PK modelling undertaken at the end of the trial 
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(using all PK data: from the Integrated PK Phase plus optional PK sampling from non-
Integrated PK Phase participants).  
Staggered Recruitment with IDMC Decision Making: 
The trial design includes steps to ensure the safety of participants throughout the study, 
independent for each sub-trial. These include the following: 
•
Within sub-trial PK analysis from each Integrated PK Phase, allowing the
physiological based pharmacokinetic (PBPK) model predictions for adult to
pediatric dose scaling to be confirmed (actual PK data in line with PBPK model
predictions), or the PBPK model to be adjusted if deemed necessary. Hgb and
safety data available from the sub-trial will also be reviewed as part of the
decision making.
•
Staggered recruitment sequential by decreasing age group, so a younger age group
cannot be opened until the Integrated PK Phase from the next older age group has
been completed and analyzed and their dosing strategy confirmed.
•
Limited recruitment per age group, until their Integrated PK Phase is completed
and analyzed.
•
IDMC oversight of each sub-trial in general and additionally responsible for all
decision making steps within each sub-trial, including permission to recruit in age
groups (see Table 15).
•
Hgb will be closely monitored and the dose adjustment algorithm allows dosing to
be tailored to the individual participant’s needs (Section 4.6).
Nested Interventional Trial within the Cohort Study 212914: 
Nesting this interventional study within the Cohort Study 212914 is considered 
advantageous for the following main reasons: 
•
Pediatric CKD patients are rare and consent rates to interventional studies are
historically lower compared to observational studies, so nesting of this
daprodustat interventional study within an observational cohort (participants pre-
screened, pre-consented for 214066 approach within the 212914 Cohort Study),
is likely to both accelerate enrollment and facilitate retention in a highly
competitive environment.
•
The time delay for recruitment of the younger age groups (until the Integrated PK
Phase is complete and analyzed in the next older age group) means for the
younger participants in the Cohort, there is a lead time. This will provide time for
younger participants and their caregivers to become familiar with research prior
to approach for enrollment in an interventional trial.
•
Because the schedule of assessments in the prospective Cohort Study 212914 is
similar with respect to outcomes of interest in this 214066 study, offering Study
214066 participation from within the Cohort allows use of the ‘control’
Comprehensive Cohort data as a comparator for the single arm 214066 study
should this be required for regulatory purposes.
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4.2.1. 
Participant Input into Design 
Patient and caregiver consultation process was undertaken in collaboration with the 
United States (US) National Kidney Foundation (NKF) and concluded in July 2021. 
Patients and caregivers feedback have informed aspects of the study design. 
4.3. 
Justification for Dose 
In vitro studies have shown that isolated erythroid colony forming units from infants and 
adults have a similar quantitative response after stimulation by EPO [Rhondeau, 1988]. 
Similarly, the approved starting doses of rhEPO used to treat anemia associated with 
CKD are the same in adult and pediatric patients [Aranesp USPI, 2019; Epogen USPI, 
2017]. It has been noted that during maintenance treatment of anemia, pediatric patients 
tend to require higher per kg doses than adult patients [KDIGO, 2012; KDOQI, 2006; 
Port, 2009], and this is reflected in data collected in the North American Pediatric Renal 
Transplant Cooperative Study [NAPRTCS, 2011], where the mean weight-normalized 
dose of rhEPO decreased over increasing age cohorts. Collectively, these data suggest the 
PK/pharmacodynamic relationship in children with CKD is not expected to be 
appreciably different to adult patients.  
Due to the time-varying ontogeny in the drug metabolism of daprodustat as well as time-
varying changes in body weight across age groups, a PBPK approach was utilized to 
estimate the potential starting doses for the different age groups using a validated PBPK 
model for daprodustat in healthy adults [GSK Document number 2019N396674_00]. The 
PBPK model was derived using the Simcyp Pediatric Absorption Distribution 
Metabolism Excretion (ADME) Simulator which has 3 components to interrogate the 
known physiological and biochemical changes in a model to predict PK changes with age 
in healthy individuals [Abduljalil, 2014]. Therefore, doses for each age group are 
predicted by matching the pediatric systemic exposure (AUC) of daprodustat to that in 
adult.  
The summary of estimated apparent clearance (dose/AUC) of daprodustat using PBPK in 
each age group is shown in Table 5, which also shows the predicted ratio of the pediatric 
to adult dose. Dose proportionality and time-independent PK is assumed when 
determining the doses in the pediatric population. It should be noted that although these 
predictions are for healthy individuals, daprodustat PK is generally similar between 
healthy individuals and renal impairment patients. 
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Table 5 
Apparent Oral Clearance of Daprodustat by Age Group and 
Predicted Dose Equivalent to a 2 mg Adult Dose 
Age Group 
PBPK Model Weight 
Range Assumptions (kg) 
CLpo (L/h) 
Geometric Mean 
Dose 
(mg) 
Ratio Pediatric 
to Adult Dose 
Adults (≥18 years) 
42.0 to 123.6 
31.7 
2 
Not applicable 
12 to <18 years 
25.3 to 123.5 
25.3 
2 
1/1 
6 to <12 years 
14.6 to 59.0 
13.5 
1 
1/2 
2 to <6 years 
9.8 to 30.0 
7.0a 
0.5 
1/4 
3 months to <2 years 
4.2 to 19.5 
2.3a 
0.25 
1/8 
Abbreviations: CLpo = Apparent oral clearance 
a.
The lowest clearance (worst case scenario) from the predictions in the respective age groups using different assumptions
of CYP2C8 ontogeny in children. Source: Table 12 GSK Document number 2019N396674_00
4.4. 
Starting Dose 
4.4.1. 
Starting Dose in the 12 to <18 years Age Group: 
For the oldest age group (12 to <18 years), the starting dose of daprodustat administered 
once daily (QD) is already pre-defined (based on the PBPK model predictions) to be the 
same as in adults and is determined, as appropriate, by the following:  
•
Baseline Hgb values in participants not on an ESA (Table 6), or
•
Prior ESA dosage requirement in participants not on dialysis (Table 7), or
•
Prior ESA dosage requirement in participants undergoing dialysis (Table 8).
4.4.2. 
Starting Dose in the Younger Age Groups: 
Assuming the PBPK model predictions are appropriate and unchanged by the PK data 
collected and analyzed during the study in the Integrated PK Phase, the starting dosing in 
the younger age groups is also provided in these tables (Table 6, Table 7 and Table 8), 
based on the predicted scaling (ratio of adult to pediatric dose) in Table 5. 
Table 6 
Starting Dose of Daprodustat for ESA Non-Users 
Baseline Hgb 
(g/dL) 
Daprodustat starting dose per age group 
(mg, QD) 
Adults and 
12 to <18 years 
6 to <12 years 
2 to <6 years 
3 months to 
<2 years 
<9 
4 
2 
1 
0.5 
9 
2 
1 
0.5 
0.25 
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Table 7 
Starting Dose of Daprodustat in ESA Users, Not on Dialysis 
Prior ESA dose at Baseline 
 
Daprodustat starting dose per age group 
(mg, QD) 
Epoetins (incl 
biosimilars) 
(convert SC to 
IV U/week)a 
Darbepoetin 
alfa 
(μg/4wk 
SC/IV)b
Methoxy 
PEG-epoetin 
beta 
(μg/month 
SC/IV)c,d
Adults and 
12 to <18 
years 
6 to <12 
years 
2 to <6 
years 
3 months 
to <2 
years 
2000 e 
≤30 
≤40 
1 
0.5 
0.25 
0.125 
>2000 to
<20,000
>30 to 300
>40 to 360
2 
1 
0.5 
0.25 
≥20,000 
>300
>360
4 
2 
1 
0.5 
Abbreviations: PEG = polyethylene glycol. SC = subcutaneous, IV = intravenous, U = units 
a.
Standard rhEPO IV dose (U/week) = 161/113 x (epoetin SC dose (units))/(frequency) [Besarab, 2002].
b.
Conversion of 250U:1μg (epoetin IV:darbepoetin alfa) utilized and rounded to the nearest available dose strength
[Sterner, 2008].
c.
Conversion of 1:1.2 μg (darbepoetin alfa:methoxy PEG-epoetin beta) utilized and rounded to the nearest available
dose strength [Choi, 2013].
d.
Conversion of 208 U:1 μg (epoetin IV:methoxy PEG-epoetin beta)
e.
This includes ESA users on a zero dose / dose-hold at the time of enrolment
Table 8 
Starting Dose of Daprodustat in ESA Users, Undergoing Dialysis 
Prior ESA dose at Baseline 
 
Daprodustat starting dose per age group 
(mg, QD) 
Epoetins (incl 
biosimilars) 
(convert SC to 
IV U/week)a 
Darbepoetin 
alfa 
(μg/4wk 
SC/IV)b
Methoxy PEG-
epoetin beta 
(μg/month 
SC/IV)c,d
Adults 
and 12 to 
<18 years 
6 to <12 
years 
2 to <6 
years 
3 months 
to <2 
years 
≤2000e 
≤30 
≤40 
4 
2 
1 
0.5 
>2000 to
<10,000
>30 to 150
>40 to 180
6 
3 
1.5 
0.75 
≥10,000 to 
<20,000 
>150 to 300
>180 to 360
8 
4 
2 
1 
≥20,000 
>300
>360
12 
6 
3 
1.5 
Abbreviations: PEG = polyethylene glycol. SC = subcutaneous, IV = intravenous, U = units, ug = micrograms 
a.
Standard rhEPO IV dose (U/week) = 161/113 x (epoetin SC dose (units))/(frequency) [Besarab, 2002].
b.
Conversion of 250U:1μg (epoetin IV:darbepoetin alfa) utilized and rounded to the nearest available dose strength
[Sterner, 2008].
c.
Conversion of 1:1.2 μg (darbepoetin alfa:methoxy PEG-epoetin beta) utilized and rounded to the nearest available
dose strength [Choi, 2013].
d.
Conversion of 208 U:1 μg (epoetin IV:methoxy PEG-epoetin beta)
e.
This includes ESA users on a zero dose / dose-hold at the time of enrollment
If the actual PK data from each sub-trial age group Integrated PK Phase are in line with 
the PBPK model predictions, then the starting dose will be as outlined above. However, 
as described in Section 9.3.1, if more than 50% of the data lie outside the 95% Prediction 
Intervals (PIs) of the PK simulations, the PBPK model will be updated and a new scaling 
(pediatric to adult ratio) proposed for use in the next younger age group (i.e., Table 6, 
Table 7 and Table 8) will be updated for the 3 younger age groups). Note: the new 
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starting doses may be rounded to the nearest available tablet strength if new scaling is 
required. 
See Section 4.7 for the role of the IDMC in communicating the starting dose for the 
3 younger age groups. 
4.5. 
Dose Adjustment Algorithm 
Between Weeks 2 to 52, the dose of daprodustat should be adjusted if required (see 
Section 4.6), one dose step at a time, to achieve/maintain a Hgb within the target range of 
10 to 12 g/dL. 
4.5.1. 
Dose Adjustment Algorithm in the 12 to <18 Years Age Group 
As exposure in the oldest age group (12 to <18 years) is predicted to be the same as 
adults, the dose adjustment algorithm will be similar to adults, see Figure 3. The dose in 
this study (for both the ND/D sub-trials), as in the adult Phase 3 program, cannot exceed 
24 mg QD. 
Figure 3 
Dose Adjustment Algorithm in the 12 to <18 Years Age Group 
4.5.2. 
Dose Adjustment Algorithm in the Younger Age Groups 
A common dose adjustment algorithm will be utilized for the 3 younger age groups, see 
Figure 4.  
Figure 4 
Dose Adjustment Algorithm in the Younger Age Groups (<12 years) 
Abbreviations: m = months; PBPK = physiological based pharmacokinetics; TfOS = tablets for oral suspension; 
y = years. 
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These dose steps (shown in Figure 4) for the 3 younger age groups are derived by 
applying the adult to pediatric ratio from the PBPK model to the dosing steps for adults 
(see Table 9) and then lining up the doses in ascending order. This is a conservative 
approach, and in some cases may mean a slightly smaller dose increment than the 
predicted to match adult exposure, e.g., a 6 to <12 year old moves between 0.5 to 0.75 to 
1 mg in a common dose algorithm rather than between 0.5 to 1 mg (see Table 9). No age 
group has a larger step than adult equivalent titration.  
Table 9 
Dose Adjustment Algorithm Predicted by the PBPK Model 
Age Group 
Ratio 
pediatric to 
adult dose 
Dose steps predicted by the PBPK model 
(mg QD) 
 
12 <18 years 
 
1/1 
1 
2 
4 
6 
8 
12 
16 
24 
6 <12 years 
 
1/2 
0.5 
1 
2 
3 
4 
6 
8 
12 
2 <6 years 
 
1/4 
0.25 
0.5 
1 
1.5 
2 
3 
4 
6 
3 months <2 years 
 
1/8 
0.125 
0.25 
0.5 
0.75 
1 
1.5 
2 
3 
Dosing Limits of the Common Dose Adjustment Algorithm for the 3 Younger Age 
Groups: 
The upper limit of dosing in each of the 3 younger age groups can be considered based 
upon the following: 
•
PBPK predicted equivalent exposure to adult dose of 24 mg in each age group
(see Table 9 or scaling adjusted as a consequence of an Integrated PK Phase), and
•
maximum dose based on the limit on the number of tablets with a TfOS
formulation (see Table 10 and also Section 6.1 for the TfOS limits per age group).
If ongoing data suggests that a pediatric population needs a higher dose than that 
predicted by the PBPK model in the younger age groups to match the top dose (24 mg) in 
adults, the IDMC may allow the dosing algorithm upper limit for the 3 younger age 
groups to include extra (higher) dose steps than the top dose predicted by the PBPK 
model. However, the maximum dose in each age of the younger age groups cannot 
exceed the limit on the number of tablets with a TfOS formulation (see Table 10). 
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Table 10 
Extra Dose Steps for the Younger Age Groups based on TfOS 
Excipient Limits 
Age Group 
Top dose 
predicted by the 
PBPK Model  
from Table 9 
(mg QD) 
Maximum dose 
permitted with 
TfOS 
see Section 6.1 
(mg QD) 
Extra dose steps that may be 
included in the dosing algorithm 
above the PBPK model top dose 
prediction if the IDMC allow 
(mg QD) 
6 <12 years 
12 
16 
16 
2 <6 years 
6 
12 
8, 12 
3 months <2 years 
3 
8 
4, 6, 8 
As described in Section 4.4.2 for the starting dose, if a new scaling (pediatric to adult 
ratio) is required based on the results of an Integrated PK Phase, the new ratio will be 
applied to adjust the upper/lower dose limits of the common dose algorithm for the next 
younger age group (the dose steps within the algorithm will remain unchanged). Note: the 
new dose limits may be rounded to the nearest available tablet strength if new scaling is 
required. 
It will be the responsibility of the IDMC to confirm the dosing strategy (starting 
dose and dose adjustment algorithm upper/lower limits) in each of the 3 younger 
age groups (see also Section 4.7), based on the following: 
•
pediatric to adult dose scaling predicted by the PBPK model (confirmed or as
adjusted by the actual PK data collected), and also
•
taking into account the ongoing knowledge of the:
o
Hgb response and safety from the 4 week Integrated PK Phases from each
age group in each sub-trial (ND/D).
o
Overall Hgb and safety data from each sub-trial to date.
Note: Participants, who with a birthday move into the next age group during the course of 
the 52-week treatment period, will be allowed to be dosed (if required based on Hgb 
response, see Table 11) to the dosing limits defined for their current age, provided they 
weigh the minimum weight for that new age group, as specified in Table 12. For 
example: 
•
A participant aged 5 years 9 months at study enrollment cannot be dosed
higher/lower than the limits set by the IDMC for a 2 to <6 year old. However,
after their 6th birthday, their upper/lower limits of the dosing algorithm will move
to their new age category of 6 to <12 years) provided they weigh at least 15.3 kg.
•
A participant aged 11 years 9 months at study enrollment cannot be dosed
higher/lower than the limits set by the IDMC for a 6 to <12 year old. However,
after their 12th birthday, they will then follow the dosing algorithm of the 12 to
<18 years old provided they weigh at least 25.3 kg and are able to swallow IR
tablets, otherwise they must remain in the 6 to <12 years age group algorithm
taking the TfOS.
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Interactive Response Technology (IRT) will ensure the participant receives the correct 
dose allocation in case of an age group change. As age is required to allow correct 
dispensing of study medication, month and year of birth will be collected at enrollment. 
4.6. 
Hemoglobin Target Range and Frequency of Checks 
In adults, the dose of daprodustat is adjusted if required, one step at a time in the range of 
1 to 24 mg, to ensure the patient’s Hgb is within a target range. 
In this study, the target range for Hgb is 10 to 12 g/dL, the same for all ages and 
regardless of dialysis status (ND or D) or within the D sub-trial population, their dialysis 
modality (PD or HD). 
For pediatric patients, nephrologists dose adjust ESA therapy in accordance with both 
Hgb and clinical response. At Study Weeks 2, 4, 8, 12, 16, 20, 24, 28, 36, 44 and 52, the 
Hgb will be checked. 
