Trial Outcomes & Findings for Anemia Study in Chronic Kidney Disease (CKD): Erythropoiesis Via a Novel Prolyl Hydroxylase Inhibitor (PHI) Daprodustat-Blood Pressure (ASCEND-BP) (NCT NCT03029247)

Last Updated: 2021-06-03

Results Overview

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.

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

105 participants

Primary outcome timeframe

Up to 6 hours post dose on Day 57

Results posted on

2021-06-03

Participant Flow

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.

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were enrolled of which 88 were randomized to receive study treatment. 17 did not receive study treatment as they were withdrawn prior to randomization due to adverse events (2); protocol deviation (2); protocol specified withdrawal criteria (3); lost to follow-up (1); physician decision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).

Participant milestones

Participant milestones
Measure	Daprodustat 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.	Recombinant Human Erythropoietin 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.
Acute Challenge 1 (Day 1) STARTED	45	43
Acute Challenge 1 (Day 1) COMPLETED	45	43
Acute Challenge 1 (Day 1) NOT COMPLETED	0	0
Hgb Maintenance Phase (8 Weeks) STARTED	45	43
Hgb Maintenance Phase (8 Weeks) COMPLETED	32	36
Hgb Maintenance Phase (8 Weeks) NOT COMPLETED	13	7
Acute Challenge 2 (Day 57) STARTED	32	36
Acute Challenge 2 (Day 57) COMPLETED	32	36
Acute Challenge 2 (Day 57) NOT COMPLETED	0	0
Follow-up Period (14 Days) STARTED	32	36
Follow-up Period (14 Days) COMPLETED	32	36
Follow-up Period (14 Days) NOT COMPLETED	0	0

Reasons for withdrawal

Reasons for withdrawal
Measure	Daprodustat 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.	Recombinant Human Erythropoietin 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.
Hgb Maintenance Phase (8 Weeks) Withdrawal by Subject	3	0
Hgb Maintenance Phase (8 Weeks) Physician Decision	1	1
Hgb Maintenance Phase (8 Weeks) Protocol-specified withdrawal criterion	7	4
Hgb Maintenance Phase (8 Weeks) Adverse Event	2	2

Baseline Characteristics

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

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Daprodustat n=45 Participants 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.	Recombinant Human Erythropoietin n=43 Participants 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 n=88 Participants Total of all reporting groups
Age, Continuous	60.9 Years STANDARD_DEVIATION 11.06 • n=5 Participants	58.7 Years STANDARD_DEVIATION 10.61 • n=7 Participants	59.8 Years STANDARD_DEVIATION 10.84 • n=5 Participants
Sex: Female, Male Female	19 Participants n=5 Participants	16 Participants n=7 Participants	35 Participants n=5 Participants
Sex: Female, Male Male	26 Participants n=5 Participants	27 Participants n=7 Participants	53 Participants n=5 Participants
Race/Ethnicity, Customized Black or African American	21 Participants n=5 Participants	23 Participants n=7 Participants	44 Participants n=5 Participants
Race/Ethnicity, Customized White-Arabic/North African Heritage	1 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants
Race/Ethnicity, Customized White-White/Caucasian/European Heritage	23 Participants n=5 Participants	20 Participants n=7 Participants	43 Participants n=5 Participants

PRIMARY outcome

Timeframe: Up to 6 hours post dose on Day 57

Population: 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.

Outcome measures

Outcome measures
Measure	Daprodustat n=27 Participants 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.	Recombinant Human Erythropoietin n=28 Participants 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.
Average of Systolic Blood Pressure (SBP) Measured by Ambulatory Blood Pressure Monitoring (ABPM) Over 6-hour Post Dosing on Day 57	142.87 Millimeters of mercury (mmHg) Standard Error 3.039	143.03 Millimeters of mercury (mmHg) Standard Error 2.995

SECONDARY outcome

Timeframe: Up to 6 hours post dose on Day 1

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

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.

Outcome measures

Outcome measures
Measure	Daprodustat n=35 Participants 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.	Recombinant Human Erythropoietin n=31 Participants 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.
Average of SBP, Diastolic Blood Pressure (DBP) and Mean Arterial Blood Pressure (MAP) Measured by ABPM Over 6-hour Post Dosing on Day 1 SBP	141.36 mmHg Standard Error 3.115	142.68 mmHg Standard Error 3.313
Average of SBP, Diastolic Blood Pressure (DBP) and Mean Arterial Blood Pressure (MAP) Measured by ABPM Over 6-hour Post Dosing on Day 1 DBP	75.97 mmHg Standard Error 1.253	77.92 mmHg Standard Error 1.332
Average of SBP, Diastolic Blood Pressure (DBP) and Mean Arterial Blood Pressure (MAP) Measured by ABPM Over 6-hour Post Dosing on Day 1 MAP	99.18 mmHg Standard Error 2.212	101.58 mmHg Standard Error 2.351

SECONDARY outcome

Timeframe: Up to 6 hours post dose on Day 1

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

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.

