Conditions: Anaemia
Keywords: Recombinant human erythropoietin Anemia Daprodustat Chronic kidney disease
Allocation: RANDOMIZED | Intervention model: CROSSOVER
Enrollment: 15
Healthy volunteers: no

Brief summary:
Daprodustat administration has the potential, by virtue of increasing hypoxia-inducible factor (HIF) levels, to increase oral iron absorption and incorporation into hemoglobin (Hgb). Therefore, the purpose of this study is to compare the effect of daprodustat to rhEPO (i.e., epoetin alfa or darbepoetin alfa) on non-heme oral iron absorption using stable isotopic iron (57Fe and 58Fe) by measuring incorporation of iron in erythrocytes. This study will be a randomized, repeat dose, open label, two period cross-over study in adult, male and female participants with anemia associated with chronic kidney disease who are not on dialysis currently treated with stable doses less than or equal to (\<=) 50 percent (%) change in 4-weekly dose) for at least 8 weeks prior to and including the screening period, of rhEPO (i.e., epoetin alfa or darbepoetin alfa). Sufficient participants will be enrolled such that at least 12 participants comprise the Evaluable Population. The study will compare the fractional iron absorption between treatment arms (daprodustat and rhEPO \[i.e., epoetin alfa or darbepoetin alfa\]) and will evaluate the difference is equal/not equal to zero.

Detailed description:

Arms:
arm 1: Participants will be randomly assigned to remain on their current therapy (either epoetin alfa or darbepoetin alfa) in Treatment Period 1. For assessment of incorporation of iron into erythrocytes, participants will be administered ferrous sulfate containing a stable isotope of iron (57Fe) orally in a randomized fashion following 2 weeks of administration of randomized study treatment. At Day 29 participants will be crossed over to receive Daprodustat in Treatment Period 2. At 2 weeks following initiation of dosing in Treatment Period 2, participants will again be administered ferrous sulfate containing the stable iron isotope (58Fe) orally. Participants will be advised to maintain use of oral iron supplementation (except ferric citrate) and acid-reducing agents (example: Histamine \[H2\] receptor antagonists, proton pump inhibitors, antacids) at a consistent dosage and frequency. arm 2: Participants will be randomly assigned to remain on their current therapy (either epoetin alfa or darbepoetin alfa) in Treatment Period 1. For assessment of incorporation of iron into erythrocytes, participants will be administered ferrous sulfate containing a stable isotope of iron (58Fe) orally in a randomized fashion following 2 weeks of administration of randomized study treatment. At Day 29 participants will be crossed over to receive Daprodustat in Treatment Period 2. At 2 weeks following initiation of dosing in Treatment Period 2, participants will again be administered ferrous sulfate containing the stable iron isotope (57Fe) orally. Participants will be advised to maintain use of oral iron supplementation (except ferric citrate) and acid-reducing agents (example: H2 receptor antagonists, proton pump inhibitors, antacids) at a consistent dosage and frequency. arm 3: Participants will be randomly assigned to receive Daprodustat in Treatment Period 1. For assessment of incorporation of iron into erythrocytes, participants will be administered ferrous sulfate containing a stable isotope of iron (57Fe) orally in a randomized fashion following 2 weeks of administration of randomized study treatment. At Day 29 participants will be crossed over to receive rhEPO (either epoetin alfa or darbepoetin alfa) in Treatment Period 2. At 2 weeks following initiation of dosing in Treatment Period 2, participants will again be administered ferrous sulfate containing the stable iron isotope (58Fe) orally. Participants will be advised to maintain use of oral iron supplementation (except ferric citrate) and acid-reducing agents (example: H2 receptor antagonists, proton pump inhibitors, antacids) at a consistent dosage and frequency. arm 4: Participants will be randomly assigned to receive Daprodustat in Treatment Period 1. For assessment of incorporation of iron into erythrocytes, participants will be administered ferrous sulfate containing a stable isotope of iron (58Fe) orally in a randomized fashion following 2 weeks of administration of randomized study treatment. At Day 29 participants will be crossed over to receive rhEPO (either epoetin alfa or darbepoetin alfa) in Treatment Period 2. At 2 weeks following initiation of dosing in Treatment Period 2, participants will again be administered ferrous sulfate containing the stable iron isotope (57Fe) orally. Participants will be advised to maintain use of oral iron supplementation (except ferric citrate) and acid-reducing agents (example: H2 receptor antagonists, proton pump inhibitors, antacids) at a consistent dosage and frequency.

Interventions: intervention 1: Daprodustat intervention 2: rhEPO intervention 3: Ferrous sulfate containing the stable iron isotope (57Fe) intervention 4: Ferrous sulfate containing the stable iron isotope (58Fe)
Intervention descriptions: intervention 1: Daprodustat will be available as 1 milligram (mg), 2 mg and 4 mg tablets strengths. One tablet to be taken daily without regard for food. intervention 2: rhEPO (epoetin alfa OR darbepoetin alfa) is commercially available in various single dose vials and single-dose prefilled syringes. It will be given as subcutaneous injection. intervention 3: 57Fe will be available in oral solution. An oral solution will be administered containing 10 mg of 57Fe as ferrous sulfate. intervention 4: 58Fe will be available in oral solution. An oral solution will be administered containing 3 mg of 58Fe as ferrous sulfate with 7 mg of 56Fe as ferrous sulfate (natural abundance Fe).

Protocol document:
Prot_000.pdf: 
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GlaxoSmithKline group of companies 
 
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TITLE PAGE 
Protocol Title: A repeat dose, open label, two period, randomized, cross over study to 
compare the effect of daprodustat to recombinant, human erythropoietin (rhEPO) on oral 
iron absorption in adult participants with anemia associated with chronic kidney disease 
who are not on dialysis 
Protocol Number: 201771 /Amendment 3 
Short Title: Anemia Studies in CKD: Erythropoiesis via a Novel PHI Daprodustat – Iron 
(ASCEND-Fe)  
Compound 
Number: 
GSK1278863 
Study Phase 2b 
Sponsor Name and Legal Registered Address: 
GlaxoSmithKline Research & Development Limited 
980 Great West Road 
Brentford 
Middlesex, TW8 9GS 
UK 
Medical Monitor Name and Contact Information can be found in the Study Reference 
Manual (SRM) 
Regulatory Agency Identifying Number(s): IND Number: 101,291 
Approval Date: 14-JUL-2021 
 
 
 
 
 
 
 
 
Copyright 2021 the GlaxoSmithKline group of companies.  All rights reserved.  
Unauthorised copying or use of this information is prohibited. 


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SPONSOR SIGNATORY: 
Protocol Title: A repeat dose, open label, two period, randomized, cross over study to 
compare the effect of daprodustat to recombinant, human erythropoietin (rhEPO) on oral 
iron absorption in adult participants with anemia associated with chronic kidney disease 
who are not on dialysis 
Protocol Number: 201771 /Amendment 3 
Compound Number 
or Name: 
GSK1278863  
 
 
 
 
Alexander R. Cobitz, MD, PhD 
Senior Director 
Daprodustat Clinical Development Lead 
Specialty (Clinical Sciences) 
GlaxoSmithKline 
 
The signed page is a separate document. 
 
 
 
 
 
Date 


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PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE 
DOCUMENT HISTORY 
Document 
Date 
Document Identifier 
Amendment 3 
14-Jul-2021 
TMF-13854840 
Amendment 2 
13-Aug-2019 
2016N298210_02 
Amendment 1 
30-Nov-2017 
2016N298210_01 
Original Protocol 
12-May-2017 
2016N298210_00 
 
Amendment 3: 14-JUL-2021  
Overall Rationale for the Amendment:  
Amendment 3 was implemented to facilitate enrolment and the maintenance of 
participants once randomized in the study and to correct noted typographical errors.   
Section # and 
Name 
Description of Change 
Brief Rationale 
5.1 Overall 
Design 
Table 1: number to be 
enrolled in each possible 
sequence corrected from 6 
to 3 
 
Day of crossover changed 
from Day 28 to Day 29 
 
To correct discrepancy  
5.4 Scientific 
Rationale for 
Study Design 
Bullet 9: deleted hepcidin 
level assessment as 
eligibility criterion 
Exclusion criterion related to hepcidin 
was removed after observing 
variability in the range of hepcidin 
results and the lack of standardization 
of hepcidin assays making it difficult 
to establish a cut-off value for this 
study population. 
6.1 Exclusion 
Criteria 
Deletion of Exclusion 
Criteria #12 Hepcidin >150 
ng/ml  
9.4.1 Entry 
Criteria (Table 
4) 
Hepcidin was removed as 
an entry criteria assessment  
8.2.1.2 Iron 
Stopping 
Criteria 
Amended to allow the 
Investigator to use his 
clinical judgement and 
removed TSAT and ferritin 
values as discontinuation 
criteria.   
The intent of the iron stopping criteria 
is to ensure participants remain on the 
same dose of oral iron supplement 
throughout the study.  Therefore, the 
stopping criteria was amended to 
allow the Investigator to use his 
clinical judgement to determine if a 


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Section # and 
Name 
Description of Change 
Brief Rationale 
participant’s iron supplement required 
adjustment.  
5.4 Scientific 
Rationale for 
Study Design 
Removed mention of 
absolute change in 
Hemoglobin to define the 
evaluable population 
Hemoglobin variability is managed 
through the hgb stopping criteria 
10.3.1.3 
Evaluable 
Population 
Deleted the criterion of 
absolute changes from 
baseline (Day 1 pre dose) in 
haemoglobin ≤0.75 g/dL 
from the evaluable 
population definition 
12.3 Appendix 
3 Risk 
Assessment 
Drug Interaction 
information updated   
Modified to maintain consistency 
with current Risk Assessment  
12.7 Appendix 
7 Contraceptive 
Guidance and 
Collection of 
Pregnancy 
Information 
Urine pregnancy testing kit 
sensitivity corrected from 2 
mIU/mL to 25 mIU/mL 
To correct typographical error. 
 
 


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TABLE OF CONTENTS 
PAGE 
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE ..................................... 3 
1. 
SYNOPSIS ............................................................................................................... 8 
2. 
SCHEDULE OF ACTIVITIES (SOA) ....................................................................... 10 
3. 
INTRODUCTION .................................................................................................... 12 
3.1. 
Study Rationale .......................................................................................... 12 
3.2. 
Background ................................................................................................ 13 
3.3. 
Benefit/Risk Assessment ............................................................................ 13 
3.3.1. 
Risk Assessment ......................................................................... 13 
3.3.2. 
Benefit Assessment ..................................................................... 14 
3.3.3. 
Overall Benefit:Risk Conclusion ................................................... 14 
4. 
OBJECTIVES AND ENDPOINTS ........................................................................... 14 
5. 
STUDY DESIGN .................................................................................................... 15 
5.1. 
Overall Design ............................................................................................ 15 
5.2. 
Number of Participants ............................................................................... 16 
5.3. 
Participant and Study Completion ............................................................... 16 
5.4. 
Scientific Rationale for Study Design .......................................................... 16 
5.5. 
Dose Justification ........................................................................................ 18 
6. 
STUDY POPULATION ........................................................................................... 18 
6.1. 
Inclusion Criteria ......................................................................................... 18 
6.2. 
Exclusion Criteria ........................................................................................ 19 
6.2.1. 
Hgb Stability Criteria .................................................................... 21 
6.3. 
Lifestyle Restrictions ................................................................................... 22 
6.4. 
Screen Failures........................................................................................... 22 
7. 
TREATMENTS ....................................................................................................... 23 
7.1. 
Treatments Administered ............................................................................ 23 
7.1.1. 
Daprodustat Dosing Information .................................................. 24 
7.1.2. 
rhEPO Dosing Information ........................................................... 24 
7.1.3. 
57Fe Dosing Information ............................................................... 24 
7.1.4. 
58Fe Dosing Information ............................................................... 24 
7.2. 
Dose Modification ....................................................................................... 25 
7.3. 
Method of Treatment Assignment ............................................................... 25 
7.4. 
Blinding ....................................................................................................... 25 
7.5. 
Preparation/Handling/Storage/Accountability .............................................. 25 
7.6. 
Treatment Compliance ................................................................................ 26 
7.7. 
Concomitant Therapy.................................................................................. 26 
7.7.1. 
Permitted Medications and Non-Drug Therapies .......................... 26 
7.7.2. 
Prohibited Medications and Non-Drug Therapies ......................... 27 
7.7.3. 
Standard of Care ......................................................................... 27 
7.8. 
Treatment after the End of the Study .......................................................... 27 
8. 
DISCONTINUATION CRITERIA ............................................................................. 27 
8.1. 
Discontinuation of Study Treatment ............................................................ 27 


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8.1.1. 
Liver Chemistry Stopping Criteria ................................................ 27 
8.2. 
Withdrawal from the Study .......................................................................... 28 
8.2.1. 
Criteria for Permanent Discontinuation from Study 
Treatment and Early Withdrawal .................................................. 29 
8.2.1.1. 
Hgb Stopping Criteria ................................................. 29 
8.2.1.2. 
Iron Stopping Criteria .................................................. 30 
8.3. 
Lost to Follow Up ........................................................................................ 30 
9. 
STUDY ASSESSMENTS AND PROCEDURES ..................................................... 31 
9.1. 
Efficacy Assessments ................................................................................. 31 
9.2. 
Adverse Events........................................................................................... 31 
9.2.1. 
Time Period and Frequency for Collecting AE and SAE 
Information ................................................................................... 32 
9.2.2. 
Method of Detecting AEs and SAEs ............................................. 32 
9.2.3. 
Follow-up of AEs and SAEs ......................................................... 32 
9.2.4. 
Adverse Events of Special Interest (AESI) ................................... 32 
9.2.5. 
Regulatory Reporting Requirements for SAEs ............................. 33 
9.2.6. 
Cardiovascular and Death Events ................................................ 33 
9.2.7. 
Possible Suicidality Related Adverse Events ............................... 34 
9.2.8. 
Pregnancy ................................................................................... 34 
9.3. 
Treatment of Overdose ............................................................................... 34 
9.4. 
Safety Assessments ................................................................................... 35 
9.4.1. 
Entry Criteria ................................................................................ 35 
9.4.2. 
Physical Examinations ................................................................. 35 
9.4.3. 
Vital Signs .................................................................................... 35 
9.4.4. 
Electrocardiograms ...................................................................... 36 
9.4.5. 
Clinical Laboratory Assessments ................................................. 36 
9.4.6. 
Liver Chemistry Monitoring .......................................................... 36 
9.5. 
Pharmacokinetics ....................................................................................... 36 
9.6. 
Pharmacodynamics .................................................................................... 37 
9.7. 
Genetics ..................................................................................................... 37 
9.8. 
Biomarkers ................................................................................................. 37 
9.8.1. 
Fractional oral iron absorption ...................................................... 37 
9.8.2. 
Iron status markers ...................................................................... 37 
9.8.3. 
Indices of erythropoiesis .............................................................. 37 
9.9. 
Health Economics OR Medical Resource Utilization and Health 
Economics .................................................................................................. 37 
10. STATISTICAL CONSIDERATIONS ........................................................................ 38 
10.1. 
Hypotheses ................................................................................................. 38 
10.2. 
Sample Size Determination ........................................................................ 38 
10.2.1. 
Sample Size Sensitivity ................................................................ 38 
10.2.2. 
Sample Size Re-estimation .......................................................... 38 
10.3. 
Data Analysis Considerations ..................................................................... 39 
10.3.1. 
Analysis Populations .................................................................... 39 
10.3.1.1. Screened Population: ................................................. 39 
10.3.1.2. Safety Population: ...................................................... 39 
10.3.1.3. Evaluable Population: ................................................. 39 
10.3.1.4. Modified Intent to Treat (mITT) Population: ................ 39 
10.3.2. 
Interim Analyses .......................................................................... 39 
10.4. 
Key Elements of Analysis Plan ................................................................... 39 
10.4.1. 
Primary Analysis .......................................................................... 39 


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10.4.2. 
Secondary Analysis ..................................................................... 40 
11. REFERENCES ....................................................................................................... 41 
12. APPENDICES ........................................................................................................ 43 
12.1. 
Appendix 1: Abbreviations and Trademarks ................................................ 43 
12.2. 
Appendix 2: Liver Safety Required Actions and Follow up 
Assessments .............................................................................................. 46 
12.3. 
Appendix 3: Risk Assessment ..................................................................... 49 
12.4. 
Appendix 4: Clinical Laboratory Assessments ............................................ 60 
12.5. 
Appendix 5: Study Governance Considerations .......................................... 62 
12.6. 
Appendix 6: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting ....................................... 66 
12.7. 
Appendix 7: Contraceptive Guidance and Collection of Pregnancy 
Information .................................................................................................. 71 
12.8. 
Appendix 8: Genetics .................................................................................. 74 
12.9. 
Appendix 9: Protocol Amendment History ................................................... 75 
 


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1. 
SYNOPSIS 
Protocol Title: A repeat dose, open label, two period, randomized, cross over study to 
compare the effect of daprodustat to recombinant, human erythropoietin (rhEPO) on oral 
iron absorption in adult participants with anemia associated with chronic kidney disease 
who are not on dialysis 
Short Title:  Anemia Studies in CKD: Erythropoiesis via a Novel PHI Daprodustat – 
Iron (ASCEND-Fe)  
Rationale:  Several proteins involved in iron absorption/metabolism are known to be HIF 
target genes.  In this regard, daprodustat is equipotent against 3 human PHD enzymes 
(PHD1, PHD2 & PHD3) thereby stabilizing both HIF1α and HIF2α.  Increased iron 
absorption correlates with increased expression in enterocytes and proerythroblasts of 
divalent metal-iron transporter 1 (DMT1), duodenal cytochrome b561 (DcytB) and 
ferroportin (FPN) mRNA.  HIF-2α is reported to up-regulate the expression of these 
genes by direct binding to consensus hypoxia response elements (HRE).  Thus, there is 
the potential that daprodustat administration, by virtue of increasing HIF levels, can 
increase oral iron absorption and incorporation into Hgb.  Therefore, the purpose of this 
study is to compare the effect of daprodustat to rhEPO (i.e., epoetin alfa or darbepoetin 
alfa) on non-heme oral iron absorption using stable isotopic iron (57Fe & 58Fe) by 
measuring incorporation of iron in erythrocytes. 
Objectives and Endpoints: 
Objectives 
Endpoints 
Primary 
• 
Compare the efficacy of daprodustat to 
rhEPO (i.e., epoetin alfa or darbepoetin 
alfa) on iron absorption 
• 
Difference in fractional oral iron 
absorption (%) between daprodustat and 
rhEPO 
Secondary 
• 
Characterize the effect of daprodustat or 
rhEPO on markers of iron status 
• 
Change from baseline (Day 1) at 14 and 
28 days following treatment with 
daprodustat or rhEPO in serum iron, 
transferrin, transferrin saturation, soluble 
transferrin receptor, ferritin, hepcidin and 
erythroferrone 
• 
Characterize the effect of daprodustat or 
rhEPO on indices of erythropoiesis 
• 
Change from baseline (Day 1) at 14 and 
28 days following treatment with 
daprodustat or rhEPO in Hgb, hematocrit, 
red blood cell number, mean corpuscular 
volume, reticulocyte Hgb and 
reticulocyte number 


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Objectives 
Endpoints 
Safety  
• 
Assess safety and tolerability 
• 
Incidence and severity of adverse events 
and serious adverse events 
• 
Reasons for discontinuation of study 
medication 
• 
Vital signs assessments 
 
Overall Design:  This study will be a randomized, repeat dose, open label, two period 
cross-over study in adult, male and female participants with anemia associated with 
chronic kidney disease who are not on dialysis currently treated with stable doses (≤ 50% 
change in 4-weekly dose) for at least 8 weeks prior to and including the screening period, 
of rhEPO (i.e., epoetin alfa or darbepoetin alfa). 
Number of Participants:  Sufficient participants will be enrolled such that at least 12 
participants comprise the Evaluable Population. 
Treatment Groups and Duration: 
 
• There will be a 4-week screening period in order to confirm that participants have 
stable Hgb levels and to assess entry criteria 
• A 28-day Treatment Period 1 for incorporation of iron into erythrocytes while on 
randomized study treatment 
• A 28-day Treatment Period 2 for a second incorporation of iron into erythrocytes 
while on randomized study treatment 
• A follow-up visit 14 ± 3 days after completing treatment. 
 


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2. 
SCHEDULE OF ACTIVITIES (SOA) 
Procedure 
Screening1 
Treatment Period2 
Follow-up1 
Week -4 
Week -2 
Day 1 
Day 15 
Day 293 
Day 43 
Day 57 
Day 70 
Informed Consent 
X 
 
 
 
 
 
 
 
Entry Criteria 
X4 
X4 
X4 
 
 
 
 
 
Physical, Medical History, Demography, 
Height  
X5,9 
X5,9 
X5,9 
 
 
 
 
 
Weight 
X 
 
X 
X 
 
X 
 
 
HemoCue Hgb 
X 
X 
X 
X 
X 
X 
X 
 
eGFR 
X 
 
 
 
 
 
 
 
Females: Urine Pregnancy Test6 
X 
 
X 
 
X 
 
X 
X 
Females: Estradiol & FSH7 
 
X 
 
 
 
 
 
 
HIV screening and Hepcidin 
X 
 
 
 
 
 
 
 
Randomization 
 
 
X 
 
 
 
 
 
Administration of isotopic iron 
 
 
 
X 
 
X 
 
 
Blood sampling for isotopic iron 
 
 
 
 
X 
X 
X 
 
Crossover8 
 
 
 
 
X 
 
 
 
ECG 
 
X 
 
 
 
 
 
X 
Vital signs 
X 
 
X 
 
X 
 
X 
X 
Clinical chemistry & hematology10 
X 
 
 
 
 
 
 
X 
Urinalysis10 
X 
 
 
 
 
 
 
X 
Liver chemistry monitoring11 
 
 
 
X 
 
X 
 
 
Folate & Vitamin B12 
 
X 
 
 
 
 
 
 
hsCRP 
 
X 
 
 
 
 
 
 
Ferritin and TSAT  
 
X 
 
 
 
 
 
 
Iron status markers12 
 
 
X 
X 
X 
X 
X 
 
Indices of erythropoiesis13 
 
 
X 
X 
X 
X 
X 
 
Blood draw for PGx 
 
 
X 
 
 
 
 
 
AE and SAE Assessment14 
X15 
X15 
X 
X 
X 
X 
X 
X 
Review Concomitant Medications 
X 
X 
X 
X 
X 
X 
X 
X 
 


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1 Allowable time window ± 3 days. 
2 Allowable time window ± 2 days. 
3 All assessments to be performed PRIOR to crossing over. 
4 Criteria to be assessed can be found in Section 9.4.1. 
5 Complete physical examination, medical history & demography to be performed at Week -4, while a brief physical examination to be performed at Week -2 and Day 1. 
6 Local urine testing will be standard for the protocol unless serum testing is required by local regulation or IRB/IEC. 
7 As detailed in Inclusion Criteria. 
8 Participants that had been administered daprodustat during treatment Period 1 will be switched to rhEPO, while those on rhEPO will be switched to daprodustat.  Examples on 
switching are provided in the Study Reference Manual (SRM).  
9 Height is only collected at Week -4.   
10 Clinical laboratory assessments guidance can be found in Section 9.4.5 
11 Liver chemistry monitoring guidance can be found in Section 9.4.6. 
12 Iron status markers include serum iron, ferritin, transferrin, transferrin saturation (TSAT), soluble transferrin receptor, hepcidin and erythroferrone and are described in Section 9.8.2. 
All samples for iron status markers to be taken pre dose. 
13 Indices of erythropoiesis include Hgb, hematocrit, red blood cell number, mean corpuscular volume, reticulocyte Hgb and reticulocyte number and are described in Section 9.8.3. 
14 Guidance on the timing and need for collection of AEs & SAEs are described in Section 9.2. 
15 SAEs assessed as related to study participation or a GSK product are collected at this visit.  See Section 9.2.1 for additional details. 
 
