Anemia Study in Chronic Kidney Disease (CKD): Erythropoiesis Via a Novel Prolyl Hydroxylase Inhibitor (PHI) Daprodustat-Blood Pressure (ASCEND-BP)

• Sponsor: GlaxoSmithKline (Industry)
• Overall Status: Completed
• CT.gov ID: NCT03029247
• Collaborator: ERT: Clinical Trial Technology Solutions (Other), Q2 Solutions (Industry), Quintiles, Inc. (Industry), HemoCue (Other)
• Enrollment: 105
• Locations: 11
• Arms: 2
• Actual Duration (Months): 35.4
• Patients Per Site: 9.5
• Patients Per Site Per Month: 0.3

Study Details

Study Description

Brief Summary

This will be an open-label, randomized, parallel-group study in hemodialysis-dependent (HD) participants with anemia associated with chronic kidney disease (CKD), designed to compare the effects of daprodustat to epoetin alfa on blood pressure (BP). Participants will be screened for eligibility within 7 and 30 days prior to erythropoesis-stimulating agent (ESA) washout. Following a 2-week ESA washout period, on Day 1 participants will be randomized 1:1 and stratified by prior ESA dose before they undergo Acute Challenge 1, a single dose challenge to compare the acute effects on BP of the highest planned once-daily maintenance dose of daprodustat (24 milligrams [mg]) to the highest starting dose of epoetin alfa (100 units/kilogram [U/kg]). This will be followed by an 8-week hemoglobin (Hgb)-maintenance period, where doses of either daprodustat or epoetin alfa will be administered and adjusted. At the end of Hgb maintenance period, on Day 57 an Acute Challenge 2 will be repeated utilizing the same treatment dose administered in Acute Challenge 1; there will be a follow-up visit within 14+/-3 days after completing treatment.

Condition or Disease	Intervention/Treatment	Phase
Anaemia	Drug: Daprodustat; Drug: Epoetin alfa	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 105 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Randomized, Open-label Study to Evaluate the Effect of Daprodustat on Blood Pressure in Subjects With Anemia Associated With Chronic Kidney Disease on Hemodialysis Switched From a Stable Dose of an Erythropoiesis-stimulating Agent
• Actual Study Start Date: Jul 27, 2017
• Actual Primary Completion Date: Jul 9, 2020
• Actual Study Completion Date: Jul 9, 2020

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Participants receiving Epoetin alfa On Day 1, participants will undergo 24-hour Acute Challenge 1, in which participants will receive a single dose of 100 U/kg epoetin alfa IV. After completing Acute Challenge 1, participants will enter in an 8-week Hgb maintenance period. At the end of Hgb maintenance period, on Day 57, Acute Challenge 2 will be performed utilizing the same treatment dose administered in Acute Challenge 1.	Drug: Epoetin alfa; Epoetin alfa will be administered according to local labelling and clinical practice guidelines to keep Hgb in the target range (10.0-11.0 g/dL)
Experimental: Participants receiving Daprodustat On Day 1, participants will undergo 24-hour Acute Challenge 1, in which participants will receive 24 mg daprodustat. After completing Acute Challenge 1, participants will enter an 8-week Hgb maintenance period. At the end of Hgb maintenance period, on Day 57, Acute Challenge 2 will be performed utilizing the same treatment dose administered in Acute Challenge 1.	Drug: Daprodustat; Daprodustat will be available as oral tablets at unit dose strength of 1, 2, 4, 6, 8 and 10 mg.

Outcome Measures

Primary Outcome Measures

1. Average of Systolic Blood Pressure (SBP) Measured by Ambulatory Blood Pressure Monitoring (ABPM) Over 6-hour Post Dosing on Day 57 [Up to 6 hours post dose on Day 57]

   The effect of daprodustat and epoetin alfa on blood pressure was compared using ABPM after 8 weeks of Hgb maintenace therapy on Day 57. Analysis was based on "analysis of covariance (ANCOVA) with terms for treatment, prior erythropoiesis-stimulating agent (ESA) dose (low/high), post-Hemodialysis dependent (HD)/pre-AC 1 SBP, difference between post-HD/pre-AC 2 SBP and post-HD/pre-AC 1 SBP and treatment by difference in post-HD SBP between AC 1 and 2 interaction." Least square (LS) mean of 6 hour average SBP post AC2 on Day 57 and its corresponding standard error has been presented.

Secondary Outcome Measures

1. Average of SBP, Diastolic Blood Pressure (DBP) and Mean Arterial Blood Pressure (MAP) Measured by ABPM Over 6-hour Post Dosing on Day 1 [Up to 6 hours post dose on Day 1]

   The initial effect of daprodustat and epoetin alfa on blood pressure was compared using ABPM over 6 hour post-dosing on Day 1. Analysis was based on ANCOVA with terms for treatment, prior ESA dose (low/high), post-HD/pre-AC1 SBP, DBP and MAP. LS mean of 6 hour average SBP, DBP and MAP post AC1 on Day 1 and its corresponding standard error has been presented.

2. Average of Heart Rate (HR) Measured by ABPM Over 6 Hour Post Dosing on Day 1 [Up to 6 hours post dose on Day 1]

   The initial effect of daprodustat and epoetin alfa on HR was compared using ABPM over 6 hour post-dosing on Day 1. Analysis was based on ANCOVA with terms for treatment, prior ESA dose (low/high), post-HD/pre-AC1 HR. LS mean of 6 hour average HR post AC1 on Day 1 and its corresponding standard error has been presented.

3. Area Under the Effect Curve (AUEC) of SBP, DBP and MAP Measured by ABPM Over 24-hour Post Dosing on Day 1 [Up to 24 hours post dose on Day 1]

   The initial effect of daprodustat and epoetin alfa on blood pressure was compared using AUEC of SBP, DBP and MAP measured by ABPM over 24-hour post dosing on Day 1. Analysis was based on ANCOVA with terms for treatment and prior ESA dose (low/high). LS mean of AUEC up to 24 hours post dose on Day 1 and its corresponding standard error has been presented.

4. AUEC of HR Measured by ABPM Over 24-hour Post Dosing on Day 1 [Up to 24 hours post dose on Day 1]

   The initial effect of daprodustat and epoetin alfa on HR was compared using AUEC of HR measured by ABPM over 24-hour post dosing. Analysis was based on ANCOVA with terms for treatment and prior ESA dose (low/high). LS mean of AUEC up to 24 hours post dose on Day 1 and its corresponding standard error has been presented.

5. Average of DBP and MAP Measured by ABPM Over 6-hour Post Dosing on Day 57 [Up to 6 hours post dose on Day 57]

   The effect of daprodustat and epoetin alfa on blood pressure was compared using ABPM over 6 hour post-dosing after AC2 on Day 57. Analysis was based on ANCOVA with terms for treatment, prior ESA dose (low/high), post-HD/pre-AC1 DBP and MAP, difference between post-HD/pre-AC2 DBP and MAP and post-HD/pre-AC1 DBP and MAP and treatment by difference in post-HD DBP and MAP between AC1 and 2 interaction. LS mean of 6 hour average DBP and MAP post AC2 on Day 57 and its corresponding standard error has been presented.

6. Average of HR Measured by ABPM Over 6 Hour Post Dosing on Day 57 [Up to 6 hours post dose on Day 57]

   The effect of daprodustat and epoetin alfa on HR was compared using ABPM over 6 hour post-dosing. Analysis was based on ANCOVA with terms for treatment, prior ESA dose (low/high), post-HD/pre-AC1 HR, difference between post-HD/pre-AC2 HR and post-HD/pre-AC1 HR and treatment by difference in post-HD HR between AC1 and 2 interaction. LS mean of 6 hour average HR post AC2 on Day 57 and its corresponding standard error has been presented.

7. AUEC of SBP, DBP and MAP Measured by ABPM Over 24-hour Post Dosing on Day 57 [Up to 24 hours post dose on Day 57]

   The effect of daprodustat and epoetin alfa on blood pressure was compared using AUEC of SBP, DBP and MAP measured by ABPM over 24-hour post dosing on Day 57. Analysis was based on ANCOVA with terms for treatment and prior ESA dose (low/high). LS mean of AUEC up to 24 hour post dose on Day 57 and its corresponding standard error has been presented.

8. AUEC of HR Measured by ABPM Over 24-hour Post Dosing on Day 57 [Up to 24 hours post dose on Day 57]

   The effect of daprodustat and epoetin alfa on HR was compared using AUEC of HR measured by ABPM over 24-hour post dosing on Day 57. Analysis was based on ANCOVA with terms for treatment and prior ESA dose (low/high). LS mean of AUEC up to 24 hour post dose on Day 57 and its corresponding standard error has been presented.

9. Change From Pre-dose in SBP, DBP and MAP at Day 1 [Day 1: Pre-dose and 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23 and 24 hours post-dose]

   The change from pre-dose in SBP, DBP and MAP was measured using ABPM to compare the initial effect of daprodustat to epoetin alfa after AC1 on Day 1. Change from pre-dose at each timepoint is calculated as measurement at post-dose minus pre-acute challenge 1 measurement.

10. Change From Pre-dose in HR at Day 1 [Day 1: Pre-dose and 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23 and 24 hours post-dose]

    The change from pre-dose in HR was measured using ABPM to compare the initial effect of daprodustat to epoetin alfa after AC1 on Day 1. Change from pre-dose at each timepoint is calculated as measurement at post-dose minus pre-acute challenge 1 measurement.

11. Plasma Concentrations of Daprodustat [Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 12, 16 and 24 hours on Days 1 and 57]

    Blood samples were collected at indicated time points for the concentrations of daprodustat.

12. Plasma Concentrations of Metabolite GSK2391220 [Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 12, 16 and 24 hours on Days 1 and 57]

    Blood samples were collected at indicated time points for the concentrations of metabolite GSK2391220.

13. Plasma Concentrations of Metabolite GSK2506104 [Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 12, 16 and 24 hours on Days 1 and 57]

    Blood samples were collected at indicated time points for the concentrations of metabolite GSK2506104.

14. Plasma Concentrations of Metabolite GSK2487818 [Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 12, 16 and 24 hours on Days 1 and 57]

    Blood samples were collected at indicated time points for the concentrations of metabolite GSK2487818.

15. Plasma Concentrations of Metabolite GSK2506102 [Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 12, 16 and 24 hours on Days 1 and 57]

    Blood samples were collected at indicated time points for the concentrations of metabolite GSK25206102.

16. Plasma Concentrations of Metabolite GSK2531398 [Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 12, 16 and 24 hours on Days 1 and 57]

    Blood samples were collected at indicated time points for the concentrations of metabolite GSK2531398.

17. Plasma Concentrations of Metabolite GSK2531401 [Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 12, 16 and 24 hours on Days 1 and 57]

    Blood samples were collected at indicated time points for the concentrations of metabolite GSK2531401.

18. Maximum Plasma Concentration (Cmax) of Daprodustat, GSK2391220, GSK2487818, GSK2506102, GSK2506104, GSK2531398 and GSK2531401 [Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 12, 16 and 24 hours on Days 1 and 57]

    Blood samples were collected at indicated time points for pharmacokinetic analysis of daprodustat and its metabolites GSK2391220, GSK2487818, GSK2506102, GSK2506104, GSK2531398 and GSK2531401. PK parameters were analyzed using standard non-compartmental analysis.

19. Time of Occurrence of Cmax (Tmax) of Daprodustat, GSK2391220, GSK2487818, GSK2506102, GSK2506104, GSK2531398 and GSK2531401 [Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 12, 16 and 24 hours on Days 1 and 57]

    Blood samples were collected at indicated time points for pharmacokinetic analysis of daprodustat and its metabolites GSK2391220, GSK2487818, GSK2506102, GSK2506104, GSK2531398 and GSK2531401. PK parameters were analyzed using standard non-compartmental analysis.

20. Terminal Phase Half-life (t1/2) of Daprodustat, GSK2391220, GSK2487818, GSK2506102, GSK2506104, GSK2531398 and GSK2531401 [Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 12, 16 and 24 hours on Days 1 and 57]

    Blood samples were collected at indicated time points for pharmacokinetic analysis of daprodustat and its metabolites GSK2391220, GSK2487818, GSK2506102, GSK2506104, GSK2531398 and GSK2531401. PK parameters were analyzed using standard non-compartmental analysis.

21. Area Under Concentration-time Curve From Time Zero to 24 Hours (AUC[0-24]) of Daprodustat, GSK2391220, GSK2487818, GSK2506102, GSK2506104, GSK2531398 and GSK2531401 [Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 12, 16 and 24 hours on Days 1 and 57]

    Blood samples were collected at indicated time points for pharmacokinetic analysis of daprodustat and its metabolites GSK2391220, GSK2487818, GSK2506102, GSK2506104, GSK2531398 and GSK2531401. PK parameters were analyzed using standard non-compartmental analysis.

Other Outcome Measures

1. Number of Participants With Any Serious Adverse Events (SAEs) [Up to Week 10]

   Any untoward event resulting in death, life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, congenital anomaly or birth defect or any other situation according to medical or scientific judgment was categorized as SAE.

2. Number of Participants With Treatment Emergent Common (>=2%) Non-serious Adverse Events (Non-SAEs) [Up to Week 8]

   An AE is any untoward medical occurrence that occurs in a participant or clinical investigation participant administered a pharmaceutical product, and which does not necessarily have to have a causal relationship with study treatment. Number of participants with treatment emergent common (>=2% non-SAEs in each arm) non-SAEs has been presented.

3. Number of Participants Who Discontinued the Study Treatment [Up to Week 10]

   Number of participants who discontinued the study treatment due to any reason are presented. The reasons for discontinuation included adverse events, protocol specified withdrawal criteria met, physician decision and withdrawal by participant.

4. Absolute Values for Clinical Chemistry Parameters: Albumin and Protein [Baseline (Day 1) and at Days 29, 57 and Week 10]

   Blood samples were collected for the analysis of clinical chemistry parameters including albumin and protein. Baseline value (Day1) is the latest non-missing pre-dose assessment.

5. Absolute Values for Clinical Chemistry Parameters: Alkaline Phosphatase (ALP), Alanine Aminotransferase (ALT) and Aspartate Aminotransferase (AST) [Baseline (Day 1) and at Days 29, 57 and Week 10]

   Blood samples were collected for the analysis of clinical chemistry parameters including ALP, ALT and AST. Baseline value (Day1) is the latest non-missing pre-dose assessment.

6. Absolute Values for Clinical Chemistry Parameters: Direct Bilirubin, Total Bilirubin and Indirect (Indrt) Bilirubin [Baseline (Day 1) and at Days 29, 57 and Week 10]

   Blood samples were collected for the analysis of clinical chemistry parameters including direct bilirubin, total bilirubin and Indrt bilirubin. Baseline value (Day1) is the latest non-missing pre-dose assessment.

7. Absolute Values for Clinical Chemistry Parameters: Calcium Corrected for Albumin (CCA), Glucose, Potassium, Phosphate and Sodium [Baseline (Day 1) and at Days 29, 57 and Week 10]

   Blood samples were collected for the analysis of clinical chemistry parameters including CCA, glucose, potassium, phosphate and sodium. Baseline value (Day1) is the latest non-missing pre-dose assessment.

8. Change From Baseline Values for Clinical Chemistry Parameters: Albumin and Protein [Baseline (Day 1) and at Days 29, 57 and Week 10]

   Blood samples were collected for the analysis of clinical chemistry parameters including albumin and protein. Baseline value (Day1) is the latest non-missing pre-dose assessment. Change from Baseline is defined as Post-dose visit value minus Baseline value.

9. Change From Baseline Values for Clinical Chemistry Parameters: ALP, ALT and AST [Baseline (Day 1) and at Days 29, 57 and Week 10]

   Blood samples were collected for the analysis of clinical chemistry parameters including ALP, ALT and AST. Baseline value (Day1) is the latest non-missing pre-dose assessment. Change from Baseline is defined as Post-dose visit value minus Baseline value.

10. Change From Baseline Values for Clinical Chemistry Parameters: Direct Bilirubin, Total Bilirubin and Indrt. Bilirubin [Baseline (Day 1) and at Days 29, 57 and Week 10]

    Blood samples were collected for the analysis of clinical chemistry parameters including direct bilirubin, total bilirubin and indrt. bilirubin. Baseline value (Day1) is the latest non-missing pre-dose assessment. Change from Baseline is defined as Post-dose visit value minus Baseline value.

11. Change From Baseline Values for Clinical Chemistry Parameters: CCA, Glucose, Potassium, Phosphate and Sodium [Baseline (Day 1) and at Days 29, 57 and Week 10]

    Blood samples were collected for the analysis of clinical chemistry parameters including CCA, glucose, potassium, phosphate and sodium. Baseline value (Day1) is the latest non-missing pre-dose assessment. Change from Baseline is defined as Post-dose visit value minus Baseline value.

12. Absolute Values for Hematology Parameters: Basophils, Eosinophils, Lymphocytes, Monocytes, Neutrophils, Platelets and Leukocytes [Baseline (Day 1) and at Days 29, 57 and Week 10]

    Blood samples were collected for the analysis of hematology parameters including basophils, eosinophils, lymphocytes, monocytes, neutrophils, platelets and leukocytes. Baseline value (Day1) is the latest non-missing pre-dose assessment.

13. Absolute Values for Hematology Parameter: Hematocrit [Baseline (Day 1) and at Days 29, 57 and Week 10]

    Blood samples were collected for the analysis of hematology parameter: hematocrit. Baseline value (Day1) is the latest non-missing pre-dose assessment.

14. Absolute Values for Hematology Parameters: Erythrocytes and Reticulocytes [Baseline (Day 1) and at Days 29, 57 and Week 10]

    Blood samples were collected for the analysis of hematology parameters: erythrocytes and reticulocytes. Baseline value (Day1) is the latest non-missing pre-dose assessment.

15. Absolute Values for Hematology Parameters: Hemoglobin and Erythrocyte Mean Corpusclar Hemoglobin Concentration ( Ery. MCHC) [Baseline (Day 1) and at Days 29, 57 and Week 10]

    Blood samples were collected for the analysis of hematology parameters: hemoglobin and ery.MCHC. Baseline value (Day1) is the latest non-missing pre-dose assessment.

16. Absolute Values for Hematology Parameter: Ery. Mean Corpuscular Hemoglobin (MCH) and Reticulocyte Corpuscular Hemoglobin Content (CHr) [Baseline (Day 1) and at Days 29, 57 and Week 10]

    Blood samples were collected for the analysis of hematology parameter: ery.MCH and CHr. Baseline value (Day1) is the latest non-missing pre-dose assessment.

17. Absolute Values for Hematology Parameter: Ery. Mean Corpuscular Volume (MCV) [Baseline (Day 1) and at Days 29, 57 and Week 10]

    Blood samples were collected for the analysis of hematology parameter: ery.MCV. Baseline value (Day1) is the latest non-missing pre-dose assessment.

18. Absolute Values for Hematology Parameter: Erythrocyte Distribution Width [Baseline (Day 1) and at Days 29, 57 and Week 10]

    Blood samples were collected for the analysis of hematology parameter: erythrocyte distribution width. Baseline value (Day1) is the latest non-missing pre-dose assessment.

19. Change From Baseline Values for Hematology Parameters: Basophils, Eosinophils, Lymphocytes, Monocytes, Neutrophils, Platelets and Leukocytes [Baseline (Day 1) and at Days 29, 57 and Week 10]

    Blood samples were collected for the analysis of hematology parameters including basophils, eosinophils, lymphocytes, monocytes, neutrophils, platelets and leukocytes. Baseline value (Day1) is the latest non-missing pre-dose assessment. Change from Baseline is defined as Post-dose visit value minus Baseline value.

20. Change From Baseline Values for Hematology Parameter: Hematocrit [Baseline (Day 1) and at Days 29, 57 and Week 10]

    Blood samples were collected for the analysis of hematology parameter: hematocrit. Baseline value (Day1) is the latest non-missing pre-dose assessment. Change from Baseline is defined as Post-dose visit value minus Baseline value.

21. Change From Baseline Values for Hematology Parameters: Erythrocytes and Reticulocytes [Baseline (Day 1) and at Days 29, 57 and Week 10]

    Blood samples were collected for the analysis of hematology parameters: erythrocytes and reticulocytes. Baseline value (Day1) is the latest non-missing pre-dose assessment. Change from Baseline is defined as Post-dose visit value minus Baseline value.

22. Change From Baseline Values for Hematology Parameters: Hemoglobin and Ery. MCHC [Baseline (Day 1) and at Days 29, 57 and Week 10]

    Blood samples were collected for the analysis of hematology parameters: hemoglobin and ery.MCHC. Baseline value (Day1) is the latest non-missing pre-dose assessment. Change from Baseline is defined as Post-dose visit value minus Baseline value.

23. Change From Baseline Values for Hematology Parameters: Ery. MCH and CHr [Baseline (Day 1) and at Days 29, 57 and Week 10]

    Blood samples were collected for the analysis of hematology parameter: ery.MCH and CHr. Baseline value (Day1) is the latest non-missing pre-dose assessment. Change from Baseline is defined as Post-dose visit value minus Baseline value.

24. Change From Baseline Values for Hematology Parameter: Ery. MCV [Baseline (Day 1) and at Days 29, 57 and Week 10]

    Blood samples were collected for the analysis of hematology parameter: ery.MCV. Baseline value (Day1) is the latest non-missing pre-dose assessment. Change from Baseline is defined as Post-dose visit value minus Baseline value.

25. Change From Baseline Values for Hematology Parameter: Erythrocyte Distribution Width [Baseline (Day 1) and at Days 29, 57 and Week 10]

    Blood samples were collected for the analysis of hematology parameter: erythrocyte distribution width. Baseline value (Day1) is the latest non-missing pre-dose assessment. Change from Baseline is defined as Post-dose visit value minus Baseline value.

26. Absolute Values for Electrocardiogram (ECG) Mean Heart Rate [Baseline (Day 1-predose) and at Day 1: 24 hours; Day 57: pre-dose; Day 57: 24 hours and Week 10]

    Full 12-lead ECGs were obtained in supine position using an ECG machine to measure mean heart rate. Baseline (Day 1-predose) is the latest non-missing pre-dose assessment.

27. Absolute Values for ECG Parameters: PR Interval, QRS Duration, QT Interval Corrected for Heart Rate (QTc) and QT Interval Corrected for Heart Rate Using Bazett's Formula (QTcB) [Baseline (Day 1-predose) and at Day 1: 24 hours; Day 57: pre-dose; Day 57: 24 hours and Week 10]

    Full 12-lead ECGs were obtained in supine position using an ECG machine to measure ECG parameters: PR interval, QRS duration, QTc interval and QTcB. Baseline (Day 1-predose) is the latest non-missing pre-dose assessment.

28. Change From Baseline Values for ECG Mean Heart Rate [Baseline (Day 1-predose) and at Day 1: 24 hours; Day 57: pre-dose; Day 57: 24 hours and Week 10]

    Full 12-lead ECGs were obtained in supine position using an ECG machine to measure mean heart rate. Baseline (Day 1-predose) is the latest non-missing pre-dose assessment. Change from Baseline is defined as Post-dose visit value minus Baseline value.

29. Change From Baseline Values for ECG Parameters: PR Interval, QRS Duration, QTc and QTcB [Baseline (Day 1-predose) and at Day 1: 24 hours; Day 57: pre-dose; Day 57: 24 hours and Week 10]

    Full 12-lead ECGs were obtained in supine position using an ECG machine to measure ECG parameters: PR interval, QRS duration, QTc interval and QTcB. Baseline (Day 1-predose) is the latest non-missing pre-dose assessment. Change from Baseline is defined as Post-dose visit value minus Baseline value.

30. Absolute Values for Vital Signs: Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) [Baseline (Day 1, predose) and at Day 1: 3, 12, 24 hours; Day 29: pre- and post-dialysis; Day 57: pre- and post-dialysis, 3, 12, 24 hours and Week 10: pre- and post-dialysis]

    Vital signs including SBP and DBP were measured in participants in a semi-supine position after 5 minutes rest. Baseline (Day 1-predose) is the latest non-missing pre-dose assessment.

31. Absolute Values for Temperature [Baseline (Day 1, predose) and at Day 1: 3, 12, 24 hours; Day 29: pre- and post-dialysis; Day 57: pre- and post-dialysis, 3, 12, 24 hours and Week 10: pre- and post-dialysis]

    Temperature was measured in participants in a semi-supine position after 5 minutes rest. Baseline (Day 1-predose) is the latest non-missing pre-dose assessment.

32. Absolute Values for Pulse Rate [Baseline (Day 1, predose) and at Day 1:3, 12, 24 hours; Day 29: pre- and post-dialysis; Day 57: pre- and post-dialysis, 3, 12, 24 hours and Week 10: pre- and post-dialysis]

    Pulse rate was measured in participants in a semi-supine position after 5 minutes rest. Baseline (Day 1-predose) is the latest non-missing pre-dose assessment.

33. Change From Baseline Values for Vital Signs: SBP and DBP [Baseline (Day 1, predose) and at Day 1: 3, 12, 24 hours; Day 29: pre- and post-dialysis; Day 57: pre- and post-dialysis, 3, 12, 24 hours and Week 10: pre- and post-dialysis]

    Vital signs including SBP and DBP were measured in participants in a semi-supine position after 5 minutes rest. Baseline (Day 1-predose) is the latest non-missing pre-dose assessment. Change from Baseline is defined as Post-dose visit value minus Baseline value.

34. Change From Baseline Values for Temperature [Baseline (Day 1, predose) and at Day 1: 3, 12, 24 hours; Day 29: pre- and post-dialysis; Day 57: pre- and post-dialysis, 3, 12, 24 hours and Week 10: pre- and post-dialysis]

    Temperature was measured in participants in a semi-supine position after 5 minutes rest. Baseline (Day 1-predose) is the latest non-missing pre-dose assessment. Change from Baseline is defined as Post-dose visit value minus Baseline value.

35. Change From Baseline Values for Pulse Rate [Baseline (Day 1, predose) and at Day 1: 3, 12, 24 hours; Day 29: pre- and post-dialysis; Day 57: pre- and post-dialysis, 3, 12, 24 hours and Week 10: pre- and post-dialysis]

    Pulse rate was measured in participants in a semi-supine position after 5 minutes rest. Baseline (Day 1-predose) is the latest non-missing pre-dose assessment. Change from Baseline is defined as Post-dose visit value minus Baseline value.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 40 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria

• More than or equal to 40 years of age, at the time of signing the informed consent

• Stable Hgb 8.5 to 11.5 grams per deciliter (g/dL) inclusive.

• Dialysis frequency: On hemodialysis (HD, hemofiltration or hemodiafiltration) three-to five-times weekly for at least 4 weeks prior to screening.

• A single pool Kt/Vurea >=1.2 based on a historical value obtained within 3 months prior to screening in order to ensure the adequacy of dialysis. If Kt/Vurea is not available, then an average of the last 2 values of urea reduction ratio should be at least 65 percent (%).

• Treated with an ESA (epoetins or their biosimilars, darbepoetin, or methoxy polyethylene glycol [PEG]-epoetin beta) for at least 4 weeks prior to screening.