Outcome measures

Outcome measures
Measure	Daprodustat n=35 Participants 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.	Recombinant Human Erythropoietin n=31 Participants 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.
Average of Heart Rate (HR) Measured by ABPM Over 6 Hour Post Dosing on Day 1	70.77 Beats per minute Standard Error 1.416	73.72 Beats per minute Standard Error 1.507

SECONDARY outcome

Timeframe: Up to 24 hours post dose on Day 1

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

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.

Outcome measures

Outcome measures
Measure	Daprodustat n=31 Participants 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.	Recombinant Human Erythropoietin n=27 Participants 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.
Area Under the Effect Curve (AUEC) of SBP, DBP and MAP Measured by ABPM Over 24-hour Post Dosing on Day 1 AUEC of SBP	3337.91 mmHg*Hours Standard Error 84.144	3351.33 mmHg*Hours Standard Error 90.217
Area Under the Effect Curve (AUEC) of SBP, DBP and MAP Measured by ABPM Over 24-hour Post Dosing on Day 1 AUEC of DBP	1763.11 mmHg*Hours Standard Error 39.814	1834.82 mmHg*Hours Standard Error 42.688
Area Under the Effect Curve (AUEC) of SBP, DBP and MAP Measured by ABPM Over 24-hour Post Dosing on Day 1 AUEC of MAP	2324.69 mmHg*Hours Standard Error 57.517	2378.93 mmHg*Hours Standard Error 61.668

SECONDARY outcome

Timeframe: Up to 24 hours post dose on Day 1

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

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.

Outcome measures

Outcome measures
Measure	Daprodustat n=31 Participants 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.	Recombinant Human Erythropoietin n=27 Participants 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.
AUEC of HR Measured by ABPM Over 24-hour Post Dosing on Day 1	1652.63 Beats per minute*Hours Standard Error 35.152	1727.03 Beats per minute*Hours Standard Error 37.690

SECONDARY outcome

Timeframe: Up to 6 hours post dose on Day 57

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

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.

Outcome measures

Outcome measures
Measure	Daprodustat n=27 Participants 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.	Recombinant Human Erythropoietin n=28 Participants 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.
Average of DBP and MAP Measured by ABPM Over 6-hour Post Dosing on Day 57 DBP	75.58 mmHg Standard Error 1.465	77.64 mmHg Standard Error 1.436
Average of DBP and MAP Measured by ABPM Over 6-hour Post Dosing on Day 57 MAP	98.98 mmHg Standard Error 2.208	101.49 mmHg Standard Error 2.169

SECONDARY outcome

Timeframe: Up to 6 hours post dose on Day 57

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

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.

Outcome measures

Outcome measures
Measure	Daprodustat n=27 Participants 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.	Recombinant Human Erythropoietin n=28 Participants 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.
Average of HR Measured by ABPM Over 6 Hour Post Dosing on Day 57	70.49 Beats per minute Standard Error 1.146	70.62 Beats per minute Standard Error 1.125

SECONDARY outcome

Timeframe: Up to 24 hours post dose on Day 57

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

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.

Outcome measures

Outcome measures
Measure	Daprodustat n=24 Participants 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.	Recombinant Human Erythropoietin n=21 Participants 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.
AUEC of SBP, DBP and MAP Measured by ABPM Over 24-hour Post Dosing on Day 57 AUEC of SBP	3288.43 mmHg*Hours Standard Error 85.805	3433.40 mmHg*Hours Standard Error 91.786
AUEC of SBP, DBP and MAP Measured by ABPM Over 24-hour Post Dosing on Day 57 AUEC of DBP	1736.11 mmHg*Hours Standard Error 38.659	1853.60 mmHg*Hours Standard Error 41.354
AUEC of SBP, DBP and MAP Measured by ABPM Over 24-hour Post Dosing on Day 57 AUEC of MAP	2299.42 mmHg*Hours Standard Error 58.712	2431.36 mmHg*Hours Standard Error 62.804

SECONDARY outcome

Timeframe: Up to 24 hours post dose on Day 57

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

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.