• The timing and number of planned study assessments, including safety or biomarker assessments may be altered during the course 
of the study based on newly available data to ensure appropriate monitoring.  
• Any changes in the timing or addition of time points for any planned study assessments must be documented and approved by the 
relevant study team member and then archived in the sponsor and site study files but will not constitute a protocol amendment.  
The IRB/IEC will be informed of any safety issues that require alteration of the safety monitoring scheme or amendment of the 
ICF. 
 


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3. 
INTRODUCTION 
Daprodustat (GSK1278863) is a small molecule, oral inhibiter of the hypoxia-inducible 
factor (HIF) prolyl-4-hydroxylase (PHD) enzymes which may present several important 
advantages over recombinant, human erythropietin (rhEPO).  It is an oral medication and 
does not require cold-chain storage as do some rhEPOs, thus increasing ease of use for 
patients.  Moreover, data indicate that, similar to other HIF-PHD inhibitors, daprodustat 
can effectively raise hemoglobin (Hgb) concentrations with lower erythropoietin (EPO) 
levels than those observed after administration of rhEPOs (Besarab, 2015; Holdstock, 
2016).  Because of the increased cardiovascular (CV) risk associated with raising Hgb 
concentrations through large increases in EPO levels (Pfeffer, 2009), daprodustat has the 
potential to treat patients with less CV risk than rhEPOs.  Additional benefits include the 
potential to treat anemia without causing rhEPO-induced hypertension, to improve iron 
availability for erythropoiesis, and the potential to successfully treat rhEPO hypo-
responders (Holdstock, 2016). 
3.1. 
Study Rationale 
Sufficient iron availability is critical for normal erythropoiesis and all rhEPO labels carry 
guidance with regard to iron availability.  It is anticipated that the majority of patients 
with chronic kidney disease (CKD) will require supplemental iron during the course of 
rhEPO therapy.  However, poor compliance is seen with oral iron therapy due to 
gastrointestinal intolerance, while intravenous (IV) iron has an increased risk of infection 
and/or iron overload as well as an increased risk of anaphalaxis and congestive heart 
failure.  Excess accumulation of iron in tissues with IV iron is clearly associated with 
increased morbidity and mortality with organ dysfunction primarily seen in the liver, 
heart, pancreas, joints and endocrine organs.  Further, most of the morbidity and 
mortality due to iron overload disorders is the result of iron accumulation in the heart 
(Macdougall, 2016).  Finally, administration of IV iron is associated with additional costs 
related to in-hospital administration and the need for patient monitoring. 
Several proteins involved in iron absorption/metabolism are known to be HIF target 
genes.  In this regard, daprodustat is equipotent against 3 human PHD enzymes (PHD1, 
PHD2 & PHD3) thereby stabilizing both HIF1α and HIF2α.  Increased iron absorption 
correlates with increased expression in enterocytes and proerythroblasts of divalent 
metal-iron transporter 1 (DMT1), duodenal cytochrome b561 (DcytB) and ferroportin 
(FPN) mRNA.  HIF-2α is reported to up-regulate the expression of these genes by direct 
binding to consensus hypoxia response elements (HRE) (Koury, 2015).  Thus, there is the 
potential that daprodustat administration, by virtue of increasing HIF levels, can increase 
oral iron absorption and incorporation into Hgb.  Therefore, the purpose of this study is to 
compare the effect of daprodustat to rhEPO (i.e., epoetin alfa or darbepoetin alfa) on non-
heme oral iron absorption using stable isotopic iron (57Fe & 58Fe) by measuring 
incorporation of iron in erythrocytes.  The coordination of erythropoietin synthesis with 
iron metabolism by HIF is shown in Figure 1. 


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Figure 1 
HIF in erythropoietin synthesis and iron metabolism 
 
DcytB: Duodenal cytochrome b reductase 1; DMT1: Divalent metal transporter-1; FPN: Ferroportin; TF: 
Transferrin; EPO: Erythropoietin; GDF15: Growth Differentiation Factor 15 (Koury, 2015) 
3.2. 
Background 
HIF prolyl hydroxylase inhibitors (PHIs) are an emerging class of agents under 
investigation for the treatment of anemia associated with CKD.  These molecules 
stimulate erythropoiesis through inhibition of HIF-prolyl hydroxylase domain enzymes 
(PHD1, PHD2, PHD3).  This activity results in the accumulation of HIFα transcription 
factors which leads to increased transcription of HIF-responsive genes, stimulating 
components of the natural response to hypoxia.  During hypoxia, the PHD enzymes are 
inhibited, resulting in the accumulation of unhydroxylated HIFα subunits, which dimerize 
with HIFβ subunits to affect the transcription of HIF-responsive genes, including EPO 
and others involved in increasing oxygen availability and utilization.  Other functions 
regulated by HIFs include iron metabolism and utilization, angiogenesis, extracellular 
matrix metabolism, apoptosis, energy and glucose metabolism, vascular tone, cell 
adhesion, and motility (Haase, 2013). 
3.3. 
Benefit/Risk Assessment 
More detailed information about the known and expected benefits and risks of 
daprodustat may be found in the Investigator’s Brochure (IB) and supplements. 
3.3.1. 
Risk Assessment 
The potential risks of clinical significance including adverse events (AEs) of special 
interest (AESI; Section 9.2.4), and the mitigation strategies for this protocol taking into 
account the results of completed clinical and nonclinical studies with daprodustat, are 
outlined in Appendix 3. 


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3.3.2. 
Benefit Assessment 
In clinical trials of up to 24 weeks in duration, in participants with anemia associated with 
CKD, daprodustat has been shown to increase Hgb to target range.  Data from prior 
studies with daprodustat suggest that the increases in Hgb are achieved with EPO levels 
lower than those observed with rhEPO (Holdstock, 2016). 
3.3.3. 
Overall Benefit:Risk Conclusion 
Daprodustat demonstrates a positive benefit vs. risk balance based on the evidence as 
follows.  In clinical trials up to 24 weeks in duration, daprodustat maintained Hgb to 
target range in participants with anemia associated with CKD (both nondialysis 
dependent (ND) and hemodialysis dependent (HD)) with a safety profile consistent with 
the patient population. 
This protocol employs precautions to mitigate known and potential risks to enrolled 
participants (See Appendix 3).  Given these precautions, as well as the potential benefit 
that daprodustat holds for the treatment of anemia associated with CKD compared to the 
current standard, the overall benefit:risk balance is considered to be positive. 
4. 
OBJECTIVES AND ENDPOINTS 
Objectives 
Endpoints 
Primary 
• 
Compare the efficacy of daprodustat to 
rhEPO (i.e., epoetin alfa or darbepoetin 
alfa) on iron absorption 
• 
Difference in fractional oral iron 
absorption (%) between daprodustat and 
rhEPO 
Secondary 
• 
Characterize the effect of daprodustat or 
rhEPO on markers of iron status 
• 
Change from baseline (Day 1) at 14 and 
28 days following treatment with 
daprodustat or rhEPO in serum iron, 
transferrin, transferrin saturation, soluble 
transferrin receptor, ferritin, hepcidin and 
erythroferrone 
• 
Characterize the effect of daprodustat or 
rhEPO on indices of erythropoiesis 
• 
Change from baseline (Day 1) at 14 and 
28 days following treatment with 
daprodustat or rhEPO in Hgb, hematocrit, 
red blood cell number, mean corpuscular 
volume, reticulocyte Hgb and 
reticulocyte number 
Safety 
• 
Assess safety and tolerability 
• 
Incidence and severity of adverse events 
and serious adverse events 
• 
Reasons for discontinuation of study 
medication 
• 
Vital signs assessments 
 


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5. 
STUDY DESIGN 
5.1. 
Overall Design 
This study will be a randomized, repeat dose, open label, two period cross-over study in 
adult, male and female participants with anemia associated with chronic kidney disease 
who are not on dialysis currently treated with stable doses (≤ 50% change in 4-weekly 
dose) for at least 8 weeks prior to and including the screening period, of rhEPO (i.e., 
epoetin alfa or darbepoetin alfa). 
Sufficient participants will be enrolled such that at least 12 participants comprise the 
Evaluable Population (See Section 10.3.1.3). 
The study design is outlined in Figure 2. 
Figure 2 
Study Design 
 
• There will be a 4-week screening period in order to confirm that participants have 
stable Hgb levels and to assess entry criteria 
• A 28-day Treatment Period 1 for incorporation of iron into erythrocytes while on 
randomized study treatment 
• A 28-day Treatment Period 2 for a second incorporation of iron into erythrocytes 
while on randomized study treatment 
• A follow-up visit 14 ± 3 days after completing treatment. 
Participants will be randomly assigned either to remain on their current therapy (either 
epoetin alfa or darbepoetin alfa) or be switched to daprodustat for Treatment Period 1.  
For assessment of incorporation of iron into erythrocytes, enrolled participants will be 
administered ferrous sulfate containing a stable isotope of iron (57Fe or 58Fe) orally in a 
randomized fashion following 2 weeks of administration of randomized study treatment.  
Thus, there are 4 possible treatment sequences as shown in Table 1.  Two weeks 
following oral iron administration a blood sample will be taken in order to assess the 
incorporation of the iron isotope into red blood cells by thermal ionization mass 


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spectrometry (TIMS) using published methods (IAEA Human Health Series No. 21, 
2012). 
At Day 29 participants will be crossed over to the study treatment they did not receive in 
Treatment Period 1, i.e., for participants that remained on their current therapy they 
would be switched to daprodustat, while subjects that had been administered daprodustat 
would be switched back to their previous therapy at the dose prior to randomization.  At 2 
weeks following initiation of dosing, participants will again be administered ferrous 
sulfate containing the stable iron isotope not administered following the assessment in 
Treatment Period 1 orally.  Two weeks following oral iron administration a blood sample 
will again be taken in order to assess the incorporation of the iron isotope into red blood 
cells by TIMS. 
Participants will attend a follow-up visit 14 ± 3 days following the final blood sample for 
assessment of red blood cell iron. 
Table 1 
Possible Treatment Sequences 
 
Sequence A 
N=3 
Sequence B 
N=3 
Sequence C 
N=3 
Sequence D 
N=3 
Treatment Period 
1 
rhEPO 
57Fe 
rhEPO 
58Fe 
Daprodustat 
57Fe 
Daprodustat 
58Fe 
Treatment Period 
2 
Daprodustat 
58Fe 
Daprodustat 
57Fe 
rhEPO 
58Fe 
rhEPO 
57Fe 
 
5.2. 
Number of Participants 
Sufficient participants will be enrolled such that at least 12 participants comprise the 
Evaluable Population (See Section 10.3.1.3). 
5.3. 
Participant and Study Completion 
A participant is considered to have completed the study if he/she has completed all 
phases of the study including the follow-up visit. 
The end of the study is defined as the date of the last visit of the last participant in the 
study. 
5.4. 
Scientific Rationale for Study Design 
This study will use a randomized, repeat dose, open label, two period cross over design in 
adult, ND, male and female participants with anemia associated with chronic kidney 
disease currently treated with stable rhEPO doses (≤ 50% change in 4-weekly dose) for at 
least 8 weeks prior to and including the screening period. 
• This will be an open label study as oral iron absorption is an objective measure 
and unlikely to be influenced by the participant’s knowledge of the treatment 
administered.  Additionally, blinding of treatment would be difficult as rhEPO is 


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administered by subcutaneous injection, while daprodustat is administered orally 
once daily as a tablet. 
• Iron absorption will be assessed over a 2 week period commencing after 2 weeks 
of study treatment, a period of time when it is anticipated that any changes in oral 
absorption mediated by changes in expression of HIF-dependent DcytB and 
DMT1 will be apparent (Shah, 2009). 
• This study will use a cross over design, with oral iron absorption assessed in each 
participant following both rhEPO and daprodustat administration, in order for 
each participant to serve as their own control. 
• Participants will need to be currently treated with stable doses (≤ 50% change in 
4-weekly dose) of rhEPO for at least 8 weeks prior to and including the screening 
period.  Additionally, participants need to have stable Hgb levels for the 4 weeks 
of screening.  Finally, participants will be switched from their current rhEPO to 
daprodustat using a switching algorithm that was designed to result in no change 
in Hgb levels.  All of these aspects are intended to minimize any potential for a 
change in erythropoiesis during the course of the study in order to minimize any 
potential change in oral iron absorption due to a change in erythropoiesis (Skikne, 
2000).   
• The planned population is participants currently on rhEPO for anemia associated 
with chronic kidney disease that are non-dialysis dependent.  This population was 
chosen as those most likely to be administered oral iron therapy for the treatment 
of anemia.  Additionally, as oral iron is inferior to IV iron likely due to elevated 
levels of hepcidin and pro-inflammatory cytokines that restrict intestinal iron 
absorption, this is the population most likely to benefit from an increase in oral 
iron absorption (Macdougall, 2016). 
• This study uses iron incorporation into erythrocytes in order to assess oral iron 
absorption.  While it is appreciated that changes in erythrocyte iron content can be 
due to many factors, erythrocyte iron content is a well-recognized surrogate for 
iron absorption (IAEA Human Health Series No. 21, 2012).  Additionally, 
fractional iron absorption as an endpoint allows for comparison to studies in non-
anemic participants. 
• At present, three methodologies are primarily recognized for assessing fractional 
iron absorption: fecal recovery of the ingested isotope, plasma appearance of the 
ingested isotope and iron incorporation into erythrocytes following oral ingestion.  
Of the three, the most frequently used approach is iron incorporation into 
erythrocytes using single or multiple oral labels as it is more sensitive than either 
the fecal recovery or plasma appearance methods (IAEA Human Health Series 
No. 21, 2012).  The majority (80%) of the iron that is absorbed is incorporated 
into red blood cells in Hgb, a process which occurs over 10 to 12 days.  Once 
incorporated, the iron is stable for the lifespan of the red blood cell, a period of up 
to 120 days in non-anemic participants and approximately 70 days in individuals 
with chronic kidney disease. 
• Iron absorbed from the diet is obtained from animal-based sources, and is known 
as heme iron, while plant-based iron is non-heme iron.  This study will assess the 


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absorption of non-heme iron as most of the understanding of iron absorption is 
related to non-heme iron which typically comprises the majority of dietary and 
supplemental iron. 
• ND-CKD patients which have elevated levels of C-reactive protein (CRP) and 
hepcidin typically experience poor intestinal iron absorption (Macdougall, 2014).  
Therefore, hsCRP will be assessed at screening for eligibility in order to minimize 
the recruitment of participants with poor intestinal iron absorption due to 
inflammation. 
• Finally, stable isotopic iron will be administered in the fasted state as the fraction 
of iron absorbed in the fasted state is typically much higher than that which occurs 
when a component of a mixed meal.  A recent publication using this methodology 
in 18 healthy, adult female participants reported an average absorption ± SD of 
14.71 ± 10.7% in the fasted state compared to 3.63 ± 6.5% in the fed state 
(Young, 2009).  In this regard, it is considered that a 30% change in oral iron 
absorption is clinically relevant. 
5.5. 
Dose Justification 
• The dose of rhEPO in this study will be the stable doses (≤ 50% change in 4-
weekly dose) administered for at least 8 weeks prior to and including the 
screening period. 
• The goal of the starting doses of daprodustat in this study is to maintain Hgb 
levels achieved on the prior rhEPO dose so that, on average, there is no change 
from baseline Hgb.  Starting doses of 1, 2 or 4 mg of daprodustat are estimated to 
maintain Hgb levels observed with participant’s prior rhEPO therapy based on 
population dose-response longitudinal modelling of Hgb data collected across the 
Phase 2 program (GlaxoSmithKline Document Number 2015N248947_00, 2016). 
6. 
STUDY POPULATION 
Prospective approval of protocol deviations to recruitment and enrolment criteria, also 
known as protocol waivers or exemptions, is not permitted. 
6.1. 
Inclusion Criteria 
Participants are eligible to be included in the study only if all the following criteria apply: 
Age 
1. Participant must be at least 18 years of age inclusive, at the time of signing the 
informed consent. 
Type of Participant and Disease Characteristics 
2. Participants who are Stage 3, 4 or 5 CKD (confirmed at Week -4 only) defined by 
eGFR using the CKD Epidemiology Collaboration (CKD-EPI) formula (Levey, 
2009).  See the Study Reference Manual (SRM) for details on calculation. 


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3. Participants who are currently treated with stable doses (≤ 50% change in 4-weekly 
dose) for at least 8 weeks prior to and including the screening period, of rhEPO (i.e., 
epoetin alfa or darbepoetin alfa). 
4. Participants with Hgb levels between 9.0 and 11.5 g/dL, inclusive, who meet the Hgb 
stability criteria as outlined in Section 6.2.1. 
5. Participants may be on stable maintenance oral iron supplementation (<50% change 
in overall dose and compliance of 80% of prescribed doses in the 4 weeks prior to 
and including the screening period).  If participants have been on IV iron, then 
participants will not have received IV iron for 8 weeks prior to the Day 1 visit. 
Sex 
6. Male or female 
a. Female participants: 
A female participant is eligible to participate if she is not pregnant (see Appendix 7), 
not breastfeeding, and at least one of the following conditions applies: 
(i) 
Not a woman of childbearing potential (WOCBP) as defined in Appendix 7 
OR 
(ii) 
A WOCBP who agrees to follow the contraceptive guidance in Appendix 7 
during the treatment period to the follow-up visit. 
Informed Consent 
7. Capable of giving signed informed consent as described in Appendix 5 which 
includes compliance with the requirements and restrictions listed in the informed 
consent form (ICF) and in this protocol. 
6.2. 
Exclusion Criteria 
Participants are excluded from the study if any of the following criteria apply: 
Medical Conditions 
1. On dialysis or clinical evidence of impending need to initiate dialysis within 90 days 
after study start (i.e., Day 1). 
2. Planned kidney transplant within 3 months after study start. 
3. A positive test for HIV antibody. 
Prior/Concomitant Therapy 
4. History of severe allergic or anaphylactic reactions or hypersensitivity to excipients 
in the investigational products (see Daprodustat IB for list of excipients). 
5. Use of any prescription or non-prescription drugs or dietary supplements that are 
prohibited from screening until the end of Treatment Period 2 (see Section 7.7.2). 
6. Planned or current administration of Mircera (methoxy PEG-epoetin beta). 


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Prior/Concurrent Clinical Study Experience 
7. The participant has participated in a clinical trial and has received an experimental 
investigational product within the prior 30 days or 5 half lives, whichever is longer, 
from screening through Day 1. 
Diagnostic assessments 
8. At or below the lower limit of the reference range at screening for Vitamin B12 (may 
rescreen in a minimum of 8 weeks). 
9. Ferritin outside the range between 100 and 500 ng/mL, inclusive, at screening. 
10. Transferrin saturation (TSAT) outside the range between 15% and 40%, inclusive, at 
Screening. 
11. Folate < 2.0 ng/mL (4.5 nmol/L; may rescreen in a minimum of 8 weeks) at 
screening. 
12. High sensitivity C-reactive protein (hsCRP) ≥ 20 µg/mL at screening. 
Other Exclusions 
13. Myocardial infarction or acute coronary syndrome: ≤ 8 weeks prior to screening 
through Day 1. 
14. Hospitalization for greater than 24 hours: ≤ 8 weeks prior to screening through Day 1 
15. Stroke or transient ischemic attack ≤ 8 weeks prior to screening through Day 1. 
16. Class IV heart failure, as defined by the New York Heart Association (NYHA) 
functional classification system. 
17. Current uncontrolled hypertension as determined by the investigator. 
18. QT interval corrected for heart rate using Bazett’s formula (QTcB): QTcB > 500 
msec, or QTcB > 530 msec in participants with Bundle Branch Block.  There is no 
QTc exclusion for participants with a predominantly paced rhythm. 
19. Active chronic inflammatory disease that could impact erythropoiesis.  A partial list 
can be found in the Study Reference Manual (SRM). 
20. History of bone marrow aplasia or pure red cell aplasia. 
21. Conditions, other than anemia associated with chronic kidney disease, which can 
affect erythropoiesis.  A partial list can be found in the SRM. 
22. Evidence of actively bleeding gastric, duodenal, or esophageal ulcer disease OR 
clinically significant GI bleeding from ≤ 4 weeks prior to screening through Day 1. 
23. Liver disease (any of the following): 
• Alanine transaminase (ALT) > 2x upper limit of normal (ULN; screening only) 
• Bilirubin > 1.5x ULN (screening only) 
NOTE: Isolated bilirubin > 1.5 x ULN is acceptable if bilirubin is fractionated and 
direct bilirubin < 35% 


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• Current or chronic history of liver disease or known hepatic or biliary abnormalities 
(with the exception of Gilbert's syndrome or asymptomatic gallstones). 
24. Major surgery (excluding vascular access surgery) within the 8 weeks prior to 
screening through Day 1 or planned during the study. 
25. Blood transfusion within 8 weeks prior to screening through Day 1, or an anticipated 
need for blood transfusion during the study. 
26. Clinical evidence of an acute infection, or history of infection requiring IV antibiotic 
therapy from 4 weeks prior to screening through Day 1. 
NOTE: Prophylactic antibiotics are allowed. 
27. History of malignancy within the two years prior to screening through Day 1 or 
currently receiving treatment for cancer, with the exception of localized squamous 
cell or basal cell carcinoma of the skin definitively treated 12 weeks prior to Day 1. 
28. 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. 
6.2.1. 
Hgb Stability Criteria 
Entry into the study requires a stable Hgb between 9.0 - 11.5 g/dL. 
• This criterion is assessed from an average of three Hgb values obtained via a 
validated point-of-care device to measure Hgb (HemoCue) on site during the 
screening period at Week -4, Week -2 and on Day 1. 
• The Hgb stability assessment is the difference between the maximum and 
minimum values of the three Hgb measurements obtained between Week -4 and 
Day 1. 
A decision algorithm for Hgb stability is shown in Figure 3. 


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Figure 3 
Hgb Stability Criteria 
 
6.3. 
Lifestyle Restrictions 
No lifestyle restrictions are required. 
6.4. 
Screen Failures 
Screen failures are defined as participants who consent to participate in the clinical study 
but are not subsequently randomized.  A minimal set of screen failure information is 
required to ensure transparent reporting of screen failure participants to meet the 
Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to 
respond to queries from regulatory authorities.  Minimal information includes 
demography, screen failure details, eligibility criteria, and any serious adverse events 
(SAEs). 
Individuals who do not meet the criteria for participation in this study (screen failure) 
may be rescreened. 
 