• Participants may be on stable (<=50% change in overall dose and compliance of 80% of prescribed doses in the 4 weeks prior to and including the screening period) maintenance oral or intravenous (IV; <=100 mg/week) iron supplementation. If participants are on oral or IV iron, then doses must be stable for the 4 weeks prior to Washout.

• Weight: Mid-week weight change between dialysis treatments <5% as assessed post-dialysis at the Screening and Washout visits.

• On at least 1 antihypertensive medication (excluding diuretics) and on that same medication and the same dose for at least 1 week prior to Washout.

• Capable of giving signed informed consent, which includes compliance with the requirements and restrictions listed in the consent form and the protocol.

• Willing and able to wear ABPM device for at least 25 hours on two separate sessions.

Exclusion Criteria

• Planned change from HD to peritoneal dialysis within the study time period, or on home dialysis.

• Planned for kidney transplant within the 16 weeks following the Screening visit.

• An epoetin alfa dose of >=360 U/kg/week IV or >=250 U/kg/week subcutaneous (SC), or darbepoetin dose of >=1.8 micrograms (μg)/kg/week IV or SC, or methoxy PEG-epoetin beta dose of >=2.2 μg/kg/week within the 8 weeks prior to screening through Week -4.

• Planned or recorded administration of Mircera (methoxy PEG-epoetin beta) within the 4 weeks prior to the Washout.

• Occurrence of myocardial infarction or acute coronary syndrome within 3 months prior to Washout.

• Stroke or transient ischemic attack within 3 months prior to Washout.

• Chronic Class 4 heart failure, as defined by the New York Heart Association functional classification system diagnosed prior to Washout.

• QT interval corrected for heart rate using Bazett's formula (QTcB) >500 milliseconds (msec), or QTcB >530 msec in participants with Bundle Branch Block. There is no QTc exclusion for participants with a predominantly paced rhythm.

• Resting post dialysis SBP >160 millimeters of mercury (mmHg); or DBP >100 mmHg at screening or uncontrolled hypertension as determined by the investigator.

• Presence of atrial fibrillation.

• Active chronic inflammatory disease that could impact erythropoiesis (e.g., scleroderma, systemic lupus erythematosus, rheumatoid arthritis, celiac disease) diagnosed prior to Washout.

• History of bone marrow aplasia or pure red cell aplasia.

• Other causes of anemia including Pernicious anemia, thalassemia major, sickle cell disease or myelodysplastic syndrome.

• Alanine transaminase (ALT) >2 times upper limit of normal (ULN) (screening only) or Bilirubin >1.5 times ULN (screening only) or Current unstable liver or biliary disease per investigator assessment, generally defined by the presence of ascites, encephalopathy, coagulopathy, hypoalbuminemia, esophageal or gastric varices, persistent jaundice, or cirrhosis.

• Major surgery (excluding vascular access surgery) within the 3 months prior to Washout or planned during the study.

• Blood transfusion within the 8 weeks prior to Washout or an anticipated need for blood transfusion during the study.

• Evidence of actively bleeding gastric, duodenal, or esophageal ulcer disease or clinically significant gastrointestinal bleeding within the 8 weeks prior to Washout.

• Clinical evidence of acute infection or history of infection requiring IV antibiotic therapy within the 8 weeks prior to Washout.

• History of malignancy within the two years prior to screening through Day 1 or currently receiving treatment for cancer, or has a known complex kidney cyst (e.g., Bosniak Category IIF, III or IV) >=3 centimeters.

• Participants with an upper arm diameter which cannot be measured by oscillometer/ sphygmomanometer cuff or for whom BP cannot be measured in the opposite arm of current vascular access.

• History of severe allergic or anaphylactic reactions or hypersensitivity to excipients in the investigational product.

• Use of any prescription or non-prescription drugs or dietary supplements that are prohibited from screening until Washout.

• The participant has participated in a clinical trial and has received an experimental investigational product within the 30 days prior to Day 1 or within 5 half lives of the investigational product prior to screening, whichever is longer.

• 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.

• A female participant is pregnant (as confirmed by a positive serum human chorionic gonadotrophin test for females of reproductive potential only), participant is breastfeeding, or participant is of reproductive potential and does not agree to follow one of the pre-specified contraceptive options

• Vitamin B12 at or below the lower limit of the reference range (may rescreen in a minimum of 8 weeks, following treatment).

• Folate at <2.0 nanograms/milliliter (ng/mL) (4.5 Nanomoles per Liter) (may rescreen in a minimum of 4 weeks, following treatment).

• Ferritin at <100 ng/mL

• Transferrin saturation at <20%.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	GSK Investigational Site	La Mesa	California	United States	91942
2	GSK Investigational Site	Lakewood	Colorado	United States	80228
3	GSK Investigational Site	Coral Gables	Florida	United States	33134
4	GSK Investigational Site	DeLand	Florida	United States	32720
5	GSK Investigational Site	Hollywood	Florida	United States	33024
6	GSK Investigational Site	Miami	Florida	United States	33133
7	GSK Investigational Site	Orlando	Florida	United States	32809
8	GSK Investigational Site	Chicago	Illinois	United States	60643
9	GSK Investigational Site	Minneapolis	Minnesota	United States	55404
10	GSK Investigational Site	Spartanburg	South Carolina	United States	29301
11	GSK Investigational Site	San Antonio	Texas	United States	78215

Sponsors and Collaborators

• GlaxoSmithKline
• ERT: Clinical Trial Technology Solutions
• Q2 Solutions
• Quintiles, Inc.
• HemoCue

Investigators

• Study Director: GSK Clinical Trials, GlaxoSmithKline

Study Documents (Full-Text)

• Study Protocol - Oct 23, 2019
• Statistical Analysis Plan - Jul 29, 2020

More Information

Publications

None provided.

• Responsible Party: GlaxoSmithKline
• ClinicalTrials.gov Identifier: NCT03029247
• Other Study ID Numbers: 205665
• First Posted: Jan 24, 2017
• Last Update Posted: Jun 3, 2021
• Last Verified: Jun 1, 2021

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by GlaxoSmithKline: Anemia; Daprodustat; Blood pressure; ESA; CKD
• Additional relevant MeSH terms: Kidney Diseases; Renal Insufficiency, Chronic; Anemia; Epoetin Alfa

Study Results

Participant Flow

Recruitment Details	This was a randomized, open label study that evaluated the effect of daprodustat on blood pressure in participants with anemia associated with chronic kidney disease on hemodialysis switched from a stable dose of an erythropoiesis-stimulating agent.
Pre-assignment Detail	A total of 105 participants were enrolled of which 88 were randomized to receive study treatment. 17 did not receive study treatment as they were withdrawn prior to randomization due to adverse events (2); protocol deviation (2); protocol specified withdrawal criteria (3); lost to follow-up (1); physician decision (2) and withdrawal by participant (7).

Arm/Group Title	Daprodustat	Recombinant Human Erythropoietin
Arm/Group Description	Participants were randomized to receive a single oral dose of Daprodustat 24 milligrams (mg) during 24-hour acute challenge 1 (AC1) on Day 1. Participants discontinued their current erythropoiesis stimulating agent (ESA) therapy and were washed out of their ESAs for 2 weeks prior to acute challenge 1. After completion of acute challenge 1, participants entered in 8-week hemoglobin (Hgb) maintenance period, where doses of daprodustat were administered and adjusted to maintain target Hgb levels within the range of 10.0 to 11.0 grams per deciliter (g/dL). Participants received acute challenge 2 (AC2) on Day 57 with the same treatment dose administered in acute challenge 1. All participants were followed up for 14 days after acute challenge 2.	Participants were randomized to receive a single intravenous (IV) dose of 100 units per kilogram (U/Kg) Epoetin alfa (Recombinant human erythropoietin) during 24-hour acute challenge 1 on Day 1. Participants discontinued their current ESA therapy and were washed out of their ESAs for 2 weeks prior to acute challenge 1. After completion of acute challenge 1, participants entered in 8-week Hgb maintenance period, where Epoetin alfa was administered according to local labelling and clinical practice guidelines to maintain target Hgb levels within the range of 10.0 to 11.0 g/dL. Participants received acute challenge 2 on Day 57 with the same treatment dose administered in acute challenge 1. All participants were followed up for 14 days after acute challenge 2.
Period Title: Acute Challenge 1 (Day 1)
STARTED	45	43
COMPLETED	45	43
NOT COMPLETED	0	0
Period Title: Acute Challenge 1 (Day 1)
STARTED	45	43
COMPLETED	32	36
NOT COMPLETED	13	7
Period Title: Acute Challenge 1 (Day 1)
STARTED	32	36
COMPLETED	32	36
NOT COMPLETED	0	0
Period Title: Acute Challenge 1 (Day 1)
STARTED	32	36
COMPLETED	32	36
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Daprodustat	Recombinant Human Erythropoietin	Total
Arm/Group Description	Participants were randomized to receive a single oral dose of Daprodustat 24 milligrams (mg) during 24-hour acute challenge 1 (AC1) on Day 1. Participants discontinued their current erythropoiesis stimulating agent (ESA) therapy and were washed out of their ESAs for 2 weeks prior to acute challenge 1. After completion of acute challenge 1, participants entered in 8-week hemoglobin (Hgb) maintenance period, where doses of daprodustat were administered and adjusted to maintain target Hgb levels within the range of 10.0 to 11.0 grams per deciliter (g/dL). Participants received acute challenge 2 (AC2) on Day 57 with the same treatment dose administered in acute challenge 1. All participants were followed up for 14 days after acute challenge 2.	Participants were randomized to receive a single intravenous (IV) dose of 100 units per kilogram (U/Kg) Epoetin alfa (Recombinant human erythropoietin) during 24-hour acute challenge 1 on Day 1. Participants discontinued their current ESA therapy and were washed out of their ESAs for 2 weeks prior to acute challenge 1. After completion of acute challenge 1, participants entered in 8-week Hgb maintenance period, where Epoetin alfa was administered according to local labelling and clinical practice guidelines to maintain target Hgb levels within the range of 10.0 to 11.0 g/dL. Participants received acute challenge 2 on Day 57 with the same treatment dose administered in acute challenge 1. All participants were followed up for 14 days after acute challenge 2.	Total of all reporting groups
Overall Participants	45	43	88
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	60.9 (11.06)	58.7 (10.61)	59.8 (10.84)
Sex: Female, Male (Count of Participants)
Female	19 42.2%	16 37.2%	35 39.8%
Male	26 57.8%	27 62.8%	53 60.2%
Race/Ethnicity, Customized (Count of Participants)
Black or African American	21 46.7%	23 53.5%	44 50%
White-Arabic/North African Heritage	1 2.2%	0 0%	1 1.1%
White-White/Caucasian/European Heritage	23 51.1%	20 46.5%	43 48.9%

Outcome Measures

1. Primary Outcome

Title	Average of Systolic Blood Pressure (SBP) Measured by Ambulatory Blood Pressure Monitoring (ABPM) Over 6-hour Post Dosing on Day 57
Description	The effect of daprodustat and epoetin alfa on blood pressure was compared using ABPM after 8 weeks of Hgb maintenace therapy on Day 57. Analysis was based on "analysis of covariance (ANCOVA) with terms for treatment, prior erythropoiesis-stimulating agent (ESA) dose (low/high), post-Hemodialysis dependent (HD)/pre-AC 1 SBP, difference between post-HD/pre-AC 2 SBP and post-HD/pre-AC 1 SBP and treatment by difference in post-HD SBP between AC 1 and 2 interaction." Least square (LS) mean of 6 hour average SBP post AC2 on Day 57 and its corresponding standard error has been presented.
Time Frame	Up to 6 hours post dose on Day 57

Outcome Measure Data

Analysis Population Description

Intent-to-Treat (ITT)-Population comprised of all randomized participants who received at least one dose of study treatment. Only those participants with data available at the specified time points were analyzed.

Arm/Group Title	Daprodustat	Recombinant Human Erythropoietin
Arm/Group Description	Participants were randomized to receive a single oral dose of Daprodustat 24 milligrams (mg) during 24-hour acute challenge 1 (AC1) on Day 1. Participants discontinued their current erythropoiesis stimulating agent (ESA) therapy and were washed out of their ESAs for 2 weeks prior to acute challenge 1. After completion of acute challenge 1, participants entered in 8-week hemoglobin (Hgb) maintenance period, where doses of daprodustat were administered and adjusted to maintain target Hgb levels within the range of 10.0 to 11.0 grams per deciliter (g/dL). Participants received acute challenge 2 (AC2) on Day 57 with the same treatment dose administered in acute challenge 1. All participants were followed up for 14 days after acute challenge 2.	Participants were randomized to receive a single intravenous (IV) dose of 100 units per kilogram (U/Kg) Epoetin alfa (Recombinant human erythropoietin) during 24-hour acute challenge 1 on Day 1. Participants discontinued their current ESA therapy and were washed out of their ESAs for 2 weeks prior to acute challenge 1. After completion of acute challenge 1, participants entered in 8-week Hgb maintenance period, where Epoetin alfa was administered according to local labelling and clinical practice guidelines to maintain target Hgb levels within the range of 10.0 to 11.0 g/dL. Participants received acute challenge 2 on Day 57 with the same treatment dose administered in acute challenge 1. All participants were followed up for 14 days after acute challenge 2.
Measure Participants	27	28
Least Squares Mean (Standard Error) [Millimeters of mercury (mmHg)]	142.87 (3.039)	143.03 (2.995)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Daprodustat, Recombinant Human Erythropoietin
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.9694
	Comments	p-value for the difference between treatment groups were presented from ANCOVA model for the superiority assessment.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.17
	Confidence Interval	(2-Sided) 95%; -8.80 to 8.47
	Parameter Dispersion	Type: Value:
	Estimation Comments	LS Mean treatment difference (daprodustat minus recombinant human erythropoietin) and its corresponding 95% confidence interval (CI) has been presented.

2. Secondary Outcome

Title	Average of SBP, Diastolic Blood Pressure (DBP) and Mean Arterial Blood Pressure (MAP) Measured by ABPM Over 6-hour Post Dosing on Day 1
Description	The initial effect of daprodustat and epoetin alfa on blood pressure was compared using ABPM over 6 hour post-dosing on Day 1. Analysis was based on ANCOVA with terms for treatment, prior ESA dose (low/high), post-HD/pre-AC1 SBP, DBP and MAP. LS mean of 6 hour average SBP, DBP and MAP post AC1 on Day 1 and its corresponding standard error has been presented.
Time Frame	Up to 6 hours post dose on Day 1

Outcome Measure Data

Analysis Population Description

ITT Population. Only those participants with data available at the specified time points were analyzed.

Arm/Group Title	Daprodustat	Recombinant Human Erythropoietin
Arm/Group Description	Participants were randomized to receive a single oral dose of Daprodustat 24 milligrams (mg) during 24-hour acute challenge 1 (AC1) on Day 1. Participants discontinued their current erythropoiesis stimulating agent (ESA) therapy and were washed out of their ESAs for 2 weeks prior to acute challenge 1. After completion of acute challenge 1, participants entered in 8-week hemoglobin (Hgb) maintenance period, where doses of daprodustat were administered and adjusted to maintain target Hgb levels within the range of 10.0 to 11.0 grams per deciliter (g/dL). Participants received acute challenge 2 (AC2) on Day 57 with the same treatment dose administered in acute challenge 1. All participants were followed up for 14 days after acute challenge 2.	Participants were randomized to receive a single intravenous (IV) dose of 100 units per kilogram (U/Kg) Epoetin alfa (Recombinant human erythropoietin) during 24-hour acute challenge 1 on Day 1. Participants discontinued their current ESA therapy and were washed out of their ESAs for 2 weeks prior to acute challenge 1. After completion of acute challenge 1, participants entered in 8-week Hgb maintenance period, where Epoetin alfa was administered according to local labelling and clinical practice guidelines to maintain target Hgb levels within the range of 10.0 to 11.0 g/dL. Participants received acute challenge 2 on Day 57 with the same treatment dose administered in acute challenge 1. All participants were followed up for 14 days after acute challenge 2.
Measure Participants	35	31
SBP	141.36 (3.115)	142.68 (3.313)
DBP	75.97 (1.253)	77.92 (1.332)
MAP	99.18 (2.212)	101.58 (2.351)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Daprodustat, Recombinant Human Erythropoietin
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.7745
	Comments	p-value for the difference between treatment groups was presented from ANCOVA model for the superiority assessment.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-1.32
	Confidence Interval	(2-Sided) 95%; -10.46 to 7.83
	Parameter Dispersion	Type: Value:
	Estimation Comments	LS Mean treatment difference (daprodustat minus recombinant human erythropoietin) of SBP and its corresponding 95% CI has been presented.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Daprodustat, Recombinant Human Erythropoietin
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.2910
	Comments	p-value for the difference between treatment groups was presented from ANCOVA model for the superiority assessment.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-1.95
	Confidence Interval	(2-Sided) 95%; -5.62 to 1.71
	Parameter Dispersion	Type: Value:
	Estimation Comments	LS Mean treatment difference (daprodustat minus recombinant human erythropoietin) of DBP and its corresponding 95% CI has been presented.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Daprodustat, Recombinant Human Erythropoietin
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.4611
	Comments	p-value for the difference between treatment groups was presented from ANCOVA model for the superiority assessment.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-2.40
	Confidence Interval	(2-Sided) 95%; -8.88 to 4.07
	Parameter Dispersion	Type: Value:
	Estimation Comments	LS Mean treatment difference (daprodustat minus recombinant human erythropoietin) of MAP and its corresponding 95% CI has been presented.

3. Secondary Outcome

Title	Average of Heart Rate (HR) Measured by ABPM Over 6 Hour Post Dosing on Day 1
Description	The initial effect of daprodustat and epoetin alfa on HR was compared using ABPM over 6 hour post-dosing on Day 1. Analysis was based on ANCOVA with terms for treatment, prior ESA dose (low/high), post-HD/pre-AC1 HR. LS mean of 6 hour average HR post AC1 on Day 1 and its corresponding standard error has been presented.
Time Frame	Up to 6 hours post dose on Day 1

Outcome Measure Data

Analysis Population Description

ITT Population. Only those participants with data available at the specified time points were analyzed.

Arm/Group Title	Daprodustat	Recombinant Human Erythropoietin
Arm/Group Description	Participants were randomized to receive a single oral dose of Daprodustat 24 milligrams (mg) during 24-hour acute challenge 1 (AC1) on Day 1. Participants discontinued their current erythropoiesis stimulating agent (ESA) therapy and were washed out of their ESAs for 2 weeks prior to acute challenge 1. After completion of acute challenge 1, participants entered in 8-week hemoglobin (Hgb) maintenance period, where doses of daprodustat were administered and adjusted to maintain target Hgb levels within the range of 10.0 to 11.0 grams per deciliter (g/dL). Participants received acute challenge 2 (AC2) on Day 57 with the same treatment dose administered in acute challenge 1. All participants were followed up for 14 days after acute challenge 2.	Participants were randomized to receive a single intravenous (IV) dose of 100 units per kilogram (U/Kg) Epoetin alfa (Recombinant human erythropoietin) during 24-hour acute challenge 1 on Day 1. Participants discontinued their current ESA therapy and were washed out of their ESAs for 2 weeks prior to acute challenge 1. After completion of acute challenge 1, participants entered in 8-week Hgb maintenance period, where Epoetin alfa was administered according to local labelling and clinical practice guidelines to maintain target Hgb levels within the range of 10.0 to 11.0 g/dL. Participants received acute challenge 2 on Day 57 with the same treatment dose administered in acute challenge 1. All participants were followed up for 14 days after acute challenge 2.
Measure Participants	35	31
Least Squares Mean (Standard Error) [Beats per minute]	70.77 (1.416)	73.72 (1.507)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Daprodustat, Recombinant Human Erythropoietin
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1648
	Comments	p-value for the difference between treatment groups was presented from ANCOVA model for the superiority assessment.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-2.95
	Confidence Interval	(2-Sided) 95%; -7.14 to 1.24
	Parameter Dispersion	Type: Value:
	Estimation Comments	LS Mean treatment difference (daprodustat minus recombinant human erythropoietin) and its corresponding 95% CI has been presented.

4. Secondary Outcome

Title	Area Under the Effect Curve (AUEC) of SBP, DBP and MAP Measured by ABPM Over 24-hour Post Dosing on Day 1
Description	The initial effect of daprodustat and epoetin alfa on blood pressure was compared using AUEC of SBP, DBP and MAP measured by ABPM over 24-hour post dosing on Day 1. Analysis was based on ANCOVA with terms for treatment and prior ESA dose (low/high). LS mean of AUEC up to 24 hours post dose on Day 1 and its corresponding standard error has been presented.
Time Frame	Up to 24 hours post dose on Day 1

Outcome Measure Data

Analysis Population Description

ITT Population. Only those participants with data available at the specified time points were analyzed.

Arm/Group Title	Daprodustat	Recombinant Human Erythropoietin
Arm/Group Description	Participants were randomized to receive a single oral dose of Daprodustat 24 milligrams (mg) during 24-hour acute challenge 1 (AC1) on Day 1. Participants discontinued their current erythropoiesis stimulating agent (ESA) therapy and were washed out of their ESAs for 2 weeks prior to acute challenge 1. After completion of acute challenge 1, participants entered in 8-week hemoglobin (Hgb) maintenance period, where doses of daprodustat were administered and adjusted to maintain target Hgb levels within the range of 10.0 to 11.0 grams per deciliter (g/dL). Participants received acute challenge 2 (AC2) on Day 57 with the same treatment dose administered in acute challenge 1. All participants were followed up for 14 days after acute challenge 2.	Participants were randomized to receive a single intravenous (IV) dose of 100 units per kilogram (U/Kg) Epoetin alfa (Recombinant human erythropoietin) during 24-hour acute challenge 1 on Day 1. Participants discontinued their current ESA therapy and were washed out of their ESAs for 2 weeks prior to acute challenge 1. After completion of acute challenge 1, participants entered in 8-week Hgb maintenance period, where Epoetin alfa was administered according to local labelling and clinical practice guidelines to maintain target Hgb levels within the range of 10.0 to 11.0 g/dL. Participants received acute challenge 2 on Day 57 with the same treatment dose administered in acute challenge 1. All participants were followed up for 14 days after acute challenge 2.
Measure Participants	31	27
AUEC of SBP	3337.91 (84.144)	3351.33 (90.217)
AUEC of DBP	1763.11 (39.814)	1834.82 (42.688)
AUEC of MAP	2324.69 (57.517)	2378.93 (61.668)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Daprodustat, Recombinant Human Erythropoietin
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.9142
	Comments	p-value for the difference between treatment groups was presented from ANCOVA model for the superiority assessment.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-13.42
	Confidence Interval	(2-Sided) 95%; -261.75 to 234.92
	Parameter Dispersion	Type: Value:
	Estimation Comments	LS Mean treatment difference (daprodustat minus recombinant human erythropoietin) for AUEC of SBP and its corresponding 95% CI has been presented.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Daprodustat, Recombinant Human Erythropoietin
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.2266
	Comments	p-value for the difference between treatment groups was presented from ANCOVA model for the superiority assessment.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-71.70
	Confidence Interval	(2-Sided) 95%; -189.21 to 45.80
	Parameter Dispersion	Type: Value:
	Estimation Comments	LS Mean treatment difference (daprodustat minus recombinant human erythropoietin) for AUEC of DBP and its corresponding 95% CI has been presented.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Daprodustat, Recombinant Human Erythropoietin
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.5246
	Comments	p-value for the difference between treatment groups was presented from ANCOVA model for the superiority assessment.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-54.24
	Confidence Interval	(2-Sided) 95%; -223.99 to 115.51
	Parameter Dispersion	Type: Value:
	Estimation Comments	LS Mean treatment difference (daprodustat minus recombinant human erythropoietin) for AUEC of MAP and its corresponding 95% CI has been presented.

5. Secondary Outcome

Title	AUEC of HR Measured by ABPM Over 24-hour Post Dosing on Day 1
Description	The initial effect of daprodustat and epoetin alfa on HR was compared using AUEC of HR measured by ABPM over 24-hour post dosing. Analysis was based on ANCOVA with terms for treatment and prior ESA dose (low/high). LS mean of AUEC up to 24 hours post dose on Day 1 and its corresponding standard error has been presented.
Time Frame	Up to 24 hours post dose on Day 1

Outcome Measure Data

Analysis Population Description

ITT Population. Only those participants with data available at the specified time points were analyzed.

Arm/Group Title	Daprodustat	Recombinant Human Erythropoietin
Arm/Group Description	Participants were randomized to receive a single oral dose of Daprodustat 24 milligrams (mg) during 24-hour acute challenge 1 (AC1) on Day 1. Participants discontinued their current erythropoiesis stimulating agent (ESA) therapy and were washed out of their ESAs for 2 weeks prior to acute challenge 1. After completion of acute challenge 1, participants entered in 8-week hemoglobin (Hgb) maintenance period, where doses of daprodustat were administered and adjusted to maintain target Hgb levels within the range of 10.0 to 11.0 grams per deciliter (g/dL). Participants received acute challenge 2 (AC2) on Day 57 with the same treatment dose administered in acute challenge 1. All participants were followed up for 14 days after acute challenge 2.	Participants were randomized to receive a single intravenous (IV) dose of 100 units per kilogram (U/Kg) Epoetin alfa (Recombinant human erythropoietin) during 24-hour acute challenge 1 on Day 1. Participants discontinued their current ESA therapy and were washed out of their ESAs for 2 weeks prior to acute challenge 1. After completion of acute challenge 1, participants entered in 8-week Hgb maintenance period, where Epoetin alfa was administered according to local labelling and clinical practice guidelines to maintain target Hgb levels within the range of 10.0 to 11.0 g/dL. Participants received acute challenge 2 on Day 57 with the same treatment dose administered in acute challenge 1. All participants were followed up for 14 days after acute challenge 2.
Measure Participants	31	27
Least Squares Mean (Standard Error) [Beats per minute*Hours]	1652.63 (35.152)	1727.03 (37.690)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Daprodustat, Recombinant Human Erythropoietin
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1563
	Comments	p-value for the difference between treatment groups was presented from ANCOVA model for the superiority assessment.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-74.40
	Confidence Interval	(2-Sided) 95%; -178.15 to 29.34
	Parameter Dispersion	Type: Value:
	Estimation Comments	LS Mean treatment difference (daprodustat minus recombinant human erythropoietin) for AUEC of HR and its corresponding 95% CI has been presented.

6. Secondary Outcome

Title	Average of DBP and MAP Measured by ABPM Over 6-hour Post Dosing on Day 57
Description	The effect of daprodustat and epoetin alfa on blood pressure was compared using ABPM over 6 hour post-dosing after AC2 on Day 57. Analysis was based on ANCOVA with terms for treatment, prior ESA dose (low/high), post-HD/pre-AC1 DBP and MAP, difference between post-HD/pre-AC2 DBP and MAP and post-HD/pre-AC1 DBP and MAP and treatment by difference in post-HD DBP and MAP between AC1 and 2 interaction. LS mean of 6 hour average DBP and MAP post AC2 on Day 57 and its corresponding standard error has been presented.
Time Frame	Up to 6 hours post dose on Day 57

Outcome Measure Data

Analysis Population Description

ITT Population. Only those participants with data available at the specified time points were analyzed.