Outcome measures

Outcome measures
Measure	Daprodustat n=24 Participants 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.	Recombinant Human Erythropoietin n=21 Participants 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.
AUEC of HR Measured by ABPM Over 24-hour Post Dosing on Day 57	1579.38 Beats per minute*Hours Standard Error 40.886	1677.06 Beats per minute*Hours Standard Error 43.736

SECONDARY outcome

Timeframe: 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

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

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.

Outcome measures

Outcome measures
Measure	Daprodustat n=35 Participants 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.	Recombinant Human Erythropoietin n=31 Participants 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.
Change From Pre-dose in SBP, DBP and MAP at Day 1 MAP, Hour 6, n=35, 31	-1.27 mmHg Standard Deviation 25.359	-2.17 mmHg Standard Deviation 19.573
Change From Pre-dose in SBP, DBP and MAP at Day 1 MAP, Hour 14, n=34, 31	-6.99 mmHg Standard Deviation 25.710	-0.75 mmHg Standard Deviation 17.024
Change From Pre-dose in SBP, DBP and MAP at Day 1 MAP, Hour 15, n=32, 26	-4.06 mmHg Standard Deviation 27.693	-5.10 mmHg Standard Deviation 19.458
Change From Pre-dose in SBP, DBP and MAP at Day 1 MAP, Hour 16, n=34, 31	-4.79 mmHg Standard Deviation 26.805	3.84 mmHg Standard Deviation 22.886
Change From Pre-dose in SBP, DBP and MAP at Day 1 MAP, Hour 17, n=32, 30	-5.10 mmHg Standard Deviation 25.873	-2.09 mmHg Standard Deviation 19.856
Change From Pre-dose in SBP, DBP and MAP at Day 1 MAP, Hour 18, n=32, 27	-6.98 mmHg Standard Deviation 24.790	1.52 mmHg Standard Deviation 18.745
Change From Pre-dose in SBP, DBP and MAP at Day 1 MAP, Hour 19, n=34, 27	-4.44 mmHg Standard Deviation 26.186	-1.02 mmHg Standard Deviation 17.275
Change From Pre-dose in SBP, DBP and MAP at Day 1 MAP, Hour 20, n=33, 27	-9.47 mmHg Standard Deviation 23.186	4.23 mmHg Standard Deviation 16.311
Change From Pre-dose in SBP, DBP and MAP at Day 1 MAP, Hour 21, n=30, 27	-7.39 mmHg Standard Deviation 22.611	3.87 mmHg Standard Deviation 20.860
Change From Pre-dose in SBP, DBP and MAP at Day 1 SBP, Hour 1, n=34, 31	1.00 mmHg Standard Deviation 17.178	5.27 mmHg Standard Deviation 20.471
Change From Pre-dose in SBP, DBP and MAP at Day 1 SBP, Hour 2, n=35, 31	-4.99 mmHg Standard Deviation 28.170	4.72 mmHg Standard Deviation 22.651
Change From Pre-dose in SBP, DBP and MAP at Day 1 SBP, Hour 3, n=35, 31	-5.85 mmHg Standard Deviation 29.636	5.09 mmHg Standard Deviation 21.163
Change From Pre-dose in SBP, DBP and MAP at Day 1 SBP, Hour 4, n=35, 31	-1.68 mmHg Standard Deviation 26.000	0.93 mmHg Standard Deviation 23.962
Change From Pre-dose in SBP, DBP and MAP at Day 1 SBP, Hour 5, n=35, 31	-1.86 mmHg Standard Deviation 29.171	-2.10 mmHg Standard Deviation 23.849
Change From Pre-dose in SBP, DBP and MAP at Day 1 SBP, Hour 6, n=35, 31	0.29 mmHg Standard Deviation 31.903	-2.54 mmHg Standard Deviation 28.908
Change From Pre-dose in SBP, DBP and MAP at Day 1 SBP, Hour 7, n=34, 26	2.30 mmHg Standard Deviation 33.896	0.63 mmHg Standard Deviation 19.016
Change From Pre-dose in SBP, DBP and MAP at Day 1 SBP, Hour 8, n=33, 29	0.43 mmHg Standard Deviation 31.418	3.83 mmHg Standard Deviation 20.723
Change From Pre-dose in SBP, DBP and MAP at Day 1 SBP, Hour 9, n=33, 30	-5.81 mmHg Standard Deviation 30.725	0.25 mmHg Standard Deviation 26.294
Change From Pre-dose in SBP, DBP and MAP at Day 1 SBP, Hour 10, n=31, 28	-5.70 mmHg Standard Deviation 28.018	1.48 mmHg Standard Deviation 25.952
Change From Pre-dose in SBP, DBP and MAP at Day 1 SBP, Hour 11, n=33, 27	-7.00 mmHg Standard Deviation 27.529	1.96 mmHg Standard Deviation 24.421