At Week 2: 
Hgb will be measured to ensure there is no rapid rise following commencement of 
daprodustat. 
•
If a rapid rise is observed (>1 g in 2 weeks), the dose should be adjusted to the next
lower dose step.
•
If the Hgb value at Week 2 is >12.5 g/dL, daprodustat will be stopped and
reintroduced at the next lower dose at a subsequent visit when the Hgb is ≤12.0 g/dL.
•
Otherwise, no change in dose is made at Study Week 2.
From Week 4 until Week 52 (end of daprodustat dosing): 
The dose may increase, decrease, be temporarily interrupted or stay the same based on 
Hgb response as shown in Table 11. 
Table 11 
Dose Adjustment Based on Hgb from Week 4 Onwards 
Dose 
adjustment 
Hgb status 
To the next 
higher dose 
•
Hgb <10.0 g/dL and is not increasing (<0.5 g/dL) compared to previous visit.
OR
•
Hgb is within the target range 10.0 to 12.0 g/dL but in the opinion of the
investigator the patient is still symptomatic due to their anemia.
Note: if the participant is already on the highest dose step and requires a dose 
increase, maintain their age-defined maximum dose and re-check Hgb in 4 weeks. 
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Dose 
adjustment 
Hgb status 
To the next 
lower dose 
•
If the Hgb is >12.0 but <12.5 g/dL.
OR
•
the Hgb increased by >2.0 g/dL in 4 weeks.
OR
•
the Hgb increased by >1.0 g/dL in 2 weeks.
Note: if the participant is already on the lowest dose step and requires a dose
reduction, withhold dosing and re-check Hgb in 4 weeks, dosing should restart at the
lowest dose step when the Hgb is ≤12.0 g/dL.
To temporarily 
stop 
•
If the Hgb is >12.5 g/dL, temporarily withhold dosing and check Hgb at the next
study visit in 4 weeks.
Restart at the next lower dose when the Hgb is <12.0 g/dL.
Note: From Week 28 if the next study visit is more than 4 weeks from date of test, 
schedule an extra Hgb check Visit in 4 weeks.  
Note: if the participant is already on the lowest dose step at the time of the temporary 
stop, dosing should restart at the lowest dose step at the next study visit when the Hgb 
is ≤12.0 g/dL. 
No change 
•
Otherwise maintain at the same dose.
The SoA (see Section 1.3) up to Week 28 requires visits every 4 weeks, where Hgb is 
checked. From Week 28 until Week 52 (when daprodustat treatment ceases), an extra 
Hgb Visit (at Week 32, 40 or 48) should be conducted 4 weeks after the previous study 
visit, if any of the following apply: 
•
At the previous study visit:
o
A dose change was required (see Table 11).
o
Dosing was temporarily withheld as follows:
▪
Hgb >12.5 g/dL (see Table 11), or
▪
the participant was already on the lowest dose in the dose
adjustment algorithm and a dose reduction was required (see Table
11 and Section 4.5).
•
The following occurs and the next study visit is not due within 4 weeks and a:
o
Moderate CYP2C8 inhibitor has been prescribed (see Section 6.8).
o
rhEPO or analogue has been administered in error (see Section 6.8.3).
o
Hgb check performed outside of the study (routine SoC or emergency)
indicates that a dose change is needed (see Table 11).
•
In the opinion of the investigator, the:
o
Participant would benefit from continued 4-weekly Hgb checks.
o
Hgb is at the upper end of the target range and waiting 8 weeks for the
next Hgb check is considered too long.
In addition to the above, an unscheduled (UNS) Visit at any time during the study may be 
conducted if, in the opinion of the investigator, the participant would benefit from 
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additional monitoring of Hgb sooner than the next scheduled visit (within 4 weeks) 
and/or for other parameters or if there is a safety concern. If an UNS Visit is performed, 
then the UNS electronic case report form (eCRF) pages should be completed. If a dose 
change is required, then the investigator should urgently contact the medical monitor, 
who can authorize a manual override of the IRT system to amend the allocated dose.  
4.7. 
Role of the IDMC in Confirming the Dosing Strategy 
The dosing strategy is expected to be the same in either sub-trial (ND/D) and although 
their Integrated PK Phases will be analyzed and considered independently, the same 
review and decision making by the IDMC will be required, see also Section 9.4.1. 
The IDMC will be responsible for confirming the decision to open up recruitment for 
each sequential age group (6 to <12 years, 2 to <6 years and 3 months to <2 years) in turn 
within each sub-trial, and for confirming the following: 
•
Starting dose in the next younger age group (Section 4.4.2).
•
Upper and lower limits of the common dose adjustment algorithm in these age
groups (Section 4.5.2).
The IDMC decision will be based (separately for each sub-trial) on the following: 
•
PBPK model predictions for adult to pediatric dose scaling, confirmed or updated
by the actual PK data analyzed after completion in each age group Integrated PK
Phase.
•
4-week Hgb and safety data from each age group’s Integrated PK Phase.
•
Ongoing Hgb and safety data from all participants in each sub-trial.
For the oldest age group (12 to <18 years), the starting dose and dose adjustment 
algorithm is already pre-defined as the same as in adults. After the 12 to <18 year PK 
data in the Integrated PK Phase is available, the appropriate pediatric dose ratio to 
achieve a matching adult exposure to daprodustat is proposed by the GSK study team and 
provided to the IDMC (i.e., PBPK model predictions are confirmed or the model updated 
in light of the actual PK data collected). Assuming no concerns from the review of the 
Hgb response and safety listings during the Integrated PK Phase of the 12 to <18 years, 
the IDMC will allow: 
•
Further recruitment into the Main Study of the 12 to <18 years age group.
•
Limited recruitment into the study with the Integrated PK Phase of the 6 to <12
years age group, also confirming the dosing strategy (starting dose and dose
adjustment algorithm limits) in this age group.
In turn, once the 6 to <12 year Integrated PK Phase data are available and provided no 
concerns (from Hgb and safety data from their Integrated PK Phase and from the 12 to 
<18 years age group also in the trial and available to date), the IDMC will permit 
recruitment into the Integrated PK Phase for the 2 to <6 years age group and also confirm 
their dosing strategy (starting dose and limits of the dose adjustment algorithm). Finally, 
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in similar fashion, the youngest age group, the 3 month to <2 years, will be opened to 
recruitment and their dosing strategy confirmed. 
Requirement for a Protocol Amendment with respect to dosing: 
A protocol amendment for dosing will not be produced and the IDMC communication, 
for both the starting dose and dose adjustment algorithm limits, will serve as the basis for 
the dosing strategy for the 3 younger age groups provided: 
•
there are no safety concerns
and
•
the 12 to <18 year age group dosing is confirmed to be the same as for adults, as
specified in this protocol for starting dose (see Section 4.4.1) and dose adjustment
(see Section 4.5.1),
and
•
for the younger age groups, all doses proposed remain within the limits specified
in Figure 4, even if the PBPK model needs updating (revised scaling for the
younger age groups).
However, a substantial protocol amendment for approval will be written, and no 
further recruitment into the study will be permitted until all required approvals for the 
revised protocol are in place, if the IDMC consider: 
•
after review of the Integrated PK Phase data that the dosing strategy for the 12 to
<18 years needs to be adjusted (i.e., is not the same as adults as specified in this
protocol)†,
and/or
•
after review of the Integrated PK Phase data, that the dosing limits for the
3 younger age groups deviates from that outlined in Figure 4,
and/or
•
safety concerns are detected.
The IDMC composition, role and format for dosing communications for the 3 younger 
age groups will be fully described in an IDMC Charter. 
4.8. 
End of Study Definition 
The end of the study (EOS) Overall is defined as the date of the last visit of the last 
participant in the study of the last sub-trial (ND or D) to finish. As these sub-trial 
populations (ND/D) are handled separately within the master basket trial protocol, their 
last participant visit will differ, particularly if recruitment rate varies between the 2 
sub-trial populations. Therefore, an EOS ND and an EOS D is also defined. However, for 
the purposes of clinical trial disclosure and EOS notification to the Health Authorities 
† Should the dosing strategy for the 12 to <18 years age group need to be adjusted, the protocol amendment 
will include a requirement for PK collection in a subset of newly recruited participants in that age group 
who will start with the revised dosing. 
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and Institutional Review Board (IRB)/Independent Ethics Committee (IEC) the EOS 
Overall will be used. 
With each sub-trial, a participant is considered to have completed: 
•
the study (“study completer”), if he/she has completed all study visits within their
sub-trial (ND or D), including the last Follow-up Visit at Week 56, regardless of
whether daprodustat treatment was received during the entire study period.
•
study intervention (“treatment completer”), if he/she has not been discontinued
prematurely from study intervention (see Section 7.1) and has completed the last
required on-treatment visit (Week 52) within their sub-trial, regardless of whether
daprodustat treatment was received during the entire study period.
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5.
STUDY POPULATION
This study will enroll patients aged 3 months to <18 years with anemia associated with 
CKD, within 2 separate sub-trial populations (ND and D). Participants may or may not be 
receiving treatment with ESAs prior to study entry. Overall, the entire study population 
describes a group of CKD patients likely to benefit from treatment with daprodustat. 
Regardless of their dialysis status, the present study will allow patients not on an ESA 
with a Hgb level 7.0 to 11.0 g/dL and those receiving treatment with ESA if they have a 
Hgb concentration of 9.5 to 12.0 g/dL to enroll in the study. The same eligibility criteria 
apply to both the sub-trials (ND/D) in this study, apart from the requirement for dialysis. 
Recruitment will close to each sub-trial, and if required within a specific age group, when 
the requisite number of participants have been enrolled. 
The prospective approval of protocol deviations to recruitment and eligibility criteria, 
also known as protocol waivers or exemptions, is not permitted. 
5.1. 
Inclusion Criteria 
The screening period can be up to 4 weeks, although Screening and Day 1 Visits can be 
performed on the same day. Blood tests for eligibility checked at Screening do not need 
to be repeated if the Day 1 Visit is performed within 7 days of the Screening Visit. 
To be eligible for this study, participants must be offered approach (as determined in 
Study 212914) and fulfill all of the following criteria at the Screening and Day 1 Visits: 
Age: 
1. Participant must be 3 months to <18 years of age.
Note: Infants born prematurely (under 32 weeks of gestation) should have a
chronological age of at least 6 months.
Type of Participant and Disease Characteristics: 
2. Participants who have anemia associated with CKD as follows:
ND sub-trial 
D sub-trial 
CKD stage 3, 4, 5 (not on dialysis) based on 
eGFR using the bedside Schwartz equation 
<60 mL/min/1.73m2 [Schwartz, 2009] 
Prevalent dialysis patients (Stage 5d CKD) 
defined as those in receipt of maintenance 
dialysis of ≥30 days duration 
AND 
•
If not using ESAs, Hgb 7.0 to 11.0 g/dL
OR 
•
If using ESAs, Hgb 9.5 to 12.0 g/dL
Weight: 
3. Weight restrictions apply to participants for each age group. This takes into account:
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•
In the 3 younger age groups (<12 years), the number of TfOS they may
receive in the trial to ensure dosing is well below excipient limits. The weight
used for excipient limit calculation in each age group is based on WHO
median weights in girls (lighter than boys) minus 2 SD for the youngest child
in each age group (i.e., 6 years, 2 years and 3 months).
•
The minimum weight used in the PBPK model assumptions, see Section 4.3.
•
Relevant for the youngest patients (3 months), the minimum weight also takes
into account the amount of blood required for study time points relative to
percentage of blood volume in order to comply with guidance for clinical
trials in children [Paediatric Population: Recommendations, 2008], see
Section 8.4.1.
Participants must weigh or exceed the minimum weight required for study entry 
tabulated for their age group, as indicated in the second column of Table 12: 
Table 12 
Minimum Weight Per Age Group 
Age Group 
Minimum Weight 
Required for Study 
Entry 
(kg) 
Minimum Weight for TfOS 
Excipient Limit  
(based on WHO Weight for 
Girls, median-2SD) 
(kg) 
Lowest Weight 
Used in the 
PBPK Model 
(kg) 
12 to <18 years 
25.3 
Not applicableb 
25.3 
6 to <12 years 
15.3 
15.3 
14.6 
2 to <6 years 
9.8 
9.0 
9.8 
3 months to <2 years 
5.0a 
4.5 
4.2 
Abbreviation: SD = standard deviation 
a.
The minimum weight of 4.5kg (WHO median weight – 2SD) for the youngest age group is revised upwards
to 5.0 kg to take into account the blood draw limit, see Section 8.4.1
b.
The 12 to <18 years age group are not dosed with TfOS, therefore the minimum weight limit in this age
group is based on the PBPK model assumptions
Sex and Contraceptive/Barrier Requirements: 
4. A female participant is eligible to participate if she is either:
•
premenarcheal, or
•
not pregnant as confirmed by a negative human chorionic gonadotrophin
(hCG) test if of reproductive potential. Testing requires serum hCG if
eGFR≤15 mL/min/1.73m2. Otherwise, a urine hCG test is acceptable.
Females of childbearing potential (FOCBP) must commit to consistent and correct 
use of a highly effective method of contraception (see Section 10.4) until at least 30 
days after the last dose of daprodustat. A pregnancy test is required for FOCBP. This 
test will be performed at the initial Screening and at each scheduled visit whilst in the 
study including the follow-up visit (see Section 8.2.5). 
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The investigator is responsible for review of medical history, menstrual history, and 
recent sexual activity to decrease the risk for inclusion of a female with an early 
undetected pregnancy. 
Note: If the childbearing potential changes after start of the study (e.g., a 
premenarcheal female participant experiences menarche) or the risk of pregnancy 
changes (e.g., a female participant who is not heterosexually active becomes active), 
the participant must discuss this with the investigator, who should determine if a 
female participant must begin a highly effective method of contraception. If 
reproductive status is questionable, additional evaluation should be considered.  
Informed Consent and Assent: 
5. The investigator, or a person designated by the investigator, will obtain written
informed consent from each study participant’s legal guardian (as defined in
Section 10.1.3) and the participant’s assent, when applicable, before any study-
specific activity is performed (unless a waiver of informed consent has been granted
by an IRB/IEC). All legal guardians should be fully informed, and participants should
be informed to the fullest extent possible, about the study in language and terms they
are able to understand.
6. The participant capable of providing signed and dated written assent, signs and dates
a written assent form (age-appropriate) and the parent/guardian signs and dates a
written informed consent form (ICF) for study participation prior to the initiation of
any study-related activities. The informed consent is described in Section 10.1.3.
Other: 
7. A legal guardian or primary caregiver must be available to help the study site
personnel ensure follow-up; support the participant to attended assessment days
according to the SoA in Section 1.3 (e.g., able to comply with scheduled visits, study
procedures, and accurately dispense study intervention as directed).
5.2. 
Exclusion Criteria 
The screening period can be up to 4 weeks, although Screening and Day 1 Visits can be 
performed on the same day. Blood tests for eligibility checked at Screening do not need 
to be repeated if the Day 1 Visit is performed within 7 days of the Screening Visit. 
Participants are excluded from the study if any of the following criteria apply at the 
Screening and Day 1 Visits (unless otherwise stated):  
CKD Related Criteria: 
1.
Kidney transplant recipient with a functioning allograft.
2.
Scheduled for elective kidney transplantation within 3 months.
Anemia Related Criteria: 
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3.
Iron deficiency, defined as:
−
Transferrin saturation (TSAT) < 20%, or
−
Ferritin <25 ng/mL.
4.
Aplasias: History of bone marrow aplasia or pure red cell aplasia.
5.
Active hemolysis.
6.
Other causes of anemia: e.g., untreated vitamin B12 deficiency, untreated folate
deficiency, thalassemia major, sickle cell disease or myelodysplastic syndrome.
Note: Sickle cell trait is acceptable if the participant otherwise meets entry criteria.
7.
GI bleeding: Evidence of actively bleeding gastric, duodenal or esophageal ulcer
disease or clinically significant GI bleeding within the last 4 weeks.
Other Disease Related Criteria: 
8.
History of malignancy within the last 2 years or currently receiving treatment for
cancer, or renal lesions, for which, in the opinion of the investigator, malignancy
cannot be excluded.
Note: In the case of localized squamous cell or basal cell carcinoma of the skin that
has been definitively treated, the exclusion timeline is within the last 4 weeks.
9.
Unresolved acute or active chronic infection requiring antimicrobial therapy.
10. History of significant thrombotic or thromboembolic events (e.g., deep venous
thrombosis, pulmonary embolism, stroke, myocardial infarction [MI]) within the last
8 weeks.
11. Heart failure (HF): Chronic Class IV HF, as defined by the New York Heart
Association (NYHA) functional classification system.
12. Current uncontrolled hypertension as determined by the investigator.
13. 12-lead electrocardiogram (ECG) finding (at Screening):
•
An abnormal ECG finding from the 12-lead ECG conducted at Screening if
considered to be clinically significant and would impact the participant’s
participation during the study based on the evaluation of the investigator and a
pediatric cardiologist.
•
QT interval corrected using Fridericia’s formula (QTcF) > 480 msec, or
•
QT interval corrected for heart rate (QTc) >500 msec in participants with bundle
branch block.