Arm/Group Title	Daprodustat	Recombinant Human Erythropoietin
Arm/Group Description	Participants were randomized to receive a single oral dose of Daprodustat 24 milligrams (mg) during 24-hour acute challenge 1 (AC1) on Day 1. Participants discontinued their current erythropoiesis stimulating agent (ESA) therapy and were washed out of their ESAs for 2 weeks prior to acute challenge 1. After completion of acute challenge 1, participants entered in 8-week hemoglobin (Hgb) maintenance period, where doses of daprodustat were administered and adjusted to maintain target Hgb levels within the range of 10.0 to 11.0 grams per deciliter (g/dL). Participants received acute challenge 2 (AC2) on Day 57 with the same treatment dose administered in acute challenge 1. All participants were followed up for 14 days after acute challenge 2.	Participants were randomized to receive a single intravenous (IV) dose of 100 units per kilogram (U/Kg) Epoetin alfa (Recombinant human erythropoietin) during 24-hour acute challenge 1 on Day 1. Participants discontinued their current ESA therapy and were washed out of their ESAs for 2 weeks prior to acute challenge 1. After completion of acute challenge 1, participants entered in 8-week Hgb maintenance period, where Epoetin alfa was administered according to local labelling and clinical practice guidelines to maintain target Hgb levels within the range of 10.0 to 11.0 g/dL. Participants received acute challenge 2 on Day 57 with the same treatment dose administered in acute challenge 1. All participants were followed up for 14 days after acute challenge 2.
Measure Participants	27	28
DBP	75.58 (1.465)	77.64 (1.436)
MAP	98.98 (2.208)	101.49 (2.169)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Daprodustat, Recombinant Human Erythropoietin
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.3247
	Comments	p-value for the difference between treatment groups was presented from ANCOVA model for the superiority assessment.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-2.06
	Confidence Interval	(2-Sided) 95%; -6.23 to 2.10
	Parameter Dispersion	Type: Value:
	Estimation Comments	LS Mean treatment difference (daprodustat minus recombinant human erythropoietin) of DBP and its corresponding 95% CI has been presented.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Daprodustat, Recombinant Human Erythropoietin
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.4235
	Comments	p-value for the difference between treatment groups was presented from ANCOVA model for the superiority assessment.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-2.51
	Confidence Interval	(2-Sided) 95%; -8.76 to 3.74
	Parameter Dispersion	Type: Value:
	Estimation Comments	LS Mean treatment difference (daprodustat minus recombinant human erythropoietin) of MAP and its corresponding 95% CI has been presented.

7. Secondary Outcome

Title	Average of HR Measured by ABPM Over 6 Hour Post Dosing on Day 57
Description	The effect of daprodustat and epoetin alfa on HR was compared using ABPM over 6 hour post-dosing. Analysis was based on ANCOVA with terms for treatment, prior ESA dose (low/high), post-HD/pre-AC1 HR, difference between post-HD/pre-AC2 HR and post-HD/pre-AC1 HR and treatment by difference in post-HD HR between AC1 and 2 interaction. LS mean of 6 hour average HR post AC2 on Day 57 and its corresponding standard error has been presented.
Time Frame	Up to 6 hours post dose on Day 57

Outcome Measure Data

Analysis Population Description

ITT Population. Only those participants with data available at the specified time points were analyzed.

Arm/Group Title	Daprodustat	Recombinant Human Erythropoietin
Arm/Group Description	Participants were randomized to receive a single oral dose of Daprodustat 24 milligrams (mg) during 24-hour acute challenge 1 (AC1) on Day 1. Participants discontinued their current erythropoiesis stimulating agent (ESA) therapy and were washed out of their ESAs for 2 weeks prior to acute challenge 1. After completion of acute challenge 1, participants entered in 8-week hemoglobin (Hgb) maintenance period, where doses of daprodustat were administered and adjusted to maintain target Hgb levels within the range of 10.0 to 11.0 grams per deciliter (g/dL). Participants received acute challenge 2 (AC2) on Day 57 with the same treatment dose administered in acute challenge 1. All participants were followed up for 14 days after acute challenge 2.	Participants were randomized to receive a single intravenous (IV) dose of 100 units per kilogram (U/Kg) Epoetin alfa (Recombinant human erythropoietin) during 24-hour acute challenge 1 on Day 1. Participants discontinued their current ESA therapy and were washed out of their ESAs for 2 weeks prior to acute challenge 1. After completion of acute challenge 1, participants entered in 8-week Hgb maintenance period, where Epoetin alfa was administered according to local labelling and clinical practice guidelines to maintain target Hgb levels within the range of 10.0 to 11.0 g/dL. Participants received acute challenge 2 on Day 57 with the same treatment dose administered in acute challenge 1. All participants were followed up for 14 days after acute challenge 2.
Measure Participants	27	28
Least Squares Mean (Standard Error) [Beats per minute]	70.49 (1.146)	70.62 (1.125)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Daprodustat, Recombinant Human Erythropoietin
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.9353
	Comments	p-value for the difference between treatment groups was presented from ANCOVA model for the superiority assessment.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.13
	Confidence Interval	(2-Sided) 95%; -3.41 to 3.14
	Parameter Dispersion	Type: Value:
	Estimation Comments	LS Mean treatment difference (daprodustat minus recombinant human erythropoietin) and its corresponding 95% CI has been presented.

8. Secondary Outcome

Title	AUEC of SBP, DBP and MAP Measured by ABPM Over 24-hour Post Dosing on Day 57
Description	The effect of daprodustat and epoetin alfa on blood pressure was compared using AUEC of SBP, DBP and MAP measured by ABPM over 24-hour post dosing on Day 57. Analysis was based on ANCOVA with terms for treatment and prior ESA dose (low/high). LS mean of AUEC up to 24 hour post dose on Day 57 and its corresponding standard error has been presented.
Time Frame	Up to 24 hours post dose on Day 57

Outcome Measure Data

Analysis Population Description

ITT Population. Only those participants with data available at the specified time points were analyzed.

Arm/Group Title	Daprodustat	Recombinant Human Erythropoietin
Arm/Group Description	Participants were randomized to receive a single oral dose of Daprodustat 24 milligrams (mg) during 24-hour acute challenge 1 (AC1) on Day 1. Participants discontinued their current erythropoiesis stimulating agent (ESA) therapy and were washed out of their ESAs for 2 weeks prior to acute challenge 1. After completion of acute challenge 1, participants entered in 8-week hemoglobin (Hgb) maintenance period, where doses of daprodustat were administered and adjusted to maintain target Hgb levels within the range of 10.0 to 11.0 grams per deciliter (g/dL). Participants received acute challenge 2 (AC2) on Day 57 with the same treatment dose administered in acute challenge 1. All participants were followed up for 14 days after acute challenge 2.	Participants were randomized to receive a single intravenous (IV) dose of 100 units per kilogram (U/Kg) Epoetin alfa (Recombinant human erythropoietin) during 24-hour acute challenge 1 on Day 1. Participants discontinued their current ESA therapy and were washed out of their ESAs for 2 weeks prior to acute challenge 1. After completion of acute challenge 1, participants entered in 8-week Hgb maintenance period, where Epoetin alfa was administered according to local labelling and clinical practice guidelines to maintain target Hgb levels within the range of 10.0 to 11.0 g/dL. Participants received acute challenge 2 on Day 57 with the same treatment dose administered in acute challenge 1. All participants were followed up for 14 days after acute challenge 2.
Measure Participants	24	21
AUEC of SBP	3288.43 (85.805)	3433.40 (91.786)
AUEC of DBP	1736.11 (38.659)	1853.60 (41.354)
AUEC of MAP	2299.42 (58.712)	2431.36 (62.804)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Daprodustat, Recombinant Human Erythropoietin
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.2573
	Comments	p-value for the difference between treatment groups was presented from ANCOVA model for the superiority assessment.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-144.97
	Confidence Interval	(2-Sided) 95%; -399.71 to 109.76
	Parameter Dispersion	Type: Value:
	Estimation Comments	LS Mean treatment difference (daprodustat minus recombinant human erythropoietin) for AUEC of SBP and its corresponding 95% CI has been presented.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Daprodustat, Recombinant Human Erythropoietin
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0450
	Comments	p-value for the difference between treatment groups was presented from ANCOVA model for the superiority assessment.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-117.49
	Confidence Interval	(2-Sided) 95%; -232.26 to -2.72
	Parameter Dispersion	Type: Value:
	Estimation Comments	LS Mean treatment difference (daprodustat minus recombinant human erythropoietin) for AUEC of DBP and its corresponding 95% CI has been presented.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Daprodustat, Recombinant Human Erythropoietin
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1341
	Comments	p-value for the difference between treatment groups was presented from ANCOVA model for the superiority assessment.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-131.94
	Confidence Interval	(2-Sided) 95%; -306.24 to 42.36
	Parameter Dispersion	Type: Value:
	Estimation Comments	LS Mean treatment difference (daprodustat minus recombinant human erythropoietin) for AUEC of MAP and its corresponding 95% CI has been presented.

9. Secondary Outcome

Title	AUEC of HR Measured by ABPM Over 24-hour Post Dosing on Day 57
Description	The effect of daprodustat and epoetin alfa on HR was compared using AUEC of HR measured by ABPM over 24-hour post dosing on Day 57. Analysis was based on ANCOVA with terms for treatment and prior ESA dose (low/high). LS mean of AUEC up to 24 hour post dose on Day 57 and its corresponding standard error has been presented.
Time Frame	Up to 24 hours post dose on Day 57

Outcome Measure Data

Analysis Population Description

ITT Population. Only those participants with data available at the specified time points were analyzed.

Arm/Group Title	Daprodustat	Recombinant Human Erythropoietin
Arm/Group Description	Participants were randomized to receive a single oral dose of Daprodustat 24 milligrams (mg) during 24-hour acute challenge 1 (AC1) on Day 1. Participants discontinued their current erythropoiesis stimulating agent (ESA) therapy and were washed out of their ESAs for 2 weeks prior to acute challenge 1. After completion of acute challenge 1, participants entered in 8-week hemoglobin (Hgb) maintenance period, where doses of daprodustat were administered and adjusted to maintain target Hgb levels within the range of 10.0 to 11.0 grams per deciliter (g/dL). Participants received acute challenge 2 (AC2) on Day 57 with the same treatment dose administered in acute challenge 1. All participants were followed up for 14 days after acute challenge 2.	Participants were randomized to receive a single intravenous (IV) dose of 100 units per kilogram (U/Kg) Epoetin alfa (Recombinant human erythropoietin) during 24-hour acute challenge 1 on Day 1. Participants discontinued their current ESA therapy and were washed out of their ESAs for 2 weeks prior to acute challenge 1. After completion of acute challenge 1, participants entered in 8-week Hgb maintenance period, where Epoetin alfa was administered according to local labelling and clinical practice guidelines to maintain target Hgb levels within the range of 10.0 to 11.0 g/dL. Participants received acute challenge 2 on Day 57 with the same treatment dose administered in acute challenge 1. All participants were followed up for 14 days after acute challenge 2.
Measure Participants	24	21
Least Squares Mean (Standard Error) [Beats per minute*Hours]	1579.38 (40.886)	1677.06 (43.736)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Daprodustat, Recombinant Human Erythropoietin
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1119
	Comments	p-value for the difference between treatment groups was presented from ANCOVA model for the superiority assessment.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-97.67
	Confidence Interval	(2-Sided) 95%; -219.05 to 23.71
	Parameter Dispersion	Type: Value:
	Estimation Comments	LS Mean treatment difference (daprodustat minus recombinant human erythropoietin) for AUEC of HR and its corresponding 95% CI has been presented.

10. Secondary Outcome

Title	Change From Pre-dose in SBP, DBP and MAP at Day 1
Description	The change from pre-dose in SBP, DBP and MAP was measured using ABPM to compare the initial effect of daprodustat to epoetin alfa after AC1 on Day 1. Change from pre-dose at each timepoint is calculated as measurement at post-dose minus pre-acute challenge 1 measurement.
Time Frame	Day 1: Pre-dose and 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23 and 24 hours post-dose

Outcome Measure Data

Analysis Population Description

ITT-Population. Only those participants with data available at specified time points has been presented (represented as n=X in category titles).

Arm/Group Title	Daprodustat	Recombinant Human Erythropoietin
Arm/Group Description	Participants were randomized to receive a single oral dose of Daprodustat 24 milligrams (mg) during 24-hour acute challenge 1 (AC1) on Day 1. Participants discontinued their current erythropoiesis stimulating agent (ESA) therapy and were washed out of their ESAs for 2 weeks prior to acute challenge 1. After completion of acute challenge 1, participants entered in 8-week hemoglobin (Hgb) maintenance period, where doses of daprodustat were administered and adjusted to maintain target Hgb levels within the range of 10.0 to 11.0 grams per deciliter (g/dL). Participants received acute challenge 2 (AC2) on Day 57 with the same treatment dose administered in acute challenge 1. All participants were followed up for 14 days after acute challenge 2.	Participants were randomized to receive a single intravenous (IV) dose of 100 units per kilogram (U/Kg) Epoetin alfa (Recombinant human erythropoietin) during 24-hour acute challenge 1 on Day 1. Participants discontinued their current ESA therapy and were washed out of their ESAs for 2 weeks prior to acute challenge 1. After completion of acute challenge 1, participants entered in 8-week Hgb maintenance period, where Epoetin alfa was administered according to local labelling and clinical practice guidelines to maintain target Hgb levels within the range of 10.0 to 11.0 g/dL. Participants received acute challenge 2 on Day 57 with the same treatment dose administered in acute challenge 1. All participants were followed up for 14 days after acute challenge 2.
Measure Participants	35	31
SBP, Hour 1, n=34, 31	1.00 (17.178)	5.27 (20.471)
SBP, Hour 2, n=35, 31	-4.99 (28.170)	4.72 (22.651)
SBP, Hour 3, n=35, 31	-5.85 (29.636)	5.09 (21.163)
SBP, Hour 4, n=35, 31	-1.68 (26.000)	0.93 (23.962)
SBP, Hour 5, n=35, 31	-1.86 (29.171)	-2.10 (23.849)
SBP, Hour 6, n=35, 31	0.29 (31.903)	-2.54 (28.908)
SBP, Hour 7, n=34, 26	2.30 (33.896)	0.63 (19.016)
SBP, Hour 8, n=33, 29	0.43 (31.418)	3.83 (20.723)
SBP, Hour 9, n=33, 30	-5.81 (30.725)	0.25 (26.294)
SBP, Hour 10, n=31, 28	-5.70 (28.018)	1.48 (25.952)
SBP, Hour 11, n=33, 27	-7.00 (27.529)	1.96 (24.421)
SBP, Hour 12, n=35, 28	-6.05 (29.932)	-1.67 (19.380)
SBP, Hour 13, n=34, 28	-2.49 (25.319)	-1.37 (25.596)
SBP, Hour 14, n=34, 31	-5.30 (30.030)	4.57 (29.767)
SBP, Hour 15, n=32, 26	-1.47 (33.573)	-0.13 (24.287)
SBP, Hour 16, n=34, 31	-4.40 (30.990)	8.59 (24.729)
SBP, Hour 17, n=32, 30	-5.05 (29.795)	1.76 (23.896)
SBP, Hour 18, n=32, 27	-5.23 (25.993)	5.48 (23.330)
SBP, Hour 19, n=34, 27	-3.01 (24.230)	1.52 (21.072)
SBP, Hour 20, n=33, 27	-13.27 (24.138)	6.89 (16.834)
SBP, Hour 21, n=30, 27	-8.32 (26.003)	1.72 (26.777)
SBP, Hour 22, n=29, 27	-3.93 (26.106)	3.50 (24.428)
SBP, Hour 23, n=31, 26	2.73 (28.343)	8.72 (24.868)
SBP, Hour 24, n=31, 27	2.63 (29.379)	5.02 (26.601)
DBP, Hour 1, n=34, 31	0.01 (9.317)	0.99 (13.110)
DBP, Hour 2, n=35, 31	-0.82 (15.399)	1.97 (11.986)
DBP, Hour 3, n=35, 31	-1.30 (14.660)	0.88 (11.858)
DBP, Hour 4, n=35, 31	-1.06 (14.552)	-1.17 (13.621)
DBP, Hour 5, n=35, 31	-0.69 (16.618)	-1.49 (11.684)
DBP, Hour 6, n=35, 31	-0.06 (14.799)	-1.49 (14.457)
DBP, Hour 7, n=34, 26	-0.12 (16.324)	-1.27 (15.272)
DBP, Hour 8, n=33, 29	1.35 (15.900)	1.79 (15.178)
DBP, Hour 9, n=33, 30	-2.14 (15.188)	-0.68 (11.874)
DBP, Hour 10, n=31, 28	-3.52 (14.246)	-0.82 (12.802)
DBP, Hour 11, n=33, 27	-4.88 (14.691)	-2.45 (10.987)
DBP, Hour 12, n=35, 28	-4.79 (14.561)	-3.95 (10.718)
DBP, Hour 13, n=34, 28	-2.15 (15.185)	-2.65 (12.841)
DBP, Hour 14, n=34, 31	-3.99 (14.153)	-1.00 (14.759)
DBP, Hour 15, n=32, 26	-0.54 (19.203)	-4.12 (13.905)
DBP, Hour 16, n=34, 31	-3.56 (15.615)	1.15 (14.186)
DBP, Hour 17, n=32, 30	-3.65 (14.949)	-2.98 (13.732)
DBP, Hour 18, n=32, 27	-2.08 (17.015)	0.30 (14.219)
DBP, Hour 19, n=34, 27	-0.36 (19.650)	-0.43 (14.965)
DBP, Hour 20, n=33, 27	-2.96 (15.579)	0.40 (14.501)
DBP, Hour 21, n=30, 27	-2.54 (15.246)	1.90 (15.507)
DBP, Hour 22, n=29, 27	-0.25 (15.037)	-1.96 (12.058)
DBP, Hour 23, n=31, 26	4.05 (19.055)	-0.44 (13.218)
DBP, Hour 24, n=31, 27	4.48 (18.097)	2.16 (15.124)
MAP, Hour 1, n=34, 31	-1.87 (15.252)	2.83 (19.439)
MAP, Hour 2, n=35, 31	-4.79 (24.742)	4.20 (17.890)
MAP, Hour 3, n=35, 31	-5.13 (22.342)	3.46 (14.940)
MAP, Hour 4, n=35, 31	-4.78 (23.640)	-1.05 (17.552)
MAP, Hour 5, n=35, 31	-3.48 (26.458)	-1.18 (16.235)
MAP, Hour 6, n=35, 31	-1.27 (25.359)	-2.17 (19.573)
MAP, Hour 7, n=34, 26	0.45 (28.445)	0.87 (18.659)
MAP, Hour 8, n=33, 29	0.08 (27.487)	2.20 (17.002)
MAP, Hour 9, n=33, 30	-7.02 (24.498)	0.61 (17.072)
MAP, Hour 10, n=31, 28	-8.18 (24.057)	0.76 (18.604)
MAP, Hour 11, n=33, 27	-8.74 (25.719)	-3.60 (19.022)
MAP, Hour 12, n=35, 28	-6.49 (26.669)	-6.15 (16.336)
MAP, Hour 13, n=34, 28	-5.72 (23.609)	-3.32 (17.660)
MAP, Hour 14, n=34, 31	-6.99 (25.710)	-0.75 (17.024)
MAP, Hour 15, n=32, 26	-4.06 (27.693)	-5.10 (19.458)
MAP, Hour 16, n=34, 31	-4.79 (26.805)	3.84 (22.886)
MAP, Hour 17, n=32, 30	-5.10 (25.873)	-2.09 (19.856)
MAP, Hour 18, n=32, 27	-6.98 (24.790)	1.52 (18.745)
MAP, Hour 19, n=34, 27	-4.44 (26.186)	-1.02 (17.275)
MAP, Hour 20, n=33, 27	-9.47 (23.186)	4.23 (16.311)
MAP, Hour 21, n=30, 27	-7.39 (22.611)	3.87 (20.860)
MAP, Hour 22, n=29, 27	-2.77 (21.938)	0.75 (16.888)
MAP, Hour 23, n=31, 26	0.88 (27.381)	4.10 (18.818)
MAP, Hour 24, n=31, 27	2.02 (26.253)	2.20 (19.276)

11. Secondary Outcome

Title	Change From Pre-dose in HR at Day 1
Description	The change from pre-dose in HR was measured using ABPM to compare the initial effect of daprodustat to epoetin alfa after AC1 on Day 1. Change from pre-dose at each timepoint is calculated as measurement at post-dose minus pre-acute challenge 1 measurement.
Time Frame	Day 1: Pre-dose and 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23 and 24 hours post-dose

Outcome Measure Data

Analysis Population Description

ITT-Population. Only those participants with data available at specified time points has been presented (represented as n=X in category titles).

Arm/Group Title	Daprodustat	Recombinant Human Erythropoietin
Arm/Group Description	Participants were randomized to receive a single oral dose of Daprodustat 24 milligrams (mg) during 24-hour acute challenge 1 (AC1) on Day 1. Participants discontinued their current erythropoiesis stimulating agent (ESA) therapy and were washed out of their ESAs for 2 weeks prior to acute challenge 1. After completion of acute challenge 1, participants entered in 8-week hemoglobin (Hgb) maintenance period, where doses of daprodustat were administered and adjusted to maintain target Hgb levels within the range of 10.0 to 11.0 grams per deciliter (g/dL). Participants received acute challenge 2 (AC2) on Day 57 with the same treatment dose administered in acute challenge 1. All participants were followed up for 14 days after acute challenge 2.	Participants were randomized to receive a single intravenous (IV) dose of 100 units per kilogram (U/Kg) Epoetin alfa (Recombinant human erythropoietin) during 24-hour acute challenge 1 on Day 1. Participants discontinued their current ESA therapy and were washed out of their ESAs for 2 weeks prior to acute challenge 1. After completion of acute challenge 1, participants entered in 8-week Hgb maintenance period, where Epoetin alfa was administered according to local labelling and clinical practice guidelines to maintain target Hgb levels within the range of 10.0 to 11.0 g/dL. Participants received acute challenge 2 on Day 57 with the same treatment dose administered in acute challenge 1. All participants were followed up for 14 days after acute challenge 2.
Measure Participants	35	31
Hour 1, n=34, 31	-1.16 (9.283)	0.13 (15.465)
Hour 2, n=35, 31	-1.05 (17.259)	-2.06 (15.409)
Hour 3, n=35, 31	0.76 (15.920)	-0.16 (14.911)
Hour 4, n=35, 31	3.18 (12.717)	-1.13 (17.798)
Hour 5, n=35, 31	0.91 (13.782)	-0.66 (14.119)
Hour 6, n=35, 31	0.97 (14.763)	-1.66 (13.023)
Hour 7, n=34, 26	2.14 (13.620)	-1.01 (11.592)
Hour 8, n=33, 29	0.62 (13.326)	-1.11 (18.376)
Hour 9, n=33, 30	0.20 (14.533)	0.67 (15.411)
Hour 10, n=31, 28	2.54 (13.575)	1.60 (13.612)
Hour 11, n=33, 27	2.07 (14.247)	1.57 (14.132)
Hour 12, n=35, 28	0.77 (12.386)	-2.01 (14.767)
Hour 13, n=34, 28	-0.25 (12.895)	-2.45 (14.861)
Hour 14, n=34, 31	-1.54 (13.148)	0.25 (13.020)
Hour 15, n=32, 26	-0.92 (13.406)	-3.06 (13.156)
Hour 16, n=34, 31	-1.02 (14.018)	-2.87 (11.762)
Hour 17, n=32, 30	-0.85 (14.631)	-4.34 (13.284)
Hour 18, n=32, 27	0.60 (15.553)	0.98 (11.443)
Hour 19, n=34, 27	-0.56 (14.407)	-2.65 (13.220)
Hour 20, n=33, 27	-1.91 (13.956)	-4.77 (17.083)
Hour 21, n=30, 27	-1.82 (13.841)	-3.00 (13.342)
Hour 22, n=29, 27	0.82 (11.686)	-2.61 (13.292)
Hour 23, n=31, 26	-1.01 (12.697)	0.24 (13.148)
Hour 24, n=31, 27	-0.89 (17.530)	-0.96 (14.651)

12. Secondary Outcome

Title	Plasma Concentrations of Daprodustat
Description	Blood samples were collected at indicated time points for the concentrations of daprodustat.
Time Frame	Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 12, 16 and 24 hours on Days 1 and 57

Outcome Measure Data

Analysis Population Description

Pharmacokinetic Population comprised of all participants in the Safety population who had at least 1 non-missing pharmacokinetic assessment. Only those participants with data available at specified time points has been presented (represented as n=X in the category titles).

Arm/Group Title	Daprodustat
Arm/Group Description	Participants were randomized to receive a single oral dose of Daprodustat 24 milligrams (mg) during 24-hour acute challenge 1 (AC1) on Day 1. Participants discontinued their current erythropoiesis stimulating agent (ESA) therapy and were washed out of their ESAs for 2 weeks prior to acute challenge 1. After completion of acute challenge 1, participants entered in 8-week hemoglobin (Hgb) maintenance period, where doses of daprodustat were administered and adjusted to maintain target Hgb levels within the range of 10.0 to 11.0 grams per deciliter (g/dL). Participants received acute challenge 2 (AC2) on Day 57 with the same treatment dose administered in acute challenge 1. All participants were followed up for 14 days after acute challenge 2.
Measure Participants	45
Day 1, Predose, n=45	0.000 (0.000)
Day 1, 0.5 hours, n=43	197.118 (329.0251)
Day 1, 1 hour, n=43	265.828 (340.7690)
Day 1, 2 hours, n=43	156.103 (150.4148)
Day 1, 3 hours, n=43	114.485 (139.8114)
Day 1, 4 hours, n=44	105.375 (150.0982)
Day 1, 6 hours, n=44	71.995 (104.2462)
Day 1, 8 hours, n=43	50.069 (91.2574)
Day 1, 12 hours, n=41	14.165 (30.2719)
Day 1, 16 hours, n=43	5.350 (11.0233)
Day 1, 24 hours, n=43	2.899 (10.8052)
Day 57, Predose, n=31	8.657 (21.3825)
Day 57, 0.5 hours, n=31	175.616 (257.3578)
Day 57, 1 hour, n=31	260.817 (307.2242)
Day 57, 2 hours, n=30	245.277 (251.2676)
Day 57, 3 hours, n=31	142.366 (154.9041)
Day 57, 4 hours, n=32	82.696 (104.8654)
Day 57, 6 hours, n=31	43.751 (55.8532)
Day 57, 8 hours, n=31	16.484 (27.2733)
Day 57, 12 hours, n=30	8.661 (16.8915)
Day 57, 16 hours, n=30	7.279 (21.2784)
Day 57, 24 hours, n=31	1.371 (2.0177)

13. Secondary Outcome

Title	Plasma Concentrations of Metabolite GSK2391220
Description	Blood samples were collected at indicated time points for the concentrations of metabolite GSK2391220.
Time Frame	Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 12, 16 and 24 hours on Days 1 and 57

Outcome Measure Data

Analysis Population Description

Pharmacokinetic Population. Only those participants with data available at specified time points has been presented (represented as n=X in the category titles).