Change From Pre-dose in SBP, DBP and MAP at Day 1 SBP, Hour 12, n=35, 28	-6.05 mmHg Standard Deviation 29.932	-1.67 mmHg Standard Deviation 19.380
Change From Pre-dose in SBP, DBP and MAP at Day 1 SBP, Hour 13, n=34, 28	-2.49 mmHg Standard Deviation 25.319	-1.37 mmHg Standard Deviation 25.596
Change From Pre-dose in SBP, DBP and MAP at Day 1 SBP, Hour 14, n=34, 31	-5.30 mmHg Standard Deviation 30.030	4.57 mmHg Standard Deviation 29.767
Change From Pre-dose in SBP, DBP and MAP at Day 1 SBP, Hour 15, n=32, 26	-1.47 mmHg Standard Deviation 33.573	-0.13 mmHg Standard Deviation 24.287
Change From Pre-dose in SBP, DBP and MAP at Day 1 SBP, Hour 16, n=34, 31	-4.40 mmHg Standard Deviation 30.990	8.59 mmHg Standard Deviation 24.729
Change From Pre-dose in SBP, DBP and MAP at Day 1 SBP, Hour 17, n=32, 30	-5.05 mmHg Standard Deviation 29.795	1.76 mmHg Standard Deviation 23.896
Change From Pre-dose in SBP, DBP and MAP at Day 1 SBP, Hour 18, n=32, 27	-5.23 mmHg Standard Deviation 25.993	5.48 mmHg Standard Deviation 23.330
Change From Pre-dose in SBP, DBP and MAP at Day 1 SBP, Hour 19, n=34, 27	-3.01 mmHg Standard Deviation 24.230	1.52 mmHg Standard Deviation 21.072
Change From Pre-dose in SBP, DBP and MAP at Day 1 SBP, Hour 20, n=33, 27	-13.27 mmHg Standard Deviation 24.138	6.89 mmHg Standard Deviation 16.834
Change From Pre-dose in SBP, DBP and MAP at Day 1 SBP, Hour 21, n=30, 27	-8.32 mmHg Standard Deviation 26.003	1.72 mmHg Standard Deviation 26.777
Change From Pre-dose in SBP, DBP and MAP at Day 1 SBP, Hour 22, n=29, 27	-3.93 mmHg Standard Deviation 26.106	3.50 mmHg Standard Deviation 24.428
Change From Pre-dose in SBP, DBP and MAP at Day 1 SBP, Hour 23, n=31, 26	2.73 mmHg Standard Deviation 28.343	8.72 mmHg Standard Deviation 24.868
Change From Pre-dose in SBP, DBP and MAP at Day 1 SBP, Hour 24, n=31, 27	2.63 mmHg Standard Deviation 29.379	5.02 mmHg Standard Deviation 26.601
Change From Pre-dose in SBP, DBP and MAP at Day 1 DBP, Hour 1, n=34, 31	0.01 mmHg Standard Deviation 9.317	0.99 mmHg Standard Deviation 13.110
Change From Pre-dose in SBP, DBP and MAP at Day 1 DBP, Hour 2, n=35, 31	-0.82 mmHg Standard Deviation 15.399	1.97 mmHg Standard Deviation 11.986
Change From Pre-dose in SBP, DBP and MAP at Day 1 DBP, Hour 3, n=35, 31	-1.30 mmHg Standard Deviation 14.660	0.88 mmHg Standard Deviation 11.858
Change From Pre-dose in SBP, DBP and MAP at Day 1 DBP, Hour 4, n=35, 31	-1.06 mmHg Standard Deviation 14.552	-1.17 mmHg Standard Deviation 13.621
Change From Pre-dose in SBP, DBP and MAP at Day 1 DBP, Hour 5, n=35, 31	-0.69 mmHg Standard Deviation 16.618	-1.49 mmHg Standard Deviation 11.684
Change From Pre-dose in SBP, DBP and MAP at Day 1 DBP, Hour 6, n=35, 31	-0.06 mmHg Standard Deviation 14.799	-1.49 mmHg Standard Deviation 14.457
Change From Pre-dose in SBP, DBP and MAP at Day 1 DBP, Hour 7, n=34, 26	-0.12 mmHg Standard Deviation 16.324	-1.27 mmHg Standard Deviation 15.272
Change From Pre-dose in SBP, DBP and MAP at Day 1 DBP, Hour 8, n=33, 29	1.35 mmHg Standard Deviation 15.900	1.79 mmHg Standard Deviation 15.178
Change From Pre-dose in SBP, DBP and MAP at Day 1 DBP, Hour 9, n=33, 30	-2.14 mmHg Standard Deviation 15.188	-0.68 mmHg Standard Deviation 11.874
Change From Pre-dose in SBP, DBP and MAP at Day 1 DBP, Hour 10, n=31, 28	-3.52 mmHg Standard Deviation 14.246	-0.82 mmHg Standard Deviation 12.802
Change From Pre-dose in SBP, DBP and MAP at Day 1 DBP, Hour 11, n=33, 27	-4.88 mmHg Standard Deviation 14.691	-2.45 mmHg Standard Deviation 10.987
Change From Pre-dose in SBP, DBP and MAP at Day 1 DBP, Hour 12, n=35, 28	-4.79 mmHg Standard Deviation 14.561	-3.95 mmHg Standard Deviation 10.718
Change From Pre-dose in SBP, DBP and MAP at Day 1 DBP, Hour 13, n=34, 28	-2.15 mmHg Standard Deviation 15.185	-2.65 mmHg Standard Deviation 12.841