14. Liver abnormality/disease:
•
Alanine aminotransferase (ALT) >2× upper limit of normal (ULN).
•
Bilirubin >1.5× ULN (isolated bilirubin >1.5× ULN is acceptable if bilirubin is
fractionated and direct bilirubin <35%).
•
Cirrhosis or current unstable liver or biliary disease per investigator assessment
defined by the presence of ascites, encephalopathy, coagulopathy,
hypoalbuminaemia, esophageal or gastric varices or persistent jaundice.
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Note: Stable non-cirrhotic chronic liver disease (including Gilbert's syndrome, 
asymptomatic gallstones and chronic hepatitis B or C) is acceptable if the 
participant otherwise meets entry criteria. 
Prior/Concomitant Therapy: 
15. Participants who have previously received treatment with any HIF-PHI, including
daprodustat within the last 30 days.
16. Participants who have previously failed to respond to treatment with daprodustat or
any other HIF-PHI.
17. Participants, who have received within the last 7 days, or anticipate receiving during
the study, strong inhibitors of CYP2C8 (e.g., gemfibrozil) or strong inducers of
CYP2C8 (e.g., rifampin/rifampicin).
Other Investigational Product/Clinical Study: 
18. Other investigational product/clinical study: Participants who have received
treatment with an investigational agent (biologic or non-biologic) within the past 30
days or 5 drug half-lives whichever is longer, with the exception of treatments or
vaccines for SARS-CoV-2 with provisional or emergency approval. The term
“investigational” applies to any drug not approved for sale in the country in which it
is being used or investigational formulations of marketed products.
19. Participants who are currently participating in any other clinical study of an
investigational medicinal product (IMP).
Other Exclusions: 
20. Females ONLY: Participant is pregnant, breastfeeding or is of reproductive potential
and does not agree to one of the contraceptive options listed in the List of Highly
Effective Methods for Avoiding Pregnancy in Section 10.4.
21. Participants with any history of hypersensitivity to daprodustat or its excipients, or to
any other HIF-PHI.
22. Any other condition, clinical or laboratory abnormality, or examination finding that
the investigator considers would put the participant at unacceptable risk, which may
affect study compliance or prevent understanding of the aims or investigational
procedures or possible consequences of the study.
5.3. 
Lifestyle Considerations 
No restrictions are required. 
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5.4. 
Screen Failures 
Screen failures are defined as participants who consent to participate in the clinical study 
but are not subsequently enrolled in the study. A minimal set of screen failure 
information is required to ensure transparent reporting of screen failure participants to 
meet the Consolidated Standards of Reporting Trials (CONSORT) publishing 
requirements and to respond to queries from regulatory authorities. Minimal information 
includes demography, screen failure details, previous trial participation, eligibility 
criteria, any protocol deviations and any SAEs. 
Individuals who do not meet the criteria for participation in this study (screen failure) 
may be rescreened within 6 weeks under the original informed consent if, in the opinion 
of investigator, the participant fails on a reversible parameter at Screening which has 
been addressed (e.g., iron status). Note: a new consent maybe required in this 6 week 
period if a birthday occurs in that time which changes the legal requirement for consent 
in their country, e.g., assent to consent requirement from the participant). Participants 
who are rescreened after 6 weeks need to be re-consented prior to undergoing any 
Screening procedures. There are no limits on the number of rescreens, provided the 
eligibility parameter(s) that the participant did not meet can be addressed.  
Rescreened participants will be assigned a new participant number for every 
screening/rescreening event.  
5.5. 
Criteria for Temporarily Delaying Enrollment /Administration 
of Study Intervention  
There is no reason for administration of study intervention (daprodustat) on Day 1 to be 
delayed when inclusion/exclusion criteria are met at the Screening and Day 1 Visits. 
Whilst the screening period can last up to 4 weeks, the Screening and Day 1 Visits can be 
performed on the same day. Blood tests for eligibility checked at Screening do not need 
to be repeated if the Day 1 Visit is performed within 7 days of Screening. 
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6.
STUDY INTERVENTION AND CONCOMITANT THERAPY
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according 
to the study protocol. The study intervention in this trial is daprodustat. 
6.1. 
Study Intervention Administered 
Daprodustat (GSK1278863) is a HIF-PHI that has been investigated as a treatment in 
adults for anemia associated with CKD in both ND and D patients. Daprodustat will be 
provided to all pediatric participant age groups as shown in Table 13. 
Table 13 
Study Intervention Formulations for Participant Groups 
Film-coated IR 
tablets 
Dosage levels 1 to 24 mg in: 
•
Age group 12 to <18 years.
•
Age group 6 to <12 years who can swallow IR tablets.
TfOS 
Dosage levels 0.125 mg to 16 mg in: 
•
Age group 6 to <12 years who can swallow the IR tablets but need a
dosage of 1.5 mg or less than 1 mg.
•
Age group 6 to <12 years who cannot swallow IR tablets.
•
Age groups 2 to <6 years and 3 months to <2 years.
Since the film-coated IR tablet and TfOS have similar formulations and tablet 
compositions, and the IR tablets and an oral solution had similar PK in previous studies, 
no dose adjustment between preparations is required. All dose levels are administered 
QD, except the lowest dose step possible, 0.125 mg QD, which is administered as 0.25 
mg three times weekly (TIW). The 0.125 mg QD dose and 0.25 mg TIW dose are 
expected to achieve similar Hgb response as was observed when 2 QD doses, 
administered as TIW doses, resulted in similar Hgb responses [Bailey, 2019]. The study 
intervention is described in Table 14 and Figure 5. 
Table 14 
Study Intervention Administered 
Intervention Label 
Daprodustat 
Type 
IR tablets 
TfOS 
Dose Formulation 
IR tablets: round, bi-convex, film coated tablets. 
•
Tablet strengths of 1 mg (gray), 2 mg (yellow) and 4 mg (white) are 7 mm
in diameter.
•
Tablet strengths of 6 mg (pink) and 8 mg (orange) are 9 mm in diameter.
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TfOS: bi-convex, film coated tablets. 
•
The 0.25 mg strength tablets are green, round, bi-convex and 6 mm in
diameter.
•
The 1.5 mg strength tablets are purple 8.5 x 4.5 mm oval and bi-convex.
•
The 2 mg strength tablets are white 8.5 x 4.5 mm oval and bi-convex.
There are no score lines for any of the current tablet formulations. 
Unit Dose 
Strength(s) 
IR tablet strengths: 
•
1 mg, 2 mg, 4 mg, 6 mg and 8 mg
TfOS: 
•
0.25 mg, 1.5 mg and 2.0 mg
Dosage Level(s) 
QD dosing dose steps with IR tablets: 
•
1 mg, 2 mg, 3 mg, 4 mg, 6 mg, 8 mg, 12 mg, 16 mg, 24 mg
QD dosing dose steps with TfOS: (except *) 
•
0.25 mg, 0.5 mg, 0.75 mg, 1 mg, 1.5 mg, 2 mg, 3 mg, 4 mg, 6 mg, 8 mg,
12 mg, 16 mg
(* The 0.125 mg QD dose step is achieved as a 0.25 mg dosed three time
weekly [TIW])
Route of 
Administration 
Oral 
Use 
Experimental 
IMP or NIMP 
IMP 
Sourcing 
Provided centrally by the Sponsor 
Packaging and 
Labelling 
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. 
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Figure 5 
IR and TfOS Dosage Steps 
IR QD dosing 
TfOS QD dosing 
Up to 4 TfOS can be suspended in a 5 mL volume and up to 8 tablets require a total volume of 
10 mL. 
TfOS TIW dosing
The 0.125 mg QD dose step is achieved by oral administration of 0.25 mg TfOS TIW
The excipients used in the IR and TfOS are safe for administration in the pediatric 
population participating in the study. To ensure dosing is well within excipients limits 
with TfOS, the maximum number of tablets able to be taken per age group has been 
defined as follows: 
•
8 TfOS in the 6 to <12 years age group (equating to a top dose of 16 mg)
•
6 TfOS in the 2 to <6 years age group (equating to a top dose of 12 mg)
•
4 TfOS in the 3 months to <2 years age group (equating to a top dose of 8 mg)
To support the correct dispensing of study medication for each study participant 
throughout the study, the IRT will be programmed with the starting dose based on their 
baseline status (Hgb, ESA usage and dialysis status, see Section 4.4) and any dose 
adjustment required based on their Hgb response to daprodustat (see Section 4.5). 
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6.2. 
Preparation, Handling, Storage and Accountability 
The investigator or designee must confirm appropriate temperature conditions (see 
Pharmacy Manual) have been maintained during transit for all daprodustat received and 
any discrepancies are reported and resolved before use of daprodustat. 
Only participants enrolled in the study may receive study intervention (daprodustat) and 
only authorized site staff may supply or administer study intervention. All study 
interventions 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 intervention accountability, reconciliation, and record maintenance 
(i.e., receipt, reconciliation, and final disposition records). 
Further guidance and information for the final disposition of unused study intervention 
are provided in the Pharmacy Manual.  
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. 
6.3. 
Measures to Minimize Bias: Randomization and Blinding 
This is an open-label, single arm study. All screened participants will be identified by a 
unique participant number that will remain consistent for the duration of the study. Upon 
completion of all the required screening assessments, eligible participants will be 
registered into the study by the investigator or authorized site staff.  
6.4. 
Study Intervention Compliance 
Participants who administer daprodustat at home will be instructed to return all unused 
medication at each clinic visit. A record of the number of daprodustat tablets, dispensed 
to and taken by, each participant will be maintained and reconciled with study 
intervention and compliance records. Deviation(s) from the prescribed dosage regimen 
should be recorded. 
Daprodustat start and stop dates, including dates for study intervention delays and/or dose 
reductions will also be recorded in the eCRF. At Week 2 and for any UNS (at any time) 
or extra Hgb (after Week 28) Visits, compliance checking will only be performed if the 
dose of daprodustat is changed. 
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6.5. 
Dose Modification 
The dose of daprodustat should be adjusted according to Hgb response (see Section 4.6) 
using the age-specific dosing algorithm (see Section 4.5). The maximum dose in this 
study is 24 mg QD (12 to <18 years age group only) and the dosing in the younger age 
groups (<12 years of age) should not exceed that specified in Table 10 in Section 4.5.2.  
6.6. 
Continued Access to Study Intervention after the End of the 
Study 
There is no existing or planned Expanded Access Program for daprodustat. If continuing 
therapy for anemia associated with CKD is needed after the completion of this study, 
licensed ESAs should be used as per SoC. However in line with GSK’s policy on 
compassionate use/expanded access, GSK recognizes that there may be instances when it 
is appropriate for healthcare professionals to seek an unapproved medicine for treatment 
use for a patient where no satisfactory alternative exists. Unsolicited requests for 
continued access to daprodustat for participants of this trial will be considered where 
licensed ESAs are not suitable.  
6.7. 
Treatment of Overdose 
There is no specific antidote for overdose with daprodustat. The expected manifestations 
of daprodustat overdosage include signs and symptoms associated with an excessive 
and/or rapid increase in Hgb concentration. Daprodustat is highly protein bound; thus, 
clearance of daprodustat by HD or PD is very low and these are not effective methods to 
enhance the elimination of daprodustat. Daprodustat metabolites are, in part, cleared via 
HD. In the event of a suspected overdose, it is recommended that the appropriate 
supportive clinical care be instituted, as dictated by the participant’s clinical status.  
In the event of an overdose, the investigator/treating physician should: 
•
Contact the medical monitor immediately.
•
Closely monitor the participant for AE/SAE and laboratory abnormalities until
daprodustat can no longer be detected systemically (at least 5 days).
•
Document the quantity of the excess dose as well as the duration of the overdosing in
the eCRF.
Decisions regarding dose interruptions or modifications will be made by the investigator 
in consultation with the medical monitor based on the clinical evaluation of the 
participant. 
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6.8. 
Concomitant Therapy 
Unless specified as a prohibited medication in Section 6.8.1, all concomitant medications 
should be considered permitted provided they are not contraindicated for the individual 
participant concerned. 
Co-administration of daprodustat with moderate CYP2C8 inhibitors (e.g., clopidogrel, 
teriflunomide, deferasirox) should be performed with caution. If one of these medications 
is started, stopped or the dose is changed, the Hgb should be checked at the next study 
visit or, between Weeks 28 to 52, an extra Hgb check Visit should be performed if the 
next study visit is not due within 4 weeks, see Section 4.6. 
Any medication or vaccine (including over-the-counter or prescription medicines, 
vitamins, and/or herbal supplements) that the participant is receiving at the time of 
enrollment or receives during the study must be recorded, along with: 
•
reason for use,
•
dates of administration including start and end dates, and
•
dosage information including dose and frequency.
The study medical monitor should be contacted if there are any questions regarding 
concomitant or prior therapy. 
6.8.1. 
Prohibited Medications 
Use of any of the following prescription drugs, from Screening until 7 days after the last 
dose of daprodustat, is prohibited and will constitute a protocol violation: 
•
Strong inhibitors of CYP2C8 (e.g., gemfibrozil)
•
Strong inducers of CYP2C8 (e.g., rifampin/rifampicin)
•
ESA agents (rhEPO and its analogues‡ and other HIF-PHIs if approved for
pediatric use during the conduct of this study).
•
No other investigational agents (including other HIF-PHIs) or devices are
permitted from study entry through completion of the study.
‡ For participants receiving ESA treatment prior to study entry, the investigator should schedule the Day 1 
Visit (and Screening Visit, if intending Screening and Day Visits are the same day) to coincide, as 
closely as possible, with the date of the next scheduled ESA administration. Examples are provided in 
the table below: 
ESA Schedule 
Last ESA Dose 
Day 1 (Baseline) 
TIW 
Monday 
Tuesday 
Wednesday 
Wednesday 
Thursday 
Friday 
Weekly 
Wednesday 
Following Wednesday 
Every two weeks 
2 weeks before Day 1 
2 weeks after last ESA dose 
Every four weeks 
4 weeks before Day 1 
4 weeks after last ESA dose 
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In general, GSK study participants can be vaccinated against COVID-19 using vaccines 
authorized via limited regulatory mechanisms (e.g., Emergency Use Authorization) or 
approved via accelerated or full approval mechanisms. Use of other candidate COVID-19 
vaccines that have not received limited, accelerated, or full authorization/approval, and 
are only in use as part of a clinical trial, are not allowed. 
6.8.2. 
Standard of Care, including Iron Management 
During the study (from Screening until the participant’s final visit), investigators are 
expected to monitor the participant’s overall clinical status to ensure standards of care are 
met to enable consistency of practice with KDIGO guidelines or local equivalent. 
Iron status is checked regularly as per the SoA (Section 1.3). If iron deplete, the 
investigator should choose the route of administration and dose of iron based on the 
participant’s iron status and local clinical practice. Investigators should be guided by 
local/regional guidelines; however it is strongly recommended that: 
•
Ferritin is maintained >100 ng/mL.
•
TSAT is maintained >20%.
•
Iron (excluding multivitamins) is not administered in the following situations:
o
Ferritin >800 ng/mL and TSAT >20%, or
o
TSAT >40%.
6.8.3. 
Rescue Therapy 
The use of rescue therapy is at the discretion of the investigator. 
For Anemia: 
Rescue therapy may be needed if Hgb fails to respond adequately despite dose 
adjustment or the participant is unable to tolerate daprodustat. 
If a participant has a low Hgb as a result of an acute or subacute event with an 
identifiable cause (e.g., GI bleed, blood loss due to surgery, vascular access or trauma), 
the treatment should be directed to the specific cause. Daprodustat should be continued at 
the current dose unless Hgb is >12.0 g/dL as a consequence of a blood transfusion, in 
which case according to Section 4.6, the daprodustat dose should be decreased (Hgb 
>12.0 to <12.5 g/dL) or withheld (Hgb >12.5 g/dL) and Hgb checked again at the next
scheduled study visit or at an extra study visit within the next 4 weeks if a study visit is
not due in that time frame.
Blood transfusions 
Blood transfusions should only be given if, in the opinion of the investigator, the benefit 
of transfusion outweighs the risks. Any blood transfusion (whole blood/packed red blood 
cells and number of units) should be recorded in the eCRF. Daprodustat can be continued 
at the current dose unless Hgb is >12.0 g/dL as a consequence of a blood transfusion, in 
which case according to Section 4.6, the daprodustat dose should be decreased 
(Hgb >12.0 to <12.5 g/dL) or withheld (Hgb >12.5 g/dL) and Hgb checked again at the 
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next scheduled study visit or at an extra study visit within the next 4 weeks if a study visit 
is not due in that time frame. 
Need for other ESA treatment  
The use of rhEPOs and their analogues should be avoided during the study 
(Section 6.8.1). If a rhEPO is given in error, the participant can continue in the study and 
on study intervention (daprodustat) ensuring that Hgb is assessed within 4 weeks of the 
administration of the rhEPO either at the next study visit (or from Study Week 28 at an 
extra Hgb check Visit if the next study visit is not within that time frame). The dose of 
daprodustat should be adjusted if required (Section 4.5) according to the Hgb response 
(Section 4.6). 