Arm/Group Title	Daprodustat
Arm/Group Description	Participants were randomized to receive a single oral dose of Daprodustat 24 milligrams (mg) during 24-hour acute challenge 1 (AC1) on Day 1. Participants discontinued their current erythropoiesis stimulating agent (ESA) therapy and were washed out of their ESAs for 2 weeks prior to acute challenge 1. After completion of acute challenge 1, participants entered in 8-week hemoglobin (Hgb) maintenance period, where doses of daprodustat were administered and adjusted to maintain target Hgb levels within the range of 10.0 to 11.0 grams per deciliter (g/dL). Participants received acute challenge 2 (AC2) on Day 57 with the same treatment dose administered in acute challenge 1. All participants were followed up for 14 days after acute challenge 2.
Measure Participants	45
Day 1, Predose, n=45	0.000 (0.000)
Day 1, 0.5 hours, n=43	9.847 (NA)
Day 1, 1 hour, n=43	14.361 (21.6405)
Day 1, 2 hours, n=43	30.036 (29.6152)
Day 1, 3 hours, n=44	32.359 (28.6734)
Day 1, 4 hours, n=43	32.892 (27.2772)
Day 1, 6 hours, n=43	33.105 (20.9136)
Day 1, 8 hours, n=42	32.267 (16.3824)
Day 1, 12 hours, n=40	23.921 (15.1007)
Day 1, 16 hours, n=42	19.771 (13.5013)
Day 1, 24 hours, n=42	12.693 (10.1135)
Day 57, Predose, n=31	3.019 (4.2327)
Day 57, 0.5 hours, n=31	10.043 (12.5832)
Day 57, 1 hour, n=31	12.410 (13.3576)
Day 57, 2 hours, n=30	23.433 (21.4154)
Day 57, 3 hours, n=31	32.861 (26.3829)
Day 57, 4 hours, n=32	38.443 (27.9354)
Day 57, 6 hours, n=31	41.432 (24.2976)
Day 57, 8 hours, n=31	33.689 (20.3669)
Day 57, 12 hours, n=31	25.771 (17.8554)
Day 57, 16 hours, n=31	21.481 (15.6404)
Day 57, 24 hours, n=32	14.836 (11.2824)

14. Secondary Outcome

Title	Plasma Concentrations of Metabolite GSK2506104
Description	Blood samples were collected at indicated time points for the concentrations of metabolite GSK2506104.
Time Frame	Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 12, 16 and 24 hours on Days 1 and 57

Outcome Measure Data

Analysis Population Description

Pharmacokinetic Population. Only those participants with data available at specified time points has been presented (represented as n=X in the category titles).

Arm/Group Title	Daprodustat
Arm/Group Description	Participants were randomized to receive a single oral dose of Daprodustat 24 milligrams (mg) during 24-hour acute challenge 1 (AC1) on Day 1. Participants discontinued their current erythropoiesis stimulating agent (ESA) therapy and were washed out of their ESAs for 2 weeks prior to acute challenge 1. After completion of acute challenge 1, participants entered in 8-week hemoglobin (Hgb) maintenance period, where doses of daprodustat were administered and adjusted to maintain target Hgb levels within the range of 10.0 to 11.0 grams per deciliter (g/dL). Participants received acute challenge 2 (AC2) on Day 57 with the same treatment dose administered in acute challenge 1. All participants were followed up for 14 days after acute challenge 2.
Measure Participants	45
Day 1, Predose, n=45	0.000 (0.000)
Day 1, 0.5 hours, n=43	9.337 (NA)
Day 1, 1 hour, n=43	13.263 (20.5510)
Day 1, 2 hours, n=43	28.986 (28.4324)
Day 1, 3 hours, n=44	32.623 (29.1622)
Day 1, 4 hours, n=43	34.266 (27.5021)
Day 1, 6 hours, n=43	37.250 (21.9404)
Day 1, 8 hours, n=42	39.463 (17.2013)
Day 1, 12 hours, n=40	33.822 (16.6962)
Day 1, 16 hours, n=42	31.224 (16.3048)
Day 1, 24 hours, n=42	24.268 (14.2298)
Day 57, Predose, n=31	4.133 (4.5315)
Day 57, 0.5 hours, n=31	10.759 (11.6369)
Day 57, 1 hour, n=31	12.902 (12.5068)
Day 57, 2 hours, n=30	23.391 (20.1627)
Day 57, 3 hours, n=31	33.561 (26.4516)
Day 57, 4 hours, n=32	41.089 (28.8815)
Day 57, 6 hours, n=31	47.511 (25.5686)
Day 57, 8 hours, n=31	43.646 (22.0075)
Day 57, 12 hours, n=31	39.685 (23.4732)
Day 57, 16 hours, n=31	36.234 (22.1830)
Day 57, 24 hours, n=32	27.808 (14.8739)

15. Secondary Outcome

Title	Plasma Concentrations of Metabolite GSK2487818
Description	Blood samples were collected at indicated time points for the concentrations of metabolite GSK2487818.
Time Frame	Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 12, 16 and 24 hours on Days 1 and 57

Outcome Measure Data

Analysis Population Description

Pharmacokinetic Population. Only those participants with data available at specified time points has been presented (represented as n=X in the category titles).

Arm/Group Title	Daprodustat
Arm/Group Description	Participants were randomized to receive a single oral dose of Daprodustat 24 milligrams (mg) during 24-hour acute challenge 1 (AC1) on Day 1. Participants discontinued their current erythropoiesis stimulating agent (ESA) therapy and were washed out of their ESAs for 2 weeks prior to acute challenge 1. After completion of acute challenge 1, participants entered in 8-week hemoglobin (Hgb) maintenance period, where doses of daprodustat were administered and adjusted to maintain target Hgb levels within the range of 10.0 to 11.0 grams per deciliter (g/dL). Participants received acute challenge 2 (AC2) on Day 57 with the same treatment dose administered in acute challenge 1. All participants were followed up for 14 days after acute challenge 2.
Measure Participants	45
Day 1, Predose, n=45	0.000 (0.000)
Day 1, 0.5 hours, n=43	8.624 (NA)
Day 1, 1 hour, n=43	13.181 (19.2280)
Day 1, 2 hours, n=43	25.204 (24.8233)
Day 1, 3 hours, n=44	23.632 (21.0661)
Day 1, 4 hours, n=43	20.726 (17.9713)
Day 1, 6 hours, n=43	15.509 (10.4545)
Day 1, 8 hours, n=42	11.654 (9.1747)
Day 1, 12 hours, n=39	5.673 (6.4670)
Day 1, 16 hours, n=43	3.298 (4.6779)
Day 1, 24 hours, n=43	1.379 (2.1969)
Day 57, Predose, n=31	1.503 (NA)
Day 57, 0.5 hours, n=31	7.760 (12.2768)
Day 57, 1 hour, n=31	10.507 (13.6474)
Day 57, 2 hours, n=30	20.254 (20.1125)
Day 57, 3 hours, n=30	25.092 (20.7688)
Day 57, 4 hours, n=32	24.865 (18.7941)
Day 57, 6 hours, n=31	21.749 (16.6572)
Day 57, 8 hours, n=31	11.419 (11.2821)
Day 57, 12 hours, n=31	5.537 (9.1160)
Day 57, 16 hours, n=30	3.613 (6.4974)
Day 57, 24 hours, n=31	1.693 (2.9455)

16. Secondary Outcome

Title	Plasma Concentrations of Metabolite GSK2506102
Description	Blood samples were collected at indicated time points for the concentrations of metabolite GSK25206102.
Time Frame	Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 12, 16 and 24 hours on Days 1 and 57

Outcome Measure Data

Analysis Population Description

Pharmacokinetic Population. Only those participants with data available at specified time points has been presented (represented as n=X in the category titles).

Arm/Group Title	Daprodustat
Arm/Group Description	Participants were randomized to receive a single oral dose of Daprodustat 24 milligrams (mg) during 24-hour acute challenge 1 (AC1) on Day 1. Participants discontinued their current erythropoiesis stimulating agent (ESA) therapy and were washed out of their ESAs for 2 weeks prior to acute challenge 1. After completion of acute challenge 1, participants entered in 8-week hemoglobin (Hgb) maintenance period, where doses of daprodustat were administered and adjusted to maintain target Hgb levels within the range of 10.0 to 11.0 grams per deciliter (g/dL). Participants received acute challenge 2 (AC2) on Day 57 with the same treatment dose administered in acute challenge 1. All participants were followed up for 14 days after acute challenge 2.
Measure Participants	45
Day 1, Predose, n=45	0.000 (0.000)
Day 1, 0.5 hours, n=43	1.862 (NA)
Day 1, 1 hour, n=44	2.575 (NA)
Day 1, 2 hours, n=43	5.999 (5.9281)
Day 1, 3 hours, n=44	7.047 (6.3772)
Day 1, 4 hours, n=43	7.554 (6.0767)
Day 1, 6 hours, n=43	8.564 (5.0888)
Day 1, 8 hours, n=42	9.379 (3.9554)
Day 1, 12 hours, n=40	8.658 (3.6930)
Day 1, 16 hours, n=42	8.225 (3.7400)
Day 1, 24 hours, n=42	7.024 (3.5347)
Day 57, Predose, n=31	1.126 (1.0181)
Day 57, 0.5 hours, n=30	2.472 (2.2298)
Day 57, 1 hour, n=31	2.890 (2.4847)
Day 57, 2 hours, n=30	5.082 (4.1937)
Day 57, 3 hours, n=31	7.688 (5.7677)
Day 57, 4 hours, n=32	9.474 (6.3929)
Day 57, 6 hours, n=30	11.507 (5.3600)
Day 57, 8 hours, n=31	10.945 (4.9425)
Day 57, 12 hours, n=31	10.286 (5.1703)
Day 57, 16 hours, n=31	9.735 (5.1306)
Day 57, 24 hours, n=32	8.449 (3.7371)

17. Secondary Outcome

Title	Plasma Concentrations of Metabolite GSK2531398
Description	Blood samples were collected at indicated time points for the concentrations of metabolite GSK2531398.
Time Frame	Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 12, 16 and 24 hours on Days 1 and 57

Outcome Measure Data

Analysis Population Description

Pharmacokinetic Population. Only those participants with data available at specified time points has been presented (represented as n=X in the category titles).

Arm/Group Title	Daprodustat
Arm/Group Description	Participants were randomized to receive a single oral dose of Daprodustat 24 milligrams (mg) during 24-hour acute challenge 1 (AC1) on Day 1. Participants discontinued their current erythropoiesis stimulating agent (ESA) therapy and were washed out of their ESAs for 2 weeks prior to acute challenge 1. After completion of acute challenge 1, participants entered in 8-week hemoglobin (Hgb) maintenance period, where doses of daprodustat were administered and adjusted to maintain target Hgb levels within the range of 10.0 to 11.0 grams per deciliter (g/dL). Participants received acute challenge 2 (AC2) on Day 57 with the same treatment dose administered in acute challenge 1. All participants were followed up for 14 days after acute challenge 2.
Measure Participants	45
Day 1, Predose, n=45	0.000 (0.000)
Day 1, 0.5 hours, n=43	4.409 (NA)
Day 1, 1 hour, n=44	6.139 (NA)
Day 1, 2 hours, n=43	13.779 (13.5109)
Day 1, 3 hours, n=44	15.087 (13.4427)
Day 1, 4 hours, n=43	14.881 (12.5678)
Day 1, 6 hours, n=43	14.907 (9.6957)
Day 1, 8 hours, n=42	13.930 (7.4098)
Day 1, 12 hours, n=40	9.784 (6.6328)
Day 1, 16 hours, n=42	7.751 (5.9158)
Day 1, 24 hours, n=42	4.687 (4.1099)
Day 57, Predose, n=31	1.246 (1.9695)
Day 57, 0.5 hours, n=30	4.482 (5.7104)
Day 57, 1 hour, n=31	5.406 (5.8321)
Day 57, 2 hours, n=30	10.580 (10.1185)
Day 57, 3 hours, n=31	15.191 (12.9991)
Day 57, 4 hours, n=32	17.904 (13.4024)
Day 57, 6 hours, n=30	19.827 (11.4600)
Day 57, 8 hours, n=31	15.038 (11.0475)
Day 57, 12 hours, n=31	10.292 (8.2309)
Day 57, 16 hours, n=31	8.348 (7.1590)
Day 57, 24 hours, n=32	5.334 (4.8807)

18. Secondary Outcome

Title	Plasma Concentrations of Metabolite GSK2531401
Description	Blood samples were collected at indicated time points for the concentrations of metabolite GSK2531401.
Time Frame	Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 12, 16 and 24 hours on Days 1 and 57

Outcome Measure Data

Analysis Population Description

Pharmacokinetic Population. Only those participants with data available at specified time points has been presented (represented as n=X in the category titles).

Arm/Group Title	Daprodustat
Arm/Group Description	Participants were randomized to receive a single oral dose of Daprodustat 24 milligrams (mg) during 24-hour acute challenge 1 (AC1) on Day 1. Participants discontinued their current erythropoiesis stimulating agent (ESA) therapy and were washed out of their ESAs for 2 weeks prior to acute challenge 1. After completion of acute challenge 1, participants entered in 8-week hemoglobin (Hgb) maintenance period, where doses of daprodustat were administered and adjusted to maintain target Hgb levels within the range of 10.0 to 11.0 grams per deciliter (g/dL). Participants received acute challenge 2 (AC2) on Day 57 with the same treatment dose administered in acute challenge 1. All participants were followed up for 14 days after acute challenge 2.
Measure Participants	45
Day 1, Predose, n=45	0.000 (0.000)
Day 1, 0.5 hours, n=43	2.927 (NA)
Day 1, 1 hour, n=44	4.134 (NA)
Day 1, 2 hours, n=43	11.013 (11.9279)
Day 1, 3 hours, n=44	13.752 (14.0238)
Day 1, 4 hours, n=43	15.497 (14.6142)
Day 1, 6 hours, n=43	18.302 (13.9244)
Day 1, 8 hours, n=42	21.139 (13.2221)
Day 1, 12 hours, n=40	20.174 (11.6828)
Day 1, 16 hours, n=42	20.127 (12.1374)
Day 1, 24 hours, n=42	18.143 (11.6065)
Day 57, Predose, n=31	2.448 (2.0199)
Day 57, 0.5 hours, n=31	4.486 (3.9244)
Day 57, 1 hour, n=31	5.480 (5.0425)
Day 57, 2 hours, n=30	9.015 (8.4201)
Day 57, 3 hours, n=31	14.027 (12.7046)
Day 57, 4 hours, n=32	17.722 (14.2802)
Day 57, 6 hours, n=30	24.285 (15.7868)
Day 57, 8 hours, n=31	25.557 (16.2248)
Day 57, 12 hours, n=31	25.288 (15.7597)
Day 57, 16 hours, n=31	24.881 (15.3688)
Day 57, 24 hours, n=32	21.914 (12.9806)

19. Secondary Outcome

Title	Maximum Plasma Concentration (Cmax) of Daprodustat, GSK2391220, GSK2487818, GSK2506102, GSK2506104, GSK2531398 and GSK2531401
Description	Blood samples were collected at indicated time points for pharmacokinetic analysis of daprodustat and its metabolites GSK2391220, GSK2487818, GSK2506102, GSK2506104, GSK2531398 and GSK2531401. PK parameters were analyzed using standard non-compartmental analysis.
Time Frame	Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 12, 16 and 24 hours on Days 1 and 57

Outcome Measure Data

Analysis Population Description

Pharmacokinetic Population. Only those participants with data available at specified time points has been presented (represented as n=X in the category titles).

Arm/Group Title	Daprodustat
Arm/Group Description	Participants were randomized to receive a single oral dose of Daprodustat 24 milligrams (mg) during 24-hour acute challenge 1 (AC1) on Day 1. Participants discontinued their current erythropoiesis stimulating agent (ESA) therapy and were washed out of their ESAs for 2 weeks prior to acute challenge 1. After completion of acute challenge 1, participants entered in 8-week hemoglobin (Hgb) maintenance period, where doses of daprodustat were administered and adjusted to maintain target Hgb levels within the range of 10.0 to 11.0 grams per deciliter (g/dL). Participants received acute challenge 2 (AC2) on Day 57 with the same treatment dose administered in acute challenge 1. All participants were followed up for 14 days after acute challenge 2.
Measure Participants	44
Daprodustat, Day 1, n=44	218.841 (187.869)
Daprodustat, Day 57, n=32	163.795 (330.249)
GSK2391220, Day 1, n=44	39.506 (66.816)
GSK2391220, Day 57, n=32	44.703 (57.029)
GSK2487818, Day 1, n=44	26.678 (79.992)
GSK2487818, Day 57, n=32	24.846 (117.570)
GSK2506102, Day 1, n=44	9.933 (62.188)
GSK2506102, Day 57, n=32	12.114 (46.563)
GSK2506104, Day 1, n=44	43.169 (61.558)
GSK2506104, Day 57, n=32	51.643 (48.087)
GSK2531398, Day 1, n=44	18.454 (67.277)
GSK2531398, Day 57, n=32	20.362 (67.040)
GSK2531401, Day 1, n=44	18.335 (96.906)
GSK2531401, Day 57, n=32	23.337 (75.801)

20. Secondary Outcome

Title	Time of Occurrence of Cmax (Tmax) of Daprodustat, GSK2391220, GSK2487818, GSK2506102, GSK2506104, GSK2531398 and GSK2531401
Description	Blood samples were collected at indicated time points for pharmacokinetic analysis of daprodustat and its metabolites GSK2391220, GSK2487818, GSK2506102, GSK2506104, GSK2531398 and GSK2531401. PK parameters were analyzed using standard non-compartmental analysis.
Time Frame	Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 12, 16 and 24 hours on Days 1 and 57

Outcome Measure Data

Analysis Population Description

Pharmacokinetic Population. Only those participants with data available at specified time points has been presented (represented as n=X in the category titles).

Arm/Group Title	Daprodustat
Arm/Group Description	Participants were randomized to receive a single oral dose of Daprodustat 24 milligrams (mg) during 24-hour acute challenge 1 (AC1) on Day 1. Participants discontinued their current erythropoiesis stimulating agent (ESA) therapy and were washed out of their ESAs for 2 weeks prior to acute challenge 1. After completion of acute challenge 1, participants entered in 8-week hemoglobin (Hgb) maintenance period, where doses of daprodustat were administered and adjusted to maintain target Hgb levels within the range of 10.0 to 11.0 grams per deciliter (g/dL). Participants received acute challenge 2 (AC2) on Day 57 with the same treatment dose administered in acute challenge 1. All participants were followed up for 14 days after acute challenge 2.
Measure Participants	44
Daprodustat, Day 1, n=44	2.000
Daprodustat, Day 57, n=32	2.000
GSK2391220, Day 1, n=44	4.160
GSK2391220, Day 57, n=32	4.000
GSK2487818, Day 1, n=44	3.090
GSK2487818, Day 57, n=32	4.000
GSK2506102, Day 1, n=44	6.000
GSK2506102, Day 57, n=32	6.000
GSK2506104, Day 1, n=44	6.000
GSK2506104, Day 57, n=32	5.990
GSK2531398, Day 1, n=44	4.160
GSK2531398, Day 57, n=32	4.000
GSK2531401, Day 1, n=44	8.015
GSK2531401, Day 57, n=32	8.000

21. Secondary Outcome

Title	Terminal Phase Half-life (t1/2) of Daprodustat, GSK2391220, GSK2487818, GSK2506102, GSK2506104, GSK2531398 and GSK2531401
Description	Blood samples were collected at indicated time points for pharmacokinetic analysis of daprodustat and its metabolites GSK2391220, GSK2487818, GSK2506102, GSK2506104, GSK2531398 and GSK2531401. PK parameters were analyzed using standard non-compartmental analysis.
Time Frame	Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 12, 16 and 24 hours on Days 1 and 57

Outcome Measure Data

Analysis Population Description

Pharmacokinetic Population. Only those participants with data available at specified time points has been presented (represented as n=X in the category titles).

Arm/Group Title	Daprodustat
Arm/Group Description	Participants were randomized to receive a single oral dose of Daprodustat 24 milligrams (mg) during 24-hour acute challenge 1 (AC1) on Day 1. Participants discontinued their current erythropoiesis stimulating agent (ESA) therapy and were washed out of their ESAs for 2 weeks prior to acute challenge 1. After completion of acute challenge 1, participants entered in 8-week hemoglobin (Hgb) maintenance period, where doses of daprodustat were administered and adjusted to maintain target Hgb levels within the range of 10.0 to 11.0 grams per deciliter (g/dL). Participants received acute challenge 2 (AC2) on Day 57 with the same treatment dose administered in acute challenge 1. All participants were followed up for 14 days after acute challenge 2.
Measure Participants	44
Daprodustat, Day 1, n=22	3.031 (40.320)
Daprodustat, Day 57, n=10	3.635 (26.884)
GSK2391220, Day 1, n=9	6.820 (22.096)
GSK2391220, Day 57, n=4	7.447 (7.539)
GSK2487818, Day 1, n=20	3.388 (22.165)
GSK2487818, Day 57, n=13	3.524 (32.634)
GSK2506102, Day 1, n=1	8.530 (NA)
GSK2506102, Day 57, n=32	NA (NA)
GSK2506104, Day 1, n=1	6.150 (NA)
GSK2506104, Day 57, n=32	NA (NA)
GSK2531398, Day 1, n=11	5.582 (22.955)
GSK2531398, Day 57, n=9	6.182 (14.307)
GSK2531401, Day 1, n=44	NA (NA)
GSK2531401, Day 57, n=32	NA (NA)

22. Secondary Outcome

Title	Area Under Concentration-time Curve From Time Zero to 24 Hours (AUC[0-24]) of Daprodustat, GSK2391220, GSK2487818, GSK2506102, GSK2506104, GSK2531398 and GSK2531401
Description	Blood samples were collected at indicated time points for pharmacokinetic analysis of daprodustat and its metabolites GSK2391220, GSK2487818, GSK2506102, GSK2506104, GSK2531398 and GSK2531401. PK parameters were analyzed using standard non-compartmental analysis.
Time Frame	Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 12, 16 and 24 hours on Days 1 and 57

Outcome Measure Data

Analysis Population Description

Pharmacokinetic Population. Only those participants with data available at specified time points has been presented (represented as n=X in the category titles).

Arm/Group Title	Daprodustat
Arm/Group Description	Participants were randomized to receive a single oral dose of Daprodustat 24 milligrams (mg) during 24-hour acute challenge 1 (AC1) on Day 1. Participants discontinued their current erythropoiesis stimulating agent (ESA) therapy and were washed out of their ESAs for 2 weeks prior to acute challenge 1. After completion of acute challenge 1, participants entered in 8-week hemoglobin (Hgb) maintenance period, where doses of daprodustat were administered and adjusted to maintain target Hgb levels within the range of 10.0 to 11.0 grams per deciliter (g/dL). Participants received acute challenge 2 (AC2) on Day 57 with the same treatment dose administered in acute challenge 1. All participants were followed up for 14 days after acute challenge 2.
Measure Participants	42
Daprodustat, Day 1, n=42	767.95 (125.63)
Daprodustat, Day 57, n=28	616.12 (168.05)
GSK2391220, Day 1, n=42	483.12 (60.42)
GSK2391220, Day 57, n=31	516.59 (61.78)
GSK2487818, Day 1, n=41	177.39 (66.83)
GSK2487818, Day 57, n=28	171.09 (93.41)
GSK2506102, Day 1, n=42	166.89 (52.93)
GSK2506102, Day 57, n=31	199.85 (44.33)
GSK2506104, Day 1, n=42	662.23 (54.48)
GSK2506104, Day 57, n=31	756.39 (50.29)
GSK2531398, Day 1, n=42	204.02 (59.48)
GSK2531398, Day 57, n=31	212.04 (66.63)
GSK2531401, Day 1, n=42	334.86 (93.49)
GSK2531401, Day 57, n=31	430.10 (73.53)

23. Other Pre-specified Outcome

Title	Number of Participants With Any Serious Adverse Events (SAEs)
Description	Any untoward event resulting in death, life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, congenital anomaly or birth defect or any other situation according to medical or scientific judgment was categorized as SAE.
Time Frame	Up to Week 10

Outcome Measure Data

Analysis Population Description

Safety Population comprises of all randomized participants who received at least one dose of study treatment.

Arm/Group Title	Daprodustat	Recombinant Human Erythropoietin
Arm/Group Description	Participants were randomized to receive a single oral dose of Daprodustat 24 milligrams (mg) during 24-hour acute challenge 1 (AC1) on Day 1. Participants discontinued their current erythropoiesis stimulating agent (ESA) therapy and were washed out of their ESAs for 2 weeks prior to acute challenge 1. After completion of acute challenge 1, participants entered in 8-week hemoglobin (Hgb) maintenance period, where doses of daprodustat were administered and adjusted to maintain target Hgb levels within the range of 10.0 to 11.0 grams per deciliter (g/dL). Participants received acute challenge 2 (AC2) on Day 57 with the same treatment dose administered in acute challenge 1. All participants were followed up for 14 days after acute challenge 2.	Participants were randomized to receive a single intravenous (IV) dose of 100 units per kilogram (U/Kg) Epoetin alfa (Recombinant human erythropoietin) during 24-hour acute challenge 1 on Day 1. Participants discontinued their current ESA therapy and were washed out of their ESAs for 2 weeks prior to acute challenge 1. After completion of acute challenge 1, participants entered in 8-week Hgb maintenance period, where Epoetin alfa was administered according to local labelling and clinical practice guidelines to maintain target Hgb levels within the range of 10.0 to 11.0 g/dL. Participants received acute challenge 2 on Day 57 with the same treatment dose administered in acute challenge 1. All participants were followed up for 14 days after acute challenge 2.
Measure Participants	45	43
Count of Participants [Participants]	10 22.2%	5 11.6%

24. Other Pre-specified Outcome

Title	Number of Participants With Treatment Emergent Common (>=2%) Non-serious Adverse Events (Non-SAEs)
Description	An AE is any untoward medical occurrence that occurs in a participant or clinical investigation participant administered a pharmaceutical product, and which does not necessarily have to have a causal relationship with study treatment. Number of participants with treatment emergent common (>=2% non-SAEs in each arm) non-SAEs has been presented.
Time Frame	Up to Week 8

Outcome Measure Data

Analysis Population Description

Safety Population.