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7. 
TREATMENTS 
Study treatment is defined as any investigational treatment(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according 
to the study protocol. 
Participants at study entry will discontinue their rhEPO therapy (i.e., epoetin alfa or 
darbepoetin alfa) prior to randomization so that the randomization date (Day 1) should 
coincide, as closely as possible, with the date of the next scheduled rhEPO 
administration.  Examples of switching are provided in the SRM. 
7.1. 
Treatments Administered 
Study 
Treatment 
Name: 
Daprodustat 
rhEPO 
(epoetin alfa 
OR 
darbepoetin 
alfa) 
57Fe 
58Fe 
Dosage 
formulation: 
Tablet 
Solution for 
injection 
57FeSO4  
Oral solution 
58FeSO4/ 56FeSO4  
Oral solution 
Unit dose 
strength(s)/ 
Dosage level(s): 
1 mg, 2 mg, 
4 mg tablet 
strengths/1 mg, 
2 mg, 4 mg 
dosage levels 
rhEPO is 
commercially 
available in 
various single-
dose vials and 
single-dose 
prefilled 
syringes 
57FeSO4 
(containing 10 
mg of 57Fe)  
 
10 mg total dose 
of Fe 
 58FeSO4 
(containing 3 mg 
of 58Fe)  
56FeSO4 
(containing 7 mg 
of 56Fe) 
10 mg total dose 
of Fe 
Route of 
Administration 
Oral 
Subcutaneous 
injection 
Oral 
Oral 
Dosing 
instructions: 
1 tablet to be 
taken daily 
without regard 
for food 
As per product 
labelling 
Full dosing 
instructions can 
be found in the 
SRM 
Full dosing 
instructions can 
be found in the 
SRM 
Packaging and 
Labeling 
Study Treatment 
will be provided 
in a bottle. Each 
bottle will be 
labeled as 
required per 
country 
requirement. 
As per product 
labelling 
N/A 
N/A 
Manufacturer 
GSK 
Amgen 
Formulated by 
extemporaneous 
compounding 
Formulated by 
extemporaneous 
compounding 


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7.1.1. 
Daprodustat Dosing Information 
Doses of daprodustat to be administered are based on the rhEPO dose at randomization 
(Day 1) as described in Table 2. 
Table 2 
Daprodustat Doses 
Darbepoetin alfa 
(µg/4 wk SC/IV) 
Epoetin alfa 
(convert SC to IV 
U/week)1 
Daprodustat dose 
(mg, once daily) 
20 to 30 
1500 to 2000 
1 
>30 to 300 
>2000 to <20000 
2 
>300 
≥20000 
4 
1 Standardized rhEPO IV dose (U/week) = 161/113 x (epoetin SC dose 
(units)/frequency) 
 
7.1.2. 
rhEPO Dosing Information 
Participants are required to be currently treated with stable doses (≤ 50% change in 4-
weekly dose) of rhEPO for at least 8 weeks prior to and including the screening period.  
The dose of rhEPO to be administered during the study as randomized study treatment 
will be the rhEPO dose at randomization (Day 1).  This dose is to be administered 
whether a participant is randomized to rhEPO on Treatment Period 1, or is switching 
back to rhEPO following 4 weeks of administration of daprodustat on Treatment Period 
2. 
7.1.3. 
57Fe Dosing Information 
An oral solution will be administered containing 10 mg of 57Fe as ferrous sulfate.  Exact 
doses will be measured, calculated, and captured for each individual participant. The 
solution is to be taken following an overnight fast.  Further details will be outlined in the 
compounding document and SRM.  
7.1.4. 
58Fe Dosing Information 
An oral solution will be administered containing 3 mg of 58Fe as ferrous sulfate with 7 
mg of 56Fe as ferrous sulfate (natural abundance Fe).  Exact doses will be measured, 
calculated, and captured for each individual participant. The solutions are to be taken 
following an overnight fast. Further details will be outlined in the compounding 
document and SRM. 


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7.2. 
Dose Modification 
No dosage modification is anticipated in this study.  However, if it becomes medically 
necessary to adjust the dose of either rhEPO or daprodustat, the participant is to be 
withdrawn from the study. 
7.3. 
Method of Treatment Assignment 
All participants will be centrally randomized using an Interactive Voice/Web Response 
System (IVRS/IWRS).  Before the study is initiated, the telephone number and call-in 
directions for the IVRS and/or the log in information & directions for the IWRS will be 
provided to each site. 
7.4. 
Blinding 
This is an open-label study; potential bias will be reduced by using central randomization.  
Further, fractional iron absorption is an objective endpoint, such that participant 
knowledge of the treatment received is unlikely to affect the results. 
7.5. 
Preparation/Handling/Storage/Accountability 
• The investigator or designee must confirm appropriate temperature conditions 
have been maintained during transit for all study treatment received and any 
discrepancies are reported and resolved before use of the study treatment. 
• Only participants enrolled in the study may receive study treatment and only 
authorized site staff may supply or administer study treatment. All study 
treatments must be stored in a secure, environmentally controlled, and monitored 
(manual or automated) area in accordance with the labeled storage conditions 
with access limited to the investigator and authorized site staff. 
• The investigator, institution, or the head of the medical institution (where 
applicable) is responsible for study treatment accountability, reconciliation, and 
record maintenance (i.e., receipt, reconciliation, and final disposition records). 
• Further guidance and information for the final disposition of unused study 
treatment are provided in the SRM. 
• Under normal conditions of handling and administration, study treatment is not 
expected to pose significant safety risks to site staff.  Take adequate precautions 
to avoid direct eye or skin contact and the generation of aerosols or mists.  In the 
case of unintentional occupational exposure notify the monitor, Medical Monitor 
and/or GSK study contact. 
• 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. 


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7.6. 
Treatment Compliance 
• When the individual dose for a participant is prepared from a bulk supply, the 
preparation of the dose will be confirmed by a second member of the study site 
staff. 
• When participants are dosed at the site, they will receive study treatment directly 
from the investigator or designee, under medical supervision.  The date and time 
of each dose administered in the clinic will be recorded in the source documents.  
The dose of study treatment and study participant identification will be confirmed 
at the time of dosing by a member of the study site staff other than the person 
administering the study treatment. 
• When participants self-administer study treatment(s) at home, compliance will be 
assessed through querying the participant during the site visits and documented in 
the source documents and eCRF.  A record of the study treatment dispensed to 
and taken by each participant must be maintained and reconciled with study 
treatment and compliance records.  Treatment start and stop dates, including dates 
for treatment delays and/or dose reductions will also be recorded in the eCRF. 
7.7. 
Concomitant Therapy 
Any medication or vaccine (including over-the-counter or prescription medicines, 
vitamins, and/or herbal supplements) that the participant is receiving at the time of 
enrolment or receives during the study must be recorded along with: 
• reason for use 
• dates of administration including start and end dates 
• dosage information including dose and frequency 
The Medical Monitor should be contacted if there are any questions regarding 
concomitant or prior therapy. 
7.7.1. 
Permitted Medications and Non-Drug Therapies 
Unless specified as a prohibited medication in Section 7.7.2, all concomitant medications 
should be considered permitted provided they are not contraindicated for the individual 
participant concerned. 
Participants are to be advised to maintain use of the following medications at a consistent 
dosage and frequency: 
• Oral iron supplementation (except ferric citrate, which is prohibited; see Section 
7.7.2) 
• Acid-reducing agents (e.g., H2 receptor antagonists, proton pump inhibitors, 
antacids) 


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7.7.2. 
Prohibited Medications and Non-Drug Therapies 
Use of any of the following prescription drugs from screening (Week -4) until the end of 
Treatment Period 2 is prohibited and will constitute a protocol deviation: 
• Strong inhibitors of CYP2C8 (e.g., gemfibrozil, high dose clopidogrel [300 mg]) 
• Strong inducers of CYP2C8 (e.g., rifampin/rifampicin) 
• The oral iron supplement ferric citrate 
• Intravenous administration of iron 
• Any rhEPO other than epoetin alfa or darbepoetin alfa 
7.7.3. 
Standard of Care 
During the study, 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. 
7.8. 
Treatment after the End of the Study 
Participants will not receive any additional treatment from GSK after completion of the 
study because the indication being studied is not life threatening or seriously debilitating 
and other treatment options are available. 
The investigator is responsible for ensuring that consideration has been given to the post-
study care of the participant’s medical condition. 
8. 
DISCONTINUATION CRITERIA 
8.1. 
Discontinuation of Study Treatment 
Participants that discontinue study treatment should be withdrawn from the study.  See 
Section 8.2 for a description of withdrawal procedures. 
8.1.1. 
Liver Chemistry Stopping Criteria 
Liver chemistry stopping and increased monitoring criteria have been designed to 
assure participant safety and evaluate liver event etiology. 
Discontinuation of study treatment for abnormal liver tests is required when: 
• a participant meets one of the conditions outlined in Figure 4 
OR 
• when in the presence of abnormal liver chemistries not meeting protocol-specified 
stopping rules, the investigator believes study treatment discontinuation is in the 
best interest of the participant. 


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Figure 4 
Phase III-IV Liver Chemistry Stopping and Increased Monitoring 
Algorithm 
Continue Study Treatment 
Discontinue Study Treatment 
Plus 
Bilirubin≥2x
ULN (>35% 
direct) or plus
INR>1.5, if 
measured*
Possible  
Hy’s Law
ALT≥3xULN
ALT
≥8xULN
Plus
Symptoms of 
liver injury
or 
hypersensitivity
No
Yes
Yes
Yes
No
No
No
See algorithm 
for continued 
therapy with 
increased liver 
chemistry 
monitoring
Yes
*INR value not applicable to subjects on anticoagulants 
ALT 
≥3xULN 
but 
<8xULN
Yes
➢Must refer to Liver Safety Required Actions and Follow up Assessments section in the Appendix
➢Report as an SAE if possible Hy’s Law case: ALT≥3xULN and  Bilirubin≥2xULN (>35% direct)  or 
INR>1.5, if measured*
 
Liver Safety Required Actions and Follow up Assessments Section can be found in 
Appendix 2. 
8.2. 
Withdrawal from the Study 
• A participant may withdraw from the study at any time at his/her own request or 
may be withdrawn at any time at the discretion of the investigator for safety, 
behavioral, compliance or administrative reasons. 
• If the participant withdraws consent for disclosure of future information, the 
sponsor may retain and continue to use any data collected before such a 
withdrawal of consent. 
• If a participant withdraws from the study, he/she may request destruction of any 
samples taken and not tested, and the investigator must document this in the site 
study records. 
• Participants that withdraw/are withdrawn from the study treatment are encouraged 
to attend the follow-up visit 14 ± 3 days following discontinuation of study 
treatment.  Assessments to be conducted are listed in the SoA (Section 2). 
 
 


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8.2.1. 
Criteria for Permanent Discontinuation from Study Treatment and 
Early Withdrawal 
Participants must permanently discontinue study treatment and be withdrawn from the 
study for the following reasons: 
• Meets Hgb stopping criteria (See Section 8.2.1.1) 
• Meets iron stopping criteria (See Section 8.2.1.2) 
• If it becomes medically necessary to adjust the dose of either rhEPO or 
daprodustat 
• Receives a blood transfusion 
• Receives a kidney transplant 
• Becomes pregnant or intends to become pregnant during the study 
• Active GI bleeding 
• Diagnosis of cancer, with the exception of squamous cell or basal cell carcinoma 
• Liver chemistry abnormalities exceeding the threshold criteria (See Section 8.1.1) 
• Use of prohibited medication (See Section 7.7.2) 
• Active chronic inflammatory disease that could impact erythropoiesis 
• Any new diagnosis of hematological disease including those affecting platelets, 
white or red blood cells, coagulation disorders, or any other cause of anemia of 
chronic disease other than renal disease 
8.2.1.1. 
Hgb Stopping Criteria 
GSK will supply a point-of-care Hgb analyzer (HemoCue) to each site for rapid and 
convenient monitoring of Hgb levels and to ensure consistency of Hgb measurements 
across sites participating in the study. 
Blood samples for measurement of Hgb concentrations via HemoCue will be collected 
and recorded in the eCRF.  Table 3 summarizes the Hgb values and corresponding action 
to be taken at each visit. 


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Table 3 
Hgb Stopping Criteria 
Hgb (g/dL) at visit 
Action 
<7.5 
Repeat HemoCue assessment on the same sample at 
same study visit to confirm; take average of 2 values.  If 
confirmed, permanently discontinue study treatment and 
withdraw participant from the study. 
7.5 - <13.0  
With: 
2.0 g/dL decrease in Hgb 
over the previous 2 weeks  
Repeat HemoCue assessment on the same sample at 
same study visit to confirm; take average of 2 values.  If 
confirmed, permanently discontinue study treatment and 
withdraw participant from the study. 
7.5 - <13.0 
With: 
<1.0 absolute change in 
Hgb over the previous 2 
weeks 
Continue study treatment. 
7.5 - <13.0 
With: 
1.0 increase in Hgb over 
the previous 2 weeks 
Repeat HemoCue assessment on the same sample at 
same study visit to confirm; take average of 2 values.  If 
confirmed, permanently discontinue study treatment and 
withdraw participant from the study. 
13.0 
Repeat HemoCue assessment on the same sample at 
same study visit to confirm; take average of 2 values.  If 
confirmed, permanently discontinue study treatment and 
withdraw participant from the study. 
 
8.2.1.2. 
Iron Stopping Criteria 
Participants must remain iron replete throughout the study, and should remain on their 
regular oral iron supplement as described in Section 7.7.1. 
Based on the PI's clinical judgement in consultation with Medical Monitor, if the subject 
cannot be maintained on the same oral iron dose during the study treatment periods, the 
subject must be withdrawn.  
8.3. 
Lost to Follow Up 
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site.  
The following actions must be taken if a participant fails to return to the clinic for a 
required study visit: 
• The site must attempt to contact the participant and reschedule the missed visit as 
soon as possible and counsel the participant on the importance of maintaining the 
assigned visit schedule and ascertain whether or not the participant wishes to 
and/or should continue in the study. 
• Before a participant is deemed lost to follow up, the investigator or designee must 
make every effort to regain contact with the participant (where possible, 3 
telephone calls and, if necessary, a certified letter to the participant’s last known 


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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 with a primary reason of lost to follow-up. 
9. 
STUDY ASSESSMENTS AND PROCEDURES 
• Study procedures and their timing are summarized in the SoA (Section 2). 
• Protocol waivers or exemptions are not allowed. 
• Immediate safety concerns should be discussed with the sponsor immediately 
upon occurrence or awareness to determine if the participant should continue or 
discontinue study treatment. 
• Adherence to the study design requirements, including those specified in the SoA, 
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., Hgb levels) and obtained before signing of ICF may be utilized for 
screening or baseline purposes provided the procedure met the protocol-specified 
criteria and was performed within the time frame defined in the SoA (Section 2). 
• The maximum amount of blood collected from each participant over the duration 
of the study, including any extra assessments that may be required, will not 
exceed 500 mL. 
• Repeat or unscheduled samples may be taken for safety reasons or for technical 
issues with the samples. 
9.1. 
Efficacy Assessments 
Efficacy is not evaluated in this study. 
9.2. 
Adverse Events 
The definitions of an AE or SAE can be found in Appendix 6. 
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 designees are responsible for detecting, documenting, and 
reporting events that meet the definition of an AE or SAE and remain responsible for 
following up AEs that are serious, considered related to the study treatment or the study, 
or that caused the participant to discontinue the study treatment (see Section 8). 


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9.2.1. 
Time Period and Frequency for Collecting AE and SAE 
Information 
• All SAEs will be collected from the start of treatment until the follow-up visit at 
the time points specified in the SoA (Section 2).  However, any SAEs assessed as 
related to study participation (e.g., study treatment, protocol-mandated 
procedures, invasive tests, or change in existing therapy) or related to a GSK 
product will be recorded from the time a subject consents to participate in the 
study. 
• All AEs will be collected from the start of treatment until the follow-up visit at 
the time points specified in the SoA (Section 2). 
• Medical occurrences that begin before the start of study treatment but after 
obtaining informed consent will be recorded on the Medical History/Current 
Medical Conditions section of the eCRF not the AE section. 
• All SAEs will be recorded and reported to the sponsor or designee immediately 
and under no circumstance should this exceed 24 hours, as indicated in Appendix 
6.  The investigator will submit any updated SAE data to the sponsor within 
24 hours of it being available. 
• Investigators are not obligated to actively seek AEs or SAEs in former study 
participants.  However, if the investigator learns of any SAE, including a death, at 
any time after a participant has been discharged from the study, and he/she 
considers the event to be reasonably related to the study treatment or study 
participation, the investigator must promptly notify the sponsor. 
• The method of recording, evaluating, and assessing causality of AEs and SAEs 
and the procedures for completing and transmitting SAE reports are provided in 
Appendix 6. 
9.2.2. 
Method of Detecting AEs and SAEs 
Care will be taken not to introduce bias when detecting AE and/or SAE.  Open-ended and 
non-leading verbal questioning of the participant is the preferred method to inquire about 
AE occurrence. 
9.2.3. 
Follow-up of AEs and SAEs 
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts.  All SAEs, and non serious AEs of special 
interest (as defined in Section 9.2.4), will be followed until the event is resolved, 
stabilized, otherwise explained, or the participant is lost to follow-up (as defined in 
Section 8.3).  Further information on follow-up procedures is given in Appendix 6. 
9.2.4. 
Adverse Events of Special Interest (AESI) 
Adverse Events of Special Interest (AESI) have been identified based on non-clinical 
studies with daprodustat, clinical experience with rhEPOs, and current information 
regarding HIF-regulated pathways in mediating hypoxia-associated pathophysiology.  
The currently identified AESI for daprodustat are as follows: 


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• Thrombosis and/or tissue ischemia secondary to excessive erythropoiesis 
• Death, MI, stroke, heart failure, venous thromboembolism, thrombosis of vascular 
access 
• Cardiomyopathy 
• Pulmonary artery hypertension 
• Cancer-related mortality and tumor progression and recurrence 
• Esophageal and gastric erosions  
• Proliferative retinopathy, macular edema, choroidal neovascularization 
• Exacerbation of rheumatoid arthritis 
• Worsening of hypertension 
9.2.5. 
Regulatory Reporting Requirements for SAEs 
• Prompt notification by the investigator to the sponsor of a SAE is essential so that 
legal obligations and ethical responsibilities towards the safety of participants and 
the safety of a study treatment under clinical investigation are met. 
• The sponsor has a legal responsibility to notify both the local regulatory authority 
and other regulatory agencies about the safety of a study treatment under clinical 
investigation.  The sponsor will comply with country-specific regulatory 
requirements relating to safety reporting to the regulatory authority, Institutional 
Review Boards (IRB)/Independent Ethics Committees (IEC), and investigators. 
• Investigator safety reports must be prepared for suspected unexpected serious 
adverse reactions (SUSAR) according to local regulatory requirements and 
sponsor policy and forwarded to investigators as necessary. 
• An investigator who receives an investigator safety report describing a SAE or 
other specific safety information (e.g., summary or listing of SAE) 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. 
9.2.6. 
Cardiovascular and Death Events 
For any cardiovascular events listed below and all deaths, whether or not they are 
considered SAEs, specific Cardiovascular (CV) and Death sections of the eCRF will be 
required to be completed.  These sections include questions regarding cardiovascular 
(including sudden cardiac death) and non-cardiovascular death. 
• Myocardial infarction/unstable angina 
• Congestive heart failure 
• Arrhythmias 
• Valvulopathy 
• Pulmonary hypertension 


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• Cerebrovascular events/stroke and transient ischemic attack 
• Peripheral arterial thromboembolism 
• Deep venous thrombosis/pulmonary embolism 
• Revascularization 
The CV eCRFs are presented as queries in response to reporting of certain CV MedDRA 
terms.  The CV information should be recorded in the specific cardiovascular section of 
the eCRF within one week of receipt of a CV Event data query prompting its completion. 
The Death eCRF is provided immediately after the occurrence or outcome of death is 
reported.  Initial and follow-up reports regarding death must be completed within one 
week of when the death is reported. 
9.2.7. 
Possible Suicidality Related Adverse Events 
If during the study there is an occurrence of an AE or SAE which in the investigator’s 
opinion is possibly related to suicidality, the Possible Suicidality Related Adverse Events 
(PSRAE) eCRF form should be completed (in addition to the AE and SAE pages, as 
appropriate). 
This event may include, but is not limited to, one that involves suicidal ideation, a 
preparatory act toward imminent suicidal behavior, a suicide attempt, or a completed 
suicide.  The investigator will exercise his or her medical and scientific judgment in 
deciding whether an event is possibly related to suicidality. 
9.2.8. 
Pregnancy 
• Details of all pregnancies in female participants and the outcome for the neonate, 
if applicable, will be collected from the start of study treatment. 
• If a pregnancy is reported, the investigator should inform GSK within 24 hours of 
learning of the pregnancy and should follow the procedures outlined in Appendix 
7. 
• Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAE. 
9.3. 
Treatment of Overdose 
For this study, any dose of daprodustat greater than 4 mg within a 24-hour time period 
will be considered an 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.  In the event of a suspected overdose, it is 
recommended that the appropriate supportive clinical care be instituted, as dictated by the 
participant’s clinical status.  Additionally, participants should be monitored closely for 
CV events, increased heart rate and hematologic abnormalities. 


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9.4. 
Safety Assessments 
Planned time points for all safety assessments are provided in the SoA (Section 2). 
9.4.1. 
Entry Criteria 
Entry criteria are to be assessed during the screening period, at Week -4, Week -2 and 
Day 1.  The timing for assessment of specific criteria are detailed in the SoA (Section 2), 
and are described in Table 4 
Table 4 
Timing of Entry Criteria Assessments 
Timing 
Procedures 
Week -4 
Informed consent, complete physical examination, medical history, 
demography, height, weight, vital signs, clinical safety laboratory assessments, 
pregnancy test, eGFR, Hgb, HIV, concomitant medications, rhEPO dose 
Week -2 
Brief physical examination, Hgb, estradiol & FSH (as needed), ECG, folate, 
Vitamin B12, hsCRP, ferritin, TSAT, concomitant medications, rhEPO dose 
Day 1 
Brief physical examination, weight, vital signs, Hgb, pregnancy test, 
concomitant medications, rhEPO dose 
 
9.4.2. 
Physical Examinations 
• A complete physical examination will include, at a minimum, assessments of the 
skin, cardiovascular, respiratory, gastrointestinal and neurological systems.  
Height and weight will also be measured and recorded. 
• A brief physical examination will include, at a minimum, assessments of the skin, 
lungs, cardiovascular system, and abdomen (liver and spleen). 
• Investigators should pay special attention to clinical signs related to previous 
serious illnesses. 
9.4.3. 
Vital Signs 
• 
Oral temperature, pulse, respiratory rate, and blood pressure will be assessed. 
• 
Blood pressure and pulse measurements will be assessed in a seated position 
with a completely automated device.  Manual techniques will be used only if an 
automated device is not available. 
• 
Blood pressure and pulse measurements should be preceded by at least 5 
minutes of rest for the participant in a quiet setting without distractions (e.g., 
television, cell phones). 
• 
Vital signs (to be taken before blood collection for laboratory tests) will consist 
of 1 pulse and 3 blood pressure measurements (3 consecutive blood pressure 


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readings will be recorded at intervals of at least 1 minute).  The average of the 3 
blood pressure readings will be recorded on the eCRF. 
9.4.4. 
Electrocardiograms 
• 
ECG measurements will be obtained as outlined in the SoA (Section 2).  Full 
12-lead ECGs will be recorded with the participant in a supine position.  Heart 
rate, PR interval, QRS duration, and QT (uncorrected) interval will be measured.  
QTcB will be calculated (machine read or manually). 
• 
At each time point at which ECGs are required, two additional ECGs are 
required if the initial ECG measurement indicates prolonged QTc (see Section 
6.1) using the automated or manually calculated QTcB value.  The average 
QTcB value of all three ECGs will be used to determine eligibility. 
9.4.5. 
Clinical Laboratory Assessments 
Refer to Appendix 4 for the list of protocol-required clinical chemistry and hematology 
(Table 8) and additional clinical laboratory assessments (Table 9) to be performed and to 
the SoA (Section 2) for the timing and frequency. 
 