If in the opinion of the investigator the participant needs an alternative to study 
intervention (daprodustat) then the participant should permanently discontinue 
daprodustat but otherwise should remain in the study as planned, unless they withdraw 
their consent (Section 7.1). The use of rhEPO or its analogues, and if applicable the 
reason for study intervention cessation, should be recorded in the eCRF.  
For Kidney Function: 
Rescue intervention may be needed during the study if a participant’s kidney function 
continues to deteriorate. 
Kidney Transplantation 
Participants should be screen failed if they are scheduled for an elective living donor 
kidney transplant within 3 months of study entry (Section 5.2). However, participants 
may still enroll in the study if they are being evaluated for (or confirmed as requiring) a 
kidney transplant but surgery is not yet booked. In case a suitable donor is found during 
the course of the study, and transplantation is performed, the participant should be 
withdrawn from the study (Section 7.2). 
Participants in the ND Sub-trial Transitioning to Dialysis 
Participants in the ND sub-trial who need to start dialysis should not be withdrawn from 
the study and should continue on study intervention (daprodustat), aiming to keep their 
Hgb within the target range of 10 to 12 g/dL (Section 4.6) as per the dose adjustment 
algorithm (Section 4.5).  
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7.
DISCONTINUATION OF STUDY INTERVENTION AND
PARTICIPANT DISCONTINUATION/WITHDRAWAL
The definition of EOS, “study completers” and “treatment completers” is provided in 
Section 4.8. Discontinuation of specific sites or of the study as a whole are detailed in 
Section 10.1. 
7.1. 
Discontinuation of Study Intervention 
In rare instances, it may be necessary for a participant to permanently discontinue study 
intervention. Participants must be permanently discontinued from treatment with 
daprodustat for any of the following reasons:  
•
Pregnancy: Any female participant who becomes pregnant.
•
Receives a diagnosis of cancer (with the exception of localized squamous cell or
basal cell carcinoma).
•
Need for, or use of, prohibited medications (Section 6.8.1) including use of strong
inhibitors of CYP2C8 (e.g., gemfibrozil) or strong inducers of CYP2C8 (e.g.,
rifampin/rifampicin) for ≥14 days.
•
Receives a kidney transplant (Section 6.8.3 and Section 7.2).
•
Need for rhEPO or its analogues (Section 6.8.3).
•
Meets the liver chemistry stopping criteria (Section 7.1.1).
Participants who discontinue study treatment prematurely for any reason should, where 
possible, continue in the study per protocol until the final Visit at Week 56 (except for 
kidney transplant participants who should be withdrawn from the study, see Section 7.2). 
Reasons for premature discontinuation of study treatment must be captured in the eCRF, 
e.g., AE, lack of efficacy, protocol deviation, pregnancy, investigator discretion, consent
withdrawal, lost to follow-up, study termination.
If a participant experiences an organ-threatening or life-threatening event, the 
investigator should discuss continuation of daprodustat with the GSK medical monitor. 
7.1.1. 
Liver Chemistry Stopping Criteria 
Liver chemistry stopping and increased monitoring criteria have been designed to 
assure participant safety and evaluate liver event etiology. 
Discontinuation of study intervention (daprodustat) for abnormal liver tests is required 
when: 
•
a participant meets one of the conditions outlined in the Liver Stopping and
Monitoring Event Algorithm (Figure 6), or
•
in the presence of abnormal liver chemistry not meeting protocol-specified
stopping rules, if the investigator believes that it is in the best interest of the
participant.
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Figure 6 
Liver Stopping and Monitoring Event Algorithm 
Abbreviations: ALT = alanine aminotransferase; INR = international normalized ratio; SAE = serious adverse event; 
ULN = upper limit of normal 
If the ALT is ≥3×ULN but <8×ULN and according to Figure 6 study intervention 
(daprodustat) can be continued with increased liver chemistry monitoring, the increased 
liver chemistry monitoring should be performed as shown in Figure 7. 
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Figure 7 
Liver Chemistry Increased Monitoring Algorithm with Continued 
Study Intervention for Participants with ALT ≥3×ULN but <8×ULN 
Abbreviations: ALT = alanine aminotransferase; INR = international normalized ratio; SAE = serious adverse event; 
ULN = upper limit of normal 
Refer to Appendix 5 for required Liver Safety Actions and Follow-up Assessments. 
7.1.2. 
QTc Stopping Criteria 
There is no QTc stopping criterion, as per the adult Phase 3 studies, in view of the 
reassuring Thorough QT study and no concerns identified to date. 
7.1.3. 
Temporary Discontinuation 
As described in Table 11 in Section 4.6, if the Hgb is >12.5 g/dL, daprodustat should be 
temporarily withheld and checked in 4 weeks at the next study visit (or from Study 
Week 28 an extra Hgb check Visit should be performed 4 weeks later if the next 
scheduled visit is not within that timeframe). Restart is permitted at the next lower dose 
when the Hgb is ≤12.0 g/dL. 
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7.1.4. 
Rechallenge 
7.1.4.1. 
Study Intervention Restart or Rechallenge after liver stopping criteria 
met 
Study intervention restart or rechallenge after liver chemistry stopping criteria are met by 
any participant in this study is not allowed. 
7.2. 
Participant Discontinuation/Withdrawal from the Study 
The legal guardian and the pediatric participant have the right to withdraw permission 
(consent or assent, respectively) at any time during the study. If the study staff identify 
any reluctance in the legal guardian or pediatric participant (e.g., signs of verbal or 
physical dissent) about continued participation in the study, the pediatric participant’s 
continuation in the study should be re-evaluated. The same principles that govern 
permission/assent/consent also govern its withdrawal.  
A participant will be withdrawn from the study for the following reason: 
•
Withdrawal of consent or assent if applicable (a pediatric participant’s dissent should
be respected).
•
Undergoes a kidney transplant.
At the time of discontinuation from the study, if possible, an early discontinuation visit 
should be conducted. See the SoA (Section 1.3) for data to be collected at the time of 
study discontinuation and follow-up and for any further evaluations that need to be 
completed. The participant will be permanently discontinued both from the study 
intervention (if applicable) and from the study at that time. 
If the participant withdraws consent for disclosure of future information, the sponsor may 
retain and continue to use any data collected before such a withdrawal of consent. 
If a participant withdraws from the study, he/she may request destruction of any samples 
taken and not tested, and the investigator must document this in the site study records. 
7.3. 
Lost to Follow-Up 
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. 
The following actions must be taken if a participant fails to return to the clinic for a 
required study visit: 
•
The site must attempt to contact the participant and reschedule the missed visit as
soon as possible and counsel the participant on the importance of maintaining the
assigned visit schedule and ascertain whether the participant wishes to and/or should
continue in the study.
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•
Before a participant is deemed lost to follow-up, the investigator or designee must
make every effort to regain contact with the participant and/or caregiver (where
possible, 3 telephone calls and, if necessary, a certified letter to the participant’s last
known mailing address or local equivalent methods). These contact attempts should
be documented in the participant’s medical record.
•
Should the participant continue to be unreachable, he/she will be considered to have
withdrawn from the study.
•
Site personnel, or an independent third party, will attempt to collect the vital status of
the participant within legal and ethical boundaries for all participants enrolled,
including those who did not get study intervention. Public sources may be searched
for vital status information. If vital status is determined as deceased, this will be
documented and the participant will not be considered lost to follow-up. Sponsor
personnel will not be involved in any attempts to collect vital status information.
Discontinuation of specific sites or of the study as a whole are handled as part of 
Section 10.1.9. 
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8.
STUDY ASSESSMENTS AND PROCEDURES
Study procedures and their timing are summarized in the SoA (Section 1.3). 
Protocol waivers or exemptions are not allowed. 
Where applicable country and local regulations and infrastructure for home healthcare 
allow, home healthcare may take place at home or alternative approved locations other 
than the clinical trial site to perform study assessments (at the discretion of the 
investigator). The site may work with GSK to use a centrally appointed home nursing 
vendor for conduct of study assessments. 
Immediate safety concerns should be discussed with the sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or discontinue 
study intervention. 
Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct. 
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable. 
Procedures conducted as part of the participant’s routine clinical management (e.g., blood 
count) and obtained before signing of ICF may be utilized for screening or baseline 
purposes provided the procedure met the protocol-specified criteria and was performed 
within the timeframe defined in the SoA (Section 1.3). 
The maximum amount of blood collected from each participant over the duration of the 
study does not exceed recommendations for blood sampling in a pediatric population by 
age or weight (see Table 12). 
Race and ethnicity will be collected for all participants in order to satisfy regulatory 
requirements for some jurisdictions and to allow appraisal of the extent to which 
disadvantaged and minority groups are represented in the trial population. 
8.1. 
Efficacy Assessments 
The dose response of participants to daprodustat will be assessed by measurement of 
Hgb. Hgb also serves to determine where a dose change is needed, see Section 4.6. 
Planned timepoints for all Hgb assessments are provided in the SoA. Hgb should be 
checked and the dose adjusted if required, as defined in the protocol in Section 4.6 and 
Section 4.5 respectively. 
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8.2. 
Safety Assessments 
Planned time points for all safety assessments are listed in the SoA (Section 1.3). 
Additional time points for safety tests (such as vital signs, physical examinations and 
laboratory safety tests) may be added during the course of the study based on newly 
available data to ensure appropriate safety monitoring. 
8.2.1. 
Physical Examinations 
Children and adolescents with CKD, particularly those with ESKD, are frequently growth 
impaired, so at a given age, they can often be expected to have the weight of a 
smaller/younger child/adolescent. 
Height (or supine length in the very young) and weight will be measured at each study 
visit as appropriate for the participant’s age and plotted on age and gender appropriate 
charts as per SoC at that site, for example using height z scores for chronological age and 
body mass index (BMI) z scores for height age (the age corresponding to the 50th 
percentile of the participant’s measured height) as a means of monitoring percentile-
parallel growth and weight gain. Any unexpected persistent change in trajectory, should 
be recorded as an AE. 
The investigator should contact the medical monitor if any participant’s weight falls 
below that specified as the minimum weight for their age group (see Table 12). 
A complete physical examination will include, at a minimum, assessments of the ears, 
nose and throat, skin, cardiovascular, respiratory, GI and neurological systems. 
8.2.2. 
Vital Signs 
Vital signs will include systolic and diastolic BP and HR. 
BP and HR will be assessed using an appropriate size cuff. BP and HR should be 
preceded by at least 5 minutes of rest for the participant in a quiet setting without 
distractions (e.g., television, cell phones). Three consecutive BP measurements will be 
obtained, of which the median will be recorded. 
8.2.3. 
Electrocardiogram 
A 12-lead ECG for screening exclusion criterion (see Section 5.2) will be obtained in the 
supine position. HR, PR interval, QRS duration and QT (uncorrected) interval will be 
measured. QTcF will be calculated (machine-read or manually). If prolonged QT/QTcF is 
noted, 2 additional ECGs measurements should be obtained. Determination of whether 
eligibility criteria are met will be based on the average of the triplicate assessment. 
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There is no QT stopping criteria Section 7.1.2 and no further ECG monitoring is required 
unless indicated as part of routine care of the participant. 
8.2.4. 
Clinical Safety Laboratory Tests 
See Appendix 2 for the list of clinical laboratory tests to be performed and to the SoA for 
the timing and frequency.  
The investigator must review the local laboratory report, document this review, and 
record any clinically significant changes occurring during the study in the AE section of 
the eCRF. The laboratory reports must be available as source documents.  
Abnormal laboratory findings associated with the underlying disease are not considered 
clinically significant, unless judged by the investigator to be more severe than expected 
for the participant’s condition. 
All laboratory tests with values considered clinically significantly abnormal during 
participation in the study or within 4 weeks after the last dose of study intervention 
should be repeated until the values return to normal or baseline or are no longer 
considered significantly abnormal by the investigator or study medical monitor. If such 
values do not return to normal/baseline within a period of time judged reasonable by the 
investigator, the etiology should be identified and the sponsor notified. 
All protocol-required laboratory tests (as defined in Section 10.2) and the PK sampling 
(see Section 8.4.1), must be conducted in accordance with the SoA (Section 1.3) and the 
laboratory manual (for PK sampling). 
If laboratory values from non-protocol-specified laboratory tests performed at the 
institution’s local laboratory require a change in participant management or are 
considered clinically significant by the investigator (e.g., SAE or AE or dose 
modification), then the results must be recorded in the eCRF. 
8.2.5. 
Pregnancy Testing 
Refer to Section 5.1 for pregnancy testing inclusion criteria. 
Pregnancy testing in FOCBP should be conducted at each study visit, including the 
56-week follow-up visit. Pregnancy testing may consist of a:
•
serum hCG test, or
•
urine hCG test if the eGFR is higher than 15mL/min/1.73m2.
Additional serum or urine pregnancy tests may be performed, as determined necessary by 
the investigator, or required by local regulation, to establish the absence of pregnancy at 
any time during the participant’s participation in the study. 
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8.3. 
Adverse Events (AEs), Serious Adverse Events (SAEs) and 
Other Safety Reporting 
The definitions of AEs or SAEs can be found in Section 10.3. 
AEs will be reported by the participant (or, when appropriate, by a caregiver, surrogate, 
or the participant’s legally authorized representative). 
The investigator and any qualified designees are responsible for detecting, documenting, 
and reporting events that meet the definition of an AE or SAE and remain responsible for 
following up AEs that are serious, considered related to the study intervention or the 
study, or that caused the participant to discontinue the study intervention (see  
Section 7.1). 
The method of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Section 10.3. 
8.3.1. 
Time Period and Frequency for Collecting AE and SAE 
Information 
All AEs and SAEs will be collected from the signing of informed consent until the 
follow-up visit (Week 56) at the time points specified in the SoA (Section 1.3). 
All SAEs will be recorded and reported to the sponsor or designee immediately and under 
no circumstance should this exceed 24 hours, as indicated in Appendix 3. 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 information on AEs or SAEs after the 
conclusion of the study participation. However, if the investigator learns of any SAE, 
including a death, at any time after a participant has been discharged from the study, and 
he/she considers the event to be reasonably related to the study intervention or study 
participation, the investigator must promptly notify the sponsor. 
8.3.2. 
Method of Detecting AEs and SAEs 
Clinical Presentation of Adverse Events: 
Study site staff should instruct the legal guardians and caregivers, on how to report signs 
and symptoms (e.g., crying and pain) in the individual pediatric participant. They will be 
instructed to report both specific and non-specific symptoms (including vomiting, 
diarrhea, sleepiness, variation in the intensity and pattern of crying, etc.). These non-
specific symptoms may be the only manifestations of some adverse reaction observed in 
young children. Care should be taken that the clinical presentation of adverse reactions is 
not misinterpreted as the manifestation of a pre-existing or unrelated condition. 
Care will be taken not to introduce bias when detecting an AE and/or SAE. Open-ended 
and non-leading verbal questioning of the participant is the preferred method to inquire 
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about AE occurrence. 
8.3.3. 
Follow-up of AEs and SAEs 
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. All SAEs, and AESIs (as defined in 
Section 8.3.6), will be followed until the event is resolved, stabilized, otherwise 
explained, or the participant is lost to follow-up (as defined in Section 7.3). Further 
information on follow-up procedures is given in Section 10.3.3. 
8.3.4. 
Regulatory Reporting Requirements for SAEs 
Prompt notification by the investigator to the sponsor of an SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of 
a study intervention under clinical investigation are met. 
The sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study intervention under clinical 
investigation. The sponsor will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, IRB/IEC and investigators. 
An investigator who receives an investigator safety report describing an SAE or other 
specific safety information (e.g., summary or listing of SAEs) from the sponsor will 
review and then file it along with the IB and will notify the IRB/IEC, if appropriate 
according to local requirements. 
Investigator safety reports must be prepared for suspected unexpected serious adverse 
reaction (SUSAR) according to local regulatory requirements and sponsor policy and 
forwarded to investigators as necessary. 
8.3.5. 
Pregnancy 
Details of all pregnancies in female participants will be collected after the start of study 
intervention and until 30 days after the last dose of study intervention. 
If a pregnancy is reported, the investigator will record pregnancy information on the 
appropriate form and submit it to GSK within 24 hours of learning of the female 
participant’s pregnancy. While pregnancy itself is not considered to be an AE or SAE, 
any pregnancy complication or elective termination of a pregnancy for medical reasons 
will be reported as an AE or SAE. 
Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAEs and will be reported as 
such. 
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The participant will be followed to determine the outcome of the pregnancy. The 
investigator will collect follow-up information on the participant and the neonate, and the 
information will be forwarded to the sponsor. 
Any post-study pregnancy-related SAE considered reasonably related to the study 
intervention by the investigator will be reported to the sponsor. While the investigator is 
not obligated to actively seek this information in former study participants he or she may 
learn of an SAE through spontaneous reporting. 
Any female participant who becomes pregnant while participating in the study will 
discontinue study intervention (Section 7.1). 
8.3.6. 
Adverse Events of Special Interest 
The investigator or site staff will be responsible for detecting, documenting and reporting 
any events that may represent the AESIs listed below (using preferred terms): 
•
Death, MI, stroke, HF, thromboembolic events, thrombosis of vascular access.