Arm/Group Title	Daprodustat	Recombinant Human Erythropoietin
Arm/Group Description	Participants were randomized to receive a single oral dose of Daprodustat 24 milligrams (mg) during 24-hour acute challenge 1 (AC1) on Day 1. Participants discontinued their current erythropoiesis stimulating agent (ESA) therapy and were washed out of their ESAs for 2 weeks prior to acute challenge 1. After completion of acute challenge 1, participants entered in 8-week hemoglobin (Hgb) maintenance period, where doses of daprodustat were administered and adjusted to maintain target Hgb levels within the range of 10.0 to 11.0 grams per deciliter (g/dL). Participants received acute challenge 2 (AC2) on Day 57 with the same treatment dose administered in acute challenge 1. All participants were followed up for 14 days after acute challenge 2.	Participants were randomized to receive a single intravenous (IV) dose of 100 units per kilogram (U/Kg) Epoetin alfa (Recombinant human erythropoietin) during 24-hour acute challenge 1 on Day 1. Participants discontinued their current ESA therapy and were washed out of their ESAs for 2 weeks prior to acute challenge 1. After completion of acute challenge 1, participants entered in 8-week Hgb maintenance period, where Epoetin alfa was administered according to local labelling and clinical practice guidelines to maintain target Hgb levels within the range of 10.0 to 11.0 g/dL. Participants received acute challenge 2 on Day 57 with the same treatment dose administered in acute challenge 1. All participants were followed up for 14 days after acute challenge 2.
Measure Participants	45	43
Count of Participants [Participants]	10 22.2%	4 9.3%

25. Other Pre-specified Outcome

Title	Number of Participants Who Discontinued the Study Treatment
Description	Number of participants who discontinued the study treatment due to any reason are presented. The reasons for discontinuation included adverse events, protocol specified withdrawal criteria met, physician decision and withdrawal by participant.
Time Frame	Up to Week 10

Outcome Measure Data

Analysis Population Description

ITT Population.

Arm/Group Title	Daprodustat	Recombinant Human Erythropoietin
Arm/Group Description	Participants were randomized to receive a single oral dose of Daprodustat 24 milligrams (mg) during 24-hour acute challenge 1 (AC1) on Day 1. Participants discontinued their current erythropoiesis stimulating agent (ESA) therapy and were washed out of their ESAs for 2 weeks prior to acute challenge 1. After completion of acute challenge 1, participants entered in 8-week hemoglobin (Hgb) maintenance period, where doses of daprodustat were administered and adjusted to maintain target Hgb levels within the range of 10.0 to 11.0 grams per deciliter (g/dL). Participants received acute challenge 2 (AC2) on Day 57 with the same treatment dose administered in acute challenge 1. All participants were followed up for 14 days after acute challenge 2.	Participants were randomized to receive a single intravenous (IV) dose of 100 units per kilogram (U/Kg) Epoetin alfa (Recombinant human erythropoietin) during 24-hour acute challenge 1 on Day 1. Participants discontinued their current ESA therapy and were washed out of their ESAs for 2 weeks prior to acute challenge 1. After completion of acute challenge 1, participants entered in 8-week Hgb maintenance period, where Epoetin alfa was administered according to local labelling and clinical practice guidelines to maintain target Hgb levels within the range of 10.0 to 11.0 g/dL. Participants received acute challenge 2 on Day 57 with the same treatment dose administered in acute challenge 1. All participants were followed up for 14 days after acute challenge 2.
Measure Participants	45	43
Adverse event	2 4.4%	2 4.7%
Protocol-specified withdrawal criteria met	7 15.6%	4 9.3%
Physician decision	1 2.2%	1 2.3%
Withdrawal by participant	3 6.7%	0 0%

26. Other Pre-specified Outcome

Title	Absolute Values for Clinical Chemistry Parameters: Albumin and Protein
Description	Blood samples were collected for the analysis of clinical chemistry parameters including albumin and protein. Baseline value (Day1) is the latest non-missing pre-dose assessment.
Time Frame	Baseline (Day 1) and at Days 29, 57 and Week 10

Outcome Measure Data

Analysis Population Description

Safety Population. Only those participants with data available at specified time points has been presented (represented by n=X in the category titles).

Arm/Group Title	Daprodustat	Recombinant Human Erythropoietin
Arm/Group Description	Participants were randomized to receive a single oral dose of Daprodustat 24 milligrams (mg) during 24-hour acute challenge 1 (AC1) on Day 1. Participants discontinued their current erythropoiesis stimulating agent (ESA) therapy and were washed out of their ESAs for 2 weeks prior to acute challenge 1. After completion of acute challenge 1, participants entered in 8-week hemoglobin (Hgb) maintenance period, where doses of daprodustat were administered and adjusted to maintain target Hgb levels within the range of 10.0 to 11.0 grams per deciliter (g/dL). Participants received acute challenge 2 (AC2) on Day 57 with the same treatment dose administered in acute challenge 1. All participants were followed up for 14 days after acute challenge 2.	Participants were randomized to receive a single intravenous (IV) dose of 100 units per kilogram (U/Kg) Epoetin alfa (Recombinant human erythropoietin) during 24-hour acute challenge 1 on Day 1. Participants discontinued their current ESA therapy and were washed out of their ESAs for 2 weeks prior to acute challenge 1. After completion of acute challenge 1, participants entered in 8-week Hgb maintenance period, where Epoetin alfa was administered according to local labelling and clinical practice guidelines to maintain target Hgb levels within the range of 10.0 to 11.0 g/dL. Participants received acute challenge 2 on Day 57 with the same treatment dose administered in acute challenge 1. All participants were followed up for 14 days after acute challenge 2.
Measure Participants	45	43
Albumin, Baseline (Day1), n=45, 43	41.2 (3.42)	40.5 (4.21)
Albumin, Day 29, n=37, 40	39.1 (3.58)	38.3 (4.02)
Albumin, Day 57, n=31, 35	41.4 (4.35)	40.9 (4.83)
Albumin, Week 10, n=39, 38	38.7 (3.20)	38.0 (5.19)
Protein, Baseline (Day 1), n=45, 43	72.3 (7.27)	72.6 (8.30)
Protein, Day 29, n=37, 40	69.4 (5.67)	68.0 (7.92)
Protein, Day 57, n=31, 35	74.0 (7.51)	73.1 (8.59)
Protein, Week 10, n=39, 38	67.5 (5.67)	67.8 (7.79)

27. Other Pre-specified Outcome

Title	Absolute Values for Clinical Chemistry Parameters: Alkaline Phosphatase (ALP), Alanine Aminotransferase (ALT) and Aspartate Aminotransferase (AST)
Description	Blood samples were collected for the analysis of clinical chemistry parameters including ALP, ALT and AST. Baseline value (Day1) is the latest non-missing pre-dose assessment.
Time Frame	Baseline (Day 1) and at Days 29, 57 and Week 10

Outcome Measure Data

Analysis Population Description

Safety Population. Only those participants with data available at specified time points has been presented (represented by n=X in the category titles).

Arm/Group Title	Daprodustat	Recombinant Human Erythropoietin
Arm/Group Description	Participants were randomized to receive a single oral dose of Daprodustat 24 milligrams (mg) during 24-hour acute challenge 1 (AC1) on Day 1. Participants discontinued their current erythropoiesis stimulating agent (ESA) therapy and were washed out of their ESAs for 2 weeks prior to acute challenge 1. After completion of acute challenge 1, participants entered in 8-week hemoglobin (Hgb) maintenance period, where doses of daprodustat were administered and adjusted to maintain target Hgb levels within the range of 10.0 to 11.0 grams per deciliter (g/dL). Participants received acute challenge 2 (AC2) on Day 57 with the same treatment dose administered in acute challenge 1. All participants were followed up for 14 days after acute challenge 2.	Participants were randomized to receive a single intravenous (IV) dose of 100 units per kilogram (U/Kg) Epoetin alfa (Recombinant human erythropoietin) during 24-hour acute challenge 1 on Day 1. Participants discontinued their current ESA therapy and were washed out of their ESAs for 2 weeks prior to acute challenge 1. After completion of acute challenge 1, participants entered in 8-week Hgb maintenance period, where Epoetin alfa was administered according to local labelling and clinical practice guidelines to maintain target Hgb levels within the range of 10.0 to 11.0 g/dL. Participants received acute challenge 2 on Day 57 with the same treatment dose administered in acute challenge 1. All participants were followed up for 14 days after acute challenge 2.
Measure Participants	45	43
ALP, Baseline (Day1), n=45, 43	100.9 (51.78)	100.0 (40.47)
ALP, Day 29, n=37, 40	104.4 (49.97)	95.7 (37.28)
ALP, Day 57, n=31, 35	109.0 (48.09)	101.7 (37.81)
ALP, Week 10, n=42, 41	98.3 (54.64)	98.8 (40.03)
ALT, Baseline (Day 1), n=45, 43	13.8 (6.74)	15.0 (6.97)
ALT, Day 29, n=37, 40	10.4 (3.95)	12.0 (5.80)
ALT, Day 57, n=31, 35	11.0 (5.75)	12.9 (5.07)
ALT, Week 10, n=42, 41	10.6 (4.71)	12.3 (7.01)
AST, Baseline (Day 1), n=45, 43	16.8 (6.63)	17.0 (6.07)
AST, Day 29, n=37, 40	13.2 (4.76)	13.7 (5.68)
AST, Day 57, n=31, 35	14.9 (5.12)	15.2 (4.23)
AST, Week 10, n=42, 41	14.0 (5.18)	15.2 (10.86)

28. Other Pre-specified Outcome

Title	Absolute Values for Clinical Chemistry Parameters: Direct Bilirubin, Total Bilirubin and Indirect (Indrt) Bilirubin
Description	Blood samples were collected for the analysis of clinical chemistry parameters including direct bilirubin, total bilirubin and Indrt bilirubin. Baseline value (Day1) is the latest non-missing pre-dose assessment.
Time Frame	Baseline (Day 1) and at Days 29, 57 and Week 10

Outcome Measure Data

Analysis Population Description

Safety Population. Only those participants with data available at specified time points has been presented (represented by n=X in the category titles).

Arm/Group Title	Daprodustat	Recombinant Human Erythropoietin
Arm/Group Description	Participants were randomized to receive a single oral dose of Daprodustat 24 milligrams (mg) during 24-hour acute challenge 1 (AC1) on Day 1. Participants discontinued their current erythropoiesis stimulating agent (ESA) therapy and were washed out of their ESAs for 2 weeks prior to acute challenge 1. After completion of acute challenge 1, participants entered in 8-week hemoglobin (Hgb) maintenance period, where doses of daprodustat were administered and adjusted to maintain target Hgb levels within the range of 10.0 to 11.0 grams per deciliter (g/dL). Participants received acute challenge 2 (AC2) on Day 57 with the same treatment dose administered in acute challenge 1. All participants were followed up for 14 days after acute challenge 2.	Participants were randomized to receive a single intravenous (IV) dose of 100 units per kilogram (U/Kg) Epoetin alfa (Recombinant human erythropoietin) during 24-hour acute challenge 1 on Day 1. Participants discontinued their current ESA therapy and were washed out of their ESAs for 2 weeks prior to acute challenge 1. After completion of acute challenge 1, participants entered in 8-week Hgb maintenance period, where Epoetin alfa was administered according to local labelling and clinical practice guidelines to maintain target Hgb levels within the range of 10.0 to 11.0 g/dL. Participants received acute challenge 2 on Day 57 with the same treatment dose administered in acute challenge 1. All participants were followed up for 14 days after acute challenge 2.
Measure Participants	45	43
Direct bilirubin,Baseline(Day1),n=45,43	2.0 (1.24)	1.8 (1.17)
Direct bilirubin, Day 29, n=37, 39	1.9 (1.05)	1.7 (1.23)
Direct bilirubin, Day 57, n=31, 35	1.9 (1.21)	1.8 (1.35)
Direct bilirubin, Week 10, n=39, 38	1.8 (0.89)	1.7 (1.09)
Total bilirubin, Baseline (Day 1),n=45,43	8.6 (3.07)	7.7 (3.25)
Total bilirubin, Day 29, n=37, 39	7.1 (2.19)	7.2 (1.93)
Total bilirubin, Day 57, n=31, 35	9.0 (3.86)	8.6 (2.69)
Total bilirubin, Week 10, n=42, 41	7.7 (2.29)	7.0 (2.20)
Indrt bilirubin, Baseline (Day 1), n=45,43	6.6 (2.28)	6.0 (2.74)
Indrt bilirubin, Day 29, n=37, 39	5.2 (1.79)	5.4 (1.89)
Indrt bilirubin, Day 57, n=31, 35	7.0 (3.30)	6.9 (2.02)
Indrt bilirubin, Week 10, n=39, 38	5.9 (2.08)	5.3 (1.83)

29. Other Pre-specified Outcome

Title	Absolute Values for Clinical Chemistry Parameters: Calcium Corrected for Albumin (CCA), Glucose, Potassium, Phosphate and Sodium
Description	Blood samples were collected for the analysis of clinical chemistry parameters including CCA, glucose, potassium, phosphate and sodium. Baseline value (Day1) is the latest non-missing pre-dose assessment.
Time Frame	Baseline (Day 1) and at Days 29, 57 and Week 10

Outcome Measure Data

Analysis Population Description

Safety Population. Only those participants with data available at specified time points has been presented (represented by n=X in the category titles).

Arm/Group Title	Daprodustat	Recombinant Human Erythropoietin
Arm/Group Description	Participants were randomized to receive a single oral dose of Daprodustat 24 milligrams (mg) during 24-hour acute challenge 1 (AC1) on Day 1. Participants discontinued their current erythropoiesis stimulating agent (ESA) therapy and were washed out of their ESAs for 2 weeks prior to acute challenge 1. After completion of acute challenge 1, participants entered in 8-week hemoglobin (Hgb) maintenance period, where doses of daprodustat were administered and adjusted to maintain target Hgb levels within the range of 10.0 to 11.0 grams per deciliter (g/dL). Participants received acute challenge 2 (AC2) on Day 57 with the same treatment dose administered in acute challenge 1. All participants were followed up for 14 days after acute challenge 2.	Participants were randomized to receive a single intravenous (IV) dose of 100 units per kilogram (U/Kg) Epoetin alfa (Recombinant human erythropoietin) during 24-hour acute challenge 1 on Day 1. Participants discontinued their current ESA therapy and were washed out of their ESAs for 2 weeks prior to acute challenge 1. After completion of acute challenge 1, participants entered in 8-week Hgb maintenance period, where Epoetin alfa was administered according to local labelling and clinical practice guidelines to maintain target Hgb levels within the range of 10.0 to 11.0 g/dL. Participants received acute challenge 2 on Day 57 with the same treatment dose administered in acute challenge 1. All participants were followed up for 14 days after acute challenge 2.
Measure Participants	45	43
CCA, Baseline (Day 1),n=45,43	2.254 (0.1147)	2.266 (0.1341)
CCA, Day 29, n=37, 40	2.242 (0.1692)	2.242 (0.1479)
CCA, Day 57, n=31, 35	2.240 (0.1389)	2.265 (0.1086)
CCA, Week 10, n=39, 38	2.227 (0.1599)	2.232 (0.1644)
Glucose, Baseline (Day 1), n=45,43	7.40 (2.794)	7.67 (3.504)
Glucose, Day 29, n=37, 40	8.28 (4.234)	7.35 (2.362)
Glucose, Day 57, n=31, 35	7.27 (2.419)	7.01 (2.690)
Glucose, Week 10, n=39, 38	7.98 (3.020)	7.36 (2.948)
Potassium, Baseline (Day 1), n=45,43	3.99 (0.509)	4.06 (0.788)
Potassium, Day 29, n=37, 40	4.39 (0.769)	4.60 (0.765)
Potassium, Day 57, n=31, 35	3.81 (0.414)	4.01 (0.663)
Potassium, Week 10, n=39, 38	4.66 (0.639)	4.65 (0.693)
Phosphate, Baseline (Day 1), n=45,43	1.129 (0.4792)	1.242 (0.5758)
Phosphate, Day 29, n=37, 40	1.455 (0.5207)	1.761 (0.6297)
Phosphate, Day 57, n=31, 35	0.953 (0.2523)	1.274 (0.6260)
Phosphate, Week 10, n=39, 38	1.629 (0.560)	1.849 (0.5431)
Sodium, Baseline (Day 1), n=45,43	137.9 (2.64)	138.0 (2.58)
Sodium, Day 29, n=37, 40	137.8 (2.41)	138.4 (2.84)
Sodium, Day 57, n=31, 35	137.7 (2.22)	138.6 (2.74)
Sodium, Week 10, n=39, 38	137.9 (2.28)	138.6 (2.77)

30. Other Pre-specified Outcome

Title	Change From Baseline Values for Clinical Chemistry Parameters: Albumin and Protein
Description	Blood samples were collected for the analysis of clinical chemistry parameters including albumin and protein. Baseline value (Day1) is the latest non-missing pre-dose assessment. Change from Baseline is defined as Post-dose visit value minus Baseline value.
Time Frame	Baseline (Day 1) and at Days 29, 57 and Week 10

Outcome Measure Data

Analysis Population Description

Safety Population. Only those participants with data available at specified time points has been presented (represented by n=X in the category titles).

Arm/Group Title	Daprodustat	Recombinant Human Erythropoietin
Arm/Group Description	Participants were randomized to receive a single oral dose of Daprodustat 24 milligrams (mg) during 24-hour acute challenge 1 (AC1) on Day 1. Participants discontinued their current erythropoiesis stimulating agent (ESA) therapy and were washed out of their ESAs for 2 weeks prior to acute challenge 1. After completion of acute challenge 1, participants entered in 8-week hemoglobin (Hgb) maintenance period, where doses of daprodustat were administered and adjusted to maintain target Hgb levels within the range of 10.0 to 11.0 grams per deciliter (g/dL). Participants received acute challenge 2 (AC2) on Day 57 with the same treatment dose administered in acute challenge 1. All participants were followed up for 14 days after acute challenge 2.	Participants were randomized to receive a single intravenous (IV) dose of 100 units per kilogram (U/Kg) Epoetin alfa (Recombinant human erythropoietin) during 24-hour acute challenge 1 on Day 1. Participants discontinued their current ESA therapy and were washed out of their ESAs for 2 weeks prior to acute challenge 1. After completion of acute challenge 1, participants entered in 8-week Hgb maintenance period, where Epoetin alfa was administered according to local labelling and clinical practice guidelines to maintain target Hgb levels within the range of 10.0 to 11.0 g/dL. Participants received acute challenge 2 on Day 57 with the same treatment dose administered in acute challenge 1. All participants were followed up for 14 days after acute challenge 2.
Measure Participants	39	40
Albumin, Day 29, n=37, 40	-2.2 (3.67)	-2.4 (3.42)
Albumin, Day 57, n=31, 35	0.4 (3.60)	0.5 (3.16)
Albumin, Week 10, n=39, 38	-2.9 (3.10)	-2.4 (3.93)
Protein, Day 29, n=37, 40	-3.7 (6.41)	-4.7 (6.03)
Protein, Day 57, n=31, 35	1.2 (6.44)	0.7 (5.64)
Protein, Week 10, n=39, 38	-5.2 (5.90)	-4.9 (5.69)

31. Other Pre-specified Outcome

Title	Change From Baseline Values for Clinical Chemistry Parameters: ALP, ALT and AST
Description	Blood samples were collected for the analysis of clinical chemistry parameters including ALP, ALT and AST. Baseline value (Day1) is the latest non-missing pre-dose assessment. Change from Baseline is defined as Post-dose visit value minus Baseline value.
Time Frame	Baseline (Day 1) and at Days 29, 57 and Week 10

Outcome Measure Data

Analysis Population Description

Safety Population. Only those participants with data available at specified time points has been presented (represented by n=X in the category titles).

Arm/Group Title	Daprodustat	Recombinant Human Erythropoietin
Arm/Group Description	Participants were randomized to receive a single oral dose of Daprodustat 24 milligrams (mg) during 24-hour acute challenge 1 (AC1) on Day 1. Participants discontinued their current erythropoiesis stimulating agent (ESA) therapy and were washed out of their ESAs for 2 weeks prior to acute challenge 1. After completion of acute challenge 1, participants entered in 8-week hemoglobin (Hgb) maintenance period, where doses of daprodustat were administered and adjusted to maintain target Hgb levels within the range of 10.0 to 11.0 grams per deciliter (g/dL). Participants received acute challenge 2 (AC2) on Day 57 with the same treatment dose administered in acute challenge 1. All participants were followed up for 14 days after acute challenge 2.	Participants were randomized to receive a single intravenous (IV) dose of 100 units per kilogram (U/Kg) Epoetin alfa (Recombinant human erythropoietin) during 24-hour acute challenge 1 on Day 1. Participants discontinued their current ESA therapy and were washed out of their ESAs for 2 weeks prior to acute challenge 1. After completion of acute challenge 1, participants entered in 8-week Hgb maintenance period, where Epoetin alfa was administered according to local labelling and clinical practice guidelines to maintain target Hgb levels within the range of 10.0 to 11.0 g/dL. Participants received acute challenge 2 on Day 57 with the same treatment dose administered in acute challenge 1. All participants were followed up for 14 days after acute challenge 2.
Measure Participants	42	41
ALP, Day 29, n=37, 40	-3.4 (19.56)	-5.3 (27.57)
ALP, Day 57, n=31, 35	0.5 (23.21)	3.4 (17.93)
ALP, Week 10, n=42, 41	-4.5 (29.46)	-1.9 (25.70)
ALT, Day 29, n=37, 40	-3.2 (5.74)	-2.6 (6.36)
ALT, Day 57, n=31, 35	-3.1 (7.93)	-1.9 (5.93)
ALT, Week 10, n=42, 41	-3.3 (7.31)	-2.8 (4.96)
AST, Day 29, n=37, 40	-3.2 (4.90)	-3.0 (5.38)
AST, Day 57, n=31, 35	-2.1 (6.10)	-1.9 (4.60)
AST, Week 10, n=42, 41	-3.3 (6.10)	-2.0 (9.11)

32. Other Pre-specified Outcome

Title	Change From Baseline Values for Clinical Chemistry Parameters: Direct Bilirubin, Total Bilirubin and Indrt. Bilirubin
Description	Blood samples were collected for the analysis of clinical chemistry parameters including direct bilirubin, total bilirubin and indrt. bilirubin. Baseline value (Day1) is the latest non-missing pre-dose assessment. Change from Baseline is defined as Post-dose visit value minus Baseline value.
Time Frame	Baseline (Day 1) and at Days 29, 57 and Week 10

Outcome Measure Data

Analysis Population Description

Safety Population. Only those participants with data available at specified time points has been presented (represented by n=X in the category titles).

Arm/Group Title	Daprodustat	Recombinant Human Erythropoietin
Arm/Group Description	Participants were randomized to receive a single oral dose of Daprodustat 24 milligrams (mg) during 24-hour acute challenge 1 (AC1) on Day 1. Participants discontinued their current erythropoiesis stimulating agent (ESA) therapy and were washed out of their ESAs for 2 weeks prior to acute challenge 1. After completion of acute challenge 1, participants entered in 8-week hemoglobin (Hgb) maintenance period, where doses of daprodustat were administered and adjusted to maintain target Hgb levels within the range of 10.0 to 11.0 grams per deciliter (g/dL). Participants received acute challenge 2 (AC2) on Day 57 with the same treatment dose administered in acute challenge 1. All participants were followed up for 14 days after acute challenge 2.	Participants were randomized to receive a single intravenous (IV) dose of 100 units per kilogram (U/Kg) Epoetin alfa (Recombinant human erythropoietin) during 24-hour acute challenge 1 on Day 1. Participants discontinued their current ESA therapy and were washed out of their ESAs for 2 weeks prior to acute challenge 1. After completion of acute challenge 1, participants entered in 8-week Hgb maintenance period, where Epoetin alfa was administered according to local labelling and clinical practice guidelines to maintain target Hgb levels within the range of 10.0 to 11.0 g/dL. Participants received acute challenge 2 on Day 57 with the same treatment dose administered in acute challenge 1. All participants were followed up for 14 days after acute challenge 2.
Measure Participants	42	41
Direct bilirubin, Day 29, n=37, 39	-0.1 (1.05)	-0.1 (1.69)
Direct bilirubin, Day 57, n=31, 35	-0.1 (1.21)	-0.1 (1.37)
Direct bilirubin, Week 10, n=39, 38	-0.3 (1.14)	-0.1 (1.18)
Total bilirubin, Day 29, n=37, 39	-1.5 (2.19)	-0.8 (3.10)
Total bilirubin, Day 57, n=31, 35	0.6 (2.74)	0.7 (2.70)
Total bilirubin, Week 10, n=42, 41	-1.0 (2.62)	-0.8 (2.23)
Indrt bilirubin, Day 29, n=37, 39	-1.4 (2.06)	-0.7 (2.92)
Indrt bilirubin, Day 57, n=31, 35	0.6 (2.80)	0.9 (2.80)
Indrt bilirubin, Week 10, n=39, 38	-0.8 (2.28)	-0.5 (2.01)

33. Other Pre-specified Outcome

Title	Change From Baseline Values for Clinical Chemistry Parameters: CCA, Glucose, Potassium, Phosphate and Sodium
Description	Blood samples were collected for the analysis of clinical chemistry parameters including CCA, glucose, potassium, phosphate and sodium. Baseline value (Day1) is the latest non-missing pre-dose assessment. Change from Baseline is defined as Post-dose visit value minus Baseline value.
Time Frame	Baseline (Day 1) and at Days 29, 57 and Week 10

Outcome Measure Data

Analysis Population Description

Safety Population. Only those participants with data available at specified time points has been presented (represented by n=X in the category titles).

Arm/Group Title	Daprodustat	Recombinant Human Erythropoietin
Arm/Group Description	Participants were randomized to receive a single oral dose of Daprodustat 24 milligrams (mg) during 24-hour acute challenge 1 (AC1) on Day 1. Participants discontinued their current erythropoiesis stimulating agent (ESA) therapy and were washed out of their ESAs for 2 weeks prior to acute challenge 1. After completion of acute challenge 1, participants entered in 8-week hemoglobin (Hgb) maintenance period, where doses of daprodustat were administered and adjusted to maintain target Hgb levels within the range of 10.0 to 11.0 grams per deciliter (g/dL). Participants received acute challenge 2 (AC2) on Day 57 with the same treatment dose administered in acute challenge 1. All participants were followed up for 14 days after acute challenge 2.	Participants were randomized to receive a single intravenous (IV) dose of 100 units per kilogram (U/Kg) Epoetin alfa (Recombinant human erythropoietin) during 24-hour acute challenge 1 on Day 1. Participants discontinued their current ESA therapy and were washed out of their ESAs for 2 weeks prior to acute challenge 1. After completion of acute challenge 1, participants entered in 8-week Hgb maintenance period, where Epoetin alfa was administered according to local labelling and clinical practice guidelines to maintain target Hgb levels within the range of 10.0 to 11.0 g/dL. Participants received acute challenge 2 on Day 57 with the same treatment dose administered in acute challenge 1. All participants were followed up for 14 days after acute challenge 2.
Measure Participants	39	40
CCA, Day 29, n=37, 40	0.000 (0.1384)	-0.021 (0.1699)
CCA, Day 57, n=31, 35	0.004 (0.1344)	-0.000 (0.1450)
CCA, Week 10, n=39, 38	-0.010 (0.1693)	-0.033 (0.1284)
Glucose, Day 29, n=37, 40	0.75 (4.331)	-0.48 (3.771)
Glucose, Day 57, n=31, 35	-0.45 (2.403)	-0.83 (2.684)
Glucose, Week 10, n=39, 38	0.62 (3.001)	-0.18 (2.916)
Potassium, Day 29, n=37, 40	0.45 (0.790)	0.53 (0.863)
Potassium, Day 57, n=31, 35	-0.14 (0.512)	-0.04 (0.696)
Potassium, Week 10, n=39, 38	0.67 (0.694)	0.58 (0.746)
Phosphate, Day 29, n=37, 40	0.389 (0.6876)	0.513 (0.7270)
Phosphate, Day 57, n=31, 35	-0.123 (0.4624)	0.004 (0.5274)
Phosphate, Week 10, n=39, 38	0.505 (0.7016)	0.599 (0.6723)
Sodium, Day 29, n=37, 40	-0.1 (3.25)	0.3 (3.22)
Sodium, Day 57, n=31, 35	0.2 (2.47)	0.6 (2.71)
Sodium, Week 10, n=39, 38	-0.2 (2.41)	0.5 (2.53)

34. Other Pre-specified Outcome

Title	Absolute Values for Hematology Parameters: Basophils, Eosinophils, Lymphocytes, Monocytes, Neutrophils, Platelets and Leukocytes
Description	Blood samples were collected for the analysis of hematology parameters including basophils, eosinophils, lymphocytes, monocytes, neutrophils, platelets and leukocytes. Baseline value (Day1) is the latest non-missing pre-dose assessment.
Time Frame	Baseline (Day 1) and at Days 29, 57 and Week 10

Outcome Measure Data

Analysis Population Description

Safety Population. Only those participants with data available at specified time points has been presented (represented by n=X in the category titles).