• 
The investigator must review the laboratory report, document this review, and 
record any clinically relevant changes occurring during the study in the AE 
section of the eCRF.  The laboratory reports must be filed with the source 
documents.  Clinically significant abnormal laboratory findings are those which 
are not associated with the underlying disease, unless judged by the investigator 
to be more severe than expected for the participant's condition. 
• 
All laboratory tests with values considered clinically significantly abnormal 
during participation in the study or within 48 hours after the last dose of study 
treatment should be repeated until the values return to normal or baseline or are 
no longer considered significantly abnormal by the investigator or 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 assessments, as defined in Appendix 4, must be 
conducted in accordance with the laboratory manual and the SoA. 
9.4.6. 
Liver Chemistry Monitoring 
Clinical laboratory assessments for liver chemistry monitoring include ALT, AST, 
bilirubin and alkaline phosphatase.  Refer to the SoA (Section 2) for the frequency of 
monitoring.  Additionally, all of these tests are also part of the Clinical Chemistry 
Assessments and will be performed at the timepoints where those assessments are done.  
These assessments must be conducted in accordance with the laboratory manual. 
9.5. 
Pharmacokinetics 
Pharmacokinetic (PK) parameters are not evaluated in this study. 


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9.6. 
Pharmacodynamics 
Pharmacodynamics (PD) are not evaluated in this study. 
9.7. 
Genetics 
A blood sample for DNA isolation will be collected from participants who have 
consented to participate in the genetics analysis component of the study.  Participation is 
optional.  Participants who do not wish to participate in the genetic research may still 
participate in the study. 
In the event of DNA extraction failure, a replacement genetic blood sample may be 
requested from the participant. Signed informed consent will be required to obtain a 
replacement sample unless it was included in the original consent. 
See Appendix 8 for information regarding genetic research.  Details on processes for 
collection and shipment and destruction of these samples can be found in the SRM. 
9.8. 
Biomarkers 
9.8.1. 
Fractional oral iron absorption 
Venous blood samples will be collected for measurement of erythrocyte iron content at 
the times specified in the SoA (Section 2).  Further details for blood collection 
procedures can be found in the SRM.  Calculations for fractional iron absorption will be 
included in the Reporting and Analysis Plan (RAP). 
9.8.2. 
Iron status markers 
Markers of iron status (i.e., serum iron, transferrin, TSAT, soluble transferrin receptor, 
ferritin, hepcidin and erythroferrone) will be assessed at the times listed in the SoA.  
Measurement of erythroferrone is dependent upon available of a suitable assay 
methodology, so may not be assessed.  All blood samples for iron status markers to be 
taken pre dose.  Further details for blood collection procedures can be found in the SRM.  
9.8.3. 
Indices of erythropoiesis 
Indices of erythropoiesis (i.e., Hgb, hematocrit, red blood cell number, mean corpuscular 
volume, reticulocyte Hgb and reticulocyte number) are planned to be assessed at the 
times listed in the SoA (Section 2).  Further details for blood collection procedures can be 
found in the SRM. 
9.9. 
Health Economics OR Medical Resource Utilization and 
Health Economics 
Health Economics/Medical Resource Utilization and Health Economics parameters are 
not evaluated in this study. 


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10. 
STATISTICAL CONSIDERATIONS 
10.1. 
Hypotheses 
The primary analysis will test whether daprodustat is superior to rhEPO (i.e., epoetin alfa 
or darbepoetin alfa) according to the following statistical hypotheses: 
Null: The difference in fractional iron absorption between treatment arms (daprodustat- 
rhEPO (i.e., epoetin alfa or darbepoetin alfa)) is equal to zero. 
Alternative: The difference in fractional iron absorption between treatment arms 
(daprodustat-rhEPO (i.e., epoetin alfa or darbepoetin alfa)) is not equal to zero. 
10.2. 
Sample Size Determination 
Sufficient participants will be enrolled such that at least 12 participants comprise the 
Evaluable Population (See Section 10.3.1.3). 
A sample size of 12 participants provides 90% power to detect a paired mean difference 
of 11% between the two treatment groups under an assumed between-participant standard 
deviation (SD) of 10.7%.  Note this is a conservative estimate of the SD of the paired 
differences as it is based on a parallel design study (Young, 2009). 
10.2.1. 
Sample Size Sensitivity 
Table 5 illustrates the impact on power for the primary efficacy analysis based on 
alternative assumptions for the between participant SD and the expected difference 
between the treatment groups. 
Table 5 
Impact on power based on alternative assumptions for the between 
participant SD and the expected difference between the treatment 
groups 
Between 
participant 
SD (%) 
Expected difference between treatments in Fractional Iron Absorption 
(%) 
(daprodustat – rhEPO (i.e., epoetin alfa or darbepoetin alfa)) 
7 
9 
11 
13 
15 
7 
88% 
98% 
>99% 
>99% 
>99% 
9 
69% 
88% 
97% 
>99% 
>99% 
10.7 
54% 
76% 
90% 
97% 
>99% 
12 
43% 
66% 
82% 
93% 
98% 
14 
35% 
53% 
70% 
83% 
92% 
 
10.2.2. 
Sample Size Re-estimation 
No sample size re-estimation will be performed. 


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10.3. 
Data Analysis Considerations 
10.3.1. 
Analysis Populations 
10.3.1.1. 
Screened Population: 
This population consists of all participants who signed an ICF to participate in the clinical 
trial.  This population will be used for summarizing screening failure rates and reasons 
for screening failure. 
10.3.1.2. 
Safety Population: 
This population consists of all randomized participants who received at least one dose of 
study treatment. This will be the primary population for the safety analyses. 
10.3.1.3. 
Evaluable Population: 
This population consists of all randomized participants who received study medication 
and completed the iron absorption assessment for both treatment periods.  This 
population will be used for the primary endpoint analysis. 
10.3.1.4. 
Modified Intent to Treat (mITT) Population: 
This population consists of all randomized participants who received study medication 
and completed the iron absorption assessment at the end of the first treatment period. 
This population will be used for the sensitivity analysis of the primary endpoint. 
10.3.2. 
Interim Analyses 
No interim analysis will be performed for this study. 
10.4. 
Key Elements of Analysis Plan 
10.4.1. 
Primary Analysis 
To compare daprodustat to rhEPO (i.e., epoetin alfa or darbepoetin alfa) on fractional 
iron absorption, a mixed effect model will be fitted with fixed effect terms for treatment, 
sequence, period and iron isotope and a random effect for participant-within-sequence.  
The term sequence will consist of the four combinations of treatment and iron isotope 
assignments.  Point estimates and corresponding 95% confidence intervals will be 
constructed for the comparison of efficacy of daprodustat to rhEPO. 
A sensitivity analysis for this primary analysis will be performed using the same mixed 
modeling approach, except with the mITT population. 
Descriptive statistics (n, arithmetic mean, standard deviation, 95% CI, minimum, median 
and maximum) will be calculated for fractional iron absorption (%) at the Day 29 and 
Day 57 visits. 


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10.4.2. 
Secondary Analysis 
Descriptive statistics (n, arithmetic mean, standard deviation, 95% CI, minimum, median 
and maximum) will be calculated for iron markers and indices of erythropoiesis at each 
scheduled visit. 
Safety data will be presented in tabular and/or graphical format and summarized 
descriptively according to GSK’s Integrated Data Standards Library (IDSL) standards. 
Further details will be given in the Reporting Analysis Plan (RAP). 


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11. 
REFERENCES 
Besarab A, Coyne DW. Iron supplementation to treat anemia in patients with chronic 
kidney disease. Nat Rev Nephrol. 2010; 6:699-710. 
Besarab A, Provenzano R, Hertel J, Zabaneh R, Klaus SJ, Lee T, Leong R, Hemmerich S, 
Yu KH, Neff TB. Randomized placebo-controlled dose-ranging and pharmacodynamics 
study of roxadustat (FG-4592) to treat anemia in nondialysis-dependent chronic kidney 
disease. Nephrol Dial Transplant. 2015; 30:1665-1673. 
GlaxoSmithKline Document Number 2015N248947_00. Phase 2 population 
pharmacodynamics analyses of GSK1278863 in anemic subjects with chronic kidney 
disease. 22-APR-2016. 
GlaxoSmithKline Document Number RM2008/00267/07 Investigator’s Brochure, 14-
OCT-2015 
Haase VH. Regulation of erythropoiesis by hypoxia-inducible factors. Blood Rev. 2013; 
27:41-53. 
Holdstock L, Meadowcroft AM, Maier R, Johnson BM, Jones D, Rastogi A, Zeig S, 
Lepore JJ, Cobitz AR. Four-week studies of oral hypoxia-inducible factor-prolyl 
hydroxylase inhibitor GSK1278863 for treatment of anemia. J Am Soc Nephrol. 2016; 
27:1234-1244. 
International Atomic Energy Agency (IAEA). Assessment of iron bioavailability in 
humans using stable iron isotope techniques. IAEA Human Health Series No. 21. 2012. 
Koury MJ, Haase VH. Anaemia in kidney disease: harnessing hypoxia responses for 
therapy. Nat Rev Nephrol. 2015; 11:394-410. 
Levey AS, Stevens LA, Schmid CH, Zhang YL, Castro AF 3rd, Feldman HI, Kusek JW, 
Eggers P, Van Lente F, Greene T, Coresh J. A new equation to estimate glomerular 
filtration rate. Ann Intern Med. 2009; 150:604-612. 
Macdougall IC, Bircher AJ, Eckardt K-U, Obrador GT, Pollock CA, Stenvinkel P, 
Swinkels DW, Wanner C, Weiss G, Chertow GM. Iron management in chronic kidney 
disease: Conclusions from a “Kidney Disease: Improving Global Outcomes” (KDIGO) 
Controversies Conference. Kidney Int. 2016; 89:28-39. 
Macdougall IC, Bock A, Carrera F, Eckardt K-U, Gaillard C, Van Wyck D, Roubert B, 
Cushway T, Roger SD. The FIND-CKD study – a randomized controlled trial of 
intravenous iron versus oral iron in non-dialysis chronic kidney disease patients: 
background and rationale. Nephrol Dial Transplant 2014; 29:843-850. 
Pfeffer MA, Burdmann EA, Chen C-Y, Cooper ME, de Zeeuw D, Eckart K-U, Feyzi JM, 
Ivanovich P, Kewalramani R, Levey AS, Lewis EF, McGill JB, McMurray JJV, Parfrey 
P, Parving H-H, Remuzzi G, Singh AJ, Solomon, SD, Toto R. A trial of darbepoetin alfa 
in Type 2 diabetes and chronic kidney disease. N Eng J Med. 2009;361:2019-2032. 


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Shah YM, Matsubara T, Ito S, Yim S-H, Gonzalez FJ. Intestinal hypoxia-inducible 
transcription factors are essential for iron absorption following iron deficiency. Cell 
Metab. 2009; 9:152-164. 
Skikne BS, Ahluwalia N, Fergusson B, Chonko A, Cook JD. Effects of erythropoietin 
therapy on iron absorption in chronic renal failure. J Lab Clin Med. 2000; 135:452-458. 
Young MF, Glahn RP, Ariza-Nieto M, Inglis J, Olbina G, Westerman M, O’Brien KO. 
Serum hepcidin is significantly associated with iron absorption from food and 
supplemental sources in healthy young women. Am J Clin Nutr. 2009; 89:533-538. 


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12. 
APPENDICES 
12.1. 
Appendix 1: Abbreviations and Trademarks 
Table 6 
List of Abbreviations 
Ab 
Antibody 
AE 
Adverse event 
AESI 
Adverse events of special interest 
ALT 
Alanine aminotransferase (SGPT) 
AST 
Aspartate aminotransferase (SGOT) 
AUC 
Area under the concentration-time curve 
BCRP 
Breast Cancer Resistance Protein 
BUN 
Blood urea nitrogen 
CI 
Confidence Interval 
CKD 
Chronic kidney disease 
CKD-EPI 
Chronic kidney disease Epidemiology Collaboration 
CIOMS 
Council for International Organizations of Medical Sciences 
Cmax 
Maximum observed concentration 
CPK 
Creatine phosphokinase 
CONSORT Consolidated Standards of Reporting Trials 
CRF 
Case Report Form 
hsCRP 
High sensitivity C-reactive protein 
CV 
Cardiovascular 
CYP 
Cytochrome P450 enzyme 
DcytB 
Duodenal cytochrome b561 
dL 
deciliter 
DMT1 
Divalent metal-iron transporter 1 
DNA 
Deoxyribonucleic acid 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
eGFR 
Estimated glomerular filtration rate 
EPO 
Erythropoietin 
ESA 
Erythropoiesis-stimulating agent 
FDA 
Food and Drug Administration 
Fe 
Iron 
FPN 
Ferroportin 
FSH 
Follicle stimulating hormone 
g 
Gram 
GCP 
Good Clinical Practice 
GDF15 
Growth differentiation factor 15 
GI 
Gastrointestinal 
GSK 
GlaxoSmithKline 
HBsAg 
Hepatitis B surface antigen 
hCG 
Human chorionic gonadotropin 
HD 
Hemodialysis dependent 
Hgb 
Hgb 
HIF 
Hypoxia-inducible factor 
HIV 
Human Immunodeficiency Virus 
HIPAA 
Health Insurance Portability and Accountability Act 


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HPLC 
High performance liquid chromatography 
HRE 
Hypoxia response element 
IAEA 
International Atomic Energy Agency 
IB 
Investigator’s Brochure 
IC50 
Half maximal inhibitory concentration 
ICH 
International Conference on Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use 
ICF 
Informed Consent Form 
IEC 
Independent ethics committee 
IgG 
Immunoglobulin G 
IgM 
Immunoglobulin M 
IND 
Investigational new drug 
INR 
International normalization ratio 
IRB 
Institutional Review Board 
IU 
International units 
IUD 
Intrauterine device 
IUS 
Intrauterine system 
IV 
Intravenous 
KDOQI 
Kidney Disease Outcomes Quality Initiative 
Kg 
Kilogram 
LDH 
Lactate dehydrogenase 
LVEF 
Left ventricular ejection fraction 
MCH 
Mean corpuscular Hgb 
MCV 
Mean corpuscular volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
Milligrams 
MI 
Myocardial infarction 
mL 
Milliliter 
mmHg 
Millimeters of mercury 
MSDS 
Material Safety Data Sheet 
msec 
Milliseconds 
μM 
Micromolar 
ng 
Nanogram 
ND 
Nondialysis dependent 
NOAEL 
No observed adverse effect level 
NYHA 
New York Heart Association 
OATP 
Organic anion transporting polypeptide 
PCI 
Potential clinical importance 
PD 
Pharmacodynamic 
PHD 
prolyl-4-hydroxylases 
PHIs 
Prolyl hydroxylase inhibitors 
PK 
Pharmacokinetic 
PRVP 
Peak right ventricular pressure 
PSRAE 
Possible Suicidality Related Adverse Events 
QTc 
Corrected QT interval 
QTcB 
QT duration corrected for heart rate by Bazett’s formula 
RAP 
Report and Analysis Plan 
RBC 
Red blood cells 
rhEPO 
Recombinant human erythropoietin 
RNA 
Ribonucleic acid 


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SAE 
Serious Adverse Event 
SD 
Standard deviation 
SGOT 
Serum glutamic-oxaloacetic transaminase 
SGPT 
Serum glutamic pyruvic transaminase 
SO4 
Sulfate 
SoA 
Schedule of Assessments 
sPAP 
systolic Pulmonary Artery Pressure 
SRM 
Study Reference Manual 
SUSAR 
Suspected unexpected serious adverse reactions 
TIMS 
Thermal ionization mass spectrometry 
TF 
Transferrin 
TSAT 
Transferrin saturation 
VEGF 
Vascular endothelial growth factor 
ULN 
Upper limit of normal 
UK 
United Kingdom 
US 
United States 
WBC 
White blood cells 
WOCBP 
Woman of Child Bearing Potential 
 
Trademark Information 
Trademarks of the GlaxoSmithKline 
group of companies 
 
Trademarks not owned by the 
GlaxoSmithKline group of companies 
NONE 
 
Aranesp (darbepoetin alfa) 
 
 
Chiron RIBA 
 
 
Epogen (epoetin alfa) 
 
 
HemoCue 
 
 
Procrit (epoetin alfa) 
 
 
SAS 
 
 
WinNonlin 
 


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12.2. 
Appendix 2: Liver Safety Required Actions and Follow up 
Assessments 
Phase III-IV liver chemistry stopping criteria have been designed to assure participant 
safety and to evaluate liver event etiology (in alignment with the FDA premarketing 
clinical liver safety guidance). 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM174090.pdf. 
Table 7 
Phase III-IV liver chemistry stopping criteria and required follow-up 
assessments 
Liver Chemistry Stopping Criteria - Liver Stopping Event 
ALT-absolute ALT  8xULN 
ALT Increase ALT  5xULN but <8xULN  persists for 2 weeks 
ALT  3xULN but <5xULN  persists for 4 weeks 
Bilirubin1, 2 
ALT  3xULN and bilirubin  2xULN (>35% direct bilirubin)  
INR2  
ALT  3xULN and INR>1.5, if INR measured 
Cannot 
Monitor 
ALT  5xULN but <8xULN and cannot be monitored weekly for 2 
weeks 
ALT  3xULN but <5xULN and cannot be monitored weekly for 4 
weeks 
Symptomatic3 ALT  3xULN associated with symptoms (new or worsening) 
believed to be related to liver injury or hypersensitivity 
Required Actions and Follow up Assessments following ANY Liver Stopping 
Event 
Actions 
Follow Up Assessments 
• 
Immediately discontinue study treatment 
• 
Report the event to GSK within 24 hours 
• 
Complete the liver event eCRF and 
complete an SAE data collection tool if the 
event also meets the criteria for an SAE2 
• 
Perform liver event follow up assessments 
• 
Monitor the participant until liver 
chemistries resolve, stabilize, or return to 
within baseline (Day 1 predose) (see 
MONITORING below) 
• 
Viral hepatitis serology4 
• 
Obtain INR and recheck with each liver 
chemistry assessment until the 
transaminases values show downward 
trend 
• 
Only in those with underlying chronic 
hepatitis B at study entry (identified by 
positive hepatitis B surface antigen) 
quantitative hepatitis B DNA and 
hepatitis delta antibody5. 


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Liver Chemistry Stopping Criteria - Liver Stopping Event 
• 
Do not restart/rechallenge participant 
 
MONITORING: 
For bilirubin or INR criteria:  
• 
Repeat liver chemistries (include ALT, 
AST, alkaline phosphatase, bilirubin) and 
perform liver event follow up assessments 
within 24 hrs 
• 
Monitor participants twice weekly until 
liver chemistries resolve, stabilize or return 
to within baseline (Day 1 predose) 
• 
A specialist or hepatology consultation is 
recommended 
For All other criteria: 
• 
Repeat liver chemistries (include ALT, 
AST, alkaline phosphatase, bilirubin) and 
perform liver event follow up assessments 
within 24-72 hrs 
• 
Monitor participants weekly until liver 
chemistries resolve, stabilize or return to 
within baseline (Day 1 predose) 
• 
Blood sample for pharmacokinetic (PK) 
analysis, obtained within 48 hrs after 
last dose6 
• 
Serum creatine phosphokinase (CPK) 
and lactate dehydrogenase (LDH). 
• 
Fractionate bilirubin, if total 
bilirubin2xULN 
• 
Obtain complete blood count with 
differential to assess eosinophilia 
• 
Record the appearance or worsening of 
clinical symptoms of liver injury, or 
hypersensitivity, on the AE report form 
• 
Record use of concomitant medications 
on the concomitant medications report 
form including acetaminophen, herbal 
remedies, other over the counter 
medications. 
• 
Record alcohol use on the liver event 
alcohol intake case report form 
For bilirubin or INR criteria: 
• 
Anti-nuclear antibody, anti-smooth 
muscle antibody, Type 1 anti-liver 
kidney microsomal antibodies, and 
quantitative total immunoglobulin G 
(IgG or gamma globulins). 
• 
Serum acetaminophen adduct HPLC 
assay (quantifies potential 
acetaminophen contribution to liver 
injury in subjects with definite or likely 
acetaminophen use in the preceding 
week [James, 2009]).  
• 
Liver imaging (ultrasound, magnetic 
resonance, or computerised 
tomography) and /or liver biopsy to 
evaluate liver disease; complete Liver 
Imaging and/or Liver Biopsy CRF 
forms. 
1 Serum bilirubin fractionation should be performed if testing is available.  If serum bilirubin fractionation is not 
immediately available, discontinue study treatment for that subject if ALT  3xULN and bilirubin  2xULN.  Additionally, 
if serum bilirubin fractionation testing is unavailable, record presence of detectable urinary bilirubin on dipstick, 
indicating direct bilirubin elevations and suggesting liver injury. 
2 All events of ALT  3xULN and bilirubin  2xULN (>35% direct bilirubin) or ALT  3xULN and INR>1.5, if INR 
measured which may indicate severe liver injury (possible ‘Hy’s Law’), must be reported as an SAE (excluding 
studies of hepatic impairment or cirrhosis); INR measurement is not required and the threshold value stated will not 
apply to subjects receiving anticoagulants 


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3 New or worsening symptoms believed to be related to liver injury (such as fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, or jaundice) or believed to be related to hypersensitivity (such as fever, rash or 
eosinophilia) 
4 Includes: Hepatitis A IgM antibody; Hepatitis B surface antigen and Hepatitis B Core Antibody (IgM); Hepatitis C RNA; 
Cytomegalovirus IgM antibody;  Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, obtain heterophile 
antibody or monospot testing);  Hepatitis E IgM antibody  
5 If hepatitis delta antibody assay cannot be performed, it can be replaced with a PCR of hepatitis D RNA virus (where 
needed) [Le Gal, 2005]. 
6 PK sample may not be required for subjects known to be receiving placebo or non-GSK comparator treatments.  
Record the date/time of the PK blood sample draw and the date/time of the last dose of study treatment prior to blood 
sample draw on the CRF. If the date or time of the last dose is unclear, provide the subject’s best approximation. If the 
date/time of the last dose cannot be approximated OR a PK sample cannot be collected in the time period indicated 
above, do not obtain a PK sample. Instructions for sample handling and shipping are in the SRM. 
References 
James LP, Letzig L, Simpson PM, Capparelli E, Roberts DW, Hinson JA, Davern TJ, Lee 
WM. Pharmacokinetics of Acetaminophen-Adduct in Adults with Acetaminophen 
Overdose and Acute Liver Failure. Drug Metab Dispos. 2009; 37:1779-1784. 
Le Gal F, Gordian E, Affolabi D, Hanslik T, Alloui C, Deny P, Gault E. Quantification of 
hepatitis delta virus RNA in serum by consensus real-time PCR indicates different 
patterns of virological response to interferon therapy in chronically infected patients. J 
Clin Microbiol. 2005; 43:2363-2369. 


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12.3. 
Appendix 3: Risk Assessment 
Potential Risk of Clinical Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
Excessive erythropoiesis leading to thrombosis 
and/or tissue ischemia 
In animal studies, excessive erythropoiesis (Hgb/Hct > upper limit 
normal) attributed to daprodustat was associated with vascular 
congestion, microthrombi, and tissue ischemia in a number of organs. 
In the phase 2 proof of concept study, a high incidence of 
discontinuation due to hemoglobin stopping criteria (Hgb > 13.5 g/dL 
or Hgb increased > 1 g/dL over any 2-week period) was observed.  In 
non-dialysis subjects administered 10 mg, 25 mg, 50 mg or 100 mg 
of daprodustat daily, a total of 21 of 61 subjects (34%) met these 
criteria.  In hemodialysis-dependent subjects administered either 10 
mg or 25 mg of daprodustat daily, a total of 8 of 31 subjects (26%) 
met these criteria. 
 