•
Thrombosis and/or tissue ischemia secondary to excessive erythropoiesis.
•
New diagnosis of hypertension or worsening of existing hypertension.§
•
Cancer related mortality and tumor progression and recurrence.
•
Esophageal and gastric erosions.
The results of any investigation should be recorded on the AE page and the relevant 
AESI page of the participant’s eCRF. 
8.3.7. 
Tertiary Endpoints 
8.3.7.1. 
Other Health Outcomes of Interest 
The incidence of the protocol-defined health outcomes of interest listed in Section 9.3.2.4 
are of particular importance in a pediatric population with anemia associated with CKD. 
At each visit, the investigator should indicate in the eCRF if one of these outcomes has 
occurred in the interval since the last study visit, ensuring that the details of any such 
outcomes are reported in the AE and/or concomitant medication eCRF pages as 
appropriate. 
§ Worsening of existing hypertension defined as occurrence of one or more of the following:
•
New resistant hypertension: hypertension despite treatment with at least 3 (maximal or maximally
tolerated doses of) antihypertensive medications.
•
Hypertensive emergency: severely elevated BP associated with acute end-organ damage.
•
Hypertensive urgency: severely elevated BP without the presence of acute end-organ damage.
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8.3.7.2. 
Acceptability and Palatability Assessment 
The acceptability and palatability of the 2 formulations used in this study (IR and TfOS) 
will be assessed by a participant questionnaire at Week 2. 
8.4. 
Pharmacokinetics 
8.4.1. 
Integrated PK Phase 
Blood samples for determination of daprodustat and its major metabolites plasma 
concentration will be collected post dosing on Day 1, and, prior and post dosing at 
Week 2. If the PK samples are not convenient to perform at the Week 2 Study Visit, then 
these can be deferred to Week 4, as indicated in the SoA (Section 1.3). The 4 PK samples 
at Week 2 may also be split between Weeks 2 and 4 provided the dose of daprodustat is 
taken in clinic (to be sure of the exact time of dosing) and the 4 samples taken across the 
2 Study Visits at Weeks 2 and 4 cover all 4 time intervals required (pre-dose, 0.5 to 
1.5 hour [h], >1.5 to 3 h and ≥4 to 8 h). 
At Day 1 and at Week 2 (or if needed at Week 4), the daily dose of daprodustat should be 
taken in the clinic and not at home. This information is summarized below: 
At Day 1: 
•
Take the first dose whilst still in the clinic.
•
Then take 3 samples: 0.5 to 1.5 h, >1.5 to 3 h and ≥4 h time (maximum 8 h)
intervals after taking the first dose of daprodustat. These limited time point
samples are needed to compare with repeat dose data.
At Week 2 Visit (and/or at Week 4 if not fully performed at Week 2): 
•
Take the pre-dose sample.
•
Then take the morning dose (as previously dispensed) whilst still in the clinic (the
participant should not have taken the dose at home before the visit).
•
Then take 3 further samples: 0.5 to 1.5 h, >1.5 to 3 h and ≥4 h time (maximum
8 h) intervals post dose.
Note: 
•
If a participant is allocated to start on 0.125 mg QD (achieved by administration
of 0.25 mg TIW), dose as normal but if a 0.25 mg tablet is due to be taken on the
Week 2 (or Week 4) Visit day, the tablet should not be given at home that
morning but administered in the clinic after the pre-dose blood sample is taken.
•
If at Week 2, a participant has already taken their daprodustat dose prior to arrival
in clinic, then reschedule the PK sampling to Week 4, reminding the participant
not to take their dose at home on the day of the Week 4 visit.
•
If the PK sampling is to be done at Week 4 (having been deferred from Week 2)
and the participant has already taken their daprodustat at home the morning of the
Week 4 Visit, omit the pre-dose sample and take those post dose samples that are
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possible to collect for the time intervals 0.5 to 1.5 h, >1.5 to 3 h and ≥4 h time 
(maximum 8 h), noting the time of PK sampling in the eCRF and the participants 
as accurate as possible estimation of the time of home administration of 
daprodustat. 
•
If PK sampling is deferred to Week 4, but the participant has been put on dose
hold at Week 2 (as the Hgb is >12.5 g/dL), then PK sampling should be delayed
until the visit after daprodustat is restarted.
•
PK samples can be taken before, during or after dialysis.
The date and timing (24-hour clock time) of PK sampling, daprodustat dosing and any 
concomitant medications taken needs to be recorded for each participant. At Week 2 
(and/or Week 4), the participant needs to provide the time of last dose before the day of 
PK assessments (for the pre-dose trough estimation). A PK reminder card will be given to 
all participants undergoing PK assessments so they may record this time. This card will 
also serve as a reminder not to take their daprodustat dose at home on the day of the PK 
assessments. 
Approximately 1.0 mL of blood (0.5 mL of plasma) is required for the assay. Therefore, 
the total blood volume for PK sampling on any occasion, and over the 2 (or 4) week 
sampling period in the PK Phase, will not exceed ~7 mL, ~1.09% of blood volume of a 
1 year old child (assuming 80 mL/kg and 8 kg body weight). Together with the other 
blood draws required in the first 4 weeks, given that the minimum body weight required 
at study entry is 5 kg (see Table 12), the total volume of blood required will not exceed 
the recommended 1% blood volume draw limit per day or 3% blood volume draw limit 
over 4 weeks [Paediatric Population: Recommendations, 2008, Minors: 
Recommendations, 2017].  
Processing, storage, and shipping procedures are provided in the laboratory manual. 
8.4.2. 
Optional PK Sampling 
For participants who cannot participate in the Integrated PK Phase as this is now closed 
in their age group, there will also be an opportunity to contribute to the PK dataset 
between Day 1 and Week 4. The sampling will replicate the requirements and schedule as 
described in the Integrated PK Phase (Section 8.4.1), but this is entirely optional. 
8.5. 
Genetics 
Genetics are not evaluated in this study. 
8.6. 
Biomarkers 
Biomarkers are not evaluated in this study. 
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8.7. 
Immunogenicity Assessments 
Not applicable. 
8.8. 
Medical Resource Utilization and Health Economics 
Medical resource utilization and health economics parameters are not evaluated in this 
study. 
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9.
STATISTICAL CONSIDERATIONS
The statistical analysis plan (SAP) will include a more technical and detailed description 
of the statistical analyses described in this section. A separate analysis plan will include 
details of the population PK modelling. This section is a summary of the planned 
statistical analyses of the study endpoints. The 2 sub-trials (ND/D), as per their 
recruitment and conduct, will be analyzed and reported separately (overall and within 
each age group, except for PK and dose change which is within each age group only). 
9.1. 
Statistical Hypotheses 
There are no formal hypotheses pre-specified. 
This study is designed to provide information on the PK profile within the trial (to 
confirm the appropriate starting dose and dose adjustment algorithm, as predicted by a 
PBPK model to achieve similar drug exposures in the pediatric population to adults) and 
at the end of the trial used for a Population PK model to derive the PK parameters Cmax 
and AUC in a pediatric population, as well as inform the safety and Hgb response of 
daprodustat over a total treatment period of 52 weeks, when used in children and 
adolescent participants aged 3 months to <18 years with anemia associated with CKD in 
ND and D populations. 
9.2. 
Analysis Sets 
For purposes of analysis, the following participant analyses sets are defined: 
Participant 
Analyses Sets 
Definition/Criteria 
Screened 
All participants who had a valid ICF and were screened for 
eligibility. 
Enrolled 
All participants who entered the study (who received study 
intervention or underwent a post screening study procedure). 
Note: screening failures (who never passed screening even if 
rescreened) and participants screened but never enrolled into the 
study (met eligibility but not needed) are excluded from the 
Enrolled analysis set as they did not enter the study. 
Safety 
All participants in the Enrolled analysis set who take at least 1 
dose of study intervention (daprodustat).  
The Safety analysis set will be used for Main Study summaries 
including: study population, safety, efficacy (Hgb) and other 
health outcomes of interest. 
Integrated PK 
All participants in the Safety analysis set who participated in the 
Integrated PK Phase of the study and who had at least 1 non-
missing PK assessment (non-quantifiable values will be 
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Participant 
Analyses Sets 
Definition/Criteria 
considered as non-missing values).  
The Integrated PK analysis set will be used for dose decision 
making during the trial (comparison of the obtained plasma 
concentration values to those predicted by the PBPK model). 
All PK 
(Integrated PK 
Phase and 
Optional 
Sampling) 
All participants in the Safety analysis who had at least 1 non-
missing PK assessment (non-quantifiable values will be 
considered as non-missing values). 
The All PK analysis set will be used for the Population PK model 
to derive the Cmax and AUC. 
9.3. 
Statistical Analyses 
9.3.1. 
PK Analyses 
During the study (Integrated PK Phase participants only): 
In each sub-trial, the PK data (all available plasma concentration data) from each age 
group will be compared with the pre-specified PK simulations using the pediatric PBPK 
model. If more than 50% of the data lie outside the 95% PIs of the PK simulations, the 
PBPK model will be updated and simulations undertaken to determine the dosing (adult 
to pediatric ratio) to be used in the next younger age group. 
A plot of the individual plasma PK concentration data overlaid with the PBPK model 
predictions will be provided. 
At the end of the study (All PK data collected): 
Population PK modelling approach will be undertaken using the All PK analysis set in 
both sub-trials, to derive Cmax and AUC of daprodustat at steady state, using the estimand 
approach as described in Section 3.1. 
Plasma concentration of daprodustat will be provided and where appropriate dose 
normalized plasma concentration of daprodustat will be summarized by nominal 
assessment time window in each age group in each sub-trial. Scatter plot of plasma 
concentration of daprodustat (dose normalized) by actual time will be plotted, separated 
where appropriate by age group and/or sub-trial. 
In addition, if sufficient data available, similar descriptive analysis and plotting as above 
will be conducted for plasma concentration data for each metabolite. 
If data permit, population PK modelling may be undertaken using all the plasma 
concentration data collected in this study, adjusting for age, weight and other covariates 
where needed, for daprodustat and/or each metabolite. 
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The final population PK model for daprodustat or its metabolites in adults will be used as 
the basis when conducting the modelling in the pediatric population. 
Full details of the population PK analyses will be provided in the analysis plan, and 
results will be reported separately. 
9.3.2. 
Main Study Analyses 
All analyses will be performed on the Safety Population using the estimand approach as 
described in Section 3.2. 
9.3.2.1. 
Primary Safety Analyses 
The primary endpoint for this study is the incidence of AEs, SAEs, AESIs and AEs 
leading to study intervention discontinuation. The number and percentage of participants 
with each event of interest will be produced separately in each sub-trial (ND/D), overall 
and by each age group. 
AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
coding dictionary and summarized by preferred term and System Organ Class. All AEs, 
SAEs, AESI, and AEs leading to study intervention discontinuation will be summarized 
as described in Section 3.2. Any AEs and SAEs prior to Day 1 and commencement of 
daprodustat will be summarized separately. Separate summaries will be provided for all 
AEs, drug-related AEs, severe AEs, SAEs, fatal SAEs, AESIs and for AEs leading to 
study intervention discontinuation. 
9.3.2.2. 
Secondary Safety Analyses 
All secondary safety endpoints will be summarized descriptively separately in each sub-
trial (ND/D) overall and where appropriate within each age group. 
Change from baseline in vital signs (BP and HR), height, weight and laboratory safety 
data (urea/BUN, creatinine, electrolytes, liver function tests [LFTs], calcium and full 
blood count with differential) will be summarized descriptively.  
9.3.2.3. 
Secondary Efficacy Analyses 
The mean Hgb value, mean change in Hgb from baseline and the proportion of 
participants with Hgb above, below and within the target range endpoints will be assessed 
at each study time point in each of the sub-trials, overall (all ages) and in each age group 
and additionally overall (all ages) by ESA use at study enrollment. The effect of 
daprodustat on maintenance of Hgb and need for change in required daprodustat dose 
over time will also be summarized. 
Descriptive statistics will be presented in tabular and graphical format for mean Hgb 
value and mean change from baseline. No inferential testing will be performed. Line 
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plots of mean Hgb value over time will be produced. In addition, individual plots will be 
presented for Hgb values. The number and the percentage of participants with Hgb 
above, below or within the target range will be produced at each study visit. 
The other secondary efficacy endpoints that describe the change in the required dose over 
time will be summarized and presented in each age group. The assigned dose by visit will 
be summarized using mean, SD, minimum, P25, median, P75, and maximum. In addition, 
the assigned dose by visit will also be summarized by using the number and percentage 
of participants assigned to each dose level. Stacked bar graphs displaying assigned dose 
at all scheduled visits starting with Day 1 will be provided. During the course of the 
study, the number and percentage of participants with 0, 1, 2…, 10, or >10 dose 
adjustments will be summarized in each age group. In addition, the number of dose 
adjustments per participant will be presented using summary statistics. 
The Hgb data collected from each study population over the total 52 weeks may be 
utilized (after the study) to develop a population PK/pharmacodynamic (dose-Hgb) 
model. This modelling work will be based on the dose-Hgb model that will be developed 
from the adult global Phase 3 studies. 
9.3.2.4. 
Tertiary Endpoints 
Other Health Outcomes of Interest 
During the study, the incidence of other health outcomes of interest listed below, will be 
presented using summary statistics (i.e., the number and percentage of participants) in 
each sub-trial (ND/D) overall and where appropriate within each age group. 
•
Related to Hgb and rescue therapy:
o
Use of iron supplements (oral/IV/both)
o
Blood transfusion
o
Use of rhEPO and analogues
•
Related to changes in kidney function or intervention:
o
Transplantation
o
ESKD (ND only)
o
Switch between dialysis modalities (D only)
•
Other:
o
Death
o
All-cause hospitalization
o
Thrombosis (defined as: vascular access thrombosis, deep vein thrombosis or
pulmonary embolism)
o
All-cause loss of vascular access patency.
Acceptability and Palatability Assessment 
The acceptability and palatability of the 2 formulations used in this study (IR and TfOS), 
as assessed by a participant questionnaire at Week 2, will be summarized descriptively by 
formulation.  
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9.4. 
Interim Analysis 
9.4.1. 
Integrated PK Phase 
There will be no formal interim analysis in the Integrated PK Phase. However, as 
described in Section 4.7, there are pre-defined time points when a decision is required in 
each sub-trial based on the Integrated PK Phase data. 
Twenty-four participants across all age groups in each sub-trial population (ND/D) are 
required to provide PK data in the Integrated PK Phase, with a minimum of 4 participants 
in each age group. As recruitment will be harder as the age groups get younger, it is 
envisioned to recruit to the Integrated PK Phase in each sub-trial (ND/D) approximately 
the following: 10, 6, 4 and 4 participants for the age groups 12 to <18 years, 6 to <12 
years, 2 to <6 years and 3 months to <2 years respectively. 
After the required number of participants have completed the 4 week Integrated PK 
Phase and the PK data has been analyzed, meetings with the GSK Study Team will be 
held to review the following from that age group’s 4-week Integrated PK Phase: 
•
Actual PK data, in comparison to the PBPK model predictions.
•
Hgb response up to Week 4 and any excursions outside the target range.
•
Listing of safety events: AEs, SAEs, AESIs and AEs leading to study intervention
discontinuation occurring during the 4-week PK Phase observation period.
In addition, Hgb and safety data available from all ages in each sub-trial to date will also 
be provided. 
The GSK Study Team will then make a proposal for the ratio of the pediatric to adult 
dose ratio for the next younger age group. This proposal along with the above raw data, 
will be shared with the IDMC, who are required to confirm: 
•
If further recruitment from the same age group can proceed with optional PK
assessment.
•
If limited recruitment (requiring the Integrated PK Phase) to the next (younger)
age group can be allowed.
•
The dosing strategy (starting dose and dose adjustment algorithm limits) in the
next younger age group.
Figure 2 (in Section 4.1) illustrates the IDMC decision points in the trial and Table 15 
illustrates the total of the 10 IDMC decisions required at the 4 distinct time points (which 
is repeated independently for each sub-trial [ND/D] population). 
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Table 15 
Decisions Required After Each Integrated PK Phase 
Decision 
point 
PK data 
available 
Decision required 
1 
12 to <18 
years 
1.
Allow further recruitment for the current age group of 12 to
<18 years (with optional PK)
2.
Permit limited recruitment (n>4) to the study with Integrated PK
Phase in the next younger age group (6 to <12 years)
3.
Confirm dosing strategy for the next younger age group (6 to
<12 years)
2 
6 to <12 
years 
4.
Allow further recruitment for the current age group of 6 to
<12 years (with optional PK)
5.
Permit limited recruitment (n>4) to the study with Integrated PK
Phase in the next younger age group (2 to <6 years)
6.
Confirm dosing strategy for the next younger age group (2 to <6
years)
3 
2 to <6 
years 
7.
Allow further recruitment for the current age group of 2 to <6 years
(with optional PK)
8.
Permit limited recruitment (n>4) to the study with Integrated PK
Phase in the youngest age group (3 months to <2 years)
9.
Confirm dosing strategy for the youngest age group (3 months to
<2 years)
4 
3 months 
to <2 years 
10. Allow further recruitment for this youngest age group of 3 months
to <2 years (with optional PK)
9.4.2. 