Change From Pre-dose in SBP, DBP and MAP at Day 1 DBP, Hour 14, n=34, 31	-3.99 mmHg Standard Deviation 14.153	-1.00 mmHg Standard Deviation 14.759
Change From Pre-dose in SBP, DBP and MAP at Day 1 DBP, Hour 15, n=32, 26	-0.54 mmHg Standard Deviation 19.203	-4.12 mmHg Standard Deviation 13.905
Change From Pre-dose in SBP, DBP and MAP at Day 1 DBP, Hour 16, n=34, 31	-3.56 mmHg Standard Deviation 15.615	1.15 mmHg Standard Deviation 14.186
Change From Pre-dose in SBP, DBP and MAP at Day 1 DBP, Hour 17, n=32, 30	-3.65 mmHg Standard Deviation 14.949	-2.98 mmHg Standard Deviation 13.732
Change From Pre-dose in SBP, DBP and MAP at Day 1 DBP, Hour 18, n=32, 27	-2.08 mmHg Standard Deviation 17.015	0.30 mmHg Standard Deviation 14.219
Change From Pre-dose in SBP, DBP and MAP at Day 1 DBP, Hour 19, n=34, 27	-0.36 mmHg Standard Deviation 19.650	-0.43 mmHg Standard Deviation 14.965
Change From Pre-dose in SBP, DBP and MAP at Day 1 DBP, Hour 20, n=33, 27	-2.96 mmHg Standard Deviation 15.579	0.40 mmHg Standard Deviation 14.501
Change From Pre-dose in SBP, DBP and MAP at Day 1 MAP, Hour 22, n=29, 27	-2.77 mmHg Standard Deviation 21.938	0.75 mmHg Standard Deviation 16.888
Change From Pre-dose in SBP, DBP and MAP at Day 1 DBP, Hour 21, n=30, 27	-2.54 mmHg Standard Deviation 15.246	1.90 mmHg Standard Deviation 15.507
Change From Pre-dose in SBP, DBP and MAP at Day 1 DBP, Hour 22, n=29, 27	-0.25 mmHg Standard Deviation 15.037	-1.96 mmHg Standard Deviation 12.058
Change From Pre-dose in SBP, DBP and MAP at Day 1 DBP, Hour 23, n=31, 26	4.05 mmHg Standard Deviation 19.055	-0.44 mmHg Standard Deviation 13.218
Change From Pre-dose in SBP, DBP and MAP at Day 1 DBP, Hour 24, n=31, 27	4.48 mmHg Standard Deviation 18.097	2.16 mmHg Standard Deviation 15.124
Change From Pre-dose in SBP, DBP and MAP at Day 1 MAP, Hour 1, n=34, 31	-1.87 mmHg Standard Deviation 15.252	2.83 mmHg Standard Deviation 19.439
Change From Pre-dose in SBP, DBP and MAP at Day 1 MAP, Hour 2, n=35, 31	-4.79 mmHg Standard Deviation 24.742	4.20 mmHg Standard Deviation 17.890
Change From Pre-dose in SBP, DBP and MAP at Day 1 MAP, Hour 3, n=35, 31	-5.13 mmHg Standard Deviation 22.342	3.46 mmHg Standard Deviation 14.940
Change From Pre-dose in SBP, DBP and MAP at Day 1 MAP, Hour 4, n=35, 31	-4.78 mmHg Standard Deviation 23.640	-1.05 mmHg Standard Deviation 17.552
Change From Pre-dose in SBP, DBP and MAP at Day 1 MAP, Hour 5, n=35, 31	-3.48 mmHg Standard Deviation 26.458	-1.18 mmHg Standard Deviation 16.235
Change From Pre-dose in SBP, DBP and MAP at Day 1 MAP, Hour 7, n=34, 26	0.45 mmHg Standard Deviation 28.445	0.87 mmHg Standard Deviation 18.659
Change From Pre-dose in SBP, DBP and MAP at Day 1 MAP, Hour 8, n=33, 29	0.08 mmHg Standard Deviation 27.487	2.20 mmHg Standard Deviation 17.002
Change From Pre-dose in SBP, DBP and MAP at Day 1 MAP, Hour 9, n=33, 30	-7.02 mmHg Standard Deviation 24.498	0.61 mmHg Standard Deviation 17.072
Change From Pre-dose in SBP, DBP and MAP at Day 1 MAP, Hour 10, n=31, 28	-8.18 mmHg Standard Deviation 24.057	0.76 mmHg Standard Deviation 18.604
Change From Pre-dose in SBP, DBP and MAP at Day 1 MAP, Hour 11, n=33, 27	-8.74 mmHg Standard Deviation 25.719	-3.60 mmHg Standard Deviation 19.022
Change From Pre-dose in SBP, DBP and MAP at Day 1 MAP, Hour 12, n=35, 28	-6.49 mmHg Standard Deviation 26.669	-6.15 mmHg Standard Deviation 16.336
Change From Pre-dose in SBP, DBP and MAP at Day 1 MAP, Hour 13, n=34, 28	-5.72 mmHg Standard Deviation 23.609	-3.32 mmHg Standard Deviation 17.660
Change From Pre-dose in SBP, DBP and MAP at Day 1 MAP, Hour 23, n=31, 26	0.88 mmHg Standard Deviation 27.381	4.10 mmHg Standard Deviation 18.818
Change From Pre-dose in SBP, DBP and MAP at Day 1 MAP, Hour 24, n=31, 27	2.02 mmHg Standard Deviation 26.253	2.20 mmHg Standard Deviation 19.276