Arm/Group Title	Daprodustat	Recombinant Human Erythropoietin
Arm/Group Description	Participants were randomized to receive a single oral dose of Daprodustat 24 milligrams (mg) during 24-hour acute challenge 1 (AC1) on Day 1. Participants discontinued their current erythropoiesis stimulating agent (ESA) therapy and were washed out of their ESAs for 2 weeks prior to acute challenge 1. After completion of acute challenge 1, participants entered in 8-week hemoglobin (Hgb) maintenance period, where doses of daprodustat were administered and adjusted to maintain target Hgb levels within the range of 10.0 to 11.0 grams per deciliter (g/dL). Participants received acute challenge 2 (AC2) on Day 57 with the same treatment dose administered in acute challenge 1. All participants were followed up for 14 days after acute challenge 2.	Participants were randomized to receive a single intravenous (IV) dose of 100 units per kilogram (U/Kg) Epoetin alfa (Recombinant human erythropoietin) during 24-hour acute challenge 1 on Day 1. Participants discontinued their current ESA therapy and were washed out of their ESAs for 2 weeks prior to acute challenge 1. After completion of acute challenge 1, participants entered in 8-week Hgb maintenance period, where Epoetin alfa was administered according to local labelling and clinical practice guidelines to maintain target Hgb levels within the range of 10.0 to 11.0 g/dL. Participants received acute challenge 2 on Day 57 with the same treatment dose administered in acute challenge 1. All participants were followed up for 14 days after acute challenge 2.
Measure Participants	45	42
Basophils, Baseline (Day 1), n=45, 41	0.050 (0.0295)	0.044 (0.0255)
Basophils, Day 29, n=37, 39	0.045 (0.0301)	0.054 (0.0312)
Basophils, Day 57, n=30, 35	0.049 (0.0349)	0.045 (0.0243)
Basophils, Week 10, n=39, 38	0.044 (0.0261)	0.054 (0.0284)
Eosinophils, Baseline (Day 1), n=45, 41	0.196 (0.1520)	0.229 (0.2324)
Eosinophils, Day 29, n=37, 39	0.238 (0.2301)	0.191 (0.1551)
Eosinophils, Day 57, n=30, 35	0.218 (0.1811)	0.160 (0.1505)
Eosinophils, Week 10, n=39, 38	0.231 (0.1918)	0.184 (0.1167)
Lymphocytes, Baseline (Day 1), n=45, 41	1.257 (0.3926)	1.307 (0.6305)
Lymphocytes, Day 29, n=37, 39	1.385 (0.5446)	1.436 (0.5798)
Lymphocytes, Day 57, n=30, 35	1.209 (0.5062)	1.225 (0.6698)
Lymphocytes, Week 10, n=39, 38	1.367 (0.5559)	1.408 (0.6788)
Monocytes, Baseline (Day 1), n=45, 41	0.398 (0.1471)	0.408 (0.1752)
Monocytes, Day 29, n=37, 39	0.442 (0.1664)	0.460 (0.1812)
Monocytes, Day 57, n=30, 35	0.432 (0.1621)	0.448 (0.2204)
Monocytes, Week 10, n=39, 38	0.469 (0.1640)	0.443 (0.1773)
Neutrophils, Baseline (Day 1), n=45, 41	4.091 (1.6571)	4.053 (1.4574)
Neutrophils, Day 29, n=37, 39	4.319 (1.3509)	4.242 (1.5623)
Neutrophils, Day 57, n=30, 35	4.381 (1.9926)	4.377 (1.6450)
Neutrophils, Week 10, n=39, 38	4.250 (1.8123)	4.369 (1.7463)
Platelets, Baseline (Day 1), n=45, 42	188.5 (67.64)	193.8 (70.03)
Platelets, Day 29, n=37, 38	195.2 (66.55)	222.1 (82.78)
Platelets, Day 57, n=30, 34	207.8 (95.04)	213.5 (67.33)
Platelets, Week 10, n=39, 38	209.3 (75.61)	229.5 (78.29)
Leukocytes, Baseline (Day 1), n=45, 41	6.00 (1.923)	6.04 (1.897)
Leukocytes, Day 29, n=37, 39	6.43 (1.678)	6.38 (2.145)
Leukocytes, Day 57, n=30, 35	6.29 (2.363)	6.25 (2.044)
Leukocytes, Week 10, n=39, 38	6.35 (2.178)	6.45 (2.297)

35. Other Pre-specified Outcome

Title	Absolute Values for Hematology Parameter: Hematocrit
Description	Blood samples were collected for the analysis of hematology parameter: hematocrit. Baseline value (Day1) is the latest non-missing pre-dose assessment.
Time Frame	Baseline (Day 1) and at Days 29, 57 and Week 10

Outcome Measure Data

Analysis Population Description

Safety Population. Only those participants with data available at specified time points has been presented (represented by n=X in the category titles).

Arm/Group Title	Daprodustat	Recombinant Human Erythropoietin
Arm/Group Description	Participants were randomized to receive a single oral dose of Daprodustat 24 milligrams (mg) during 24-hour acute challenge 1 (AC1) on Day 1. Participants discontinued their current erythropoiesis stimulating agent (ESA) therapy and were washed out of their ESAs for 2 weeks prior to acute challenge 1. After completion of acute challenge 1, participants entered in 8-week hemoglobin (Hgb) maintenance period, where doses of daprodustat were administered and adjusted to maintain target Hgb levels within the range of 10.0 to 11.0 grams per deciliter (g/dL). Participants received acute challenge 2 (AC2) on Day 57 with the same treatment dose administered in acute challenge 1. All participants were followed up for 14 days after acute challenge 2.	Participants were randomized to receive a single intravenous (IV) dose of 100 units per kilogram (U/Kg) Epoetin alfa (Recombinant human erythropoietin) during 24-hour acute challenge 1 on Day 1. Participants discontinued their current ESA therapy and were washed out of their ESAs for 2 weeks prior to acute challenge 1. After completion of acute challenge 1, participants entered in 8-week Hgb maintenance period, where Epoetin alfa was administered according to local labelling and clinical practice guidelines to maintain target Hgb levels within the range of 10.0 to 11.0 g/dL. Participants received acute challenge 2 on Day 57 with the same treatment dose administered in acute challenge 1. All participants were followed up for 14 days after acute challenge 2.
Measure Participants	45	42
Baseline (Day 1), n=45, 42	0.3133 (0.03111)	0.3242 (0.03046)
Day 29, n=37, 39	0.3066 (0.03195)	0.3113 (0.03307)
Day 57, n=31, 35	0.3196 (0.03046)	0.3397 (0.02476)
Week 10, n=39, 38	0.3050 (0.03743)	0.3209 (0.03375)

36. Other Pre-specified Outcome

Title	Absolute Values for Hematology Parameters: Erythrocytes and Reticulocytes
Description	Blood samples were collected for the analysis of hematology parameters: erythrocytes and reticulocytes. Baseline value (Day1) is the latest non-missing pre-dose assessment.
Time Frame	Baseline (Day 1) and at Days 29, 57 and Week 10

Outcome Measure Data

Analysis Population Description

Safety Population. Only those participants with data available at specified time points has been presented (represented by n=X in the category titles).

Arm/Group Title	Daprodustat	Recombinant Human Erythropoietin
Arm/Group Description	Participants were randomized to receive a single oral dose of Daprodustat 24 milligrams (mg) during 24-hour acute challenge 1 (AC1) on Day 1. Participants discontinued their current erythropoiesis stimulating agent (ESA) therapy and were washed out of their ESAs for 2 weeks prior to acute challenge 1. After completion of acute challenge 1, participants entered in 8-week hemoglobin (Hgb) maintenance period, where doses of daprodustat were administered and adjusted to maintain target Hgb levels within the range of 10.0 to 11.0 grams per deciliter (g/dL). Participants received acute challenge 2 (AC2) on Day 57 with the same treatment dose administered in acute challenge 1. All participants were followed up for 14 days after acute challenge 2.	Participants were randomized to receive a single intravenous (IV) dose of 100 units per kilogram (U/Kg) Epoetin alfa (Recombinant human erythropoietin) during 24-hour acute challenge 1 on Day 1. Participants discontinued their current ESA therapy and were washed out of their ESAs for 2 weeks prior to acute challenge 1. After completion of acute challenge 1, participants entered in 8-week Hgb maintenance period, where Epoetin alfa was administered according to local labelling and clinical practice guidelines to maintain target Hgb levels within the range of 10.0 to 11.0 g/dL. Participants received acute challenge 2 on Day 57 with the same treatment dose administered in acute challenge 1. All participants were followed up for 14 days after acute challenge 2.
Measure Participants	45	42
Erythrocytes, Baseline (Day 1), n=45, 42	3.31 (0.378)	3.45 (0.388)
Erythrocytes, Day 29, n=37, 39	3.20 (0.361)	3.27 (0.499)
Erythrocytes, Day 57, n=31, 35	3.34 (0.393)	3.53 (0.357)
Erythrocytes, Week 10, n=39, 38	3.13 (0.388)	3.38 (0.470)
Reticulocytes, Baseline (Day 1), n=45, 42	0.0302 (0.01536)	0.0401 (0.02614)
Reticulocytes, Day 29, n=37, 39	0.0486 (0.01676)	0.0733 (0.03493)
Reticulocytes, Day 57, n=31, 35	0.0489 (0.01681)	0.0627 (0.03344)
Reticulocytes, Week 10, n=39, 38	0.0613 (0.03932)	0.0566 (0.03060)

37. Other Pre-specified Outcome

Title	Absolute Values for Hematology Parameters: Hemoglobin and Erythrocyte Mean Corpusclar Hemoglobin Concentration ( Ery. MCHC)
Description	Blood samples were collected for the analysis of hematology parameters: hemoglobin and ery.MCHC. Baseline value (Day1) is the latest non-missing pre-dose assessment.
Time Frame	Baseline (Day 1) and at Days 29, 57 and Week 10

Outcome Measure Data

Analysis Population Description

Safety Population. Only those participants with data available at specified time points has been presented (represented by n=X in the category titles).

Arm/Group Title	Daprodustat	Recombinant Human Erythropoietin
Arm/Group Description	Participants were randomized to receive a single oral dose of Daprodustat 24 milligrams (mg) during 24-hour acute challenge 1 (AC1) on Day 1. Participants discontinued their current erythropoiesis stimulating agent (ESA) therapy and were washed out of their ESAs for 2 weeks prior to acute challenge 1. After completion of acute challenge 1, participants entered in 8-week hemoglobin (Hgb) maintenance period, where doses of daprodustat were administered and adjusted to maintain target Hgb levels within the range of 10.0 to 11.0 grams per deciliter (g/dL). Participants received acute challenge 2 (AC2) on Day 57 with the same treatment dose administered in acute challenge 1. All participants were followed up for 14 days after acute challenge 2.	Participants were randomized to receive a single intravenous (IV) dose of 100 units per kilogram (U/Kg) Epoetin alfa (Recombinant human erythropoietin) during 24-hour acute challenge 1 on Day 1. Participants discontinued their current ESA therapy and were washed out of their ESAs for 2 weeks prior to acute challenge 1. After completion of acute challenge 1, participants entered in 8-week Hgb maintenance period, where Epoetin alfa was administered according to local labelling and clinical practice guidelines to maintain target Hgb levels within the range of 10.0 to 11.0 g/dL. Participants received acute challenge 2 on Day 57 with the same treatment dose administered in acute challenge 1. All participants were followed up for 14 days after acute challenge 2.
Measure Participants	45	42
Hemoglobin, Baseline (Day 1), n=45, 42	102.2 (9.15)	104.5 (8.83)
Hemoglobin, Day 29, n=37, 39	100.2 (10.01)	99.7 (9.63)
Hemoglobin, Day 57, n=31, 35	105.2 (9.61)	107.9 (6.01)
Hemoglobin, Week 10, n=39, 38	99.6 (12.44)	102.9 (10.54)
ery.MCHC, Baseline (Day 1), n=45, 42	326.7 (9.01)	322.6 (8.41)
ery.MCHC, Day 29, n=37, 39	327.1 (6.57)	320.8 (11.50)
ery.MCHC, Day 57, n=31, 35	329.0 (6.62)	318.3 (15.46)
ery.MCHC, Week 10, n=39, 38	326.7 (9.26)	320.6 (9.17)

38. Other Pre-specified Outcome

Title	Absolute Values for Hematology Parameter: Ery. Mean Corpuscular Hemoglobin (MCH) and Reticulocyte Corpuscular Hemoglobin Content (CHr)
Description	Blood samples were collected for the analysis of hematology parameter: ery.MCH and CHr. Baseline value (Day1) is the latest non-missing pre-dose assessment.
Time Frame	Baseline (Day 1) and at Days 29, 57 and Week 10

Outcome Measure Data

Analysis Population Description

Safety Population. Only those participants with data available at specified time points has been presented (represented by n=X in the category titles).

Arm/Group Title	Daprodustat	Recombinant Human Erythropoietin
Arm/Group Description	Participants were randomized to receive a single oral dose of Daprodustat 24 milligrams (mg) during 24-hour acute challenge 1 (AC1) on Day 1. Participants discontinued their current erythropoiesis stimulating agent (ESA) therapy and were washed out of their ESAs for 2 weeks prior to acute challenge 1. After completion of acute challenge 1, participants entered in 8-week hemoglobin (Hgb) maintenance period, where doses of daprodustat were administered and adjusted to maintain target Hgb levels within the range of 10.0 to 11.0 grams per deciliter (g/dL). Participants received acute challenge 2 (AC2) on Day 57 with the same treatment dose administered in acute challenge 1. All participants were followed up for 14 days after acute challenge 2.	Participants were randomized to receive a single intravenous (IV) dose of 100 units per kilogram (U/Kg) Epoetin alfa (Recombinant human erythropoietin) during 24-hour acute challenge 1 on Day 1. Participants discontinued their current ESA therapy and were washed out of their ESAs for 2 weeks prior to acute challenge 1. After completion of acute challenge 1, participants entered in 8-week Hgb maintenance period, where Epoetin alfa was administered according to local labelling and clinical practice guidelines to maintain target Hgb levels within the range of 10.0 to 11.0 g/dL. Participants received acute challenge 2 on Day 57 with the same treatment dose administered in acute challenge 1. All participants were followed up for 14 days after acute challenge 2.
Measure Participants	45	43
ery. MCH, Baseline (Day 1), n=45, 42	31.03 (2.295)	30.57 (2.880)
ery. MCH, Day 29, n=37, 39	31.56 (2.302)	30.83 (3.051)
ery. MCH, Day 57, n=31, 35	31.75 (2.312)	30.88 (3.140)
ery. MCH, Week 10, n=39, 38	31.96 (2.246)	30.66 (2.823)
CHr, Baseline (Day 1), n=45, 43	30.70 (1.730)	29.97 (2.088)
CHr, Day 29, n=36, 40	30.55 (1.799)	30.19 (2.242)
CHr, Day 57, n=32, 36	30.71 (1.852)	29.85 (2.462)
CHr, Week 10, n=39, 39	30.55 (2.116)	29.76 (2.079)

39. Other Pre-specified Outcome

Title	Absolute Values for Hematology Parameter: Ery. Mean Corpuscular Volume (MCV)
Description	Blood samples were collected for the analysis of hematology parameter: ery.MCV. Baseline value (Day1) is the latest non-missing pre-dose assessment.
Time Frame	Baseline (Day 1) and at Days 29, 57 and Week 10

Outcome Measure Data

Analysis Population Description

Safety Population. Only those participants with data available at specified time points has been presented (represented by n=X in the category titles).

Arm/Group Title	Daprodustat	Recombinant Human Erythropoietin
Arm/Group Description	Participants were randomized to receive a single oral dose of Daprodustat 24 milligrams (mg) during 24-hour acute challenge 1 (AC1) on Day 1. Participants discontinued their current erythropoiesis stimulating agent (ESA) therapy and were washed out of their ESAs for 2 weeks prior to acute challenge 1. After completion of acute challenge 1, participants entered in 8-week hemoglobin (Hgb) maintenance period, where doses of daprodustat were administered and adjusted to maintain target Hgb levels within the range of 10.0 to 11.0 grams per deciliter (g/dL). Participants received acute challenge 2 (AC2) on Day 57 with the same treatment dose administered in acute challenge 1. All participants were followed up for 14 days after acute challenge 2.	Participants were randomized to receive a single intravenous (IV) dose of 100 units per kilogram (U/Kg) Epoetin alfa (Recombinant human erythropoietin) during 24-hour acute challenge 1 on Day 1. Participants discontinued their current ESA therapy and were washed out of their ESAs for 2 weeks prior to acute challenge 1. After completion of acute challenge 1, participants entered in 8-week Hgb maintenance period, where Epoetin alfa was administered according to local labelling and clinical practice guidelines to maintain target Hgb levels within the range of 10.0 to 11.0 g/dL. Participants received acute challenge 2 on Day 57 with the same treatment dose administered in acute challenge 1. All participants were followed up for 14 days after acute challenge 2.
Measure Participants	45	42
Baseline (Day 1), n=45, 42	95.0 (6.33)	94.8 (8.37)
Day 29, n=37, 39	96.5 (6.92)	96.2 (8.76)
Day 57, n=31, 35	96.5 (7.18)	97.1 (9.04)
Week 10, n=39, 38	97.9 (6.61)	95.7 (8.37)

40. Other Pre-specified Outcome

Title	Absolute Values for Hematology Parameter: Erythrocyte Distribution Width
Description	Blood samples were collected for the analysis of hematology parameter: erythrocyte distribution width. Baseline value (Day1) is the latest non-missing pre-dose assessment.
Time Frame	Baseline (Day 1) and at Days 29, 57 and Week 10

Outcome Measure Data

Analysis Population Description

Safety Population. Only those participants with data available at specified time points has been presented (represented by n=X in the category titles).

Arm/Group Title	Daprodustat	Recombinant Human Erythropoietin
Arm/Group Description	Participants were randomized to receive a single oral dose of Daprodustat 24 milligrams (mg) during 24-hour acute challenge 1 (AC1) on Day 1. Participants discontinued their current erythropoiesis stimulating agent (ESA) therapy and were washed out of their ESAs for 2 weeks prior to acute challenge 1. After completion of acute challenge 1, participants entered in 8-week hemoglobin (Hgb) maintenance period, where doses of daprodustat were administered and adjusted to maintain target Hgb levels within the range of 10.0 to 11.0 grams per deciliter (g/dL). Participants received acute challenge 2 (AC2) on Day 57 with the same treatment dose administered in acute challenge 1. All participants were followed up for 14 days after acute challenge 2.	Participants were randomized to receive a single intravenous (IV) dose of 100 units per kilogram (U/Kg) Epoetin alfa (Recombinant human erythropoietin) during 24-hour acute challenge 1 on Day 1. Participants discontinued their current ESA therapy and were washed out of their ESAs for 2 weeks prior to acute challenge 1. After completion of acute challenge 1, participants entered in 8-week Hgb maintenance period, where Epoetin alfa was administered according to local labelling and clinical practice guidelines to maintain target Hgb levels within the range of 10.0 to 11.0 g/dL. Participants received acute challenge 2 on Day 57 with the same treatment dose administered in acute challenge 1. All participants were followed up for 14 days after acute challenge 2.
Measure Participants	45	42
Baseline (Day 1), n=45, 42	16.06 (1.618)	15.71 (1.917)
Day 29, n=37, 39	16.52 (1.802)	16.75 (2.230)
Day 57, n=31, 35	16.11 (1.476)	16.67 (2.034)
Week 10, n=39, 38	16.42 (2.036)	16.45 (1.696)

41. Other Pre-specified Outcome

Title	Change From Baseline Values for Hematology Parameters: Basophils, Eosinophils, Lymphocytes, Monocytes, Neutrophils, Platelets and Leukocytes
Description	Blood samples were collected for the analysis of hematology parameters including basophils, eosinophils, lymphocytes, monocytes, neutrophils, platelets and leukocytes. Baseline value (Day1) is the latest non-missing pre-dose assessment. Change from Baseline is defined as Post-dose visit value minus Baseline value.
Time Frame	Baseline (Day 1) and at Days 29, 57 and Week 10

Outcome Measure Data

Analysis Population Description

Safety Population. Only those participants with data available at specified time points has been presented (represented by n=X in the category titles).

Arm/Group Title	Daprodustat	Recombinant Human Erythropoietin
Arm/Group Description	Participants were randomized to receive a single oral dose of Daprodustat 24 milligrams (mg) during 24-hour acute challenge 1 (AC1) on Day 1. Participants discontinued their current erythropoiesis stimulating agent (ESA) therapy and were washed out of their ESAs for 2 weeks prior to acute challenge 1. After completion of acute challenge 1, participants entered in 8-week hemoglobin (Hgb) maintenance period, where doses of daprodustat were administered and adjusted to maintain target Hgb levels within the range of 10.0 to 11.0 grams per deciliter (g/dL). Participants received acute challenge 2 (AC2) on Day 57 with the same treatment dose administered in acute challenge 1. All participants were followed up for 14 days after acute challenge 2.	Participants were randomized to receive a single intravenous (IV) dose of 100 units per kilogram (U/Kg) Epoetin alfa (Recombinant human erythropoietin) during 24-hour acute challenge 1 on Day 1. Participants discontinued their current ESA therapy and were washed out of their ESAs for 2 weeks prior to acute challenge 1. After completion of acute challenge 1, participants entered in 8-week Hgb maintenance period, where Epoetin alfa was administered according to local labelling and clinical practice guidelines to maintain target Hgb levels within the range of 10.0 to 11.0 g/dL. Participants received acute challenge 2 on Day 57 with the same treatment dose administered in acute challenge 1. All participants were followed up for 14 days after acute challenge 2.
Measure Participants	39	37
Basophils, Day 29, n=37, 37	-0.007 (0.0317)	0.010 (0.0329)
Basophils, Day 57, n=30, 33	-0.002 (0.0331)	0.004 (0.0335)
Basophils, Week 10, n=39, 36	-0.004 (0.0349)	0.009 (0.0323)
Eosinophils, Day 29, n=37, 37	0.040 (0.1717)	-0.039 (0.1728)
Eosinophils, Day 57, n=30, 33	0.016 (0.1513)	-0.038 (0.1202)
Eosinophils, Week 10, n=39, 36	0.042 (0.1435)	-0.036 (0.1702)
Lymphocytes, Day 29, n=37, 37	0.095 (0.3613)	0.102 (0.4154)
Lymphocytes, Day 57, n=30, 33	-0.090 (0.3036)	-0.099 (0.3277)
Lymphocytes, Week 10, n=39, 36	0.103 (0.3893)	0.078 (0.4660)
Monocytes, Day 29, n=37, 37	0.033 (0.1600)	0.035 (0.1266)
Monocytes, Day 57, n=30, 33	0.024 (0.1621)	0.025 (0.1543)
Monocytes, Week 10, n=39, 36	0.070 (0.1398)	0.053 (0.1248)
Neutrophils, Day 29, n=37, 37	0.071 (1.1706)	0.061 (1.3382)
Neutrophils, Day 57, n=30, 33	0.081 (1.2291)	0.325 (1.1549)
Neutrophils, Week 10, n=39, 36	0.218 (1.3096)	0.181 (0.9586)
Platelets, Day 29, n=37, 37	0.6 (31.12)	22.7 (52.46)
Platelets, Day 57, n=30, 33	13.9 (47.04)	16.4 (39.51)
Platelets, Week 10, n=39, 37	20.6 (36.08)	26.3 (41.87)
Leukocytes, Day 29, n=37, 37	0.23 (1.296)	0.17 (1.555)
Leukocytes, Day 57, n=30, 33	0.02 (1.456)	0.21 (1.231)
Leukocytes, Week 10, n=39, 36	0.42 (1.442)	0.28 (1.220)

42. Other Pre-specified Outcome

Title	Change From Baseline Values for Hematology Parameter: Hematocrit
Description	Blood samples were collected for the analysis of hematology parameter: hematocrit. Baseline value (Day1) is the latest non-missing pre-dose assessment. Change from Baseline is defined as Post-dose visit value minus Baseline value.
Time Frame	Baseline (Day 1) and at Days 29, 57 and Week 10

Outcome Measure Data

Analysis Population Description

Safety Population. Only those participants with data available at specified time points has been presented (represented by n=X in the category titles).

Arm/Group Title	Daprodustat	Recombinant Human Erythropoietin
Arm/Group Description	Participants were randomized to receive a single oral dose of Daprodustat 24 milligrams (mg) during 24-hour acute challenge 1 (AC1) on Day 1. Participants discontinued their current erythropoiesis stimulating agent (ESA) therapy and were washed out of their ESAs for 2 weeks prior to acute challenge 1. After completion of acute challenge 1, participants entered in 8-week hemoglobin (Hgb) maintenance period, where doses of daprodustat were administered and adjusted to maintain target Hgb levels within the range of 10.0 to 11.0 grams per deciliter (g/dL). Participants received acute challenge 2 (AC2) on Day 57 with the same treatment dose administered in acute challenge 1. All participants were followed up for 14 days after acute challenge 2.	Participants were randomized to receive a single intravenous (IV) dose of 100 units per kilogram (U/Kg) Epoetin alfa (Recombinant human erythropoietin) during 24-hour acute challenge 1 on Day 1. Participants discontinued their current ESA therapy and were washed out of their ESAs for 2 weeks prior to acute challenge 1. After completion of acute challenge 1, participants entered in 8-week Hgb maintenance period, where Epoetin alfa was administered according to local labelling and clinical practice guidelines to maintain target Hgb levels within the range of 10.0 to 11.0 g/dL. Participants received acute challenge 2 on Day 57 with the same treatment dose administered in acute challenge 1. All participants were followed up for 14 days after acute challenge 2.
Measure Participants	39	38
Day 29, n=37, 38	-0.0131 (0.03062)	-0.0136 (0.02614)
Day 57, n=31, 34	-0.0016 (0.03717)	0.0131 (0.03609)
Week 10, n=39, 37	-0.0096 (0.04571)	-0.0054 (0.04944)

43. Other Pre-specified Outcome

Title	Change From Baseline Values for Hematology Parameters: Erythrocytes and Reticulocytes
Description	Blood samples were collected for the analysis of hematology parameters: erythrocytes and reticulocytes. Baseline value (Day1) is the latest non-missing pre-dose assessment. Change from Baseline is defined as Post-dose visit value minus Baseline value.
Time Frame	Baseline (Day 1) and at Days 29, 57 and Week 10

Outcome Measure Data

Analysis Population Description

Safety Population. Only those participants with data available at specified time points has been presented (represented by n=X in the category titles).