Phase 2 dose-ranging studies, and associated statistical and 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 2b studies (24-week 
treatment duration) and 2 Japanese phase 3 studies (52-week 
treatment duration)]: Few subjects experienced a possible thrombosis 
related adverse event in the setting of excessive erythropoiesis 
[3/688 (0.5%) subjects on daprodustat vs. 0/404 on rhEPO]. 
 
Following review of clinical data received to date, this has not been 
identified as a safety concern for daprodustat when dose is managed 
appropriately according to target Hgb. However, experience with 
daprodustat is currently insufficient to fully characterize this risk. 
• 
Specific eligibility criteria related to 
requirements for entry Hgb are detailed in 
Section 6.2.1. 
• 
Hgb will be closely monitored throughout the 
dosing period as outlined in the SoA Table 
Section 2. 
• 
Specific guidance for discontinuation of 
daprodustat based on achieved Hgb is 
provided in Section 8.2.1.1. 
• 
Monitoring of emerging safety data by an 
internal GSK Safety Review Team. 
Worsening hypertension 
In a dog cardiovascular study, single oral doses of daprodustat (up to 
90 mg/kg) did not produce effects on blood pressure. 
Marketed rhEPO and its analogues have been associated with risks 
related to uncontrolled hypertension, including the need for initiation 
of or increases in antihypertensive therapy when used in patients with 
• 
Specific eligibility criteria related to blood 
pressure, including exclusion of subjects with 
uncontrolled hypertension, are detailed in 
Section 6.2 . 


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Potential Risk of Clinical Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
anemia of CKD (i.e. 25% Epogen, 27% Mircera, and 40% Aranesp 
treated patients with renal anemia required initiation or increase in 
their anti-hypertensive medications; hypertensive encephalopathy 
and seizures have been reported. The contribution of rhEPO-
associated hypertension to the unfavourable effects on 
cardiovascular outcomes remains uncertain). 
Integrated AE data from clinical trials with daprodustat [including 2 
global phase 2b studies (24-week treatment duration) and 2 
Japanese phase 3 studies (52-week treatment duration)]:  
o 
The majority (>90%) of subjects had baseline history of 
hypertension. 
o 
No meaningful difference was seen between treatment groups in 
AEs (preferred term) of “hypertension” [29/688 (4%) daprodustat 
vs. 19/404 (4%) rhEPO; 0.91 relative risk (RR) (95% confidence 
interval: 0.5, 1.67)] or “blood pressure increased” [16 (2%) 
daprodustat vs. 7 (2%) rhEPO; RR 1.22 (0.48,3.11)]. Results 
were not substantively different between non-dialysis and 
haemodialysis subjects. 
o 
Although no clinically meaningful changes in blood pressure 
were observed, subjects in both treatment groups required 
increases in anti-HTN medications: 
o 
In the 24-week global phase 2b studies, 25/170 (15%) 
of ND subjects receiving daprodustat vs. 18/80 (14%) 
control and 22/177 (12%) of HD subjects receiving 
daprodustat vs. 2/39 (5%) control. 
o 
In the 52-week Japan phase 3 studies, 57/149 (38%) 
of ND subjects receiving daprodustat vs. 68/150 (45%)  
rhEPO and 51/136 (38%) of HD subjects receiving 
daprodustat vs. 66/135 (49%) for rhEPO. 
The data received to date from completed clinical trials with 
daprodustat are insufficient to refute this risk. 
• 
Blood pressure will be closely monitored 
throughout the dosing period as outlined in 
the SoA Table Section 2. 
• 
Monitoring of emerging safety data by an 
internal GSK Safety Review Team. 


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Potential Risk of Clinical Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
Death, MI, stroke, heart failure, thromboembolic 
events, thrombosis of vascular access at Hgb levels 
which are within the normal range (i.e. not 
polycythemic conditions) 
Marketed rhEPO/ESAs have been associated with an increased risk 
for death and serious cardiovascular events when used in patients 
with anemia of CKD. Clinical studies with marketed rhEPO/analogs 
have suggested “higher” target hemoglobin, rate of hemoglobin rise 
of greater than 1 g/dL in any 2-week period, and/or higher doses may 
contribute to these risks. 
Integrated AE data from clinical trials with daprodustat [including 2 
global phase 2b studies (24-week treatment duration) and 2 
Japanese phase 3 studies (52-week treatment duration)]: No 
meaningful difference was seen between treatment groups in the 
overall incidence of this AESI: [39/688 (5.5%) daprodustat vs. 25/404 
(6%) rhEPO; 0.92 relative risk (95% confidence interval: 0.55, 1.53)]. 
Within this composite AESI, the most frequent event types were heart 
failure (at least 12 events daprodustat vs. at least 13 events rhEPO) 
and thrombosis (at least 14 events daprodustat vs. at least 8 event 
rhEPO); and a numerical imbalance was noted in events of 
myocardial ischemia (at least 7 events daprodustat vs. at least 1 
event rhEPO). The small number of events makes it difficult to draw 
any firm conclusions. 
The data received to date from completed clinical trials with 
daprodustat are insufficient to substantiate or refute this risk. 
• 
Specific eligibility criteria related to CV risk are 
outlined in Section 6.2. 
• 
Hgb will be closely monitored throughout the 
dosing period as outlined in the SoA (Section 
2). 
• 
Monitoring of emerging safety data by an 
internal GSK Safety Review Team. 
Esophageal and gastric erosions 
In animal studies, undesirable GI effects including emesis, abnormal 
feces and/or decreased food consumption/body weight loss and 
stomach erosions/ulcers with hemorrhage were observed with 
daprodustat. 
In rodents stomach erosions observed with intravenous and oral 
administration of daprodustat. 
Gender-averaged systemic exposure (AUC) at the no observed 
adverse effect levels (NOAEL) are 3.3 -fold (monkeys) and 737 -fold 
(rats) above human exposure (25 mg daprodustat). 
• 
Suspected GI bleeding or significant 
symptoms consistent with erosion should be 
investigated diagnostically (i.e. endoscopic 
examination) as clinically warranted. 
• 
Monitoring of emerging safety data by an 
internal GSK Safety Review Team. 


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Potential Risk of Clinical Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
In clinical trials to date with daprodustat, mild-moderate GI signs and 
symptoms represent the most frequently reported adverse event, 
however causal association has not been established. 
Integrated AE data from clinical trials with daprodustat [including 2 
global phase 2b studies (24-week treatment duration) and 2 
Japanese phase 3 studies (52-week treatment duration)]: No 
meaningful difference was seen between treatment groups in reports 
of this AESI [17 (2.7%) daprodustat vs. 10 (2.3%) rhEPO; 1.16 
relative risk (95% confidence interval: 0.52, 2.58)]. 
Following review of clinical data received to date, GI erosions have 
not been identified as a safety concern for daprodustat. 
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 VEGF while significant EPO increases were 
observed. 
In clinical studies with daprodustat up to 4 weeks duration, a dose-
ordered increase in VEGF plasma concentrations, an angiogenic 
factor that has been implicated in tumor growth, was observed at 
doses ranging from 10 to 150 mg.  In clinical studies up to 24 weeks 
duration at doses up to 25 mg, changes in VEGF plasma 
concentrations were variable but similar relative to control. 
Integrated AE data [including 2 global phase 2b studies (24-week 
treatment duration) and 2 Japanese phase 3 studies (52-week 
treatment duration)]: No meaningful difference was seen between 
treatment groups in the occurrence of this AESI: [8/688 (1.1%) 
daprodustat vs. 4/404 (0.9%) rhEPO; 1.14 relative risk (95% 
confidence interval: 0.31, 4.28)]. 
Clinical experience to date is not yet sufficient to substantiate or 
refute this as a safety concern for daprodustat. 
• 
Specific eligibility criteria related to personal 
history of malignancy are outlined in Section 
6.2. 
• 
Stopping criteria for participants with 
treatment emergent malignancy are outlined 
in Section 8.2.1. 
• 
Monitoring of emerging safety data by an 
internal GSK Safety Review Team. 


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Potential Risk of Clinical Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
Pulmonary artery hypertension (PAH) 
A role for HIF-regulated pathways in the pathophysiology of PAH has 
been suggested based on well-established effects of acute and 
chronic hypoxia in man on the pulmonary vasculature 
(vasoconstriction), and by findings in patients with naturally occurring 
mutations that result in decreased HIF degradation [Smith, 2006; 
Formenti, 2011]. 
There have been no histopathologic findings suggestive of PAH in 
pre-clinical safety studies with daprodustat (up to 13 weeks duration 
in mice and dog, up to 26 weeks in rat, and up to 39 weeks in 
monkeys. 
Acute hypoxic challenge (rats):  Daprodustat produced increases in 
peak right ventricular pressure (PRVP) during acute hypoxia that 
were slightly higher than the vehicle control group.  These hypoxia-
induced PRVP changes fall within the range of PRVP differences 
noted among non-treated rats. 
Results from a clinical study of acute hypoxic challenge in healthy 
volunteers demonstrated that short-term (5 days) therapy with 
daprodustat 5 mg or 100 mg has no clinically significant effect on 
echocardiographically-estimated systolic pulmonary artery pressure 
(sPAP) under either normoxic or hypoxic conditions. 
ECHO assessments performed in Phase 2b studies (24 weeks 
treatment duration) did not identify any clinically-meaningful changes 
in sPAP in participants not on dialysis for daprodustat.  In 
hemodialysis participants, mean absolute change from baseline in 
sPAP was similar for both treatment groups; however, there was a 
numeric imbalance (Daprodustat: 8 [7%]; Control 0) in participants 
reaching the sPAP PCI (>20 mmHg increase from baseline).  
Regarding this imbalance, there were a number of confounding 
factors in the study, most notably a 4.5:1 randomization scheme and 
inconsistency in timing of ECHOs relative to dialysis day.  
Additionally, 2 of 3 participants with resolution of sPAP on safety 
follow-up ECHOs had confounding conditions that could contribute to 
resolution other than discontinuation of study treatment; and there 
was no dose relationship for participants meeting the sPAP PCI 
• 
Monitoring of emerging safety data by an 
internal GSK Safety Review Team. 


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Potential Risk of Clinical Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
criterion.  Overall, there is insufficient evidence to conclude a 
relationship to treatment with daprodustat. A post-hoc analysis was 
performed using a definition of PAH commonly cited in the literature 
[Navaneethan, 2016].  Subjects with sPAP >35 mmHg and/or 
tricuspid regurgitation maximum jet velocity (TRV) >2.5 m/s were 
considered as having PAH.  Regardless of baseline status of PAH, 
there was no clinically meaningful difference in the proportion of 
subjects with on-treatment PAH between the two treatment groups: 
o 
Subjects with PAH at baseline: 35/113 (31%) vs. 21/54 
(39%) (ND) and 37/115 (32%) vs. 7/21 (33%) (HD), 
daprodustat vs. control, respectively. 
o 
Subjects without PAH at baseline: 25/113 (22%) vs. 
12/54 (22%) (ND) and 22/115 (19%) vs. 6/21 (29%) 
(HD), daprodustat vs. control, respectively.  
Integrated AE data [including 2 global phase 2b studies (24-week 
treatment duration) and 2 Japanese phase 3 studies (52-week 
treatment duration)]: Four (0.5%) non-serious AEs in the daprodustat 
group vs 0 in rhEPO.  
• 
Review of subject level information did not suggest adverse 
treatment effect: 2 subjects from phase2b that met protocol 
specified stopping criteria on scheduled ECHO had non-serious 
AEs of ‘pulmonary arterial pressure increased’ and 2 subjects 
from Japan Phase 3 had non-serious AE ‘pulmonary 
hypertension’ in setting of concurrent serious AEs of acute 
pulmonary embolus and mitral regurgitation identified during 
hospitalization for coronary angiography. 
Following review of clinical data received to date, this has not been 
identified as a safety concern for daprodustat. 
Cardiomyopathy 
Published data suggest that cardiac effects of HIF stabilization are 
likely a function of the mechanism, extent, and duration of the effects, 
and can range from protective to detrimental depending upon the 
specific model and experimental conditions utilized. 
• 
Monitoring of emerging safety data by an 
internal GSK Safety Review Team 


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


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Potential Risk of Clinical Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
to 150 mg.  In studies up to 24 weeks duration at doses up to 25 mg, 
changes in VEGF plasma concentrations were variable but similar 
relative to control. 
Ophthalmologic assessments performed in phase 2b studies (24 
weeks treatment duration) did not identify any clinically meaningful 
changes in proliferative retinopathy, macular edema, or choroidal 
neovascularization with daprodustat. 
Integrated AE data [including 2 global phase 2b studies (24-week 
treatment duration) and 2 Japanese phase 3 studies (52-week 
treatment duration)]: No meaningful difference was seen between 
treatment groups in reports of this AESI [9 (2.9%) daprodustat vs. 6 
(2.5%) rhEPO; 1.19 relative risk; (95% confidence interval: 0.42, 
3.43)]. 
Following review of clinical data with daprodustat received to date, 
this has not been identified as a safety concern for daprodustat. 
Exacerbation of rheumatoid arthritis 
In inflamed rheumatic joints, activation of HIF-related genes 
secondary to decreased oxygen and pro-inflammatory cytokines has 
been postulated to contribute to the neo-angiogenesis, proliferation 
and infiltration of rheumatoid synovial fibroblasts [Campochiaro, 
2006; Westra, 2010; Muz, 2009]. 
No abnormalities seen in non-clinical studies conducted to date for 
daprodustat. 
Integrated AE data [including 2 global phase 2b studies (24-week 
treatment duration) and 2 Japanese phase 3 studies (52-week 
treatment duration)]: No meaningful difference was seen between 
treatment groups in reports of this AESI [2 (0.3%) daprodustat vs. 1 
(0.2%) rhEPO; 1.20 relative risk; (95% confidence interval: 0.07, 
20.87) and the incidence of musculoskeletal AEs was generally lower 
in the daprodustat treatment group]. 
Following review of clinical data received to date, this has not been 
identified as a safety concern for daprodustat. 
• 
Monitoring of emerging safety data by an 
internal GSK Safety Review Team. 


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Potential Risk of Clinical Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
Drug-drug interactions 
Daprodustat is a substrate of CYP2C8.  Co-administration of 
daprodustat with the strong CYP2C8 inhibitor, gemfibrozil increased 
the Cmax and 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, 
coadministration 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 7.7.2. 
• 
Specific guidance on the management of 
potential drug-drug interactions and 
concomitant medications is provided in 
Section 7.7. 
• 
Hgb will be closely monitored throughout the 
dosing period as outlined in the SoA in 
Section 2. 
• 
Specific guidance for discontinuation of 
daprodustat based on achieved Hgb is 
provided in Section 8.2.1.1. 
• 
Monitoring of emerging safety data by an 
internal GSK Safety Review Team. 
Cyst progression in patients with autosomal 
dominant polycystic kidney disease (ADPKD) 
Published data provide in vivo evidence for a potential role of HIF-1a 
in the growth of polycystic kidneys; Hif-1a deletion was sufficient to 
significantly mitigate a progressive polycystic phenotype in an 
ADPKD mouse model, while conversely pharmacologic HIF-1a 
stabilization was sufficient to convert a mild polycystic disease into a 
severely aggravated phenotype with marked loss of renal function. 
However, the dose of FG-2216 (a PHI) used resulted in a significant 
erythropoietic response as reflected by ≥10% relative increases in 
hematocrit over the course of the study.  (Kraus, 2018; Hofherr, 
2018). 
A review of the non-clinical data from toxicity studies conducted with 
daprodustat does not indicate an exacerbation in incidence or 
severity of kidney cysts in daprodustat-treated animals in comparison 
to controls.  However, the wild type animals used in these toxicity 
• 
Kidney function  will be monitored throughout 
the dosing period as outlined in the SoA 
(Section 2). 
• 
Monitoring of emerging safety data by an 
internal GSK Safety Review Team. 


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Potential Risk of Clinical Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
studies have a very low background incidence of renal cysts and are 
not comparable to the mice used in the Kraus article (Kraus, 2018) 
which are an inducible kidney epithelium-specific Pkd1-deletion 
model. 
There is limited experience with daprodustat in subjects with ADPKD 
in completed clinical trials. In the Japan phase 3 study in non-dialysis 
subjects, there were 5 subjects with ADPKD (all CKD stage 5) in 
each treatment group.  Mean baseline eGFR was 10 mL/min/1.73m2 
in the daprodustat subjects vs. 16 mL/min/1.73m2 in the rhEPO 
subjects.  The mean (SD) percent change from baseline at Week 52 
in eGFR was: -18% (8) vs. -21% (14) in daprodustat vs. rhEPO, 
respectively. 
Following review of clinical data received to date, this has not been 
identified as a safety concern for daprodustat. 


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References 
Campochiaro PA and the first ARVO/Pfizer Institute Working Group et al. Ocular versus 
extraocular neovascularization: Mirror images or vague resemblances. Invest Ophthalmol 
& Vis Sci. 2006; 47:462-474. 
Formenti F, Beer PA, Croft QPP, Dorrington KL, Gale DP, Lappin TRJ, Lucas GS, 
Maher ER, Maxwell PH, McMullin MF, O’Connor DF, Percy MJ, Pugh CW, Ratcliffe 
PJ, Smith TG, Talbot NP, Robbins PA. Cardiopulmonary function in two human 
disorders of the hypoxia-inducible factor (HIF) pathway: von Hippel-Lindau disease and 
HIF-2α gain-of-function mutation. FASEB J. 2011; 25:2001-2011. 
Hofherr, A., et al, HIF-1α drives cyst growth in advanced stages of autosomal dominant 
polycystic kidney disease; Kidney International (2018) 94, 849–851. 
Kraus, A., et al, HIF-1α promotes cyst progression in a mouse model of autosomal 
dominant polycystic kidney disease; Kidney International, 2018.  
Muz B, Khan MN, Kiriakidis S, Paleolog EM. The role of hypoxia and HIF-dependent 
signalling events in rheumatoid arthritis. Arthritis Research & Therapy 2009; 11:201-
209. 
Navaneethan SD, for CRIC investigators: Prevalence, Predictors, and Outcomes of 
Pulmonary Hypertension in CKD. J Am Soc Nephrol 2016, 27:877–886. 
Smith TG, Brooks JT, Balanos GM, Lappin TR, Layton DM, Leedham DL, Liu C, 
Maxwell PH, Treacy M, Robbins PA. Mutations of von Hippel-Lindau tumour 
suppressor and heman cardiopulmonary physiology. PLos Med. 2006; 3:3290. 
Westra J, Molema G, Kallenberg CG. Hypoxia-inducible factor-1 as regulator of 
angiogenesis in rheumatoid arthritis - therapeutic implications. Curr Med Chem. 2010; 
17:254-63. 


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12.4. 
Appendix 4: Clinical Laboratory Assessments 
The tests detailed in Table 8 will be performed by a central laboratory. 
 
 
• 
Local laboratory results are only required in the event that the central laboratory 
results are not available in time for either study treatment administration and/or 
response evaluation.  If a local sample is required, it is important that the sample 
for central analysis is obtained at the same time.  Additionally, if the local 
laboratory results are used to make either a study treatment decision or response 
evaluation, the results must be entered into the eCRF. 
• 
Protocol-specific requirements for inclusion or exclusion of participants are 
detailed in Section 6 of the protocol. 
• 
Additional tests may be performed at any time during the study as determined 
necessary by the investigator or required by local regulations. 
 
Table 8 
Clinical Laboratory Assessments 
Assessments 
Parameters 
Hematology 
Platelet Count 
RBC Count 
Hgb 
Hematocrit 
RBC Indices: 
MCV 
MCH 
%Reticulocytes 
WBC count with Differential: 
Neutrophils 
Lymphocytes 
Monocytes 
Eosinophils 
Basophils 
Clinical 
Chemistry1 
BUN 
Potassium 
Aspartate 
Aminotransferase 
(AST)/ Serum 
Glutamic-
Oxaloacetic 
Transaminase 
(SGOT) 
Total and direct 
bilirubin 
 
Creatinine 
Sodium 
Alanine 
Aminotransferase 
 (ALT)/ Serum 
Glutamic-Pyruvic 
Transaminase 
(SGPT) 
Total Protein 
 
Glucose 
Calcium 
Alkaline 
phosphatase 
 
Routine 
Urinalysis 
• 
Specific gravity 
• 
pH, glucose, protein, blood, ketones, bilirubin, urobilinogen, nitrite, 
leukocyte esterase by dipstick 
• 
Microscopic examination (if blood or protein is abnormal) 


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Assessments 
Parameters 
Other 
Laboratory 
Analyses 
• 
Follicle-stimulating hormone and estradiol (as needed in women of non-
childbearing potential only) 
• 
Urine human chorionic gonadotropin (hCG) pregnancy test (as needed 
for women of childbearing potential)2 
• 
HIV antibody 
• 
Folate, high sensitivity C-reactive protein, Vitamin B12 
• 
Serum iron, ferritin, transferrin, transferrin saturation, soluble transferrin 
receptor, hepcidin, erythroferrone 
• 
Hemoglobin, hematocrit, red blood cell number, mean corpuscular 
volume, reticulocyte hemoglobin, reticulocyte number 
1 Details of liver chemistry stopping criteria and required actions and follow-up assessments after liver 
stopping or monitoring event are given in Section 8.1.1 and Appendix 2.  All events of ALT 3 × upper 
limit of normal (ULN) and 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 as an SAE (excluding studies of hepatic impairment or cirrhosis). 
2 Local urine testing will be standard for the protocol unless serum testing is required by local regulation 
or IRB/IEC. 
 


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12.5. 
Appendix 5: Study Governance Considerations 
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 ICH Good Clinical Practice (GCP) Guidelines 
• Applicable laws and regulations 
• 
The protocol, protocol amendments, ICF, Investigator Brochure, 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 IEC/IRB approval before 
implementation of changes made to the study design, except for changes 
necessary to eliminate an immediate hazard to study participants.  
• 
The investigator will be responsible for the following: 
• Providing written summaries of the status of the study to the IRB/IEC 
annually or more frequently in accordance with the requirements, policies, 
and procedures established by the IRB/EC 
• Notifying the IRB/IEC of SAE or other significant safety findings as 
required by IRB/IEC procedures 
• Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH guidelines, the IRB/IEC, European 
regulation 536/2014 for clinical studies (if applicable), and all other 
applicable local regulations 
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. 
Informed Consent Process 
• 
The investigator or his/her representative will explain the nature of the study to 
the participant or his/her legally authorized representative and answer all 
questions regarding the study.  
• 
Participants must be informed that their participation is voluntary. Participants 
or their legally authorized representative will be required to sign a statement of 
informed consent that meets the requirements of 21 CFR 50, local regulations, 


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ICH guidelines, Health Insurance Portability and Accountability Act (HIPAA) 
requirements, where applicable, and the IRB/IEC or study center. 
• 
The medical record must include a statement that written informed consent was 
obtained before the participant was enrolled in the study and the date the written 
consent was obtained. The authorized person obtaining the informed consent 
must also sign the ICF. 
• 
Participants must be re-consented to the most current version of the ICF(s) 
during their participation in the study.  
• 
A copy of the ICF(s) must be provided to the participant or the participant’s 
legally authorized representative.  
• 
Participants who are rescreened are required to sign a new ICF. 
The ICF may contain a separate section that addresses the use of remaining mandatory 
samples for optional exploratory research in accordance with SOP-GSKF-410.  The 
investigator or authorized designee will explain to each participant the objectives of the 
exploratory research.  Participants will be told that they are free to refuse to participate 
and may withdraw their consent at any time and for any reason during the storage period.  
A separate signature will be required to document a participant's agreement to allow any 
remaining specimens to be used for exploratory research.  Participants who decline to 
participate will not provide this separate signature. 
Data Protection 
• 
Participants will be assigned a unique identifier by the sponsor. Any participant 
records or datasets that are transferred to the sponsor will contain the identifier 
only; participant names or any information which would make the participant 
identifiable will not be transferred.  
• 
The participant must be informed that his/her personal study-related data will be 
used by the sponsor in accordance with local data protection law. The level of 
disclosure must also be explained to the participant.  
• 
The participant must be informed that his/her medical records may be examined 
by Clinical Quality Assurance auditors or other authorized personnel appointed 
by the sponsor, by appropriate IRB/IEC members, and by inspectors from 
regulatory authorities. 
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. 