SECONDARY outcome

Timeframe: 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

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

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.

Outcome measures

Outcome measures
Measure	Daprodustat n=35 Participants 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.	Recombinant Human Erythropoietin n=31 Participants 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.
Change From Pre-dose in HR at Day 1 Hour 1, n=34, 31	-1.16 Beats per minute Standard Deviation 9.283	0.13 Beats per minute Standard Deviation 15.465
Change From Pre-dose in HR at Day 1 Hour 2, n=35, 31	-1.05 Beats per minute Standard Deviation 17.259	-2.06 Beats per minute Standard Deviation 15.409
Change From Pre-dose in HR at Day 1 Hour 3, n=35, 31	0.76 Beats per minute Standard Deviation 15.920	-0.16 Beats per minute Standard Deviation 14.911
Change From Pre-dose in HR at Day 1 Hour 4, n=35, 31	3.18 Beats per minute Standard Deviation 12.717	-1.13 Beats per minute Standard Deviation 17.798
Change From Pre-dose in HR at Day 1 Hour 5, n=35, 31	0.91 Beats per minute Standard Deviation 13.782	-0.66 Beats per minute Standard Deviation 14.119
Change From Pre-dose in HR at Day 1 Hour 6, n=35, 31	0.97 Beats per minute Standard Deviation 14.763	-1.66 Beats per minute Standard Deviation 13.023
Change From Pre-dose in HR at Day 1 Hour 7, n=34, 26	2.14 Beats per minute Standard Deviation 13.620	-1.01 Beats per minute Standard Deviation 11.592
Change From Pre-dose in HR at Day 1 Hour 8, n=33, 29	0.62 Beats per minute Standard Deviation 13.326	-1.11 Beats per minute Standard Deviation 18.376
Change From Pre-dose in HR at Day 1 Hour 9, n=33, 30	0.20 Beats per minute Standard Deviation 14.533	0.67 Beats per minute Standard Deviation 15.411
Change From Pre-dose in HR at Day 1 Hour 10, n=31, 28	2.54 Beats per minute Standard Deviation 13.575	1.60 Beats per minute Standard Deviation 13.612
Change From Pre-dose in HR at Day 1 Hour 11, n=33, 27	2.07 Beats per minute Standard Deviation 14.247	1.57 Beats per minute Standard Deviation 14.132
Change From Pre-dose in HR at Day 1 Hour 12, n=35, 28	0.77 Beats per minute Standard Deviation 12.386	-2.01 Beats per minute Standard Deviation 14.767
Change From Pre-dose in HR at Day 1 Hour 13, n=34, 28	-0.25 Beats per minute Standard Deviation 12.895	-2.45 Beats per minute Standard Deviation 14.861
Change From Pre-dose in HR at Day 1 Hour 14, n=34, 31	-1.54 Beats per minute Standard Deviation 13.148	0.25 Beats per minute Standard Deviation 13.020
Change From Pre-dose in HR at Day 1 Hour 15, n=32, 26	-0.92 Beats per minute Standard Deviation 13.406	-3.06 Beats per minute Standard Deviation 13.156
Change From Pre-dose in HR at Day 1 Hour 16, n=34, 31	-1.02 Beats per minute Standard Deviation 14.018	-2.87 Beats per minute Standard Deviation 11.762
Change From Pre-dose in HR at Day 1 Hour 17, n=32, 30	-0.85 Beats per minute Standard Deviation 14.631	-4.34 Beats per minute Standard Deviation 13.284
Change From Pre-dose in HR at Day 1 Hour 18, n=32, 27	0.60 Beats per minute Standard Deviation 15.553	0.98 Beats per minute Standard Deviation 11.443
Change From Pre-dose in HR at Day 1 Hour 19, n=34, 27	-0.56 Beats per minute Standard Deviation 14.407	-2.65 Beats per minute Standard Deviation 13.220
Change From Pre-dose in HR at Day 1 Hour 20, n=33, 27	-1.91 Beats per minute Standard Deviation 13.956	-4.77 Beats per minute Standard Deviation 17.083
Change From Pre-dose in HR at Day 1 Hour 21, n=30, 27	-1.82 Beats per minute Standard Deviation 13.841	-3.00 Beats per minute Standard Deviation 13.342
Change From Pre-dose in HR at Day 1 Hour 22, n=29, 27	0.82 Beats per minute Standard Deviation 11.686	-2.61 Beats per minute Standard Deviation 13.292
Change From Pre-dose in HR at Day 1 Hour 23, n=31, 26	-1.01 Beats per minute Standard Deviation 12.697	0.24 Beats per minute Standard Deviation 13.148
Change From Pre-dose in HR at Day 1 Hour 24, n=31, 27	-0.89 Beats per minute Standard Deviation 17.530	-0.96 Beats per minute Standard Deviation 14.651