Arm/Group Title	Daprodustat	Recombinant Human Erythropoietin
Arm/Group Description	Participants were randomized to receive a single oral dose of Daprodustat 24 milligrams (mg) during 24-hour acute challenge 1 (AC1) on Day 1. Participants discontinued their current erythropoiesis stimulating agent (ESA) therapy and were washed out of their ESAs for 2 weeks prior to acute challenge 1. After completion of acute challenge 1, participants entered in 8-week hemoglobin (Hgb) maintenance period, where doses of daprodustat were administered and adjusted to maintain target Hgb levels within the range of 10.0 to 11.0 grams per deciliter (g/dL). Participants received acute challenge 2 (AC2) on Day 57 with the same treatment dose administered in acute challenge 1. All participants were followed up for 14 days after acute challenge 2.	Participants were randomized to receive a single intravenous (IV) dose of 100 units per kilogram (U/Kg) Epoetin alfa (Recombinant human erythropoietin) during 24-hour acute challenge 1 on Day 1. Participants discontinued their current ESA therapy and were washed out of their ESAs for 2 weeks prior to acute challenge 1. After completion of acute challenge 1, participants entered in 8-week Hgb maintenance period, where Epoetin alfa was administered according to local labelling and clinical practice guidelines to maintain target Hgb levels within the range of 10.0 to 11.0 g/dL. Participants received acute challenge 2 on Day 57 with the same treatment dose administered in acute challenge 1. All participants were followed up for 14 days after acute challenge 2.
Measure Participants	39	38
Erythrocytes, Day 29, n=37, 38	-0.17 (0.331)	-0.20 (0.273)
Erythrocytes, Day 57, n=31, 34	-0.06 (0.410)	0.04 (0.307)
Erythrocytes, Week 10, n=39, 37	-0.18 (0.488)	-0.11 (0.497)
Reticulocytes, Day 29, n=37, 38	0.0156 (0.01432)	0.0315 (0.03821)
Reticulocytes, Day 57, n=31, 34	0.0169 (0.01709)	0.0204 (0.02182)
Reticulocytes, Week 10, n=39, 37	0.0314 (0.04385)	0.0159 (0.02321)

44. Other Pre-specified Outcome

Title	Change From Baseline Values for Hematology Parameters: Hemoglobin and Ery. MCHC
Description	Blood samples were collected for the analysis of hematology parameters: hemoglobin and ery.MCHC. Baseline value (Day1) is the latest non-missing pre-dose assessment. Change from Baseline is defined as Post-dose visit value minus Baseline value.
Time Frame	Baseline (Day 1) and at Days 29, 57 and Week 10

Outcome Measure Data

Analysis Population Description

Safety Population. Only those participants with data available at specified time points has been presented (represented by n=X in the category titles).

Arm/Group Title	Daprodustat	Recombinant Human Erythropoietin
Arm/Group Description	Participants were randomized to receive a single oral dose of Daprodustat 24 milligrams (mg) during 24-hour acute challenge 1 (AC1) on Day 1. Participants discontinued their current erythropoiesis stimulating agent (ESA) therapy and were washed out of their ESAs for 2 weeks prior to acute challenge 1. After completion of acute challenge 1, participants entered in 8-week hemoglobin (Hgb) maintenance period, where doses of daprodustat were administered and adjusted to maintain target Hgb levels within the range of 10.0 to 11.0 grams per deciliter (g/dL). Participants received acute challenge 2 (AC2) on Day 57 with the same treatment dose administered in acute challenge 1. All participants were followed up for 14 days after acute challenge 2.	Participants were randomized to receive a single intravenous (IV) dose of 100 units per kilogram (U/Kg) Epoetin alfa (Recombinant human erythropoietin) during 24-hour acute challenge 1 on Day 1. Participants discontinued their current ESA therapy and were washed out of their ESAs for 2 weeks prior to acute challenge 1. After completion of acute challenge 1, participants entered in 8-week Hgb maintenance period, where Epoetin alfa was administered according to local labelling and clinical practice guidelines to maintain target Hgb levels within the range of 10.0 to 11.0 g/dL. Participants received acute challenge 2 on Day 57 with the same treatment dose administered in acute challenge 1. All participants were followed up for 14 days after acute challenge 2.
Measure Participants	39	38
Hemoglobin, Day 29, n=37, 38	-4.1 (9.35)	-5.1 (8.21)
Hemoglobin, Day 57, n=31, 34	0.5 (10.60)	2.5 (8.54)
Hemoglobin, Week 10, n=39, 37	-3.2 (14.35)	-1.8 (14.46)
ery.MCHC, Day 29, n=37, 38	0.3 (8.41)	-2.0 (10.38)
ery.MCHC, Day 57, n=31, 34	2.3 (8.83)	-4.4 (14.46)
ery.MCHC, Week 10, n=39, 37	-0.6 (9.37)	-0.8 (11.20)

45. Other Pre-specified Outcome

Title	Change From Baseline Values for Hematology Parameters: Ery. MCH and CHr
Description	Blood samples were collected for the analysis of hematology parameter: ery.MCH and CHr. Baseline value (Day1) is the latest non-missing pre-dose assessment. Change from Baseline is defined as Post-dose visit value minus Baseline value.
Time Frame	Baseline (Day 1) and at Days 29, 57 and Week 10

Outcome Measure Data

Analysis Population Description

Safety Population. Only those participants with data available at specified time points has been presented (represented by n=X in the category titles).

Arm/Group Title	Daprodustat	Recombinant Human Erythropoietin
Arm/Group Description	Participants were randomized to receive a single oral dose of Daprodustat 24 milligrams (mg) during 24-hour acute challenge 1 (AC1) on Day 1. Participants discontinued their current erythropoiesis stimulating agent (ESA) therapy and were washed out of their ESAs for 2 weeks prior to acute challenge 1. After completion of acute challenge 1, participants entered in 8-week hemoglobin (Hgb) maintenance period, where doses of daprodustat were administered and adjusted to maintain target Hgb levels within the range of 10.0 to 11.0 grams per deciliter (g/dL). Participants received acute challenge 2 (AC2) on Day 57 with the same treatment dose administered in acute challenge 1. All participants were followed up for 14 days after acute challenge 2.	Participants were randomized to receive a single intravenous (IV) dose of 100 units per kilogram (U/Kg) Epoetin alfa (Recombinant human erythropoietin) during 24-hour acute challenge 1 on Day 1. Participants discontinued their current ESA therapy and were washed out of their ESAs for 2 weeks prior to acute challenge 1. After completion of acute challenge 1, participants entered in 8-week Hgb maintenance period, where Epoetin alfa was administered according to local labelling and clinical practice guidelines to maintain target Hgb levels within the range of 10.0 to 11.0 g/dL. Participants received acute challenge 2 on Day 57 with the same treatment dose administered in acute challenge 1. All participants were followed up for 14 days after acute challenge 2.
Measure Participants	39	40
ery. MCH, Day 29, n=37, 38	0.39 (0.676)	0.40 (0.672)
ery. MCH, Day 57, n=31, 34	0.70 (1.161)	0.49 (0.871)
ery. MCH, Week 10, n=39, 37	0.78 (1.249)	0.38 (1.000)
CHr, Day 29, n=36, 40	-0.23 (0.937)	0.20 (1.060)
CHr, Day 57, n=32, 36	-0.12 (1.067)	-0.09 (1.617)
CHr, Week 10, n=39, 39	-0.29 (1.696)	-0.03 (1.478)

46. Other Pre-specified Outcome

Title	Change From Baseline Values for Hematology Parameter: Ery. MCV
Description	Blood samples were collected for the analysis of hematology parameter: ery.MCV. Baseline value (Day1) is the latest non-missing pre-dose assessment. Change from Baseline is defined as Post-dose visit value minus Baseline value.
Time Frame	Baseline (Day 1) and at Days 29, 57 and Week 10

Outcome Measure Data

Analysis Population Description

Safety Population. Only those participants with data available at specified time points has been presented (represented by n=X in the category titles).

Arm/Group Title	Daprodustat	Recombinant Human Erythropoietin
Arm/Group Description	Participants were randomized to receive a single oral dose of Daprodustat 24 milligrams (mg) during 24-hour acute challenge 1 (AC1) on Day 1. Participants discontinued their current erythropoiesis stimulating agent (ESA) therapy and were washed out of their ESAs for 2 weeks prior to acute challenge 1. After completion of acute challenge 1, participants entered in 8-week hemoglobin (Hgb) maintenance period, where doses of daprodustat were administered and adjusted to maintain target Hgb levels within the range of 10.0 to 11.0 grams per deciliter (g/dL). Participants received acute challenge 2 (AC2) on Day 57 with the same treatment dose administered in acute challenge 1. All participants were followed up for 14 days after acute challenge 2.	Participants were randomized to receive a single intravenous (IV) dose of 100 units per kilogram (U/Kg) Epoetin alfa (Recombinant human erythropoietin) during 24-hour acute challenge 1 on Day 1. Participants discontinued their current ESA therapy and were washed out of their ESAs for 2 weeks prior to acute challenge 1. After completion of acute challenge 1, participants entered in 8-week Hgb maintenance period, where Epoetin alfa was administered according to local labelling and clinical practice guidelines to maintain target Hgb levels within the range of 10.0 to 11.0 g/dL. Participants received acute challenge 2 on Day 57 with the same treatment dose administered in acute challenge 1. All participants were followed up for 14 days after acute challenge 2.
Measure Participants	39	38
Day 29, n=37, 38	1.2 (2.47)	1.8 (3.32)
Day 57, n=31, 34	1.5 (3.50)	2.9 (3.54)
Week 10, n=39, 37	2.7 (4.80)	1.4 (3.62)

47. Other Pre-specified Outcome

Title	Change From Baseline Values for Hematology Parameter: Erythrocyte Distribution Width
Description	Blood samples were collected for the analysis of hematology parameter: erythrocyte distribution width. Baseline value (Day1) is the latest non-missing pre-dose assessment. Change from Baseline is defined as Post-dose visit value minus Baseline value.
Time Frame	Baseline (Day 1) and at Days 29, 57 and Week 10

Outcome Measure Data

Analysis Population Description

Safety Population. Only those participants with data available at specified time points has been presented (represented by n=X in the category titles).

Arm/Group Title	Daprodustat	Recombinant Human Erythropoietin
Arm/Group Description	Participants were randomized to receive a single oral dose of Daprodustat 24 milligrams (mg) during 24-hour acute challenge 1 (AC1) on Day 1. Participants discontinued their current erythropoiesis stimulating agent (ESA) therapy and were washed out of their ESAs for 2 weeks prior to acute challenge 1. After completion of acute challenge 1, participants entered in 8-week hemoglobin (Hgb) maintenance period, where doses of daprodustat were administered and adjusted to maintain target Hgb levels within the range of 10.0 to 11.0 grams per deciliter (g/dL). Participants received acute challenge 2 (AC2) on Day 57 with the same treatment dose administered in acute challenge 1. All participants were followed up for 14 days after acute challenge 2.	Participants were randomized to receive a single intravenous (IV) dose of 100 units per kilogram (U/Kg) Epoetin alfa (Recombinant human erythropoietin) during 24-hour acute challenge 1 on Day 1. Participants discontinued their current ESA therapy and were washed out of their ESAs for 2 weeks prior to acute challenge 1. After completion of acute challenge 1, participants entered in 8-week Hgb maintenance period, where Epoetin alfa was administered according to local labelling and clinical practice guidelines to maintain target Hgb levels within the range of 10.0 to 11.0 g/dL. Participants received acute challenge 2 on Day 57 with the same treatment dose administered in acute challenge 1. All participants were followed up for 14 days after acute challenge 2.
Measure Participants	39	38
Day 29, n=37, 38	0.38 (1.197)	1.09 (1.435)
Day 57, n=31, 34	0.12 (1.262)	0.85 (1.609)
Week 10, n=39, 37	0.35 (1.998)	0.59 (1.650)

48. Other Pre-specified Outcome

Title	Absolute Values for Electrocardiogram (ECG) Mean Heart Rate
Description	Full 12-lead ECGs were obtained in supine position using an ECG machine to measure mean heart rate. Baseline (Day 1-predose) is the latest non-missing pre-dose assessment.
Time Frame	Baseline (Day 1-predose) and at Day 1: 24 hours; Day 57: pre-dose; Day 57: 24 hours and Week 10

Outcome Measure Data

Analysis Population Description

Safety Population. Only those participants with data available at specified time points has been presented (represented by n=X in the category titles).

Arm/Group Title	Daprodustat	Recombinant Human Erythropoietin
Arm/Group Description	Participants were randomized to receive a single oral dose of Daprodustat 24 milligrams (mg) during 24-hour acute challenge 1 (AC1) on Day 1. Participants discontinued their current erythropoiesis stimulating agent (ESA) therapy and were washed out of their ESAs for 2 weeks prior to acute challenge 1. After completion of acute challenge 1, participants entered in 8-week hemoglobin (Hgb) maintenance period, where doses of daprodustat were administered and adjusted to maintain target Hgb levels within the range of 10.0 to 11.0 grams per deciliter (g/dL). Participants received acute challenge 2 (AC2) on Day 57 with the same treatment dose administered in acute challenge 1. All participants were followed up for 14 days after acute challenge 2.	Participants were randomized to receive a single intravenous (IV) dose of 100 units per kilogram (U/Kg) Epoetin alfa (Recombinant human erythropoietin) during 24-hour acute challenge 1 on Day 1. Participants discontinued their current ESA therapy and were washed out of their ESAs for 2 weeks prior to acute challenge 1. After completion of acute challenge 1, participants entered in 8-week Hgb maintenance period, where Epoetin alfa was administered according to local labelling and clinical practice guidelines to maintain target Hgb levels within the range of 10.0 to 11.0 g/dL. Participants received acute challenge 2 on Day 57 with the same treatment dose administered in acute challenge 1. All participants were followed up for 14 days after acute challenge 2.
Measure Participants	45	43
Baseline (Day 1-predose), n=45, 43	72.2 (9.52)	73.6 (9.03)
Day 1: 24 hours, n=40, 38	71.6 (9.38)	74.8 (9.42)
Day 57: predose, n=32, 36	71.2 (8.58)	72.7 (9.47)
Day 57: 24 hours, n=32, 36	71.2 (8.22)	75.1 (9.12)
Week 10, n=39, 40	72.3 (10.03)	74.3 (9.53)

49. Other Pre-specified Outcome

Title	Absolute Values for ECG Parameters: PR Interval, QRS Duration, QT Interval Corrected for Heart Rate (QTc) and QT Interval Corrected for Heart Rate Using Bazett's Formula (QTcB)
Description	Full 12-lead ECGs were obtained in supine position using an ECG machine to measure ECG parameters: PR interval, QRS duration, QTc interval and QTcB. Baseline (Day 1-predose) is the latest non-missing pre-dose assessment.
Time Frame	Baseline (Day 1-predose) and at Day 1: 24 hours; Day 57: pre-dose; Day 57: 24 hours and Week 10

Outcome Measure Data

Analysis Population Description

Safety Population. Only those participants with data available at specified time points has been presented (represented by n=X in the category titles).

Arm/Group Title	Daprodustat	Recombinant Human Erythropoietin
Arm/Group Description	Participants were randomized to receive a single oral dose of Daprodustat 24 milligrams (mg) during 24-hour acute challenge 1 (AC1) on Day 1. Participants discontinued their current erythropoiesis stimulating agent (ESA) therapy and were washed out of their ESAs for 2 weeks prior to acute challenge 1. After completion of acute challenge 1, participants entered in 8-week hemoglobin (Hgb) maintenance period, where doses of daprodustat were administered and adjusted to maintain target Hgb levels within the range of 10.0 to 11.0 grams per deciliter (g/dL). Participants received acute challenge 2 (AC2) on Day 57 with the same treatment dose administered in acute challenge 1. All participants were followed up for 14 days after acute challenge 2.	Participants were randomized to receive a single intravenous (IV) dose of 100 units per kilogram (U/Kg) Epoetin alfa (Recombinant human erythropoietin) during 24-hour acute challenge 1 on Day 1. Participants discontinued their current ESA therapy and were washed out of their ESAs for 2 weeks prior to acute challenge 1. After completion of acute challenge 1, participants entered in 8-week Hgb maintenance period, where Epoetin alfa was administered according to local labelling and clinical practice guidelines to maintain target Hgb levels within the range of 10.0 to 11.0 g/dL. Participants received acute challenge 2 on Day 57 with the same treatment dose administered in acute challenge 1. All participants were followed up for 14 days after acute challenge 2.
Measure Participants	45	43
PR interval, Baseline (Day 1-predose), n=45, 43	156.5 (30.81)	160.5 (30.79)
PR interval, Day 1: 24 hours, n=39, 38	158.1 (30.26)	163.3 (34.38)
PR interval, Day 57: predose, n=32, 35	155.8 (27.69)	152.1 (26.90)
PR interval, Day 57: 24 hours, n=32, 36	156.4 (29.83)	160.3 (32.98)
PR interval, Week 10, n=39, 40	162.5 (29.19)	159.9 (31.16)
QRS duration, Baseline (Day 1-predose), n=45, 43	106.2 (18.40)	107.4 (16.22)
QRS duration, Day 1: 24 hours, n=40, 38	106.0 (17.31)	107.4 (17.85)
QRS duration, Day 57: predose, n=32, 36	106.7 (14.46)	112.4 (21.89)
QRS duration, Day 57: 24 hours, n=32, 36	106.4 (15.05)	111.0 (20.75)
QRS duration, Week 10, n=39, 40	108.5 (15.56)	109.1 (20.69)
QTc interval, Baseline (Day 1-predose), n=9, 17	440.6 (22.41)	429.4 (27.49)
QTc interval, Day 1: 24 hours, n=7, 11	446.1 (18.94)	424.7 (27.73)
QTc interval, Day 57: predose, n=5, 8	452.8 (13.92)	436.1 (21.72)
QTc interval, Day 57: 24 hours, n=5, 8	430.6 (14.84)	431.8 (31.98)
QTc interval, Week 10, n=6, 10	438.8 (13.01)	428.3 (31.87)
QTcB, Baseline (Day 1-predose), n=45, 43	448.0 (40.17)	445.6 (31.00)
QTcB, Day 1: 24 hours, n=40, 38	438.9 (35.02)	439.3 (25.64)
QTcB, Day 57: predose, n=32, 36	442.3 (38.12)	449.1 (32.58)
QTcB, Day 57: 24 hours, n=32, 36	437.4 (33.58)	442.0 (37.61)
QTcB, Week 10, n=39, 39	442.0 (37.28)	441.6 (28.11)

50. Other Pre-specified Outcome

Title	Change From Baseline Values for ECG Mean Heart Rate
Description	Full 12-lead ECGs were obtained in supine position using an ECG machine to measure mean heart rate. Baseline (Day 1-predose) is the latest non-missing pre-dose assessment. Change from Baseline is defined as Post-dose visit value minus Baseline value.
Time Frame	Baseline (Day 1-predose) and at Day 1: 24 hours; Day 57: pre-dose; Day 57: 24 hours and Week 10

Outcome Measure Data

Analysis Population Description

Safety Population. Only those participants with data available at specified time points has been presented (represented by n=X in the category titles).

Arm/Group Title	Daprodustat	Recombinant Human Erythropoietin
Arm/Group Description	Participants were randomized to receive a single oral dose of Daprodustat 24 milligrams (mg) during 24-hour acute challenge 1 (AC1) on Day 1. Participants discontinued their current erythropoiesis stimulating agent (ESA) therapy and were washed out of their ESAs for 2 weeks prior to acute challenge 1. After completion of acute challenge 1, participants entered in 8-week hemoglobin (Hgb) maintenance period, where doses of daprodustat were administered and adjusted to maintain target Hgb levels within the range of 10.0 to 11.0 grams per deciliter (g/dL). Participants received acute challenge 2 (AC2) on Day 57 with the same treatment dose administered in acute challenge 1. All participants were followed up for 14 days after acute challenge 2.	Participants were randomized to receive a single intravenous (IV) dose of 100 units per kilogram (U/Kg) Epoetin alfa (Recombinant human erythropoietin) during 24-hour acute challenge 1 on Day 1. Participants discontinued their current ESA therapy and were washed out of their ESAs for 2 weeks prior to acute challenge 1. After completion of acute challenge 1, participants entered in 8-week Hgb maintenance period, where Epoetin alfa was administered according to local labelling and clinical practice guidelines to maintain target Hgb levels within the range of 10.0 to 11.0 g/dL. Participants received acute challenge 2 on Day 57 with the same treatment dose administered in acute challenge 1. All participants were followed up for 14 days after acute challenge 2.
Measure Participants	40	40
Day 1: 24 hours, n=40, 38	-0.6 (6.85)	0.8 (5.61)
Day 57: predose, n=32, 36	-1.6 (7.25)	0.1 (8.22)
Day 57: 24 hours, n=32, 36	-1.7 (6.58)	2.5 (8.21)
Week 10, n=39, 40	-0.1 (9.01)	0.4 (8.86)

51. Other Pre-specified Outcome

Title	Change From Baseline Values for ECG Parameters: PR Interval, QRS Duration, QTc and QTcB
Description	Full 12-lead ECGs were obtained in supine position using an ECG machine to measure ECG parameters: PR interval, QRS duration, QTc interval and QTcB. Baseline (Day 1-predose) is the latest non-missing pre-dose assessment. Change from Baseline is defined as Post-dose visit value minus Baseline value.
Time Frame	Baseline (Day 1-predose) and at Day 1: 24 hours; Day 57: pre-dose; Day 57: 24 hours and Week 10

Outcome Measure Data

Analysis Population Description

Safety Population. Only those participants with data available at specified time points has been presented (represented by n=X in the category titles).

Arm/Group Title	Daprodustat	Recombinant Human Erythropoietin
Arm/Group Description	Participants were randomized to receive a single oral dose of Daprodustat 24 milligrams (mg) during 24-hour acute challenge 1 (AC1) on Day 1. Participants discontinued their current erythropoiesis stimulating agent (ESA) therapy and were washed out of their ESAs for 2 weeks prior to acute challenge 1. After completion of acute challenge 1, participants entered in 8-week hemoglobin (Hgb) maintenance period, where doses of daprodustat were administered and adjusted to maintain target Hgb levels within the range of 10.0 to 11.0 grams per deciliter (g/dL). Participants received acute challenge 2 (AC2) on Day 57 with the same treatment dose administered in acute challenge 1. All participants were followed up for 14 days after acute challenge 2.	Participants were randomized to receive a single intravenous (IV) dose of 100 units per kilogram (U/Kg) Epoetin alfa (Recombinant human erythropoietin) during 24-hour acute challenge 1 on Day 1. Participants discontinued their current ESA therapy and were washed out of their ESAs for 2 weeks prior to acute challenge 1. After completion of acute challenge 1, participants entered in 8-week Hgb maintenance period, where Epoetin alfa was administered according to local labelling and clinical practice guidelines to maintain target Hgb levels within the range of 10.0 to 11.0 g/dL. Participants received acute challenge 2 on Day 57 with the same treatment dose administered in acute challenge 1. All participants were followed up for 14 days after acute challenge 2.
Measure Participants	40	40
PR interval, Day 1: 24 hours, n=39, 38	3.0 (11.02)	1.9 (11.16)
PR interval, Day 57: predose, n=32, 35	0.2 (17.58)	-3.9 (11.34)
PR interval, Day 57: 24 hours, n=32, 36	0.8 (15.89)	1.8 (13.03)
PR interval, Week 10, n=39, 40	4.9 (15.21)	1.2 (17.11)
QRS duration, Day 1: 24 hours, n=40, 38	-0.5 (7.60)	0.0 (4.73)
QRS duration, Day 57: predose, n=32, 36	0.3 (9.53)	2.8 (15.01)
QRS duration, Day 57: 24 hours, n=32, 36	0.0 (11.13)	1.4 (13.22)
QRS duration, Week 10, n=39, 40	0.8 (12.62)	0.7 (18.38)
QTc interval, Day 1: 24 hours, n=7, 11	2.1 (14.59)	-9.4 (14.87)
QTc interval, Day 57: predose, n=4, 8	-6.3 (20.14)	1.0 (5.71)
QTc interval, Day 57: 24 hours, n=4, 8	-29.0 (31.89)	-3.4 (14.79)
QTc interval, Week 10, n=6, 9	-6.7 (25.15)	-10.3 (11.74)
QTcB, Day 1: 24 hours, n=40, 38	-7.0 (24.13)	-3.1 (12.31)
QTcB, Day 57: predose, n=32, 36	-7.0 (30.14)	4.9 (12.36)
QTcB, Day 57: 24 hours, n=32, 36	-12.0 (29.93)	-2.2 (23.15)
QTcB, Week 10, n=39, 39	-7.2 (35.84)	-3.0 (15.34)

52. Other Pre-specified Outcome

Title	Absolute Values for Vital Signs: Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP)
Description	Vital signs including SBP and DBP were measured in participants in a semi-supine position after 5 minutes rest. Baseline (Day 1-predose) is the latest non-missing pre-dose assessment.
Time Frame	Baseline (Day 1, predose) and at Day 1: 3, 12, 24 hours; Day 29: pre- and post-dialysis; Day 57: pre- and post-dialysis, 3, 12, 24 hours and Week 10: pre- and post-dialysis

Outcome Measure Data

Analysis Population Description

Safety Population. Only those participants with data available at specified time points has been presented (represented by n=X in the category titles).