Main Study 
No interim analyses is planned to be performed in the main study, but can be provided if 
requested by the IDMC or Regulatory Authorities 
9.5. 
Sample Size Determination 
9.5.1. 
Integrated PK Phase 
Sample size for the Integrated PK Phase is based on feasibility, since it will be 
increasingly difficult as the age groups get younger to collect such data. Overall, 
24 participants for each sub-trial (ND/D) will provide PK data. A minimum of 4 
participants (aiming for at least the following: 10, 6, 4 and 4 participants for the 4 age 
groups [oldest to youngest respectively]) with PK data from each age group is required to 
confirm (or adjust if required) the PK predicted dosing strategy for the 3 younger age 
groups. 
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9.5.2. 
Main Study 
In each sub-trial (ND/D), a total of approximately 60 participants across all age groups 
will be enrolled. 
The sub-trials are not formally powered, but the sample size is based on feasibility and 
also ensures that frequent AEs would likely be detected. Since a minimum of 
60 participants will be exposed to daprodustat in each sub-trial, there is at least a 90% 
chance of observing at least 1 participant with the AE if the rate of the AE occurs with a 
frequency greater than 3.76%.  
Change in Hgb from baseline will be assessed at every study visit. By way of illustration, 
at the 12 week time point with 60 participants enrolled and assuming a combined 17% 
dropout and ICE rate, 50 participants are expected to have a Hgb measurement. This will 
allow estimation of mean Hgb change from baseline to Week 12 with a precision of 
0.4 g/dL, where precision is defined as the symmetrical 95% CI half width, assuming a 
population rate SD of 1.4 g/dL [KDOQI, 2006]. No sample size re-assessment is planned. 
Sufficient number of patients will be screened to enable 60 participants to be enrolled. 
The screen failure rate is estimated to be low given pre-screening in the Cohort Study 
(212914) from which these participants are recruited. 
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10.
SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight
Considerations
10.1.1. 
Regulatory and Ethical Considerations 
This study will be conducted in accordance with the protocol and with: 
•
Consensus ethical principles derived from international guidelines including the
Declaration of Helsinki and Council for International Organizations of Medical
Sciences (CIOMS) International Ethical Guidelines.
•
Applicable International Conference for Harmonisation (ICH) Good Clinical
Practice (GCP) Guidelines.
•
Applicable laws and regulations.
The protocol, protocol amendments, ICF, IB, and other relevant documents (e.g., 
advertisements) must be submitted to an IRB/IEC by the investigator and reviewed and 
approved by the IRB/IEC before the study is initiated.  
Any amendments to the protocol will require IRB/IEC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an 
immediate hazard to study participants.  
Protocols and any substantial amendments to the protocol will require health authority 
approval prior to initiation except for changes necessary to eliminate an immediate 
hazard to study participants. 
The investigator will be responsible for the following: 
• Providing written summaries of the status of the study to the IRB/IEC annually or
more frequently in accordance with the requirements, policies, and procedures
established by the IRB/IEC.
• Notifying the IRB/IEC of SAE or other significant safety findings as required by
IRB/IEC procedures.
• Providing oversight of the conduct of the study at the site and adherence to
requirements of 21 Code of Federal Regulations (CFR), ICH guidelines, the IRB/IEC,
European regulation 536/2014 for clinical studies (if applicable), European Medical
Device Regulation 2017/745 for clinical device research (if applicable), and all other
applicable local regulations.
• Reporting cases of suspected child abuse and/or neglect according to local medical
association (e.g., American Academy of Pediatrics [AAP], European Union Academy
of Paediatrics) or Health Department guidelines.
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10.1.2. 
Financial Disclosure 
Investigators and sub-investigators will provide the sponsor with sufficient, accurate 
financial information as requested to allow the sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate regulatory authorities. 
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study. 
10.1.3. 
Informed Consent and Assent Process 
Legal Guardian Consent and Pediatric Participant Assent Processes: 
•
The investigator, or a person designated by the investigator, will provide the legal
guardian with the written ICF and the participant with the assent if applicable. They
must be informed that participation is voluntary. The legal guardian will be required
to sign written consent, and the participant if applicable will be required to sign
written assent, that meets the requirements of 21 CFR 50, local regulations, ICH
guidelines, privacy and data protect requirements, where applicable, and the IRB/IEC
or study center after the nature of the study has been fully explained and before
performance of any study-related activity.
•
Assent requirements for pediatric participants may vary across regions and countries;
local regulations should be followed as appropriate.
•
The medical record must include a statement that written informed consent from the
legal guardian and assent from the pediatric participant (if deemed appropriate by
local ethics review or local regulations) were obtained before the participant was
enrolled in the study and the date the written consent and assent were obtained. The
medical record should describe how the clinical investigator determined that the
person signing the ICF was the participant’s legal guardian. The authorized person
obtaining the informed consent must also sign the ICF and assent form attesting that
the pediatric participant did not show signs of dissent particularly in those studies
including toddlers and small children; it should be written in language appropriate to
the child’s developmental and functional status.
•
Participants and their legal guardian must be re-consented and re-assented to the most
current version of the ICF(s) during their participation in the study.
•
Minor participants who assent to a study and later withdraw that assent should not be
maintained in the study against their will, even if their legal guardian still wants them
to participate.
•
Minor participants must be re-consented if they reach the age of majority during the
course of the study, in order to continue participating.
•
A copy of the informed consent and assent forms must be provided to the participant
and the participant’s legal guardian.
•
As appropriate, participants may be given the opportunity to meet privately with a
member of the site staff to ask confidential questions and to decline assent for
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confidential reasons, which, at their request, would not be shared with their legal 
guardian, unless required by local law. 
•
Stored samples will be coded throughout the sample storage and analysis process and
will not be labelled with personal identifiers. Participants may withdraw their
consent/assent for their samples to be stored for research.
10.1.4. 
Data Protection 
•
Participants will be assigned a unique identifier by the sponsor. Any participant
records or datasets that are transferred to the sponsor will contain the identifier only;
participant names or any information that would make the participant identifiable will
not be transferred.
•
The participant and legal guardian must be informed that his/her personal study-
related data will be used by the sponsor in accordance with local data protection law.
The level of disclosure must also be explained to the participant who will be required
to give consent for his/her data to be used as described in the informed consent.
•
The participant and legal guardian must be informed that his/her medical records may
be examined by Clinical Quality Assurance auditors or other authorized personnel
appointed by the sponsor, by appropriate IRB/IEC members, and by inspectors from
regulatory authorities.
10.1.5. 
Committees Structure 
10.1.5.1. 
Independent Data Monitoring Committee 
An IDMC with external experts experienced in treating pediatric patients with CKD will 
be utilized to ensure external objective review of the safety data at regular intervals 
throughout the study and to provide the decision making as outlined in Section 4.7 and 
Section 9.4.1. 
Details of the structure and function of the IDMC, and analysis plan for IDMC reviews, 
are outlined in the IDMC Charter.  
10.1.6. 
Dissemination of Clinical Study Data 
•
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 all investigators who participated in the study with a summary
of the study results and will tell the investigators what treatment their participants’
received. The investigator(s) is/are encouraged to share the summary results with the
study participants, as appropriate.
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•
Under the framework of the SHARE initiative, GSK intends to make anonymized
participant-level data from this trial available to external researchers for scientific
analyses or to conduct further research that can help advance medical science or
improve patient care. This helps ensure the data provided by trial participants are used
to maximum effect in the creation of knowledge and understanding. Requests for
access may be made through www.clinicalstudydatarequest.com.
•
The procedures and timing for public disclosure of the protocol and results summary
and for development of a manuscript for publication for this study will be in
accordance with GSK Policy.
•
GSK intends to make anonymized patient-level data from this trial available to
external researchers for scientific analyses or to conduct further research that can help
advance medical science or improve patient care. This helps ensure the data provided
by trial participants are used to maximum effect in the creation of knowledge and
understanding.
•
A manuscript will be progressed for publication in the scientific literature if the
results provide important scientific or medical knowledge.
10.1.7. 
Data Quality Assurance 
• All participant data relating to the study will be recorded on a printed case report form
(CRF) or eCRF unless transmitted to the sponsor or designee electronically (e.g.,
laboratory data). The investigator is responsible for verifying that data entries are
accurate and correct by physically or electronically signing the CRF.
• Guidance on completion of CRFs will be provided in the CRF Guidelines.
• Quality tolerance limits (QTLs) will be pre-defined in the QTL plan to identify
systematic issues that can impact participant safety and/or reliability of study results.
These pre-defined parameters will be monitored during and at the end of the study and
all deviations from the QTLs and remedial actions taken will be summarized in the
Clinical Study Report (CSR).
• The investigator must permit study-related monitoring, audits, IRB/IEC review, and
regulatory agency inspections and provide direct access to source data documents.
• Monitoring details describing strategy including definition of study critical data items
and processes (e.g., risk-based initiatives in operations and quality such as Risk
Management and Mitigation Strategies and Analytical Risk-Based Monitoring),
methods, responsibilities, and requirements, including handling of noncompliance
issues and monitoring techniques (central, remote, or on-site monitoring) are provided
in the Monitoring Plan.
• The sponsor or designee is responsible for the data management of this study
including quality checking of the data. Detailed information about study data
collection and management process including systems used can be found in the study
Data Management Plan or equivalent Contract Research Organizations (CRO)
document.
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• The sponsor assumes accountability for actions delegated to other individuals (e.g.,
CROs).
• Records and documents, including signed ICF, pertaining to the conduct of this study
must be retained by the investigator for 25 years from the issue of the final CSR/
equivalent summary unless local regulations or institutional policies require a longer
retention period. No records may be destroyed during the retention period without the
written approval of the sponsor. No records may be transferred to another location or
party without written notification to the sponsor.
10.1.8. 
Source Documents 
•
Source documents provide evidence for the existence of the participant and
substantiate the integrity of the data collected. Source documents are filed at the
investigator’s site.
•
Data reported on the CRF or entered in the eCRF that are transcribed from source
documents must be consistent with the source documents or the discrepancies
must be explained. The investigator may need to request previous medical records
or transfer records, depending on the study. Also, current medical records must be
available.
•
Definition of what constitutes source data and its origin can be found in the
Source Data Acknowledgment.
•
The investigator must maintain accurate documentation (source data) that
supports the information entered in the CRF.
•
Study monitors will perform ongoing source data verification to confirm that data
entered into the CRF by authorized site personnel are accurate, complete, and
verifiable from source documents; that the safety and rights of participants are
being protected; and that the study is being conducted in accordance with the
currently approved protocol and any other study agreements, ICH GCP, and all
applicable regulatory requirements.
10.1.9. 
Study and Site Start and Closure 
First Act of Recruitment: 
The First Center Initiated will counted as the study start date. 
Study/Site Termination: 
GSK or designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of GSK. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study 
supplies have been collected and a study site closure visit has been performed. 
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The investigator may initiate study site closure at any time, provided there is reasonable 
cause and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the sponsor or investigator may include 
but are not limited to: 
For site termination: 
•
Failure of the investigator to comply with the protocol, the requirements of the
IRB/IEC or local health authorities, the sponsor’s procedures, or GCP guidelines
•
Inadequate or no recruitment of participants (evaluated after a reasonable amount
of time) by the investigator
•
If the study is prematurely terminated or suspended, the sponsor shall promptly
inform the investigators, the IRB/IECs, the regulatory authorities, and any
contract research organization(s) used in the study of the reason for termination or
suspension, as specified by the applicable regulatory requirements. The
investigator shall promptly inform the participant and should assure appropriate
participant therapy and/or follow-up.
10.1.10. 
Publication Policy 
• The results of this study may be published or presented at scientific meetings. If this is
foreseen, the investigator agrees to submit all manuscripts or abstracts to the sponsor
before submission. This allows the sponsor to protect proprietary information and to
provide comments.
• The sponsor will comply with the requirements for publication of study results. In
accordance with standard editorial and ethical practice, the sponsor will generally
support publication of multicenter studies only in their entirety and not as individual
site data. In this case, a coordinating investigator will be designated by mutual
agreement.
• Authorship will be determined by mutual agreement and in line with International
Committee of Medical Journal Editors authorship requirements.
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10.2. 
Appendix 2: Clinical Laboratory Tests 
The tests detailed in Table 16 will be performed by the local laboratory of the trial site. 
Protocol-specific requirements for inclusion or exclusion of participants are detailed in 
Section 5. Additional tests may be performed at any time during the study as determined 
necessary by the investigator or required by local regulations. Investigators must 
document their review of each laboratory safety report. 
Table 16 
Protocol-Required Safety Laboratory Tests 
Laboratory 
Assessments 
Parameters 
Hematology 
Platelet count 
Red blood cell indices: 
- Mean cell volume
- mean corpuscular
hemoglobin
- %Reticulocytes
White Blood Cell count 
with differential: 
Neutrophils 
Lymphocytes 
Monocytes 
Eosinophils 
Basophils 
Red blood cell count 
Hgb 
Hematocrit 
International Normalized 
Ratio (INR)1 
Clinical 
Chemistry1 
Sodium 
Potassium 
Aspartate 
aminotransferase 
(AST)/Serum 
Glutamic-
Oxaloacetic 
Transaminase 
(SGOT) 
Total and direct 
bilirubin 
Urea/Blood Urea 
Nitrogen (BUN) 
Creatinine 
Alanine 
aminotransferase 
(ALT)/Serum 
Glutamic-Pyruvic 
Transaminase 
(SGPT) 
Total protein 
Iron indices: 
- Ferritin
- Transferrin
saturation (TSAT)
Calcium 
Alkaline phosphatase2 
Pregnancy 
testing 
•
Highly sensitive human chorionic gonadotropin (hCG) pregnancy test (as
needed for FOCBP)3
NOTES: 
1.
Details of liver chemistry stopping criteria and required actions and follow-up assessments after liver
stopping or monitoring event are given in Section 7.1 and Section 10.5 All events of ALT ≥3 ULN
and total bilirubin ≥2 × ULN (>35% direct bilirubin) or ALT ≥3 × ULN and international normalized
ratio (INR) >1.5, if INR measured, which may indicate severe liver injury (possible Hy’s Law), must
be reported to GSK in an expedited manner (excluding studies of hepatic impairment or cirrhosis).
2.
If alkaline phosphatase is elevated, consider fractionating.
3.
Local urine testing will be standard for the protocol unless the eGFR is less than or equal to
15 mL/min/1.73m2 or participants are dialysis dependent, in which case serum testing is required.
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10.3. 
Appendix 3: AEs and SAEs: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting 
10.3.1. 
Definition of AE 
AE Definition 
•
An AE is any untoward medical occurrence in a clinical study participant,
temporally associated with the use of a study intervention, whether or not
considered related to the study intervention.
NOTE: An AE can therefore be any unfavorable and unintended sign (including an
abnormal laboratory finding), symptom, or disease (new or exacerbated)
temporally associated with the use of a study intervention.
Events Meeting the AE Definition 
•
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis)
or other safety assessments (e.g., ECG, radiological scans, vital signs
measurements), including those that worsen from baseline, considered clinically
significant in the medical and scientific judgment of the investigator (i.e., not
related to progression of underlying disease).
•
Exacerbation of a chronic or intermittent pre-existing condition including either an
increase in frequency and/or intensity of the condition.
•
New condition detected or diagnosed after study intervention administration even
though it may have been present before the start of the study.
•
Signs, symptoms, or the clinical sequelae of a suspected intervention- intervention
interaction.
•
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study
intervention or a concomitant medication. Overdose per se will not be reported as
an AE/SAE unless it is an intentional overdose taken with possible suicidal/self-
harming intent. Such overdoses should be reported regardless of sequelae.
•
“Lack of efficacy” or “failure of expected pharmacological action” per se will not
be reported as an AE or SAE. Such instances will be captured in the efficacy
assessments. However, the signs, symptoms, and/or clinical sequelae resulting from
lack of efficacy will be reported as AE or SAE if they fulfil the definition of an AE
or SAE.
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Events NOT Meeting the AE Definition 
•
Any clinically significant abnormal laboratory findings or other abnormal safety
assessments that are associated with the underlying disease, unless judged by the
investigator to be more severe than expected for the participant’s condition.
•
The disease/disorder being studied or expected progression, signs, or symptoms of
the disease/disorder being studied, unless more severe than expected for the
participant’s condition.
•
Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that
leads to the procedure is the AE.
•
Situations in which an untoward medical occurrence did not occur (social and/or
convenience admission to a hospital).
•
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s)
present or detected at the start of the study that do not worsen.
10.3.2. 
Definition of SAE 
An SAE is defined as any untoward medical occurrence that, at any dose, meets one or 
more of the criteria listed: 
a. Results in death
b. Is life-threatening
The term ‘life-threatening’ in the definition of ‘serious’ refers to an event in which the
participant was at risk of death at the time of the event. It does not refer to an event,
which hypothetically might have caused death, if it were more severe.
c.
Requires inpatient hospitalization or prolongation of existing hospitalization
•
In general, hospitalization signifies that the participant has been admitted
(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 outpatient setting. Complications that occur during
hospitalization are AE. If a complication prolongs hospitalization or fulfil 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 persistent or significant disability/incapacity
•
The term disability means a substantial disruption of a person’s ability to
conduct normal life functions.