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• 
Authorship will be determined by mutual agreement and in line with 
International Committee of Medical Journal Editors authorship requirements. 
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 the investigator with the full summary of the study results.  
The investigator is encouraged to share the summary results with the study 
subjects, as appropriate. 
• The procedures and timing for public disclosure of the results summary and for 
development of a manuscript for publication will be in accordance with GSK 
Policy. 
Data Quality Assurance 
• 
All participant data relating to the study will be recorded on printed or electronic 
CRF unless transmitted to the sponsor or designee electronically (e.g., 
laboratory data).  The investigator is responsible for verifying that data entries 
are accurate and correct by physically or electronically signing the CRF. 
• 
The investigator must maintain accurate documentation (source data) that 
supports the information entered in the eCRF.  
• 
The investigator must permit study-related monitoring, audits, IRB/IEC review, 
and regulatory agency inspections and provide direct access to source data 
documents.  
• 
The sponsor or designee is responsible for the data management of this study 
including quality checking of the data. 
• 
Study monitors will perform ongoing source data verification to confirm that 
data entered into the eCRF by authorized site personnel are accurate, complete, 
and verifiable from source documents; that the safety and rights of participants 
are being protected; and that the study is being conducted in accordance with the 
currently approved protocol and any other study agreements, ICH GCP, and all 
applicable regulatory requirements.  
• 
Records and documents, including signed ICF, pertaining to the conduct of this 
study must be retained by the investigator for 15 years after study completion 
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.  


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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 can be found in the SRM. 
Study and Site Closure 
GSK or its designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of GSK. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study 
supplies have been collected and a study-site closure visit has been performed. 
The investigator may initiate study-site closure at any time, provided there is reasonable 
cause and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the sponsor or investigator may include 
but are not limited to: 
• 
Failure of the investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the sponsor's procedures, or GCP guidelines 
• 
Inadequate recruitment of participants by the investigator 
• 
Discontinuation of further study treatment development 


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12.6. 
Appendix 6: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting 
Definition of AE 
AE Definition 
• 
An AE is any untoward medical occurrence in a clinical study participant, temporally 
associated with the use of a study 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 (ie, not related to progression of underlying 
disease). 
• 
Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition. 
• 
New conditions detected or diagnosed after study intervention administration even though 
it may have been present before the start of the study. 
• 
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
• 
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
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. 
 
Events NOT Meeting the AE Definition  
• 
Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the participant’s condition. 
• 
The disease/disorder being studied or expected progression, signs, or symptoms of the 
disease/disorder being studied, unless more severe than expected for the participant’s 
condition. 
• 
Medical or surgical procedure (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). 


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• 
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. 
Definition of SAE 
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met (e.g., hospitalization for signs/symptoms of the disease under study, 
death due to progression of disease). 
A SAE is defined as any untoward medical occurrence that, at any dose: 
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 detained (usually involving at 
least an overnight stay) at the hospital or emergency ward for observation and/or treatment that 
would not have been appropriate in the physician’s office or outpatient setting.  Complications 
that occur during hospitalization are AE.  If a complication prolongs hospitalization or fulfils 
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 disability/incapacity 
• 
The term disability means a substantial disruption of a person’s ability to conduct normal 
life functions. 
• 
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, and 
accidental trauma (e.g., sprained ankle) which may interfere with or prevent everyday life 
functions but do not constitute a substantial disruption. 
e. 
Is a congenital anomaly/birth defect 
f. 
Other situations: 
• 
Medical or scientific judgment should be exercised in deciding whether SAE reporting is 
appropriate in other situations such as important medical events that may not be 
immediately life-threatening or result in death or hospitalization but may jeopardize the 
participant or may require medical or surgical intervention to prevent one of the other 
outcomes listed in the above definition.  These events should usually be considered 
serious. 
Examples of such events include invasive or malignant cancers, intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or convulsions 
that do not result in hospitalization, or development of drug dependency or drug abuse. 
 


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Definition of Cardiovascular Events 
Cardiovascular Events (CV) Definition: 
Investigators will be required to fill out the specific CV event page of the CRF for the 
following AEs and SAEs: 
• Myocardial infarction/unstable angina 
• Congestive heart failure 
• Arrhythmias 
• Valvulopathy 
• Pulmonary hypertension 
• Cerebrovascular events/stroke and transient ischemic attack 
• Peripheral arterial thromboembolism 
• Deep venous thrombosis/pulmonary embolism 
• Revascularization 
 
Recording 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 in the eCRF. 
• 
It is not acceptable for the investigator to send photocopies of the participant’s medical 
records to GSK in lieu of completion of the GSK/AE/SAE eCRF page. 
• 
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. 
Assessment of Intensity 
The investigator will make an assessment of intensity for each AE and SAE reported during the 
study and assign it to 1 of the following categories: 
• 
Mild: An event that is easily tolerated by the participant, causing minimal discomfort and 
not interfering with everyday activities. 
• 
Moderate: An event that causes sufficient discomfort and interferes with normal everyday 
activities. 


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• 
Severe: An event that prevents normal everyday activities. An AE that is assessed as 
severe should not be confused with an SAE.  Severe is a category utilized for rating the 
intensity of an event; and both AE and SAE can be assessed as severe. 
An event is defined as ‘serious’ when it meets at least 1 of the predefined outcomes as 
described in the definition of an SAE, NOT when it is rated as severe. 
 
Assessment of Causality 
• 
The investigator is obligated to assess the relationship between study treatment and each 
occurrence of each AE/SAE. 
• 
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. 
• 
The investigator will use clinical judgment to determine the relationship. 
• 
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 Investigator’s Brochure (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. 
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 completed eCRF. 
• 
The investigator will submit any updated SAE data to GSK within 24 hours of receipt of 
the information. 
 


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Reporting of SAE to GSK 
SAE Reporting to GSK via Electronic Data Collection Tool 
• 
The primary mechanism for reporting SAE to GSK will be the electronic data collection 
tool. 
• 
If the electronic system is unavailable, then the site will use the paper SAE data collection 
tool (see next section) in order to report the event within 24 hours. 
• 
The site will enter the SAE data into the electronic system as soon as it becomes available. 
• 
The investigator or medically-qualified sub-investigator must show evidence within the 
eCRF (e.g., check review box, signature, etc.) of review and verification of the 
relationship of each SAE to IP/study participation (causality) within 72 hours of SAE 
entry into the eCRF. 
• 
After the study is completed at a given site, the electronic data collection tool will be 
taken off-line to prevent the entry of new data or changes to existing data. 
• 
If a site receives a report of a new SAE from a study participant or receives updated data 
on a previously reported SAE after the electronic data collection tool has been taken off-
line, then the site can report this information on a paper SAE form (see next section) or to 
the Medical Monitor by telephone. 
• 
Contacts for SAE reporting can be found in the SRM. 
 
SAE Reporting to GSK via Paper CRF 
• 
Facsimile transmission of the SAE paper CRF 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 CRF pages within the designated reporting time frames. 
• 
Contacts for SAE reporting can be found in SRM. 
 


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12.7. 
Appendix 7: Contraceptive Guidance and Collection of 
Pregnancy Information 
Definitions 
Woman of Childbearing Potential (WOCBP) 
A woman is considered fertile following menarche and until becoming post-menopausal 
unless permanently sterile (see below) 
Women in the following categories are not considered WOCBP 
1. Premenarchal 
2. Premenopausal female with ONE of the following: 
• 
Documented hysterectomy 
• 
Documented bilateral salpingectomy 
• 
Documented bilateral oophorectomy 
Note:  Documentation can come from the site personnel’s review of participant’s 
medical records, medical examination, or medical history interview. 
3. Postmenopausal female 
• 
A postmenopausal state is defined as no menses for 12 months without an 
alternative medical cause.  A high follicle stimulating hormone (FSH) level in 
the postmenopausal range may be used to confirm a postmenopausal state in 
women not using hormonal contraception or hormonal replacement therapy 
(HRT).  However, in the absence of 12 months of amenorrhea, a single FSH 
measurement is insufficient. 
• 
Females on HRT and whose menopausal status is in doubt will be required to 
use one of the non-hormonal highly effective contraception methods if they wish 
to continue their HRT during the study.  Otherwise, they must discontinue HRT 
to allow confirmation of postmenopausal status before study enrolment. 
Contraception Guidance 
Female participants 
Female participants of childbearing potential are eligible to participate if they agree to 
use a highly effective method of contraception consistently and correctly as described in 
Table 9. 
 
 
 
 


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Table 9 
Highly Effective Contraceptive Methods 
Highly Effective Contraceptive Methods That Are User Dependent1 
Failure rate of <1% per year when used consistently and correctly.  
Combined (estrogen- and progestogen-containing) hormonal contraception associated with 
inhibition of ovulation2 
• 
oral 
• 
intravaginal 
• 
transdermal 
Progestogen-only hormonal contraception associated with inhibition of ovulation2 
• 
injectable 
Highly Effective Methods That Are User Independent  
• 
Implantable progestogen-only hormonal contraception associated with inhibition of 
ovulation2 
• 
Intrauterine device (IUD) 
• 
Intrauterine hormone-releasing system (IUS) 
• 
bilateral tubal occlusion 
Vasectomized partner 
(A vasectomized partner is a highly effective contraception method provided that the partner 
is the sole male sexual partner of the WOCBP and the absence of sperm has been confirmed. 
If not, an additional highly effective method of contraception should be used.)  
Sexual abstinence  
(Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study drug. The 
reliability of sexual abstinence needs to be evaluated in relation to the duration of the study 
and the preferred and usual lifestyle of the participant.) 
1 Typical use failure rates may differ from those when used consistently and correctly.  Use should be consistent with 
local regulations regarding the use of contraceptive methods for participants in clinical studies. 
2 Hormonal contraception may be susceptible to interaction with the study drug, which may reduce the efficacy of the 
contraceptive method.  In this case two highly effective methods of contraception should be utilized during the 
treatment period and at least to the follow-up visit. 
 
Pregnancy Testing 
• 
WOCBP should only be included after a confirmed menstrual period and a negative 
highly sensitive urine pregnancy test. 
• 
Pregnancy testing will be performed whenever a menstrual cycle is missed or when 
pregnancy is otherwise suspected. 
• 
Pregnancy testing, with a sensitivity of 25 mIU/mL will be performed using the test 
kit provided by the central laboratory and in accordance with instructions provided in 
its package insert. 


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Collection of Pregnancy Information 
Female Participants who become pregnant 
• 
Investigator will collect pregnancy information on any female participant, who 
becomes pregnant while participating in this study. 
• 
Information will be recorded on the appropriate form and submitted to GSK within 
24 hours of learning of a participant's pregnancy. 
• 
Participant will be followed to determine the outcome of the pregnancy. The 
investigator will collect follow up information on participant and neonate, which will 
be forwarded to GSK.  Generally, follow-up will not be required for longer than 6 to 
8 weeks beyond the estimated delivery date. 
• 
Any termination of pregnancy will be reported, regardless of fetal status (presence or 
absence of anomalies) or indication for procedure. 
• 
While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy will be reported as an AE or 
SAE. 
• 
A spontaneous abortion is always considered to be an SAE and will be reported as 
such. 
• 
Any SAE occurring as a result of a post-study pregnancy which is considered 
reasonably related to the study treatment by the investigator, will be reported to GSK 
as described in Appendix 6.  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 will discontinue study 
treatment and be withdrawn from the study. 


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12.8. 
Appendix 8: Genetics 
USE/ANALYSIS OF DNA 
• 
Genetic variation may impact a participant’s response to therapy, susceptibility, 
severity and progression of disease.  Variable response to therapy may be due to 
genetic determinants that impact drug absorption, distribution, metabolism, and 
excretion; mechanism of action of the drug; disease etiology; and/or molecular 
subtype of the disease being treated.  Therefore, where local regulations and 
IRB/IEC allow, a blood sample will be collected for DNA analysis. 
• 
DNA samples will be used for research related to daprodustat or anemia of chronic 
kidney disease and related diseases.  They may also be used to develop tests/assays 
(including diagnostic tests) related to daprodustat or anemia of chronic kidney 
disease.  Genetic research may consist of the analysis of one or more candidate genes 
or the analysis of genetic markers throughout the genome [or analysis of the entire 
genome] (as appropriate). 
• 
DNA samples will be analyzed if it is hypothesized that this may help further 
understand the clinical data. 
• 
The samples may be analyzed as part of a multi-study assessment of genetic factors 
involved in the response to daprodustat or study treatments of this class.  The results 
of genetic analyses may be reported in the clinical study report or in a separate study 
summary. 
• 
The sponsor will store the DNA samples in a secure storage space with adequate 
measures to protect confidentiality.  
• 
The samples will be retained while research on daprodustat (or study treatments of 
this class) or anemia of chronic kidney disease continues but no longer than 15 years 
or other period as per local requirements. 
 


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12.9. 
Appendix 9: Protocol Amendment History 
The Protocol Amendment Summary of Changes Table for the current amendment is 
located directly before the Table of Contents (TOC). 
Previous Amendment: 
Amendment 2 13-Aug-2019 
Overall Rationale for the Amendment:  
After the publication of the first protocol amendment, the iron for ingestion needed to be 
compounded differently. 
In order to ensure tighter control of iron supplementation given the purpose of this study, 
specific parameters for iron supplementation were provided.  Similarly, a revision was 
made to include additional weight measurements of participants in case of significant 
unexpected weight loss or gain during the study.  This could have bearing on blood 
volume and ultimately iron content within an individual.  
 
Exclusion criterion #18 was revised to exclude all individuals with hypertension deemed 
“uncontrolled” per the discretion of the primary investigator instead of specific blood 
pressure parameters in order to align with the daprodustat program. 
 
Discrepancies were noted between Section 9.2.8 and the pregnancy guidance in 
Appendix 7; these respective sections were updated accordingly.  
 
Revisions were made throughout the protocol to align with GSK standard language and 
for clarity where necessary.  More specific rationales are provided for each item in this 
category in the table below. 
 
Section # and 
Name 
Description of Change 
Brief Rationale 
Short title and 
1 Synopsis 
The short title was changed. 
All studies for this asset have a similar 
nomenclature; this change is to align globally. 
1 and 4 
Objectives and 
Endpoints 
Safety endpoints were moved into 
their own section. No additions or 
deletions in the endpoint text. 
To permit easier identification of safety 
endpoints.  
2 Schedule of 
Activities 
A weight assessment was added to 
several visits throughout the study 
period.  
To allow more accurate calculations of the 
fractional iron absorption should a participant 
experience a significant weight change during 
the study. 
6.1 Inclusion 
Criteria 
Criterion 5 was updated to provide 
parameters for consistent provision of 
iron supplementation. 
For clarity. 
6.2 Exclusion 
Criteria 
Updated the language in the 
exclusion criterion #18 surrounding 
blood pressure. 
To align with the daprodustat program.  


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Section # and 
Name 
Description of Change 
Brief Rationale 
7.1 Treatments 
Administered 
The revised formulation of the iron 
isotope solution was provided. 
To reflect the contents of the revised iron 
isotope solution.  
7.1.3 57Fe 
Dosing 
Information 
The description and formulation of 
the iron isotope (57Fe) was updated. 
To reflect the revised procedure for provision 
of the 57Fe isotope used in the study. 
7.1.4 58Fe 
Dosing 
Information 
The description, dosing, and 
formulation of the iron isotope (58Fe) 
was updated. 
To reflect the revised procedure for provision 
of the 58Fe isotope used in the study. 
7.7.2 
Prohibited 
Medications  
High dose clopidogrel (300 mg) was 
added. 
An additional example of a strong CYP2C8 
inhibitor was added. 
8.2.1.1 Hgb 
Stopping 
Criteria 
The structure of Table 2 was 
modified. 
For clear distinction between assessment of 
the Hgb and resultant action(s). 
9.2 Adverse 
Events 
Updated GSK standard language. 
For consistency among GSK protocols. 
9.2.8 
Pregnancy 
Text was updated to reflect guidance 
given in Appendix 5. 
Correction of error . 
10.3.2 Interim 
Analysis 
The potential for an interim analysis 
was removed. 
GSK deemed the interim analysis was no 
longer necessary in support of the 
daprodustat program. 
12.3 Appendix 
3: Risk 
Assessment 
Several updates were made to the 
risk assessment table. 
The benefit-risk table was recently updated. 
12.6 Appendix 
6: Definition of 
Cardiovascular 
Events 
The table with definitions of 
cardiovascular events was added. 
For consistency among GSK protocols. 
12.6 Appendix 
6: Reporting of 
SAE to GSK 
Additional text surrounding the 
requirement for the PI to review SAEs 
and to provide causality within 72 
hours of the SAE entry into the eCRF 
was added. 
For consistency among GSK protocols. 
 
Amendment 1 30-Nov-2017 
Overall Rationale for the Amendment: It was noted that one exclusion criterion was 
incorrect. This amendment serves to revise that as well as streamline the study 
procedures, as noted from investigators.  Lastly, minor spelling and context errors were 
corrected. 


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Section # 
and Name 
Description of Change 
Brief Rationale 
6.2 Exclusion 
Criteria 
Changed criterion to high 
sensitivity CRP; Corrected value 
for hsCRP exclusionary criterion 
To have clear exclusion criteria; ensure 
consistency with other program protocols 
6.2 Exclusion 
Criteria 
Changed the prior clinical study 
experience criteria from 120 days 
to 30 days 
Ensure consistency with other program 
protocols; re-evaluation determined this 
duration is not necessary; improve 
recruitment. 
2 Schedule of 
Assessments 
Updated pregnancy testing time 
points.   
More complete pregnancy testing 
throughout the study; better compliance 
with GSK standards. 
2 Schedule of 
Assessments 
Changed routine urinalysis to 
coincide with urine pregnancy 
testing. 
Ease of procedural parameters for the 
sites. 
2 Schedule of 
Assessments 
Added in one time point for 
isotopic iron blood sampling 
Affords more robust analysis of absorption 
of one isotope vs the other 
2 Schedule of 
Assessments 
Added/changed various time 
points for vital signs 
More complete monitoring throughout 
study; better compliance with GSK 
standards. 
2 Schedule of 
Assessments; 
Appendix 4 
Ferritin included in a footnote for 
the iron status markers and added 
to the Laboratory Assessments 
Table 
Initial intention was to include ferritin in the 
iron status markers.  Adds consistency 
throughout the document as ferritin is 
listed in the Objectives and Endpoints as 
well as the Iron Status Markers Section 
(9.8.2) 
Appendix 4 
Clinical Laboratory Assessments 
Table 8 and Table 9 were 
combined 
The two tables were combined for a more 
clear understanding of the laboratory 
assessments for the study. 
Section 9.4.1  
Table 4 was updated to reflect the 
changes in the Schedule of 
Assessments.  
For consistency. 
2 Schedule of 
Assessments, 
Section 9.8.2 
Iron status markers collection 
Additional guidance given for blood draw 
relative to IP dosing 
Section 12.4, 
Table 8 
Fasting Glucose 
Removed the fasting requirement for this 
lab value; determined to be unnecessary 
for this study. 
 

SAP_001.pdf: 
 
 
Statistical Analysis Plan 
 
 
Study ID:  201771 
 
Official Title of Study: A repeat dose, open label, two period, randomized, cross over 
study to compare the effect of daprodustat to recombinant, human erythropoietin (rhEPO) 
on oral iron absorption in adult participants with anemia associated with chronic kidney 
disease who are not on dialysis 
 
NCT ID: NCT03457701 
 
Date of Document: 14 Sep 2022 
 
 


CONFIDENTIAL 
The GlaxoSmithKline group of companies 
201771 
XBU Statistical Analysis Plan (SAP) Template v1.0  24 March 2021
Page 1 of 41
 Information Type: 
Statistical Analysis Plan (SAP) 
TITLE PAGE 
Protocol Title: 
A repeat dose, open label, two period, randomized, cross over 
study to compare the effect of daprodustat to recombinant, 
human erythropoietin (rhEPO) on oral iron absorption in adult 
participants with anemia associated with chronic kidney disease 
who are not on dialysis  
Study Number: 
201771  
Compound Number: 
GSK1278863 
Abbreviated Title: 
Anemia Studies in CKD: Erythropoiesis via a Novel PHI 
Daprodustat – Iron (ASCEND-Fe) 
Sponsor Name: GlaxoSmithKline Research & Development Limited 
Regulatory Agency Identifier Number(s)  
Registry 
ID 
Clintrials.gov 
IND Number 
NCT03457701 
101,291 
Copyright 2022 the GlaxoSmithKline group of companies. All rights reserved.  
Unauthorised copying or use of this information is prohibited. 


 
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TABLE OF CONTENTS 
PAGE 
1. 
INTRODUCTION ...................................................................................................... 3 
1.1. 
Objectives, Estimands and Endpoints ........................................................... 3 
1.2. 
Study Design ................................................................................................ 5 
2. 
STATISTICAL HYPOTHESES ................................................................................. 7 
2.1. 
Multiplicity Adjustment .................................................................................. 7 
3. 
ANALYSIS SETS ..................................................................................................... 8 
4. 
STATISTICAL ANALYSES ....................................................................................... 8 
4.1. 
General Considerations ................................................................................ 8 
4.1.1. 
General Methodology .................................................................... 8 
4.1.2. 
Baseline Definition ......................................................................... 9 
4.2. 
Primary Endpoint(s) Analyses ....................................................................... 9 
4.2.1. 
Definition of endpoint(s) ................................................................. 9 
4.2.2. 
Main analytical approach ............................................................. 26 
4.2.3. 
Sensitivity analyses ..................................................................... 27 
4.3. 
Secondary Endpoint(s) Analyses ................................................................ 28 
4.4. 
Safety Analyses .......................................................................................... 28 
4.4.1. 
Extent of Exposure ...................................................................... 28 
4.4.2. 
Adverse Events............................................................................ 28 
4.4.3. 
Additional Safety Assessments .................................................... 30 
4.5. 
Changes to Protocol Defined Analyses ....................................................... 31 
5. 
SAMPLE SIZE DETERMINATION ......................................................................... 32 
6. 
SUPPORTING DOCUMENTATION ....................................................................... 33 
6.1. 
Appendix 1 Study Population Analyses ....................................................... 33 
6.1.1. 
Participant Disposition ................................................................. 33 
6.1.2. 
Demographic and Baseline Characteristics .................................. 33 
6.1.3. 
Protocol Deviations ...................................................................... 33 
6.1.4. 
Prior and Concomitant Medications ............................................. 34 
6.1.5. 
Study Intervention Compliance .................................................... 34 
6.1.6. 
Additional Analyses Due to the COVID-19 Pandemic .................. 34 
6.2. 
Appendix 2 Data Derivations Rule .............................................................. 35 
6.2.1. 
Criteria for Potential Clinical Importance ...................................... 35 
6.2.2. 
Study Period ................................................................................ 37 
6.2.3. 
Study Day and Reference Dates .................................................. 37 
6.2.4. 
Assessment Window ................................................................... 37 
6.2.5. 
Multiple measurements at One Analysis Time Point .................... 38 
6.2.6. 
Handling of Partial Dates ............................................................. 38 
6.2.7. 
Early PK Access Key Activities .................................................... 40 
Trademarks ................................................................................................ 40 
7. 
REFERENCES ....................................................................................................... 41 
 


 
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1. 
INTRODUCTION 
The purpose of this SAP is to describe the planned analysis to be included in the Clinical 
Study Report for Protocol 201771. Details of the planned final analysis provided.  
Additional detail with regards to data handling conventions and the specification of data 
displays will be provided in the Output and Programming Specification (OPS) document. 
Listings not required by ICH guidelines may be produced via the RAPIDO data viewer 
tool.  
 