SECONDARY outcome

Timeframe: Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 12, 16 and 24 hours on Days 1 and 57

Population: 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).

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

Outcome measures

Outcome measures
Measure	Daprodustat n=45 Participants 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.	Recombinant Human Erythropoietin 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.
Plasma Concentrations of Daprodustat Day 1, Predose, n=45	0.000 Nanograms per milliliter Standard Deviation 0.000	—
Plasma Concentrations of Daprodustat Day 1, 0.5 hours, n=43	197.118 Nanograms per milliliter Standard Deviation 329.0251	—
Plasma Concentrations of Daprodustat Day 1, 1 hour, n=43	265.828 Nanograms per milliliter Standard Deviation 340.7690	—
Plasma Concentrations of Daprodustat Day 1, 2 hours, n=43	156.103 Nanograms per milliliter Standard Deviation 150.4148	—
Plasma Concentrations of Daprodustat Day 1, 3 hours, n=43	114.485 Nanograms per milliliter Standard Deviation 139.8114	—
Plasma Concentrations of Daprodustat Day 1, 4 hours, n=44	105.375 Nanograms per milliliter Standard Deviation 150.0982	—
Plasma Concentrations of Daprodustat Day 1, 6 hours, n=44	71.995 Nanograms per milliliter Standard Deviation 104.2462	—
Plasma Concentrations of Daprodustat Day 1, 8 hours, n=43	50.069 Nanograms per milliliter Standard Deviation 91.2574	—
Plasma Concentrations of Daprodustat Day 1, 12 hours, n=41	14.165 Nanograms per milliliter Standard Deviation 30.2719	—
Plasma Concentrations of Daprodustat Day 1, 16 hours, n=43	5.350 Nanograms per milliliter Standard Deviation 11.0233	—
Plasma Concentrations of Daprodustat Day 1, 24 hours, n=43	2.899 Nanograms per milliliter Standard Deviation 10.8052	—
Plasma Concentrations of Daprodustat Day 57, Predose, n=31	8.657 Nanograms per milliliter Standard Deviation 21.3825	—
Plasma Concentrations of Daprodustat Day 57, 0.5 hours, n=31	175.616 Nanograms per milliliter Standard Deviation 257.3578	—
Plasma Concentrations of Daprodustat Day 57, 1 hour, n=31	260.817 Nanograms per milliliter Standard Deviation 307.2242	—
Plasma Concentrations of Daprodustat Day 57, 2 hours, n=30	245.277 Nanograms per milliliter Standard Deviation 251.2676	—
Plasma Concentrations of Daprodustat Day 57, 3 hours, n=31	142.366 Nanograms per milliliter Standard Deviation 154.9041	—
Plasma Concentrations of Daprodustat Day 57, 4 hours, n=32	82.696 Nanograms per milliliter Standard Deviation 104.8654	—
Plasma Concentrations of Daprodustat Day 57, 6 hours, n=31	43.751 Nanograms per milliliter Standard Deviation 55.8532	—
Plasma Concentrations of Daprodustat Day 57, 8 hours, n=31	16.484 Nanograms per milliliter Standard Deviation 27.2733	—
Plasma Concentrations of Daprodustat Day 57, 12 hours, n=30	8.661 Nanograms per milliliter Standard Deviation 16.8915	—
Plasma Concentrations of Daprodustat Day 57, 16 hours, n=30	7.279 Nanograms per milliliter Standard Deviation 21.2784	—
Plasma Concentrations of Daprodustat Day 57, 24 hours, n=31	1.371 Nanograms per milliliter Standard Deviation 2.0177	—