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•
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) that may
interfere with or prevent everyday life functions but do not constitute a
substantial disruption.
e.
Is a congenital anomaly/birth defect
f.
Other situations:
•
Possible Hy’s Law case: ALT ≥3×ULN AND total bilirubin ≥2×ULN (>35%
direct bilirubin) or INR >1.5 must be reported as SAE
•
Medical or scientific judgment should be exercised by the investigator in
deciding whether SAE reporting is appropriate in other situations such as
significant medical events that may jeopardize the participant or may require
medical or surgical intervention to prevent one of the other outcomes listed in
the above definition. These events should usually be considered serious.
o
Examples of such events include invasive or malignant cancers,
intensive treatment for allergic bronchospasm, blood dyscrasias,
convulsions, or development of intervention dependency or intervention
abuse.
10.3.3. 
Recording and Follow-Up of AE and SAE 
AE 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)
related to the event.
•
The investigator will then record all relevant AE/SAE information.
•
It is not acceptable for the investigator to send photocopies of the participant’s
medical records to GSK in lieu of completion of the GSK required form.
•
There may be instances when copies of medical records for certain cases are
requested by GSK. In this case, all participant identifiers, with the exception of the
participant number, will be redacted on the copies of the medical records before
submission to GSK.
•
The investigator will attempt to establish a diagnosis of the event based on signs,
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not
the individual signs/symptoms) will be documented as the AE/SAE.
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Assessment of Intensity 
The investigator will make an assessment of intensity for each AE and SAE reported 
during the study and assign it to one of the following categories:  
•
Mild: Asymptomatic or mild symptoms; clinical or diagnostic observations only;
intervention not indicated.
•
Moderate: Minimal, local or non-invasive intervention indicated; limiting age-
appropriate instrumental Activities of Daily Living (ADL). Instrumental ADL
refers to preparing meals, shopping for groceries or clothes, using the telephone,
managing money, etc.
•
Severe: Severe or medically significant but not immediately life-threatening;
hospitalization or prolongation of hospitalization indicated; disabling, limiting self-
care ADL. Self-care ADL refers to bathing, dressing and undressing, feeding self,
using the toilet, taking medications, and not bedridden.
Assessment of Causality 
•
The investigator is obligated to assess the relationship between study intervention
and each occurrence of each AE/SAE. The investigator will use clinical judgment
to determine the relationship.
•
A reasonable possibility of a relationship conveys that there are facts, evidence,
and/or arguments to suggest a causal relationship, rather than a relationship cannot
be ruled out.
•
Alternative causes, such as underlying disease(s), concomitant therapy, and other
risk factors, as well as the temporal relationship of the event to study intervention
administration will be considered and investigated.
•
The investigator will also consult the IB and/or Product Information, for marketed
products, in 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 in which 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 before the initial transmission of the SAE data to GSK.
•
The investigator may change his/her opinion of causality in light of follow-up
information and send an SAE follow-up report with the updated causality
assessment.
•
The causality assessment is one of the criteria used when determining regulatory
reporting requirements.
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Follow-up of AE and SAE 
•
The investigator is obligated to perform or arrange for the conduct of supplemental
measurements and/or evaluations as medically indicated or as requested by GSK to
elucidate the nature and/or causality of the AE or SAE as fully as possible. This
may include additional laboratory tests or investigations, histopathological
examinations, or consultation with other health care professionals.
•
If a participant 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 submitted
documents.
•
The investigator will submit any updated SAE data to GSK within 24 hours of
receipt of the information.
10.3.4. 
Reporting of SAE to GSK 
SAE Reporting to GSK via Electronic Data Collection Tool 
•
The primary mechanism for reporting SAE to GSK will be the electronic data
collection tool.
•
If the electronic system is unavailable, then the site will use the paper SAE data
collection tool (see next section) to report the event within 24 hours.
•
The site will enter the SAE data into the electronic system as soon as it becomes
available.
•
After the study is completed at a given site, the electronic data collection tool will
be taken off-line to prevent the entry of new data or changes to existing data.
•
If a site receives a report of a new SAE from a study participant or receives updated
data on a previously reported SAE after the electronic data collection tool has been
taken off-line, then the site can report this information on a paper SAE form (see
next section) or to Medical Monitor by telephone.
•
Contacts for SAE reporting can be found in Study Reference Manual.
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SAE Reporting to GSK via Paper Data Collection Tool 
•
Facsimile transmission of the SAE paper data collection tool is the preferred
method to transmit this information to the Medical Monitor.
•
In rare circumstances and in the absence of facsimile equipment, notification by
telephone is acceptable with a copy of the SAE data collection tool sent by
overnight mail or courier service.
•
Initial notification via telephone does not replace the need for the investigator to
complete and sign the SAE data collection tool within the designated reporting time
frames.
•
Contacts for SAE reporting can be found in Study Reference Manual.
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10.4. 
Appendix 4: Contraceptive and Barrier Guidance 
10.4.1. 
Definitions 
Females are considered FOCBP (fertile) following menarche. For individuals with 
permanent infertility due to a medical cause, investigator discretion should be applied.
10.4.2. 
Contraception Guidance 
CONTRACEPTIVES1 ALLOWED DURING THE STUDY INCLUDE: 
Highly Effective Methods2 That Have Low User Dependency  
Failure rate of <1% per year when used consistently and correctly. 
•
Implantable progestogen-only hormone contraception associated with inhibition of ovulation2
•
Intrauterine device (IUD)
•
Intrauterine hormone-releasing system (IUS)2
•
Bilateral tubal occlusion
•
Azoospermic partner (vasectomized or due to a medical cause)
Azoospermia is a highly effective contraceptive method provided that the partner is the sole
sexual partner of the female of childbearing potential and the absence of sperm has been
confirmed. If not, an additional highly effective method of contraception should be used.
Spermatogenesis cycle is approximately 90 days.
Highly Effective Methods3 That Are User Dependent  
Failure rate of <1% per year when used consistently and correctly. 
•
Combined (oestrogen- and progestogen-containing) hormonal contraception associated with
inhibition of ovulation3
o
Oral
o
Intravaginal
o
Transdermal
o
Injectable
•
Progestogen-only hormone contraception associated with inhibition of ovulation3
o
Oral
o
Injectable
o
Sexual abstinence
Sexual abstinence is considered a highly effective method only if defined as
refraining from heterosexual intercourse during the entire period of risk associated
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with the study intervention. The reliability of sexual abstinence needs to be 
evaluated in relation to the duration of the study and the preferred and usual lifestyle 
of the participant. 
1.
Contraceptive use by males or females should be consistent with local regulations regarding the use of
contraceptive methods for those participating in clinical studies.
2.
2Failure rate of <1% per year when used consistently and correctly. Typical use failure rates differ from those
when used consistently and correctly.
3.
Male condoms must be used in addition to hormonal contraception. If locally required, in accordance with
Clinical Trial Facilitation Group (CTFG) guidelines, acceptable contraceptive methods are limited to those that
inhibit ovulation as the primary mode of action.
Note: Periodic abstinence (calendar, sympto-thermal, post-ovulation methods), withdrawal (coitus interruptus), 
spermicides only, and lactational amenorrhea method (LAM) are not acceptable methods of contraception. Male 
condom and female condom should not be used together (due to risk of failure from friction) 
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10.5. 
Appendix 5: Liver Safety: Required Actions and Follow-up 
Assessments 
Phase 3-4 Liver Chemistry Stopping and Increased Monitoring Criteria are designed 
to ensure participant safety and evaluate liver event etiology. Liver chemistry stopping 
criteria are shown in Table 17 and increased liver chemistry monitoring criteria are 
shown in Table 18. 
Table 17 
Liver Chemistry Stopping Criteria and Required Follow-Up 
Assessments 
Liver Chemistry Stopping Criteria 
ALT absolute 
ALT ≥8 × ULN 
ALT increase 
ALT 5xULN but <8xULN persists for 2 weeks 
ALT 3xULN but <5xULN persists for 4 weeks 
Bilirubin1, 2 
ALT ≥3 × ULN and total bilirubin ≥2 × ULN (>35% direct bilirubin) 
INR2  
ALT ≥3 × ULN and INR>1.5 
Cannot monitor 
ALT 5xULN but <8xULN and cannot be monitored weekly for 2 weeks 
ALT 3xULN but <5xULN and cannot be monitored weekly for 4 weeks 
Symptomatic3 
Both ALT ≥3 × ULN associated with symptoms (new or worsening) believed to 
be related to liver injury or hypersensitivity 
Required Actions, Monitoring and Follow-up Assessments 
Actions 
Follow-up Assessments 
•
Immediately discontinue study intervention.
Report the event to GSK within 24 hours
•
Complete the liver event form and complete
SAE data collection tool if the event also meets
the criteria for an SAE2
•
Perform liver event follow-up assessments as
described in the Follow-up Assessments column
•
Monitor the participant until liver chemistry
levels resolve, stabilize, or return to within
baseline (see MONITORING)
MONITORING: 
If ALT ≥3 × ULN AND total bilirubin ≥2 × ULN or 
INR >1.5:  
• Repeat liver chemistries (include ALT, AST,
alkaline phosphatase, total bilirubin, and INR)
and perform liver event follow-up assessments
within 24 hours
• Viral hepatitis serology4
• Obtain INR and re-check with each liver
chemistry assessment until the
aminotransferases values show a downward
trend
• Blood sample for PK analysis, obtained within
1 week after last dose5
• Obtain a serum creatine phosphokinase
(CPK), lactate dehydrogenase (LDH), gamma
glutamyl transferase [GGT], glutamate
dehydrogenase [GLDH], and serum albumin
•
Fractionate bilirubin if total bilirubin ≥2 × ULN
•
Obtain complete blood count with differential
to assess eosinophilia
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• Monitor participants twice weekly until liver
chemistries resolve, stabilize, or return to within
baseline
• A specialist or hepatology consultation is
recommended
For All other criteria (total bilirubin <2 × ULN and 
INR ≤1.5):  
• Repeat liver chemistries (include ALT, AST,
alkaline phosphatase, total bilirubin, and INR)
and perform liver event follow-up assessments
within 24 to 72 hours
• Monitor participants weekly until liver chemistries
resolve, stabilize, or return to within baseline
RESTART/RECHALLENGE 
Do not restart/rechallenge participant with study 
intervention since not allowed per protocol; 
continue participant in the study for any protocol-
specified follow-up assessments. 
•
Record the appearance or worsening of
clinical symptoms of liver injury, or
hypersensitivity, on the liver event form
•
Record use of concomitant medications on
the concomitant medications report form
including acetaminophen, herbal remedies,
recreational drugs and other over-the-counter
medications
•
Record alcohol use on the liver event alcohol
intake form
If ALT ≥3 × ULN AND total bilirubin ≥2 × ULN 
or INR >1.5 obtain the following in addition to the 
assessments listed above: 
• 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 assay should
be conducted (if available) to assess potential
acetaminophen contribution to liver injury
unless acetaminophen use is very unlikely in
the preceding week. (e.g., where the
participant has been resident in the clinical
unit throughout)
• Liver imaging (ultrasound, magnetic
resonance, or computed tomography) to
evaluate liver disease; complete Liver
Imaging form
• Liver biopsy may be considered and
discussed with local specialist if available, for
instance:
o
In participants when serology raises the
possibility of autoimmune hepatitis (AIH)
o
In participants when suspected
druginduced liver injury (DILI)
progresses or fails to resolve on
withdrawal of study intervention
o
In participants with acute or chronic
atypical presentation
• If liver biopsy conducted complete liver biopsy
form.
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1. Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin fractionation is not
immediately available, discontinue study intervention for that participant if ALT ≥3xULN and total 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 total bilirubin ≥2xULN (>35% direct bilirubin) or ALT ≥3xULN and INR>1.5, which
may indicate severe liver injury (possible ‘Hy’s Law’), must be reported as an SAE (excluding studies of
hepatic impairment or cirrhosis); the INR threshold value stated will not apply to participants receiving
anticoagulants
3. New or worsening symptoms believed to be related to liver injury (such as fatigue, nausea, vomiting, right upper
quadrant pain or tenderness, or jaundice) or believed to be related to hypersensitivity (such as fever, rash, or
eosinophilia)
4. Includes: Hepatitis A IgM antibody; Hepatitis B surface antigen and hepatitis B core antibody (IgM); Hepatitis C
RNA; Cytomegalovirus IgM antibody; Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, obtain
heterophile antibody or monospot testing); Hepatitis E IgM antibody. In those with underlying chronic hepatitis B at
study entry (identified by positive hepatitis B surface antigen) quantitative hepatitis B DNA and hepatitis delta
antibody. If hepatitis delta antibody assay cannot be performed, it can be replaced with a polymerase chain
reaction (PCR) of hepatitis D RNA virus (where needed) [Le Gal, 2005].
5. Record the date/time of the PK blood sample draw and the date/time of the last dose of study intervention prior to
blood sample draw on the CRF. If the date or time of the last dose is unclear, provide the participant’s best
approximation. If the date/time of the last dose cannot be approximated OR a PK sample cannot be collected in
the time period indicated above, do not obtain a PK sample. Instructions for sample handling and shipping are in
the SRM.
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Table 18 
Liver Chemistry Increased Monitoring Criteria with Continued 
Therapy (Daprodustat) 
Liver Chemistry Increased Monitoring Criteria and Actions with Continued Study Intervention 
Criteria 
Actions 
ALT 5xULN and <8xULN and total 
bilirubin <2xULN or INR ≤1.5 without 
symptoms believed to be related to liver 
injury or hypersensitivity, and who can be 
monitored weekly for 2 weeks. 
OR 
ALT 3xULN and <5xULN and total 
bilirubin <2xULN or INR ≤1.5 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 participant
safety.
•
Participant can continue study intervention
•
Participant must return weekly for repeat liver
chemistries (ALT, AST, alkaline phosphatase, total
bilirubin and INR) until they resolve, stabilize or return
to within baseline
•
If at any time participant meets the liver chemistry
stopping criteria, proceed as described above
•
If ALT decreases from ALT 5xULN and <8xULN to
≥3xULN but <5xULN, (total bilirubin <2xULN and
INR ≤1.5) continue to monitor liver chemistries weekly.
•
If, after 4 weeks of monitoring, ALT <3xULN and total
bilirubin <2xULN and INR ≤1.5, monitor participants
twice monthly until liver chemistries resolve or return
to within baseline.
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10.6. 
Appendix 6: Country-specific Requirements 
10.6.1. 
Country-Specific Requirements for Japan  
Purpose and Justification:  
Daprodustat IR has been commercially available as a treatment for renal anemia in adults 
(≥15 years of age) since August 2020. However, the 8 mg IR tablet is not commercially 
available and not planned to be developed in Japan. In consultation with the Japanese 
Pharmaceuticals and Medical Devices Agency (PMDA), it has been agreed that the 8 mg 
IR tablet will not be used for Japanese participants. Therefore, multiples of the 4 mg or 
6 mg IR tablets will be used to achieve IR dose steps of 8, 16 and 24 mg. The IRT set up 
for Japan will be amended as such. The IR and TfOS Dosage Steps shown in Section 6.1 
are therefore revised for Japan as shown below. 
In order to provide sufficient PK data from participants recruited in Japan, all participants 
recruited in Japan will be required to undertake PK sampling. Section 8.4.2 is therefore 
amended for Japan as detailed below. 
IR and TfOS Dosage Steps (Japan only) 
IR QD dosing 
TfOS QD dosing 
Up to 4 TfOS can be suspended in a 5 mL volume and up to 8 tablets require a total volume of 10 mL. 
TfOS TIW dosing
The 0.125 mg QD dose step is achieved by oral administration of 0.25 mg TfOS TIW
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PK Sampling 
Participants in Japan who cannot participate in the Integrated PK Phase, as this is now 
closed in their age group, will still be required to contribute to the PK dataset between 
Day 1 and Week 4. The sampling will replicate the requirements and schedule as 
described in the Integrated PK Phase (Section 8.4.1) and for these participants will not be 
optional. 
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10.7. 
Appendix 7: Protocol amendment history 
Amendment 01 / 22 June 2022 
This amendment is considered to be substantial based on the criteria set forth in Article 
10(a) of Directive 2001/20/EC of the European Parliament and the Council of the 
European Union. 
Overall Rationale for the Amendment: The primary rationale for Amendment 01 is to 
add the requirement for a temporary dose hold if the hemoglobin (Hgb) at Week 2 is 
greater than 12.5 g/dL. Additional changes are to provide further clarity of study 
requirements and to address regulatory feedback. A description and brief rationale for 
each change are provided in the table below. 
Section # and Name 
Description of Change 
Brief Rationale 
1.1. Synopsis - Brief 
Summary 
4.1. Overall Design  
5.1. Inclusion Criteria 
5.2. Exclusion Criteria 
5.5 Criteria for Temporarily 
Delaying Enrollment / 
Administration of Study 
Intervention 
The qualifying time period 
(between Day 1 and Screening 
Visits) for not repeating blood 
tests for eligibility was changed 
from 5 to 7 days. 