1.1. 
Objectives, Estimands and Endpoints 
Since the primary endpoint analyses are based on the Evaluable Population, subjects with 
intercurrent events who discontinue treatment in either period will be excluded from the 
primary analysis. Missing data post withdrawal will not be imputed. 
Objectives 
Endpoints 
Primary 
 
• 
Compare the efficacy of daprodustat 
to rhEPO (i.e., epoetin alfa or 
darbepoetin alfa) on iron absorption 
• 
Difference in fractional oral iron 
absorption (%) between daprodustat 
and rhEPO 
 
Secondary 
 
• 
Characterize the effect of daprodustat 
or rhEPO on markers of iron status 
 
 
 
• 
Characterize the effect of daprodustat 
or rhEPO on indices of erythropoiesis 
• 
Change from baseline (Day 1) at 14 
and 28 days following treatment 
with daprodustat or rhEPO in serum 
iron, transferrin, transferrin 
saturation, soluble transferrin 
receptor, ferritin, hepcidin and 
erythroferrone 
 
• 
Change from baseline (Day 1) at 14 
and 28 days following treatment 
with daprodustat or rhEPO in Hgb, 
hematocrit, red blood cell number, 
mean corpuscular volume, 
reticulocyte Hgb and reticulocyte 
number 
 


 
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Objectives 
Endpoints 
Safety 
 
• 
Assess safety and tolerability 
• 
Incidence and severity of adverse 
events and serious adverse events 
• 
Reasons for discontinuation of study 
medication 
Vital signs assessments 
 
 


 
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1.2. 
Study Design 
Overview of Study Design and Key Features 
 
Design 
Features 
This study will be a randomized, repeat dose, open label, two period cross-
over study in adult, male and female participants with anemia associated 
with chronic kidney disease who are not on dialysis currently treated with 
stable doses (≤ 50% change in 4-weekly dose) for at least 8 weeks prior to 
and including the screening period, of rhEPO (i.e.,epoetin alfa or 
darbepoetin alfa). 
• There will be a 4-week screening period in order to confirm that 
participants have stable Hgb levels and to assess entry criteria 
• A 28-day Treatment Period 1 for incorporation of iron into erythrocytes 
while on randomized study treatment 
• A 28-day Treatment Period 2 for a second incorporation of iron into 
erythrocytes while on randomized study treatment 
• A follow-up visit 14 ± 3 days after completing treatment. 
Study 
intervention 
• Daprodustat dosing information: 
 
Darbepoetin alfa 
(μg/4 wk SC/IV) 
Epoetin alfa 
(convert SC to IV 
U/week)1 
Daprodustat 
dose 
(mg, once daily) 
20 to 30 
1500 to 2000 
1 
>30 to 300 
>2000 to <20000 
2 
>300 
≥20000 
4 
1 
Standardized rhEPO IV dose (U/week) = 161/113 x (epoetin 
SC dose (units)/frequency) 
 
•  rhEPO Dosing Information 
➢ Participants are treated with stable doses (≤ 50% change in 4-
weekly dose) of rhEPO for at least 8 weeks prior to and including 
the screening period. 


 
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Overview of Study Design and Key Features 
• 57Fe Dosing Information 
➢ A 57Fe ferrous sulfate oral solution (10 mL) will be administered 
containing 10 mg of 57Fe (iron concentration at 1 mg/mL with 1:1 
molar ratio ascorbic acid in the solution). 
• 58Fe Dosing Information 
A 58Fe ferrous sulfate oral solution (3 mL) will be administered containing 
3 mg of 58Fe followed by a 56Fe (natural abundance) ferrous sulfate oral 
solution (7 mL) containing 7 mg of 56Fe. Both solution contains iron at 1 
mg/mL with ascorbic acid at 1:1 molar ratio. 
Study 
intervention 
Assignment 
Participants will be randomly assigned either to remain on their current 
therapy (either epoetin alfa or darbepoetin alfa) or be switched to 
daprodustat for Treatment Period 1. 
For assessment of incorporation of iron into erythrocytes, enrolled 
participants will be administered ferrous sulfate containing a stable isotope 
of iron (57Fe or 58Fe) orally in a randomized fashion following 2 weeks of 
administration of randomized study treatment. Two weeks following oral 
iron administration a blood sample will be taken in order to assess the 
incorporation of the iron isotope into red blood cells by thermal ionization 
mass spectrometry(TIMS). 
 
At Day 29 participants will be crossed over to the study treatment they did 
not receive in Treatment Period 1. At 2 weeks following initiation of 
dosing, participants will again be administered ferrous sulfate containing 
the stable iron isotope not administered following the assessment in 
Treatment Period 1 orally. Two weeks following oral iron administration a 
blood sample will again be taken in order to assess the incorporation of the 
iron isotope into red blood cells by TIMS. 
Participants will attend a follow-up visit 14 ± 3 days following the final 
blood sample for assessment of red blood cell iron. 
 
There are 4 possible treatment sequences: 
 
Possible Treatment 
Sequences:
 
Interim 
Analysis 
• No interim analysis will be performed in this study. 
 


 
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2. 
STATISTICAL HYPOTHESES  
The primary analysis will test whether daprodustat is superior to rhEPO (i.e., epoetin alfa 
or darbepoetin alfa) according to the following statistical hypotheses: 
Null: The difference in fractional iron absorption between treatment arms (daprodustat-
rhEPO (i.e., epoetin alfa or darbepoetin alfa)) is equal to zero. 
Alternative: The difference in fractional iron absorption between treatment arms 
(daprodustat-rhEPO (i.e., epoetin alfa or darbepoetin alfa)) is not equal to zero. 
2.1. 
Multiplicity Adjustment 
No multiplicity adjustments will be performed.  


 
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3. 
ANALYSIS SETS 
 Analysis Set 
Definition / Criteria 
Analyses Evaluated 
Screened 
Population 
• This population consists of all participants who 
signed an ICF to participate in the clinical trial. 
• This population will be used for summarizing 
screening failure rates and reasons for screening 
failure. 
• Study 
Population 
Enrolled 
population  
• This population consists of all randomized 
subjects.  
• Study 
Population  
Safety Population 
• This population consists of all randomized 
participants who received at least one dose of 
study treatment. 
• Study 
Population 
• Safety 
Evaluable 
Population 
• This population consists of all randomized 
participants who received study medication and 
completed the iron absorption assessment for 
both treatment periods.  
• Primary 
Endpoint 
 
• Secondary 
Endpoints 
Modified Intent to 
Treat (mITT) 
Population 
• This population consists of all randomized 
participants who received study medication and 
completed the iron absorption assessment at the 
end of the first treatment period. 
• This population will be used for the sensitivity 
analysis of the primary endpoint. 
Sensitivity analyses 
of Primary 
Endpoint 
 
4. 
STATISTICAL ANALYSES 
4.1. 
General Considerations 
4.1.1. 
General Methodology 
 
Unless otherwise specified, continuous data will be summarized using descriptive 
statistics: n, mean, standard deviation (SD), median, minimum, and maximum. 
Categorical data will be summarized as the number and percentage of participants in each 
category. 
It is anticipated that patient accrual will be spread thinly across centers and summaries of 
data by center would unlikely be informative and may not, therefore, be provided. 
 


 
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4.1.2. 
Baseline Definition 
For all endpoints the baseline value will be the latest pre-dose assessment with a non-
missing value, including those from 
unscheduled visits in the associated treatment period. If time is not collected, Day 1 and 
Day 29 
assessments are assumed to be taken prior to first dose and used as baseline. 
Parameter 
Study Assessments Considered as Baseline 
Baseline Used 
in Data Display 
Screening 
(Week -4) 
Screening 
(Week -2) 
Day 1 (Pre-
Dose) 
Day 29 (Pre-
Dose) 
 
 
Vital Signs 
X 
 
X 
 
Day 1 
Iron Status 
Markers 
X 
X 
X 
X 
Day 1 for Period 
1, Day 29 for 
Period 2 
Indices of 
erythropoiesis 
 
 
X 
X 
Day 1 for Period 
1, Day 29 for 
Period 2 
 
 
Unless otherwise stated, if baseline data is missing no derivation will be performed and 
baseline will be set to missing.  
 
4.2. 
Primary Endpoint(s) Analyses 
The primary objective of this study is to compare daprodustat to rhEPO (i.e., epoetin alfa 
or darbepoetin alfa) on fractional iron absorption. Evaluable population will be used for 
this analysis. 
4.2.1. 
Definition of endpoint(s) 
Objectives 
Endpoints 
Primary Objectives 
Primary Endpoints 
• Compare the efficacy of 
daprodustat to rhEPO (i.e., 
epoetin alfa or darbepoetin 
alfa) on iron absorption 
• Difference in fractional oral iron absorption (%) 
between daprodustat and rhEPO 
 
The process for calculating the factional iron absorption will depend on the sequence and 
is defined separately for each iron isotope. Formulas will be based on IAEA guidance for 
assessment of iron bioavailability in humans (IAEA 2012). 
 


 
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Sequences A and C: 
S.
N
o. 
Para
meter
s 
Period 1 -57Fe Fractional Oral 
Iron Absorption 
Period 2 -58Fe Fractional Oral 
Iron Absorption  
Detail
s 
Parameters provided in data 
1 
Hgb in 
g/dL 
 
 
We 
will 
use the 
Hgb 
(g/dL) 
measur
ement 
from 
the day 
of 
isotope 
dosing 
(Day 
15 for 
Period 
1, Day 
43 for 
Period 
2) 
2 
BV in 
mL 
 
 
We 
will 
assum
e a 
blood 
volume 
(BV) of 
70 
mL/kg 
and a 
fixed 
volume 
per kg. 
Weight 
repres
ents 
the 


 
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S.
N
o. 
Para
meter
s 
Period 1 -57Fe Fractional Oral 
Iron Absorption 
Period 2 -58Fe Fractional Oral 
Iron Absorption  
Detail
s 
weight 
measur
ement 
(kg) 
taken 
on the 
day of 
dosing 
(Day 
15 for 
Period 
1, Day 
43 for 
Period 
2). 
3a 
Baseli
ne 
57Fe/
56Fe 
0.02317 
N/A 
Natura
l 
abunda
nce 
measur
e for 
iron 
isotope
, which 
is an 
assum
ed 
consta
nt for 
this 
analysi
s. 
3b 
Baseli
ne 
58Fe/
56Fe 
N/A 
Value3b 
Baselin
e 
measur
ement 
for 
58Fe in 


 
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S.
N
o. 
Para
meter
s 
Period 1 -57Fe Fractional Oral 
Iron Absorption 
Period 2 -58Fe Fractional Oral 
Iron Absorption  
Detail
s 
Period 
2 will 
utilize 
the 
Day 43 
blood 
sampli
ng for 
isotopi
c iron, 
as the 
57Fe 
solutio
n in 
Period 
1 may 
contain 
small 
quantit
ies of 
58Fe. 
This 
measur
ement 
will be 
provid
ed by 
Cornell 
Univer
sity. 
4a 
Enrich
ed 
57Fe/
56Fe 
Value4a 
N/A 
Enrich
ed iron 
value 
is 
calcula
ted 
interna
lly on 
the 


 
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S.
N
o. 
Para
meter
s 
Period 1 -57Fe Fractional Oral 
Iron Absorption 
Period 2 -58Fe Fractional Oral 
Iron Absorption  
Detail
s 
spectro
scopy 
instru
ment 
and 
provid
ed by 
Cornell 
Univer
sity. 
4b 
Enrich
ed 
58Fe/
56Fe 
N/A 
Value4b 
Enrich
ed iron 
value 
is 
calcula
ted 
interna
lly on 
the 
spectro
scopy 
instru
ment 
and 
provid
ed by 
Cornell 
Univer
sity. 
Parameters derived by S&P 
5 
% 
excess 
 * 100 
* 100 
S&P 
will 
derive 
this 
value. 
Δ% 
excess 
is used 


 
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XBU Statistical Analysis Plan (SAP) Template v1.0  24 March 2021  
Page 14 of 41 
S.
N
o. 
Para
meter
s 
Period 1 -57Fe Fractional Oral 
Iron Absorption 
Period 2 -58Fe Fractional Oral 
Iron Absorption  
Detail
s 
to 
expres
s 
measur
ements 
of 
enrich
ment 
relativ
e to 
baselin
e. We 
will 
use the 
followi
ng 
formul
a 
sugges
ted by 
the 
IAEA 
for the 
assess
ment 
of iron 
bioavai
lability 
(IAEA 
pg.20).  
6 
Total 
circul
ating 
Fe 
(mg) 
 
 
S&P 
will 
derive 
this 
value, 
using 
the 
formul
a 


 
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XBU Statistical Analysis Plan (SAP) Template v1.0  24 March 2021  
Page 15 of 41 
S.
N
o. 
Para
meter
s 
Period 1 -57Fe Fractional Oral 
Iron Absorption 
Period 2 -58Fe Fractional Oral 
Iron Absorption  
Detail
s 
sugges
ted by 
the 
IAEA 
for the 
assess
ment 
of iron 
bioavai
lability 
(IAEA 
pg.33). 
7 
Total 
incorp
orated 
iron 
isotop
e (mg) 
S&P 
will 
derive 
this 
value. 
We 
assume 
the 
fraction
al 
abunda
nce of 
57Fe in 
mg is 
(0.0214 
g * 
0.01), 
and the 
fraction
al 
abunda
nce of 
58Fe in 
mg is 
(0.0028
7 g * 


 
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XBU Statistical Analysis Plan (SAP) Template v1.0  24 March 2021  
Page 16 of 41 
S.
N
o. 
Para
meter
s 
Period 1 -57Fe Fractional Oral 
Iron Absorption 
Period 2 -58Fe Fractional Oral 
Iron Absorption  
Detail
s 
0.01). 
8 
% 
iron 
isotop
e 
incorp
orated 
S&P 
will 
derive 
percen
t of 
iron 
isotope 
incorp
orated. 
57Fe 
and 
58Fe 
doses 
(mg) 
will be 
determ
ined 
using 
the 
density 
of 
ferrous 
sulfate 
(FeSO4
) oral 
solutio
n 
(1g/m
L), the 
dose of 
oral 
solutio
n (in 
mL), 


 
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XBU Statistical Analysis Plan (SAP) Template v1.0  24 March 2021  
Page 17 of 41 
S.
N
o. 
Para
meter
s 
Period 1 -57Fe Fractional Oral 
Iron Absorption 
Period 2 -58Fe Fractional Oral 
Iron Absorption  
Detail
s 
and 
concen
tration 
of 
elemen
tal iron 
(1mg/
mL).  
9 
Assu
med 
% 
iron 
isoto
pe  
absor
bed if 
80% 
S&P 
will 
derive 
this 
value, 
using 
the 
formul
a 
sugges
ted by 
the 
IAEA 
for the 
assess
ment 
of iron 
bioavai
lability 
(IAEA 
pg.38). 
Param
eter 9 
defines 
the 
fractio
nal 
oral 
iron 
absorp
tion 


 
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Page 18 of 41 
S.
N
o. 
Para
meter
s 
Period 1 -57Fe Fractional Oral 
Iron Absorption 
Period 2 -58Fe Fractional Oral 
Iron Absorption  
Detail
s 
endpoi
nt, 
assumi
ng 
80% of 
the 
absorb
ed Fe 
is 
incorp
orated 
into 
RBCs.   
 
Sequences B and D: 
S.
N
o. 
Para
meter
s 
Period 1 -58Fe Fractional Oral 
Iron Absorption 
Period 2 -57Fe Fractional Oral 
Iron Absorption  
Detail
s 
Parameters provided in data 
1 
Hgb in 
g/dL 
 
 
We 
will 
use the 
Hgb 
(g/dL) 
measur
ement 
from 
the day 
of 
isotope 
dosing 
(Day 
15 for 
Period 
1, Day 
43 for 


 
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Page 19 of 41 
S.
N
o. 
Para
meter
s 
Period 1 -58Fe Fractional Oral 
Iron Absorption 
Period 2 -57Fe Fractional Oral 
Iron Absorption  
Detail
s 
Period 
2) 
2 
BV in 
mL 
 
 
We 
will 
assum
e a 
blood 
volume 
(BV) of 
70 
mL/kg 
and a 
fixed 
volume 
per kg. 
Weight 
repres
ents 
the 
weight 
measur
ement 
(kg) 
taken 
on the 
day of 
dosing 
(Day 
15 for 
Period 
1, Day 
43 for 
Period 
2). 
3a 
Baseli
ne 
57Fe/
N/A 
Value3a 
Baselin
e 
measur
ement 


 
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S.
N
o. 
Para
meter
s 
Period 1 -58Fe Fractional Oral 
Iron Absorption 
Period 2 -57Fe Fractional Oral 
Iron Absorption  
Detail
s 
56Fe 
for 
57Fe in 
Period 
2 will 
utilize 
the 
Day 43 
blood 
sampli
ng for 
isotopi
c iron, 
as the 
58Fe 
solutio
n in 
Period 
1 may 
contain 
small 
quantit
ies of 
57Fe. 
This 
measur
ement 
will be 
provid
ed by 
Cornell 
Univer
sity. 
3b 
Baseli
ne 
58Fe/
56Fe 
0.00307 
N/A 
Natura
l 
abunda
nce 
measur
e for 
iron 


 
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S.
N
o. 
Para
meter
s 
Period 1 -58Fe Fractional Oral 
Iron Absorption 
Period 2 -57Fe Fractional Oral 
Iron Absorption  
Detail
s 
isotope
, which 
is an 
assum
ed 
consta
nt for 
this 
analysi
s. 
4a 
Enrich
ed 
57Fe/
56Fe 
N/A 
Value4a 
Enrich
ed iron 
value 
is 
calcula
ted 
interna
lly on 
the 
spectro
scopy 
instru
ment 
and 
provid
ed by 
Cornell 
Univer
sity. 
4b 
Enrich
ed 
58Fe/
56Fe 
Value4b 
N/A 
Enrich
ed iron 
value 
is 
calcula
ted 
interna
lly on 
the 


 
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XBU Statistical Analysis Plan (SAP) Template v1.0  24 March 2021  
Page 22 of 41 
S.
N
o. 
Para
meter
s 
Period 1 -58Fe Fractional Oral 
Iron Absorption 
Period 2 -57Fe Fractional Oral 
Iron Absorption  
Detail
s 
spectro
scopy 
instru
ment 
and 
provid
ed by 
Cornell 
Univer
sity. 
Parameters derived by S&P 
5 
% 
excess 
 * 100 
 * 100 
S&P 
will 
derive 
this 
value. 
Δ% 
excess 
is used 
to 
expres
s 
measur
ements 
of 
enrich
ment 
relativ
e to 
baselin
e. We 
will 
use the 
followi
ng 
formul
a 
sugges
ted by 


 
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XBU Statistical Analysis Plan (SAP) Template v1.0  24 March 2021  
Page 23 of 41 
S.
N
o. 
Para
meter
s 
Period 1 -58Fe Fractional Oral 
Iron Absorption 
Period 2 -57Fe Fractional Oral 
Iron Absorption  
Detail
s 
the 
IAEA 
for the 
assess
ment 
of iron 
bioavai
lability 
(IAEA 
pg.20).  
6 
Total 
circul
ating 
Fe 
(mg) 
 
 
S&P 
will 
derive 
this 
value, 
using 
the 
formul
a 
sugges
ted by 
the 
IAEA 
for the 
assess
ment 
of iron 
bioavai
lability 
(IAEA 
pg.33). 
7 
Total 
incorp
orated 
iron 
isotop
e (mg) 
S&P 
will 
derive 
this 
value. 
We 
assume 


 
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XBU Statistical Analysis Plan (SAP) Template v1.0  24 March 2021  
Page 24 of 41 
S.
N
o. 
Para
meter
s 
Period 1 -58Fe Fractional Oral 
Iron Absorption 
Period 2 -57Fe Fractional Oral 
Iron Absorption  
Detail
s 
the 
fraction
al 
abunda
nce of 
57Fe in 
mg is 
(0.0214 
g * 
0.01), 
and the 
fraction
al 
abunda
nce of 
58Fe in 
mg is 
(0.0028
7 g * 
0.01). 
8 
% 
iron 
isotop
e 
incorp
orated 
S&P 
will 
derive 
percen
t of 
iron 
isotope 
incorp
orated. 
57Fe 
and 
58Fe 
doses 
(mg) 
will be 
determ
ined 
using 
the 


 
CONFIDENTIAL 
 
 
201771 
 
 
 
 
XBU Statistical Analysis Plan (SAP) Template v1.0  24 March 2021  
Page 25 of 41 
S.
N
o. 
Para
meter
s 
Period 1 -58Fe Fractional Oral 
Iron Absorption 
Period 2 -57Fe Fractional Oral 
Iron Absorption  
Detail
s 
density 
of 
ferrous 
sulfate 
(FeSO4
) oral 
solutio
n 
(1g/m
L), the 
dose of 
oral 
solutio
n (in 
mL), 
and 
concen
tration 
of 
elemen
tal iron 
(1mg/
mL). 
9 
Assu
med 
% 
iron 
isoto
pe  
absor
bed if 
80% 
S&P 
will 
derive 
this 
value, 
using 
the 
formul
a 
sugges
ted by 
the 
IAEA 
for the 
assess
ment 


 
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XBU Statistical Analysis Plan (SAP) Template v1.0  24 March 2021  
Page 26 of 41 
S.
N
o. 
Para
meter
s 
Period 1 -58Fe Fractional Oral 
Iron Absorption 
Period 2 -57Fe Fractional Oral 
Iron Absorption  
Detail
s 
of iron 
bioavai
lability 
(IAEA 
pg.38). 
Param
eter 9 
defines 
the 
fractio
nal 
oral 
iron 
absorp
tion 
endpoi
nt, 
assumi
ng 
80% of 
the 
absorb
ed Fe 
is 
incorp
orated 
into 
RBCs.   
 
4.2.2. 
Main analytical approach 
Endpoint / Variables 
• Fractional oral iron absorption (%) 
Model Specification 
• To compare daprodustat to rhEPO on fractional iron absorption, a mixed effects 
model will be fitted  
• Terms fitted in the mixed effect model will include: 


 
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Endpoint / Variables 
• Fixed effect: treatment, period, and iron isotope 
• Random effect: participant 
• The Kenward and Roger method for approximating the denominator degrees of 
freedom and correcting for bias in the estimated variance-covariance of the fixed 
effects will be used. 
• Using PROC MIXED in SAS, the covariance for the random participant effect (G 
matrix) will be fit using an unstructured covariance structure by specifying 
‘type=UN’ on the RANDOM line.  
• In the event that this model fails to converge, alternative covariance 
structures may be considered such as Variance Components or Compound 
Symmetry.  
• 
Akaike’s Information Criteria (AIC) will be used to assist with the 
selection of covariance structure. 
Model Checking & Diagnostics 
• For the Mixed Model, model assumptions will be checked, and appropriate 
adjustments may be applied based on the data. 
• Distributional assumptions underlying the model used for analysis will be examined 
by obtaining a normal probability plot of the residuals and a plot of the residuals 
versus the fitted values (i.e. checking the normality assumption and constant variance 
assumption of the model respectively) to gain confidence that the model assumptions 
are reasonable. 
• If there are any departures from the distributional assumptions, alternative 
transformations, such as data squared or square root of data, will be explored. 
• Non-parametric analyses will be conducted if the normality assumption does not hold. 
Model Results Presentation 
Fractional oral iron absorption will be summarized using n, mean, SD, median, 
minimum, and maximum. 
Point estimates, corresponding 95% confidence intervals, and two-sided p-values will be 
constructed for the comparison of efficacy of daprodustat to rhEPO. 
 