Arm/Group Title	Daprodustat	Recombinant Human Erythropoietin
Arm/Group Description	Participants were randomized to receive a single oral dose of Daprodustat 24 milligrams (mg) during 24-hour acute challenge 1 (AC1) on Day 1. Participants discontinued their current erythropoiesis stimulating agent (ESA) therapy and were washed out of their ESAs for 2 weeks prior to acute challenge 1. After completion of acute challenge 1, participants entered in 8-week hemoglobin (Hgb) maintenance period, where doses of daprodustat were administered and adjusted to maintain target Hgb levels within the range of 10.0 to 11.0 grams per deciliter (g/dL). Participants received acute challenge 2 (AC2) on Day 57 with the same treatment dose administered in acute challenge 1. All participants were followed up for 14 days after acute challenge 2.	Participants were randomized to receive a single intravenous (IV) dose of 100 units per kilogram (U/Kg) Epoetin alfa (Recombinant human erythropoietin) during 24-hour acute challenge 1 on Day 1. Participants discontinued their current ESA therapy and were washed out of their ESAs for 2 weeks prior to acute challenge 1. After completion of acute challenge 1, participants entered in 8-week Hgb maintenance period, where Epoetin alfa was administered according to local labelling and clinical practice guidelines to maintain target Hgb levels within the range of 10.0 to 11.0 g/dL. Participants received acute challenge 2 on Day 57 with the same treatment dose administered in acute challenge 1. All participants were followed up for 14 days after acute challenge 2.
Measure Participants	45	43
SBP, Baseline (Day1, predose), n=45, 43	135.87 (20.813)	137.00 (16.547)
SBP, Day 1: 3 hours, n=44, 43	140.64 (18.183)	144.05 (22.184)
SBP, Day1: 12 hours, n=44, 43	142.05 (23.150)	143.56 (20.566)
SBP, Day 1: 24 hours, n=41, 40	140.24 (20.960)	142.05 (14.822)
SBP, Day 29: pre-dialysis, n=38, 40	143.05 (20.351)	148.10 (20.445)
SBP, Day 29: post dialysis, n=38, 40	130.97 (20.608)	141.93 (19.038)
SBP, Day 57: pre-dialysis, n=32, 36	142.75 (22.599)	151.53 (19.893)
SBP, Day 57: post dialysis, n=32, 36	135.66 (18.314)	141.64 (20.304)
SBP, Day 57: 3 hours, n=32, 36	140.94 (22.623)	148.06 (20.316)
SBP, Day 57: 12 hours, n=32, 36	130.47 (22.492)	145.47 (18.599)
SBP, Day 57: 24 hours, n=32, 36	143.78 (17.783)	144.83 (15.497)
SBP, Week 10: pre-dialysis, n=42, 42	142.71 (20.123)	147.12 (18.285)
SBP, Week 10: post dialysis, n=41, 42	138.73 (19.584)	136.74 (22.105)
DBP, Baseline (Day1, predose), n=45, 43	70.00 (10.967)	72.05 (11.307)
DBP, Day 1: 3 hours, n=44, 43	74.91 (12.676)	75.53 (11.701)
DBP, Day1: 12 hours, n=44, 43	77.11 (13.784)	77.19 (12.557)
DBP, Day 1: 24 hours, n=41, 40	74.22 (11.010)	76.18 (10.318)
DBP, Day 29: pre-dialysis, n=38, 40	71.92 (10.794)	77.95 (12.850)
DBP, Day 29: post dialysis, n=38, 40	69.47 (11.272)	73.30 (10.823)
DBP, Day 57: pre-dialysis, n=32, 36	72.69 (9.855)	76.69 (12.578)
DBP, Day 57: post dialysis, n=32, 36	71.47 (10.586)	72.56 (10.383)
DBP, Day 57: 3 hours, n=32, 36	72.44 (13.023)	75.72 (11.732)
DBP, Day 57: 12 hours, n=32, 36	67.38 (10.536)	75.94 (10.376)
DBP, Day 57: 24 hours, n=32, 36	76.44 (12.425)	74.81 (8.756)
DBP, Week 10: pre-dialysis, n=42, 42	73.86 (12.479)	75.83 (10.087)
DBP, Week 10: post dialysis, n=41, 42	71.05 (12.008)	69.52 (10.341)

53. Other Pre-specified Outcome

Title	Absolute Values for Temperature
Description	Temperature was measured in participants in a semi-supine position after 5 minutes rest. Baseline (Day 1-predose) is the latest non-missing pre-dose assessment.
Time Frame	Baseline (Day 1, predose) and at Day 1: 3, 12, 24 hours; Day 29: pre- and post-dialysis; Day 57: pre- and post-dialysis, 3, 12, 24 hours and Week 10: pre- and post-dialysis

Outcome Measure Data

Analysis Population Description

Safety Population. Only those participants with data available at specified time points has been presented (represented by n=X in the category titles).

Arm/Group Title	Daprodustat	Recombinant Human Erythropoietin
Arm/Group Description	Participants were randomized to receive a single oral dose of Daprodustat 24 milligrams (mg) during 24-hour acute challenge 1 (AC1) on Day 1. Participants discontinued their current erythropoiesis stimulating agent (ESA) therapy and were washed out of their ESAs for 2 weeks prior to acute challenge 1. After completion of acute challenge 1, participants entered in 8-week hemoglobin (Hgb) maintenance period, where doses of daprodustat were administered and adjusted to maintain target Hgb levels within the range of 10.0 to 11.0 grams per deciliter (g/dL). Participants received acute challenge 2 (AC2) on Day 57 with the same treatment dose administered in acute challenge 1. All participants were followed up for 14 days after acute challenge 2.	Participants were randomized to receive a single intravenous (IV) dose of 100 units per kilogram (U/Kg) Epoetin alfa (Recombinant human erythropoietin) during 24-hour acute challenge 1 on Day 1. Participants discontinued their current ESA therapy and were washed out of their ESAs for 2 weeks prior to acute challenge 1. After completion of acute challenge 1, participants entered in 8-week Hgb maintenance period, where Epoetin alfa was administered according to local labelling and clinical practice guidelines to maintain target Hgb levels within the range of 10.0 to 11.0 g/dL. Participants received acute challenge 2 on Day 57 with the same treatment dose administered in acute challenge 1. All participants were followed up for 14 days after acute challenge 2.
Measure Participants	45	43
Baseline (Day1, predose), n=45, 43	36.456 (0.3708)	36.442 (0.3692)
Day 1: 3 hours, n=44, 43	36.427 (0.3480)	36.374 (0.3102)
Day1: 12 hours, n=44, 43	36.470 (0.4032)	36.507 (0.4125)
Day 1: 24 hours, n=41, 40	36.459 (0.3598)	36.380 (0.3539)
Day 29: pre-dialysis, n=38, 40	36.389 (0.3547)	36.418 (0.3169)
Day 29: post dialysis, n=38, 40	36.316 (0.3576)	36.380 (0.3040)
Day 57: pre-dialysis, n=32, 36	36.419 (0.3685)	36.403 (0.3410)
Day 57: post dialysis, n=32, 36	36.384 (0.3028)	36.378 (0.2977)
Day 57: 3 hours, n=32, 36	36.422 (0.3066)	36.497 (0.4018)
Day 57: 12 hours, n=32, 36	36.525 (0.4363)	36.414 (0.3474)
Day 57: 24 hours, n=32, 36	36.447 (0.3360)	36.506 (0.3014)
Week 10: pre-dialysis, n=42, 42	36.414 (0.3375)	36.383 (0.2469)
Week 10: post dialysis, n=41, 42	36.461 (0.3767)	36.450 (0.2625)

54. Other Pre-specified Outcome

Title	Absolute Values for Pulse Rate
Description	Pulse rate was measured in participants in a semi-supine position after 5 minutes rest. Baseline (Day 1-predose) is the latest non-missing pre-dose assessment.
Time Frame	Baseline (Day 1, predose) and at Day 1:3, 12, 24 hours; Day 29: pre- and post-dialysis; Day 57: pre- and post-dialysis, 3, 12, 24 hours and Week 10: pre- and post-dialysis

Outcome Measure Data

Analysis Population Description

Safety Population. Only those participants with data available at specified time points has been presented (represented by n=X in the category titles).

Arm/Group Title	Daprodustat	Recombinant Human Erythropoietin
Arm/Group Description	Participants were randomized to receive a single oral dose of Daprodustat 24 milligrams (mg) during 24-hour acute challenge 1 (AC1) on Day 1. Participants discontinued their current erythropoiesis stimulating agent (ESA) therapy and were washed out of their ESAs for 2 weeks prior to acute challenge 1. After completion of acute challenge 1, participants entered in 8-week hemoglobin (Hgb) maintenance period, where doses of daprodustat were administered and adjusted to maintain target Hgb levels within the range of 10.0 to 11.0 grams per deciliter (g/dL). Participants received acute challenge 2 (AC2) on Day 57 with the same treatment dose administered in acute challenge 1. All participants were followed up for 14 days after acute challenge 2.	Participants were randomized to receive a single intravenous (IV) dose of 100 units per kilogram (U/Kg) Epoetin alfa (Recombinant human erythropoietin) during 24-hour acute challenge 1 on Day 1. Participants discontinued their current ESA therapy and were washed out of their ESAs for 2 weeks prior to acute challenge 1. After completion of acute challenge 1, participants entered in 8-week Hgb maintenance period, where Epoetin alfa was administered according to local labelling and clinical practice guidelines to maintain target Hgb levels within the range of 10.0 to 11.0 g/dL. Participants received acute challenge 2 on Day 57 with the same treatment dose administered in acute challenge 1. All participants were followed up for 14 days after acute challenge 2.
Measure Participants	45	43
Baseline (Day1, predose), n=45, 43	72.09 (9.860)	76.19 (11.450)
Day 1: 3 hours, n=44, 43	72.48 (9.931)	76.21 (10.432)
Day1: 12 hours, n=44, 43	71.95 (9.101)	72.65 (9.564)
Day 1: 24 hours, n=41, 40	73.37 (10.495)	76.43 (8.388)
Day 29: pre-dialysis, n=38, 40	72.92 (11.751)	76.05 (8.688)
Day 29: post dialysis, n=38, 40	74.00 (10.051)	76.18 (11.437)
Day 57: pre-dialysis, n=32, 36	74.59 (12.793)	77.17 (10.997)
Day 57: post dialysis, n=32, 36	72.63 (10.354)	75.75 (9.927)
Day 57: 3 hours, n=32, 36	70.91 (11.360)	75.25 (9.755)
Day 57: 12 hours, n=32, 36	70.50 (11.259)	75.11 (9.858)
Day 57: 24 hours, n=32, 36	71.16 (10.097)	75.36 (7.650)
Week 10: pre-dialysis, n=42, 42	73.07 (10.744)	75.81 (9.823)
Week 10: post dialysis, n=41, 42	71.76 (10.138)	74.55 (11.096)

55. Other Pre-specified Outcome

Title	Change From Baseline Values for Vital Signs: SBP and DBP
Description	Vital signs including SBP and DBP were measured in participants in a semi-supine position after 5 minutes rest. Baseline (Day 1-predose) is the latest non-missing pre-dose assessment. Change from Baseline is defined as Post-dose visit value minus Baseline value.
Time Frame	Baseline (Day 1, predose) and at Day 1: 3, 12, 24 hours; Day 29: pre- and post-dialysis; Day 57: pre- and post-dialysis, 3, 12, 24 hours and Week 10: pre- and post-dialysis

Outcome Measure Data

Analysis Population Description

Safety Population. Only those participants with data available at specified time points has been presented (represented by n=X in the category titles).

Arm/Group Title	Daprodustat	Recombinant Human Erythropoietin
Arm/Group Description	Participants were randomized to receive a single oral dose of Daprodustat 24 milligrams (mg) during 24-hour acute challenge 1 (AC1) on Day 1. Participants discontinued their current erythropoiesis stimulating agent (ESA) therapy and were washed out of their ESAs for 2 weeks prior to acute challenge 1. After completion of acute challenge 1, participants entered in 8-week hemoglobin (Hgb) maintenance period, where doses of daprodustat were administered and adjusted to maintain target Hgb levels within the range of 10.0 to 11.0 grams per deciliter (g/dL). Participants received acute challenge 2 (AC2) on Day 57 with the same treatment dose administered in acute challenge 1. All participants were followed up for 14 days after acute challenge 2.	Participants were randomized to receive a single intravenous (IV) dose of 100 units per kilogram (U/Kg) Epoetin alfa (Recombinant human erythropoietin) during 24-hour acute challenge 1 on Day 1. Participants discontinued their current ESA therapy and were washed out of their ESAs for 2 weeks prior to acute challenge 1. After completion of acute challenge 1, participants entered in 8-week Hgb maintenance period, where Epoetin alfa was administered according to local labelling and clinical practice guidelines to maintain target Hgb levels within the range of 10.0 to 11.0 g/dL. Participants received acute challenge 2 on Day 57 with the same treatment dose administered in acute challenge 1. All participants were followed up for 14 days after acute challenge 2.
Measure Participants	44	43
SBP, Day 1: 3 hours, n=44, 43	5.34 (20.307)	7.05 (18.639)
SBP, Day1: 12 hours, n=44, 43	6.75 (25.642)	6.56 (17.633)
SBP, Day 1: 24 hours, n=41, 40	3.90 (21.846)	6.23 (18.150)
SBP, Day 29: pre-dialysis, n=38, 40	8.24 (27.069)	12.00 (25.314)
SBP, Day 29: post dialysis, n=38, 40	-3.84 (20.676)	5.83 (21.882)
SBP, Day 57: pre-dialysis, n=32, 36	6.63 (25.125)	16.03 (20.492)
SBP, Day 57: post dialysis, n=32, 36	-0.47 (22.747)	6.14 (20.699)
SBP, Day 57: 3 hours, n=32, 36	4.81 (22.938)	12.56 (20.832)
SBP, Day 57: 12 hours, n=32, 36	-5.66 (25.575)	9.97 (20.520)
SBP, Day 57: 24 hours, n=32, 36	7.66 (21.919)	9.33 (22.080)
SBP, Week 10: pre-dialysis, n=42, 42	7.36 (21.412)	10.48 (19.261)
SBP, Week 10: post dialysis, n=41, 42	2.73 (19.005)	0.10 (23.472)
DBP, Day 1: 3 hours, n=44, 43	5.07 (12.617)	3.49 (13.170)
DBP, Day1: 12 hours, n=44, 43	7.27 (13.588)	5.14 (13.105)
DBP, Day 1: 24 hours, n=41, 40	4.07 (13.129)	4.18 (11.569)
DBP, Day 29: pre-dialysis, n=38, 40	2.63 (14.749)	5.88 (14.650)
DBP, Day 29: post dialysis, n=38, 40	0.18 (13.854)	1.23 (12.259)
DBP, Day 57: pre-dialysis, n=32, 36	2.94 (13.457)	5.86 (13.316)
DBP, Day 57: post dialysis, n=32, 36	1.72 (11.277)	1.72 (12.230)
DBP, Day 57: 3 hours, n=32, 36	2.69 (17.087)	4.89 (14.540)
DBP, Day 57: 12 hours, n=32, 36	-2.38 (13.760)	5.11 (14.186)
DBP, Day 57: 24 hours, n=32, 36	6.69 (15.995)	3.97 (13.729)
DBP, Week 10: pre-dialysis, n=42, 42	3.71 (13.328)	3.50 (12.975)
DBP, Week 10: post dialysis, n=41, 42	1.00 (10.151)	-2.81 (12.934)

56. Other Pre-specified Outcome

Title	Change From Baseline Values for Temperature
Description	Temperature was measured in participants in a semi-supine position after 5 minutes rest. Baseline (Day 1-predose) is the latest non-missing pre-dose assessment. Change from Baseline is defined as Post-dose visit value minus Baseline value.
Time Frame	Baseline (Day 1, predose) and at Day 1: 3, 12, 24 hours; Day 29: pre- and post-dialysis; Day 57: pre- and post-dialysis, 3, 12, 24 hours and Week 10: pre- and post-dialysis

Outcome Measure Data

Analysis Population Description

Safety Population. Only those participants with data available at specified time points has been presented (represented by n=X in the category titles).

Arm/Group Title	Daprodustat	Recombinant Human Erythropoietin
Arm/Group Description	Participants were randomized to receive a single oral dose of Daprodustat 24 milligrams (mg) during 24-hour acute challenge 1 (AC1) on Day 1. Participants discontinued their current erythropoiesis stimulating agent (ESA) therapy and were washed out of their ESAs for 2 weeks prior to acute challenge 1. After completion of acute challenge 1, participants entered in 8-week hemoglobin (Hgb) maintenance period, where doses of daprodustat were administered and adjusted to maintain target Hgb levels within the range of 10.0 to 11.0 grams per deciliter (g/dL). Participants received acute challenge 2 (AC2) on Day 57 with the same treatment dose administered in acute challenge 1. All participants were followed up for 14 days after acute challenge 2.	Participants were randomized to receive a single intravenous (IV) dose of 100 units per kilogram (U/Kg) Epoetin alfa (Recombinant human erythropoietin) during 24-hour acute challenge 1 on Day 1. Participants discontinued their current ESA therapy and were washed out of their ESAs for 2 weeks prior to acute challenge 1. After completion of acute challenge 1, participants entered in 8-week Hgb maintenance period, where Epoetin alfa was administered according to local labelling and clinical practice guidelines to maintain target Hgb levels within the range of 10.0 to 11.0 g/dL. Participants received acute challenge 2 on Day 57 with the same treatment dose administered in acute challenge 1. All participants were followed up for 14 days after acute challenge 2.
Measure Participants	44	43
Day 1: 3 hours, n=44, 43	-0.027 (0.3744)	-0.067 (0.3220)
Day1: 12 hours, n=44, 43	0.016 (0.4011)	0.065 (0.3981)
Day 1: 24 hours, n=41, 40	0.015 (0.3712)	-0.050 (0.3359)
Day 29: pre-dialysis, n=38, 40	-0.089 (0.5451)	-0.033 (0.3731)
Day 29: post dialysis, n=38, 40	-0.163 (0.4790)	-0.070 (0.4027)
Day 57: pre-dialysis, n=32, 36	-0.003 (0.4447)	-0.028 (0.4158)
Day 57: post dialysis, n=32, 36	-0.038 (0.3774)	-0.053 (0.3247)
Day 57: 3 hours, n=32, 36	0.000 (0.4048)	0.067 (0.4697)
Day 57: 12 hours, n=32, 36	0.103 (0.5196)	-0.017 (0.3085)
Day 57: 24 hours, n=32, 36	0.025 (0.4501)	0.075 (0.3557)
Week 10: pre-dialysis, n=42, 42	-0.055 (0.4840)	-0.062 (0.4328)
Week 10: post dialysis, n=41, 42	-0.002 (0.5270)	0.005 (0.4311)

57. Other Pre-specified Outcome

Title	Change From Baseline Values for Pulse Rate
Description	Pulse rate was measured in participants in a semi-supine position after 5 minutes rest. Baseline (Day 1-predose) is the latest non-missing pre-dose assessment. Change from Baseline is defined as Post-dose visit value minus Baseline value.
Time Frame	Baseline (Day 1, predose) and at Day 1: 3, 12, 24 hours; Day 29: pre- and post-dialysis; Day 57: pre- and post-dialysis, 3, 12, 24 hours and Week 10: pre- and post-dialysis

Outcome Measure Data

Analysis Population Description

Safety Population. Only those participants with data available at specified time points has been presented (represented by n=X in the category titles).

Arm/Group Title	Daprodustat	Recombinant Human Erythropoietin
Arm/Group Description	Participants were randomized to receive a single oral dose of Daprodustat 24 milligrams (mg) during 24-hour acute challenge 1 (AC1) on Day 1. Participants discontinued their current erythropoiesis stimulating agent (ESA) therapy and were washed out of their ESAs for 2 weeks prior to acute challenge 1. After completion of acute challenge 1, participants entered in 8-week hemoglobin (Hgb) maintenance period, where doses of daprodustat were administered and adjusted to maintain target Hgb levels within the range of 10.0 to 11.0 grams per deciliter (g/dL). Participants received acute challenge 2 (AC2) on Day 57 with the same treatment dose administered in acute challenge 1. All participants were followed up for 14 days after acute challenge 2.	Participants were randomized to receive a single intravenous (IV) dose of 100 units per kilogram (U/Kg) Epoetin alfa (Recombinant human erythropoietin) during 24-hour acute challenge 1 on Day 1. Participants discontinued their current ESA therapy and were washed out of their ESAs for 2 weeks prior to acute challenge 1. After completion of acute challenge 1, participants entered in 8-week Hgb maintenance period, where Epoetin alfa was administered according to local labelling and clinical practice guidelines to maintain target Hgb levels within the range of 10.0 to 11.0 g/dL. Participants received acute challenge 2 on Day 57 with the same treatment dose administered in acute challenge 1. All participants were followed up for 14 days after acute challenge 2.
Measure Participants	44	43
Day 1: 3 hours, n=44, 43	0.61 (7.735)	0.02 (10.859)
Day1: 12 hours, n=44, 43	0.09 (8.232)	-3.53 (12.473)
Day 1: 24 hours, n=41, 40	1.39 (10.954)	-0.35 (11.005)
Day 29: pre-dialysis, n=38, 40	0.87 (9.393)	0.03 (10.850)
Day 29: post dialysis, n=38, 40	1.95 (11.203)	0.15 (12.593)
Day 57: pre-dialysis, n=32, 36	2.50 (10.522)	2.14 (10.805)
Day 57: post dialysis, n=32, 36	0.53 (9.308)	0.72 (12.523)
Day 57: 3 hours, n=32, 36	-1.19 (11.998)	0.22 (12.547)
Day 57: 12 hours, n=32, 36	-1.59 (12.104)	0.08 (10.811)
Day 57: 24 hours, n=32, 36	-0.94 (11.435)	0.33 (10.368)
Week 10: pre-dialysis, n=42, 42	1.33 (10.195)	-0.48 (13.457)
Week 10: post dialysis, n=41, 42	-0.54 (9.344)	-1.74 (11.232)

Adverse Events

Time Frame	Non-SAEs were reported from start of study treatment and up to 8 weeks in treatment period and SAEs were reported from the start of the study treatment and up to 2 weeks in follow up period (Up to Week 10).
Adverse Event Reporting Description	Non-SAEs and SAEs were reported for Safety Population.
Arm/Group Title	Daprodustat		Recombinant Human Erythropoietin
Arm/Group Description	Participants were randomized to receive a single oral dose of Daprodustat 24 milligrams (mg) during 24-hour acute challenge 1 (AC1) on Day 1. Participants discontinued their current erythropoiesis stimulating agent (ESA) therapy and were washed out of their ESAs for 2 weeks prior to acute challenge 1. After completion of acute challenge 1, participants entered in 8-week hemoglobin (Hgb) maintenance period, where doses of daprodustat were administered and adjusted to maintain target Hgb levels within the range of 10.0 to 11.0 grams per deciliter (g/dL). Participants received acute challenge 2 (AC2) on Day 57 with the same treatment dose administered in acute challenge 1. All participants were followed up for 14 days after acute challenge 2.		Participants were randomized to receive a single intravenous (IV) dose of 100 units per kilogram (U/Kg) Epoetin alfa (Recombinant human erythropoietin) during 24-hour acute challenge 1 on Day 1. Participants discontinued their current ESA therapy and were washed out of their ESAs for 2 weeks prior to acute challenge 1. After completion of acute challenge 1, participants entered in 8-week Hgb maintenance period, where Epoetin alfa was administered according to local labelling and clinical practice guidelines to maintain target Hgb levels within the range of 10.0 to 11.0 g/dL. Participants received acute challenge 2 on Day 57 with the same treatment dose administered in acute challenge 1. All participants were followed up for 14 days after acute challenge 2.
All Cause Mortality
	Daprodustat		Recombinant Human Erythropoietin
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/45 (0%)		0/43 (0%)
Serious Adverse Events
	Daprodustat		Recombinant Human Erythropoietin
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	10/45 (22.2%)		5/43 (11.6%)
Blood and lymphatic system disorders
Anaemia	2/45 (4.4%)	4	0/43 (0%)	0
Cardiac disorders
Cardiac failure congestive	1/45 (2.2%)	1	0/43 (0%)	0
Cardio-respiratory arrest	1/45 (2.2%)	1	0/43 (0%)	0
Gastrointestinal disorders
Abdominal pain	0/45 (0%)	0	1/43 (2.3%)	1
Enteritis	0/45 (0%)	0	1/43 (2.3%)	1
Haematemesis	0/45 (0%)	0	1/43 (2.3%)	1
Melaena	0/45 (0%)	0	1/43 (2.3%)	1
General disorders
Non-cardiac chest pain	0/45 (0%)	0	1/43 (2.3%)	1
Infections and infestations
Pneumonia	2/45 (4.4%)	2	0/43 (0%)	0
Osteomyelitis	1/45 (2.2%)	1	0/43 (0%)	0
Injury, poisoning and procedural complications
Upper limb fracture	0/45 (0%)	0	1/43 (2.3%)	1
Metabolism and nutrition disorders
Fluid overload	3/45 (6.7%)	3	0/43 (0%)	0
Hyperkalaemia	0/45 (0%)	0	1/43 (2.3%)	1
Musculoskeletal and connective tissue disorders
Osteoarthritis	1/45 (2.2%)	1	0/43 (0%)	0
Psychiatric disorders
Delirium	1/45 (2.2%)	1	0/43 (0%)	0
Renal and urinary disorders
Renal pain	0/45 (0%)	0	1/43 (2.3%)	1
Respiratory, thoracic and mediastinal disorders
Acute respiratory failure	1/45 (2.2%)	1	0/43 (0%)	0
Pulmonary oedema	0/45 (0%)	0	1/43 (2.3%)	1
Vascular disorders
Hypertensive urgency	2/45 (4.4%)	2	0/43 (0%)	0
Hypotension	2/45 (4.4%)	3	0/43 (0%)	0
Other (Not Including Serious) Adverse Events
	Daprodustat		Recombinant Human Erythropoietin
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	10/45 (22.2%)		4/43 (9.3%)
Endocrine disorders
Hypothyroidism	1/45 (2.2%)	1	0/43 (0%)	0
Gastrointestinal disorders
Constipation	1/45 (2.2%)	1	0/43 (0%)	0
Diarrhoea	0/45 (0%)	0	1/43 (2.3%)	2
Nausea	0/45 (0%)	0	1/43 (2.3%)	1
Vomiting	0/45 (0%)	0	1/43 (2.3%)	1
General disorders
Asthenia	0/45 (0%)	0	1/43 (2.3%)	2
Infections and infestations
Gastroenteritis	1/45 (2.2%)	1	0/43 (0%)	0
Suspected COVID-19	0/45 (0%)	0	1/43 (2.3%)	1
Upper respiratory tract infection	1/45 (2.2%)	1	0/43 (0%)	0
Injury, poisoning and procedural complications
Contusion	1/45 (2.2%)	1	0/43 (0%)	0
Metabolism and nutrition disorders
Fluid overload	1/45 (2.2%)	1	0/43 (0%)	0
Hypokalaemia	1/45 (2.2%)	1	0/43 (0%)	0
Hypophosphataemia	1/45 (2.2%)	1	0/43 (0%)	0
Musculoskeletal and connective tissue disorders
Pain in extremity	1/45 (2.2%)	1	0/43 (0%)	0
Nervous system disorders
Headache	0/45 (0%)	0	2/43 (4.7%)	2
Dizziness	1/45 (2.2%)	1	0/43 (0%)	0
Paraesthesia	1/45 (2.2%)	1	0/43 (0%)	0
Presyncope	1/45 (2.2%)	2	0/43 (0%)	0
Vascular disorders
Hypertension	0/45 (0%)	0	2/43 (4.7%)	6
Hypertensive urgency	1/45 (2.2%)	1	0/43 (0%)	0

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

GSK agreements may vary with individual investigators, but will not prohibit any investigator from publishing. GSK supports the publication of results from all centers of a multi-center trial but requests that reports based on single-site data not precede the primary publication of the entire clinical trial.