To better align with a 
washout for Erythropoiesis 
Stimulating Agents (ESA). 
1.1 Synopsis – Objectives 
and Endpoints 
3. Objectives, Endpoints and
Estimands
Pharmacokinetic Objectives and 
Endpoints were clarified as 
being ‘Secondary’. 
Clarification needed for the 
purpose of trial disclosure. 
1.3. Schedule of Activities – 
Table 1 
For the ‘Extra Hgb Check Visit’ 
column, specific timepoints were 
added in brackets (Weeks 32, 
40 and 48). 
To specify additional 
qualifying timepoints for a 
Hgb check after Week 28 
and before Week 52. 
The procedure ‘Daprodustat 
dispensing’ was moved to occur 
in its own row. 
For clarity and 
differentiation from the 
Interactive Response 
Technology (IRT) 
procedure. 
The footer ‘g’ related to IRT and 
daprodustat dispensing (if 
needed) for the additional 
4-weekly visits for a Hgb check
was removed.
Extra 4-weekly Hgb Check 
Visits (if required) will be a 
dispensing visit, so footnote 
‘g’ is not applicable.  
1.3. Schedule of Activities – 
Table 1 
For IRT, ‘Xs’ were added to the 
early discontinuation/withdrawal 
visit and follow-up. 
An IRT transaction is 
required to update the 
participant status.  
For ‘Laboratory Assessments’, 
blood urea nitrogen (BUN) 
In some regions, BUN is 
measured instead of urea. 
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Section # and Name 
Description of Change 
Brief Rationale 
added as an alternate 
measurement to urea. 
For ‘Other’ procedures, 
Acceptability and Palatability 
Questionnaire was added.  
Requested by the European 
Medicines Agency (EMA) 
Paediatric Investigation 
Plan (PIP; M04) 
Under the ‘Notes’: a new first 
bullet was added indicating visit 
timings are relative to Day 1; the 
next bullet was updated and 5 
days changed to 7 days. 
To clarify visit timings and 
daprodustat dispensing 
visits and to better align with 
an ESA washout. 
For footer ‘j’, the time intervals 
were updated:  maximum 
timepoint of 8 h included and 
the 4-h interval corrected to 4 
h. 
To align with Section 8.4.1. 
For footer ‘k’, an additional 
statement was added regarding 
the delay of PK sampling if a 
participant undergoes a dose 
hold.  
To align with Section 8.4.1. 
Footer ‘l’ was added to state 
that 4-weekly pregnancy tests 
for females of child-bearing 
potential to be conducted in 
Argentina.  
Required by local law. 
2.1. Study Rationale 
Date of commercial availability 
in Japan corrected to August 
2020. 
To correctly reflect the date 
of commercial availability in 
Japan. 
3. Objectives, Endpoints and
Estimands
A tertiary endpoint was added 
related to acceptability and 
palatability of the tablets. 
Requested by the EMA (PIP 
M04). 
3.2 Main Study Estimands 
In the 2nd paragraph, wording 
related to the secondary efficacy 
target estimands (Hgb 
endpoints at each timepoint) 
was updated. 
To correctly reflect the 
estimand strategy for Hgb 
values.  
3.2 Main Study Estimands 
In the table describing ‘attributes 
for primary and key secondary 
estimands’:  regarding ICEs, 
‘hypothetical strategy’ was 
replaced with ‘while-on-
treatment strategy’; regarding 
Secondary Efficacy Summary 
Measure, the summary 
measures for mean change in 
To correctly reflect the 
estimand strategy for Hgb 
values and to clarify Hgb 
summary measures.  
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Section # and Name 
Description of Change 
Brief Rationale 
Hgb from baseline were 
specified. 
3.2 Main Study Estimands 
In the ‘Rationale for estimand’ 
section: in the 2nd paragraph, 
regarding ICEs, ‘hypothetical 
strategy’ was replaced with 
‘while-on-treatment strategy’; in 
the last paragraph, for 
participants who undergo a 
kidney transplantation, the 
wording was updated to state 
they discontinue the study.  
To correctly reflect the 
estimand strategy for Hgb 
values and to make a 
correction that participants 
who undergo a kidney 
transplantation discontinue 
the study.  
4.2. Scientific Rationale for 
Study Design 
Below ‘Nested Interventional 
Trial within the Cohort Study 
212914’, wording was updated 
in the 3rd bullet and the term 
‘random selection’ removed. 
Participation in Study 
214066 will be offered to all 
participants of Study 
212914 when eligible, rather 
than by random selection.  
4.5.2. Dose Adjustment 
Algorithm in the Younger Age 
Groups 
In the last paragraph, a 
statement was removed 
regarding how a change in age 
year is counted. 
IRT will confirm correct age 
with the Investigator in the 
birthday month.  
4.6. Hemoglobin Target 
Range and Frequency of 
Checks 
Below the ‘At Week 2’ 
paragraph, a second bullet was 
added regarding a dose stop if 
Hgb value is >12.5 g/dL.  
To add an applicable dose 
stop. 
In the 1st paragraph below Table 
11, the additional qualifying Hgb 
visits were specified in brackets 
(Week 32, 40, 48). 
To clarify the additional 
qualifying Hgb visits. 
In the last paragraph, ‘extra 
check Hgb’ was removed. 
To focus the paragraph on 
unscheduled visits.  
4.7. Role of the IDMC in 
Confirming the Dosing 
Strategy 
Related to the paragraph on 
potential substantial 
amendments, a footer (†) was
added to the 1st bullet to include 
the requirement for PK 
collection in a subset of newly 
recruited participants (12 to <18 
years of age) who start with the 
revised dosing. 
To incorporate feedback 
from the US Food and Drug 
Administration (FDA) to 
include additional PK 
collection if the oldest age 
group requires revised 
dosing. 
5. Study Population
In the 2nd paragraph, the 
acceptable range of Hgb for 
patients not on an ESA was 
corrected to 7.0 to 11.0 g/dL. 
To align with the Hgb range 
presented in the inclusion 
criteria. 
5.1. Inclusion Criteria 
The 2nd paragraph was updated 
to indicate that participants in 
To reiterate that participants 
must have met eligibility 
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Section # and Name 
Description of Change 
Brief Rationale 
Study 212914 must have met 
eligibility criteria to be 
approached for this study. 
criteria stated in Study 
212914  and have been 
offered approach for 
enrolment into this study 
from Study 212914. 
5.1. Inclusion Criteria 
8.3.5. Pregnancy 
In inclusion criterion #4, for 
females of child-bearing 
potential, the commitment for 
using an acceptable method of 
contraception was changed to 
‘until at least 30 days after the 
last dose of daprodustat’, and 
16 weeks was removed. 
To align with adult 
daprodustat studies wherein 
contraception is only 
required post the last dose 
of daprodustat for 5 times 
the terminal half-life 
(approximately 2.4-4 hours) 
plus 1 menstrual cycle. 
Section 8.3.5 was aligned with 
inclusion criterion #4 to state 
that details of all pregnancies in 
female participants will be 
collected after the start of study 
intervention and until 30 days 
(not 16 weeks) after the last 
dose of study intervention. 
5.2. Exclusion Criteria 
Regarding ‘Other Disease 
Related Criteria’, the ‘note’ 
below criterion #8 related to 
history of malignancy was 
updated and exclusion criterion 
#9 was added (related to 
unresolved acute or active 
chronic infection requiring 
antimicrobial therapy). 
For improved clarity and for 
safety reasons, 
respectively. 
Regarding 'Prior/Concomitant 
Therapy': the wording in 
criterion #15 was updated to 
include daprodustat treatment 
(in the last 30 days) alongside 
other HIF-PHIs; additionally, the 
wording in criterion #16 was 
improved. 
To take into account the 
approved uses of 
daprodustat and other 
hypoxia-inducible factor 
(HIF)-prolyl hydroxylase 
inhibitor (PHI) in Japan (15 
years of age and older) and 
improve the clarity of the 
wording related to previous 
failed response to HIF-PHIs 
including daprodustat. 
5.4 Screen Failures 
A statement was added to the 
2nd paragraph to state there are 
no limits on the number of 
rescreens provided the eligibility 
parameter(s) can be addressed. 
To clarify there is no 
rescreen limit. 
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Section # and Name 
Description of Change 
Brief Rationale 
6.1. Study Intervention 
Administered 
In the paragraph below Table 
13, explanatory text was added 
regarding the expected similar 
responses on Hgb levels with 
0.125 mg once daily and 0.25 
mg three times weekly dosing. 
To provide additional 
context regarding the 
administration of the lowest 
dose (0.125 mg once daily) 
as 0.25 mg three times 
weekly. 
In Figure 5 (IR and TfOS 
Dosage Steps), for the TfOS QD 
and TIW dosing, ‘GSK863’ was 
changed to ‘GSK1278863’. 
To apply a consistent GSK 
number to the study 
intervention.  
6.8.1. Prohibited Medications 
Regarding ESA agents and 
participants receiving ESA prior 
to study entry, a footer was 
added (‡) to explain the
scheduling of the Day 1 visit. 
To provide additional 
guidance in the protocol on 
daprodustat initiation if 
switching from an ESA. 
8. Study Assessments and
Procedures
A new paragraph was added 
regarding race and ethnicity.  
To confirm that race and 
ethnicity will be collected for 
all participants. 
8.2.4. Clinical Safety 
Laboratory Tests 
In the 5th paragraph, wording 
was updated to associate the 
laboratory manual to just PK 
sampling. 
The laboratory manual only 
relates to PK sampling and 
not also to other protocol-
required laboratory tests. 
8.3.7. Other Health Outcomes 
of Interest (previous heading) 
renamed to ‘Tertiary 
Endpoints’ 
Section 8.3.7. was renamed to 
‘Tertiary Endpoints’ and a 
subsection was added related to 
‘Acceptability and Palatability 
Assessment’. 
Acceptability and palatability 
assessments of the 
formulations was requested 
by the EMA (PIP M04). 
8.4.1. Integrated PK Phase 
For the ‘At Week 2 Visit’: in the 
2nd bullet, ‘as previously 
dispensed’ was added to the 
instruction of taking the morning 
dose; below the ‘note’, a bullet 
was added regarding the delay 
of PK sampling if participant is 
put on a dose hold at Week 2.  
To clarify how PK sampling 
should be handled if 
participant is put on a dose 
hold at Week 2. 
9.3.2.2. Secondary Safety 
Analyses 
BUN included as an alternate 
measurement to urea. 
In some regions, BUN is 
measured instead of urea. 
9.3.2.4. Tertiary Other Health 
Outcomes of Interest 
(previous heading) renamed 
to ‘Tertiary Endpoints’ 
Section 9.3.2.4. was renamed to 
‘Tertiary Endpoints’ and an 
additional endpoint was added 
related to ‘Acceptability and 
Palatability Assessment’. 
Acceptability and palatability 
assessments of the 
formulations were 
requested by the EMA (PIP 
M04). 
9.5.2. Main Study 
Wording was updated to state 
there is ‘at least’ a 90% chance 
of observing a participant with 
To make the wording more 
specific. 
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Section # and Name 
Description of Change 
Brief Rationale 
an AE; and the SD of 1.4 g/dL 
for Hgb change from baseline to 
Week 12 was updated to state it 
is a ‘population rate’ SD. 
10.2 Appendix 2: Clinical 
Laboratory Tests 
Table 16 was updated to include 
BUN as an alternate 
measurement to urea. 
In some regions, BUN is 
measured instead of urea. 
The 1st ‘note’ below Table 16 
was updated to include the 
quantitative cut-off for total 
bilirubin (i.e., 2 x ULN). 
The number 2 was missing 
in error. 
10.6. Appendix 6: Country-
specific Requirements 
The purpose and justification 
statement was updated to 
indicate the 8 mg IR tablet is not 
commercially available in Japan 
and will not be used for 
Japanese participants. An 
updated Japan-specific 
figure on IR and TfOS Dosage 
Steps was included. The PK 
Sampling section was updated 
to clarify the PK sampling will be 
required for all Japanese 
participants.  
Requested by the Japanese 
Pharmaceuticals and 
Medical Devices Agency 
(PMDA). 
11. References
An additional reference was 
added (Bailey, 2019) and 
electronic links to 2 other 
references were updated. 
To support the updates in 
Section 6.1. and to ensure 
active links are cited. 
Throughout protocol 
Minor editorial updates. 
To correct spelling and 
formatting. 
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10.8. 
Appendix 8: Abbreviations and Trademarks 
AAP 
American Academy of Pediatrics 
ADME 
Absorption Distribution Metabolism Excretion 
AE 
Adverse Event 
AESI 
Adverse Event of Special Interest 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
AUC 
Area under the curve 
BMI 
Body Mass Index 
BP 
Blood Pressure 
BUN 
Blood Urea Nitrogen 
CFR 
Code of Federal Regulations 
CI 
Confidence Interval 
CIOMS 
Council for International Organizations of Medical Sciences 
CKD 
Chronic Kidney Disease 
CkiD 
Chronic Kidney Disease in children 
CLpo 
Apparent Oral Clearance 
Cmax 
Maximum plasma concentration 
CONSORT 
Consolidated Standards of Reporting Trials 
CRF 
Case Report Form 
CRO 
Contract Research Organization 
CSR 
Clinical Study Report 
D 
Dialysis 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
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eGFR 
Estimated Glomerular Filtration Rate 
EPO 
Erythropoietin 
EPPWG 
European Pediatric Peritoneal Dialysis Working Group 
EOS 
End of Study 
ESA 
Erythropoiesis Stimulating Agent 
ESKD 
End Stage Kidney Disease 
FOCBP 
Females of Childbearing Potential 
GCP 
Good Clinical Practice 
GFR 
Glomerular Filtration Rate 
GI 
Gastrointestinal 
g/dL 
Grams per decilter 
h 
Hour 
hCG 
Human Chorionic Gonadotrophin 
HD 
Hemodialysis 
HDPE 
High-Density Polyethylene 
HF 
Heart Failure 
Hgb 
Hemoglobin 
HIF 
Hypoxia-Inducible Factor 
HR 
Heart Rate 
IB 
Investigator’s Brochure 
ICE 
Intercurrent Event 
ICF 
Informed Consent Form 
ICH 
International Conference for Harmonisation 
IDMC 
Independent Data Monitoring Committee 
IEC 
Independent Ethics Committee 
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IMP 
Investigational Medicinal Product 
INR 
International Normalized Ratio 
IR 
Immediate Release 
IRB 
Institutional Review Board 
IRT 
Interactive Response Technology 
IUD 
Intrauterine Device 
IUS 
Intrauterine Hormone-Releasing System 
IU 
International Units 
IV 
Intravenous 
KDIGO 
Kidney Disease Improving Global Outcomes 
KDOQI 
Kidney Disease Outcomes Quality Initiative 
kg 
Kilogram 
LFTs 
Liver Function Tests 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
Milligrams 
MI 
Myocardial Infarction 
mL 
Milliliter 
msecs 
Milliseconds 
MSDS 
Material Safety Data Sheet 
NAPRTCS 
North American Pediatric Renal Trials and Clinical Studies 
ND 
Non-Dialysis 
NHANES 
National Health and Nutrition Examination Survey 
NKF 
National Kidney Foundation 
NKF-KDOQI National Kidney Foundation Kidney Disease Outcomes Quality 
Initiative 
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NOAEL 
No Observed Adverse Effect Level 
NYHA 
New York Heart Association 
P25 
25th Percentile 
P75 
75th Percentile 
PBPK 
Physiological Based Pharmacokinetics 
PD 
Peritoneal Dialysis 
PEG 
Polyethylene Glycol
PHI 
Prolyl hydroxylase inhibitor 
PI 
Prediction interval 
PK 
Pharmacokinetics 
PMDA 
Pharmaceuticals and Medical Device Agency 
QD 
Once daily 
QTc 
QT interval corrected for heart rate 
QTcF 
QT interval corrected using Fridericia’s formula 
QTLs 
Quality tolerance limits 
rhEPO 
Recombinant Human Erythropoietin 
RR 
Relative Risk 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SC 
Subcutaneous 
SD 
Standard Deviation 
SGOT 
Serum Glutamic-Oxaloacetic Transaminase 
SGPT 
Serum Glutamic-Pyruvic Transaminase 
SoA 
Schedule of Activities 
SoC 
Standard of Care 
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SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TfOS 
Tablets for Oral Suspension 
TIW 
Three times weekly 
TSAT 
Transferrin Saturation 
U 
Units 
ug 
Micrograms 
ULN 
Upper Limit of Normal 
UNS 
Unscheduled 
US 
United States 
USPI 
United States Prescribing Information 
VEGF 
Vascular Endothelial Growth Factor 
WHO 
World Health Organization 
Trademark Information 
Trademarks of the GSK group of 
companies 
Trademarks not owned by the GSK 
group of companies 
NONE 
Aranesp 
Epogen 
Mircera 
Simcyp Pediatric ADME Simulator 
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11.
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Signature Page for  214066 TMF-15144431 v1.0
Signature Page for TMF-15144431 v1.0
Reason for signing: Approved
Name:
Role: Approver
Date of signature: 18-Nov-2022 14:11:03 GMT+0000
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