4.2.3. 
Sensitivity analyses 
A sensitivity analysis for the primary analysis will be performed using the same mixed 
modelling approach, except with the mITT population. 
 


 
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4.3. 
Secondary Endpoint(s) Analyses 
Markers of iron status endpoints will include serum iron, transferrin, transferrin 
saturation, soluble transferrin receptor, ferritin, hepcidin, and erythroferrone.  
Indices of erythropoiesis endpoints will include Hgb, haematocrit, red blood cell number, 
mean corpuscular volume, reticulocyte Hgb, and reticulocyte number. 
Change from baseline (n, mean, standard deviation, 95% CI of mean, median, minimum, 
and maximum) at Day 14, Day 29, Day 43, and Day 57 will be calculated for iron 
markers and indices of erythropoiesis by treatment group. Day 1 (Pre-dose) and Day 29 
(Pre-dose) will be the baseline for both iron markers as well as indices of erythropoiesis 
for their respective periods.  
Descriptive statistics (n, arithmetic mean, standard deviation, 95% CI, minimum, median, 
and maximum) will be calculated for iron markers and indices of erythropoiesis at each 
scheduled visit by treatment group. No formal statistical testing will be performed. 
Hepcidin and ferritin values will be log-transformed prior to summary. 
All analyses on secondary endpoints will be based on the “Evaluable” population, unless 
otherwise specified.  
4.4. 
Safety Analyses 
The safety analyses will be based on the “Safety” population, unless otherwise specified. 
4.4.1. 
Extent of Exposure 
• Number of days of exposure to study drug will be calculated based on the formula:   
Duration of Exposure in Days = Treatment Stop Date – (Treatment Start Date) + 
1 
• Duration will be summarized by treatment group. Each subject will contribute 
duration of exposure to the treatment taken.  
• 
Participants who were randomized but did not report a treatment start date will be 
categorised as having zero days of exposure. 
 
A listing and summary table of exposure will be created.  
4.4.2. 
Adverse Events 
Adverse events analyses including the analysis of adverse events (AEs), Serious AEs 
(SAEs) and other significant AEs will be based on GSK Core Data Standards. An 
overview summary of AEs, including counts and percentages of participants with any 
AE, AEs related to study intervention, SAEs related to study intervention, fatal SAEs, 
and fatal SAEs related to study intervention will be produced. Adverse events will be 
coded using the standard Medical Dictionary for Regulatory Affairs (MedDRA 
dictionary). A summary of number and percentage of participants with any adverse 
events by maximum severity will be produced. A separate summary will be provided for 


 
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study intervention-related AEs. A study intervention-related AE is defined as an AE for 
which the investigator classifies the possible relationship to study intervention as “Yes”. 
A worst-case scenario approach will be taken to handle missing relatedness data, i.e. the 
summary table will include events with the relationship to study intervention as ‘Yes’ or 
missing. The summary table will be displayed by PT only. All SAEs will be tabulated 
based on the number and percentage of participants who experienced the event. Separate 
summaries will also be provided for study intervention-related SAEs. The summary 
tables will be displayed by PT and SOC. A study intervention-related SAE is defined as 
an SAE for which the investigator classifies the relationship to study intervention as 
“Yes”. A worst-case scenario approach will be taken to handle missing data, i.e. the 
summary table will include events with the relationship to study intervention as ‘Yes’ or 
missing. Summaries and listings of adverse events will include treatment sequence. A 
listing of AEs that occur during Follow-up will be provided. AEs leading to permanent 
discontinuation of study intervention and study intervention related AEs leading to 
permanent discontinuation of study intervention will be listed. 
 
4.4.2.1. 
Adverse Events of Special Interest 
Adverse Events of Special Interest (AESI) have been identified based on non-clinical 
studies with daprodustat, clinical experience with rhEPOs, and current information 
regarding HIF-regulated pathways in mediating hypoxia-associated pathophysiology. The 
following will be considered adverse events of special interest for the purpose of 
analyses: 
• Thrombosis and/or tissue ischemia secondary to excessive erythropoiesis 
• Death, MI, stroke, heart failure, venous thromboembolism, thrombosis of vascular 
access 
• Cardiomyopathy 
• Pulmonary artery hypertension 
• Cancer-related mortality and tumor progression and recurrence 
• Esophageal and gastric erosions 
• Proliferative retinopathy, macular edema, choroidal neovascularization 
• Exacerbation of rheumatoid arthritis 
• Worsening of hypertension 
The summary of event characteristics will be provided for each AESI respectively, 
including number of participants with any event, number of events, number of 
participants with any event that is serious. The percentage will be calculated in two ways, 
one with number of participants with event as the denominator and the other with total 
number of participants as the denominator.  The worst-case approach will be applied at 
participant level for the maximum grade, i.e. a participant will only be counted once as 
the worst case from all the events experienced by the participant. For action taken to an 
event, a participant will be counted once under each action, e.g. if a participant has an 
event leading to both study intervention discontinuation and dose reduction, the 
participants will be counted once under both actions. 
 


 
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4.4.2.2. 
COVID-19 Assessment and COVID-19 AEs 
A standardized MedDRA Query (SMQ) will be used to identify all COVID-19 AEs. 
COVID-19 assessments for participants with COVID-19 AEs will be summarized. 
4.4.3. 
Additional Safety Assessments 
4.4.3.1. 
Possible Suicidality Related Adverse Events 
A listing of possible suicidality related- adverse events (PSRAE) will be produced based 
on GSK Core Data Standards. The listing will be sorted by site id, unique subject id, then 
chronologically within subject.  
4.4.3.2. 
Laboratory Data 
Laboratory evaluations including the analyses of Chemistry laboratory tests, Hematology 
laboratory tests, Urinalysis, and liver function tests will be based on GSK Core Data 
Standards. When collected throughout the treatment period, laboratory data will be 
summarized based on observed values by visit and treatment sequence, as well as change 
from baseline by visit and treatment sequence. For laboratory data collected only at 
screening and follow-up visits, no summary will be produced. A listing of all laboratory 
data and a listing of PCI laboratory data will be produced. 
 
Laboratory data includes the following variables: 
Assessments 
Parameters 
Haematology 
• Platelet Count 
• Hematocrit 
• Hgb 
RBC Indices:  
• MCV 
• MCH 
• %Reticulocytes 
WBC count with 
Differential:  
• Neutrophils 
• Lymphocytes 
• Monocytes 
• Eosinophils 
• Basophils 
Clinical 
Chemistry 
• BUN 
• Creatinine 
• Glucose 
• Potassium 
• Sodium 
• Calcium 
• Aspartate 
Aminotransfera
se (AST)/Serum 
Glutamic-
Oxaloacetic 
Transaminase 
(SGOT) 
• Total and 
direct 
bilirubin 
 
• Alanine 
Aminotransferase 
(ALT)/ Serum 
Glutamic-Pyruvic 
Transaminase 
(SGPT) 
• Alkaline 
phosphatase 
• Total Protein 


 
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Assessments 
Parameters 
Routine 
Urinalysis 
• Specific gravity  
• pH, glucose, protein, blood, ketones, bilirubin, urobilinogen, 
nitrite, leukocyte esterase by dipstick  
• Microscopic examination (if blood or protein is abnormal) 
Other Laboratory 
Analyses 
• Follicle-stimulating hormone and estradiol (as needed in women 
of non-childbearing potential only)  
• Urine human chorionic gonadotropin (hCG) pregnancy test (as 
needed for women of childbearing potential)  
• HIV antibody  
• 
Folate, high sensitivity C-reactive protein, Vitamin B12  
 
Separate summary tables for haematology, and chemistry laboratory tests will be 
produced. Liver function laboratory tests will be included with chemistry lab tests. 
Summaries of other laboratory analyses collected only at screening will not be produced.  
Summaries of hepatobiliary laboratory events including possible Hy’s law cases will be 
provided in addition to what has been described above. Possible Hy’s law cases are 
defined as any elevated alanine aminotransferase (ALT)>3×upper limit of normal (ULN), 
total bilirubin≥2×ULN and alkaline phosphatase (ALP)<3×ULN/missing. Total 
bilirubin≥2×ULN can be within 28 days following the ALT elevation and if direct 
bilirubin is available on the same day, it must be ≥ 35% of total bilirubin. 
ALP<3×ULN/missing means it is satisfied unless the ALP is 3xULN at the time of 
bilirubin elevation. The summary will be produced for worst case post baseline only. 
4.4.3.3. 
Vital Signs 
Vital signs data will be summarized based on observed values by treatment sequence and 
visit, as well as change from baseline by treatment sequence and visit.  Change from 
baseline will be calculated using one baseline for both periods (Day 1). A listing of all 
Vital signs data and a listing of PCI Vital signs data will be produced.  
Vital signs data includes the following variables: 
• Heart rate 
• Blood pressure (SBP, DBP) 
 
4.4.3.4. 
ECG  
A listing of all ECG data and a listing of PCI ECG data will be produced. 
4.5. 
Changes to Protocol Defined Analyses 
The fixed sequence effect has been removed from the mixed model specified for the 
primary analysis in protocol amendment 3 (Dated: 14-JUL-2021) to better align with 
recommendations in the literature (Kenward and Roger, 2009).  


 
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5. 
SAMPLE SIZE DETERMINATION 
Sufficient participants will be enrolled such that at least 12 participants comprise the 
Evaluable Population. A sample size of 12 participants provides 90% power to detect a 
paired mean difference in fractional iron absorption of 11% between the two treatment 
groups under an assumed between-participant standard deviation (SD) of 10.7%. Note 
this is a conservative estimate of the SD of the paired differences as it is based on a 
parallel design study (Young, 2009). No sample size re-estimation will be performed. 


 
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6. 
SUPPORTING DOCUMENTATION 
6.1. 
Appendix 1 Study Population Analyses 
Unless otherwise specified, the study population analyses will be based on the “Safety” 
population, unless otherwise specified. Screen failures will be summarized or listed based 
on the “Screened” population. A summary of the number of participants in each of the 
participant level analysis set will be provided. 
 
6.1.1. 
Participant Disposition 
A summary of the number and percentage of participants who completed the study as 
well as those who prematurely withdrew from the study will be provided overall and by 
study period. Reasons for study withdrawal will be summarized overall and by study 
period. For those who have neither completed nor withdrawn, they will be categorized as 
on study intervention or in follow up.  
A summary of study intervention status will be provided. This display will show the 
number and percentage of participants who have completed the scheduled study 
intervention, are ongoing with study intervention, or have discontinued study intervention 
prematurely, as well as primary reasons for discontinuation of study intervention.  
A summary of the number of subjects in the “Enrolled” population by country and site ID 
will be provided 
 
6.1.2. 
Demographic and Baseline Characteristics 
The demographic characteristics including age, sex, ethnicity, height at screening and 
race will be summarized with descriptive statistics. In addition, the following age 
categories will be summarized: 18-64, 65-84 and >=85 based on the Enrolled Analysis 
Set. 
Listings of demographic characteristics and race will also be produced.  
 
6.1.3. 
Protocol Deviations 
Important protocol deviations will be summarized. 
Protocol deviations will be tracked by the study team throughout the conduct of the 
study. These protocol deviations will be reviewed to identify those considered as 
important as follows: 
o Data will be reviewed prior to freezing the database to ensure all important 
deviations (where possible without knowing the study intervention details) are 
captured and categorised in the protocol deviations dataset.  


 
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o This dataset will be the basis for the summaries of important protocol deviations. 
In addition to the overall summary of important protocol deviations, separate summaries 
will be produced for important protocol deviations related to COVID-19, and important 
protocol deviations not related to COVID-19 respectively. 
6.1.4. 
Prior and Concomitant Medications 
Prior and concomitant medications will be coded using both the GSK Drug and WHO 
Drug dictionaries. However, the summary will be based on GSK Drug dictionary only. 
However, they will only be presented in the form of ICH Listing. 
For classifying study phase for concomitant medication, use the following definition. 
Study Phase Definition 
Prior 
If medication end date is not missing and is before 28 days prior to 
screening visit 
Concomitant 
Any medication that is not a prior 
 
Please refer to 6.2.6: for handling of missing and partial dates for concomitant 
medication. Use the rules in this table if concomitant medication date is completely 
missing. 
 
6.1.5. 
Study Intervention Compliance  
A summary of overall compliance for daprodustat based on the exposure data will be 
produced. Overall compliance will be summarized using descriptive statistics as well as 
the categories <80%, 80%-105%, and >105%.  
Study intervention Compliance (%) = [Total cumulative actual dose / Total cumulative 
scheduled dose] *100. 
6.1.6. 
Additional Analyses Due to the COVID-19 Pandemic  
A participant is defined as having a suspected, probable, or confirmed COVID-19 
infection during the study if the answer is “Confirmed”, “Probable” or “Suspected” to the 
case diagnosis question from the COVID-19 coronavirus infection assessment eCRF. 
Numbers of participants with a suspected, probable, or confirmed COVID-19 infection, 
and of COVID-19 test results will be summarized. 


 
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6.2. 
Appendix 2 Data Derivations Rule 
6.2.1. 
Criteria for Potential Clinical Importance 
A laboratory value that is outside the reference range is considered either high abnormal 
(value above the upper limit of the reference range) or low abnormal (value below the 
lower limit of the reference range). Note: a high abnormal or low abnormal laboratory 
value is not necessarily of clinical concern. 
In addition, the following criteria will be used to flag potential clinical importance (PCI) 
in the Safety population:  
• 
Haematology 
Laboratory Parameter 
 
Units 
Category 
Clinical Concern Range 
Low Flag (< x) 
High Flag (>x) 
Hematocrit 
 
Ratio of 1 
Male 
0.225 
0.54 
Female 
0.225 
0.46 
Hemoglobin 
g/L 
 
Male 
75 
175 
Female 
75 
153 
Platelet Count 
x109/ L 
 
<80 
>500 
RBC Count 
x1012/ L 
 
              <4 
            >5 
WBC Count with Differential: 
 
 
 
   < LLRR 
 
       > 5x ULRR 
 
Neutrophils 
 
mm3 
 
 
< 0. 5 
 
N/A 
Lymphocytes 
 
mm3 
 
<0.5 
N/A 
Monocytes 
mm3 
 
<0. 2 
>1.0 
Eosinophils 
mm3 
 
N/A 
>0. 5 
Basophils 
mm3 
 
N/A 
>0. 1 
RBC Indices: 
 
 
 
 
MCV 
Femtolitres/cell  
<80 
>96 
MCH 
picograms/cell 
 
<27 
>33 
%Reticulocytes 
% 
 
<0.5 
>1.5 
 
Clinical Chemistry 
Laboratory Parameter 
Units 
Category 
Clinical Concern Range 
Low Flag (< x) 
High Flag (>x) 
Calcium 
mmol/L 
 
 <1.75 
         >2.74 
Creatinine 
umol/L 
 
   <44.21 
>884 
Glucose 
mmol/L 
 
<3.9  
          >18 
Total Protein 
g/L 
 
            <60 
          >90 
Potassium 
mmol/L 
 
<3.5 
          > 6.0 


 
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Clinical Chemistry 
Laboratory Parameter 
Units 
Category 
Clinical Concern Range 
Low Flag (< x) 
High Flag (>x) 
Sodium 
mmol/L 
 
  < 130  
          > 150  
 
Liver Function 
Test Analyte 
Units 
Category 
Clinical Concern Range 
ALT/SGPT  
U/L 
High 
>= 3x ULRR 
AST/SGOT  
U/L 
High 
>= 3x ULRR 
AlkPhos  
U/L 
High 
                          >150  
T Bilirubin  
µmol/L 
High 
>= 2x ULRR 
 
Direct Bilirubin 
µmol/L 
High 
                           >8.0 
 
Other Laboratory analyses 
Laboratory Parameter 
Units 
Category 
Clinical Concern Range 
Low Flag (< x) 
High Flag (>x) 
Ferritin 
 
ng/ml 
 
<100 
          >800  
TSAT 
 
% 
 
            <15 
          >40 
Folate 
 ng/ml 
 
            <2.0 
          N/A 
high sensitivity C-reactive protein 
micrograms
/ml 
 
           N/A 
          >/=20 
Vitamin B12 
 
 
</= LLRR at 
screening 
N/A 
 
ECG Parameter 
Units 
Clinical Concern Range 
Lower 
Upper 
Absolute 
Heart rate  
bpm 
40 
125 
PR Interval  
msec 
80 
230 
QRS Duration  
msec 
50 
130 
RR 
breaths/mit 
8 
25 
Uncorrected QT Interval  
msec 
300 
500 
QTcF  
msec 
300 
500 
QTcB  
msec 
300 
500 
QTc (Unspecified)  
msec 
300 
500 
RR Interval 
msec 
545 
1500 
 


 
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Vital Sign Parameter 
(Absolute) 
Units 
Clinical Concern Range 
Lower 
Upper 
Systolic Blood Pressure 
mmHg 
85 
170 
Diastolic Blood Pressure 
mmHg 
50 
110 
Heart Rate 
bpm 
40 
125 
Change from baseline 
 
 
 
Systolic Blood Pressure 
mmHg 
 
>30 
Diastolic Blood Pressure 
mmHg 
 
>50 
Heart Rate 
bpm 
 
>30 
 
6.2.2. 
Study Period  
Assessments and events (e.g., study withdrawal) will be classified according to the time 
of occurrence relative to the study intervention period.  
Study Phase 
Definition 
Pre-Intervention 
Reference Day <= Previous Day of Dosing Start Date in Period 1 
Period 1 
Dosing Start Date in Period 1 < Reference Day <= Previous Day of 
Dosing Start Date in Period 2 
Period 2 
Dosing Start Date in Period 2 <= Reference Day 
 
 
6.2.3. 
Study Day and Reference Dates 
The safety reference date is the study intervention start date and will be used to calculate 
study day for safety measures.  
The efficacy reference date is the study intervention start date and will be used to 
calculate study day for efficacy measures and baseline characteristics, as well as efficacy 
durations.  
The study day is calculated as below: 
• 
Assessment Date = Missing              → Study Day = Missing  
• 
Assessment Date < Reference Date → Study Day = Assessment Date – Ref Date 
• 
Assessment Data ≥ Reference Date → Study Day = Assessment Date – Ref Date + 1     
 
6.2.4. 
Assessment Window  
For data summaries by visit, scheduled visits with nominal visit description will be 
displayed. Unscheduled visits will not be displayed or slotted into a visit window but will 
be included in the derivation of worst-case post baseline assessment. All un-scheduled 
visits will be displayed in listings, as appropriate. 


 
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6.2.5. 
Multiple measurements at One Analysis Time Point 
When triplicate ECG assessments are taken, mean of the measurement will be calculated 
first and summary statistics will be based on the calculated mean. This will apply to both 
baseline and post baseline assessments. 
For lab tests on a study day, if more than one assessment is taken on the same day, the 
test from a central lab will be taken over the test from a local lab. If multiple assessments 
are taken from the same type of lab, the worst case will be used. 
 
6.2.6. 
Handling of Partial Dates 
Element 
Reporting Detail 
General 
• 
Partial dates will be displayed as captured in participant listing displays.   
• 
However, where necessary, display macros may impute dates as temporary 
variables for sorting data in listings only. In addition, partial dates may be 
imputed for ‘slotting’ data to study phases or for specific analysis purposes as 
outlined below. 
• 
Imputed partial dates will not be used to derive study day, time to onset or 
duration (e.g., time to onset or duration of adverse events), or elapsed time 
variables (e.g., time since diagnosis).  
Adverse 
Events 
• 
Partial dates for AE recorded in the CRF will be imputed using the following 
conventions: 
Missing start 
day 
If study intervention start date is missing (i.e. 
participant did not start study intervention), then set 
start date = 1st of month. 
Else if study intervention start date is not missing: 
o If month and year of start date = month and 
year of study intervention start date, then 
▪ If stop date contains a full date and 
stop date is earlier than study 
intervention start date, then set start 
date= 1st of month. 
▪ Else set start date = study 
intervention start date. 
Else set start date = 1st of month. 
Missing start 
day and month 
If study intervention start date is missing (i.e. 
participant did not start study intervention), then 
set start date = January 1. 


 
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Element 
Reporting Detail 
Else if study intervention start date is not missing: 
If year of start date = year of study intervention 
start date, then 
If stop date contains a full date and stop date is 
earlier than study intervention start date, then set 
start date = January 1. 
Else set start date = study intervention start 
date.       
Else set start date = January 1. 
Missing end day  A '28/29/30/31' will be used for the day (dependent 
on the month and year). 
Missing end day 
and month 
No Imputation 
Completely 
missing 
start/end date 
No imputation 
Concomitant 
Medications/
Medical 
History 
• 
Partial dates for any concomitant medications recorded in the CRF will be 
imputed using the following convention: 
 
Missing start 
day 
If study intervention start date is missing (i.e. 
participant did not start study intervention), then set 
start date = 1st of month. 
Else if study intervention start date is not missing: 
o If month and year of start date = month and 
year of study intervention start date, then 
▪ If stop date contains a full date and stop 
date is earlier than study intervention 
start date, then set start date= 1st of 
month. 
▪ Else set start date = study intervention 
start date. 
Else set start date = 1st of month. 
Missing start 
day and month 
If study intervention start date is missing (i.e. 
participant did not start study intervention), then 


 
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Element 
Reporting Detail 
set start date = January 1. 
Else if study intervention start date is not missing: 
o If year of start date = year of study 
intervention start date, then 
▪ If stop date contains a full date and 
stop date is earlier than study 
intervention start date, then set start 
date = January 1. 
▪ Else set start date = study. 
intervention start date.       
Else set start date = January 1. 
Missing end day 
A '28/29/30/31' will be used for the day (dependent on 
the month and year).  
Missing end day 
and month 
A '31' will be used for the day and 'Dec' will be used for 
the month. 
Completely 
missing start/end 
date 
No imputation 
 
6.2.7. 
Early PK Access Key Activities 
NA 
 
Trademarks 
Trademarks of the [GlaxoSmithKline / 
ViiV Healthcare] Group of Companies 
 
Trademarks not owned by the 
[GlaxoSmithKline / ViiV Healthcare] 
Group of Companies 
HARP 
 
SAS 
 
 
 


 
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7. 
REFERENCES 
International Atomic Energy Agency (IAEA). Assessment of iron bioavailability in 
humans using stable iron isotope techniques. IAEA Human Health Series. 2012; 21:19-
39.  
 
GlaxoSmithKline Document Numbers TMF-13854840 (Amendment 3) A repeat dose, 
open label, two period, randomized, cross over study to compare the effect of daprodustat 
to recombinant, human erythropoietin (rhEPO) on oral iron absorption in adult 
participants with anemia associated with chronic kidney disease who are not on dialysis. 
 
Roger, JH and Kenward, MG. The use of baseline covariates in crossover studies. 
Biostatistics. 2009; 11(1): 1-17. 
Young MF, Glahn RP, Ariza-Nieto M, Inglis J, Olbina G, Westerman M, O’Brien KO. 
Serum hepcidin is significantly associated with iron absorption from food and 
supplemental sources in healthy young women. Am J Clin Nutr. 2009; 89:533-538.