SECONDARY outcome

Timeframe: Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 12, 16 and 24 hours on Days 1 and 57

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

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

Outcome measures

Outcome measures
Measure	Daprodustat n=45 Participants 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.	Recombinant Human Erythropoietin 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.
Plasma Concentrations of Metabolite GSK2391220 Day 1, Predose, n=45	0.000 Nanograms per milliliter Standard Deviation 0.000	—
Plasma Concentrations of Metabolite GSK2391220 Day 1, 0.5 hours, n=43	9.847 Nanograms per milliliter Standard Deviation NA Not applicable (NA) indicates Standard deviation (SD) could not be calculated due to the high proportion of non-quantifiable (NQ) values (\>30% of values were imputed) which affected the SD.	—
Plasma Concentrations of Metabolite GSK2391220 Day 1, 1 hour, n=43	14.361 Nanograms per milliliter Standard Deviation 21.6405	—
Plasma Concentrations of Metabolite GSK2391220 Day 1, 2 hours, n=43	30.036 Nanograms per milliliter Standard Deviation 29.6152	—
Plasma Concentrations of Metabolite GSK2391220 Day 1, 3 hours, n=44	32.359 Nanograms per milliliter Standard Deviation 28.6734	—
Plasma Concentrations of Metabolite GSK2391220 Day 1, 4 hours, n=43	32.892 Nanograms per milliliter Standard Deviation 27.2772	—
Plasma Concentrations of Metabolite GSK2391220 Day 1, 6 hours, n=43	33.105 Nanograms per milliliter Standard Deviation 20.9136	—
Plasma Concentrations of Metabolite GSK2391220 Day 1, 8 hours, n=42	32.267 Nanograms per milliliter Standard Deviation 16.3824	—
Plasma Concentrations of Metabolite GSK2391220 Day 1, 12 hours, n=40	23.921 Nanograms per milliliter Standard Deviation 15.1007	—
Plasma Concentrations of Metabolite GSK2391220 Day 1, 16 hours, n=42	19.771 Nanograms per milliliter Standard Deviation 13.5013	—
Plasma Concentrations of Metabolite GSK2391220 Day 1, 24 hours, n=42	12.693 Nanograms per milliliter Standard Deviation 10.1135	—
Plasma Concentrations of Metabolite GSK2391220 Day 57, Predose, n=31	3.019 Nanograms per milliliter Standard Deviation 4.2327	—
Plasma Concentrations of Metabolite GSK2391220 Day 57, 0.5 hours, n=31	10.043 Nanograms per milliliter Standard Deviation 12.5832	—
Plasma Concentrations of Metabolite GSK2391220 Day 57, 1 hour, n=31	12.410 Nanograms per milliliter Standard Deviation 13.3576	—
Plasma Concentrations of Metabolite GSK2391220 Day 57, 2 hours, n=30	23.433 Nanograms per milliliter Standard Deviation 21.4154	—
Plasma Concentrations of Metabolite GSK2391220 Day 57, 3 hours, n=31	32.861 Nanograms per milliliter Standard Deviation 26.3829	—
Plasma Concentrations of Metabolite GSK2391220 Day 57, 4 hours, n=32	38.443 Nanograms per milliliter Standard Deviation 27.9354	—
Plasma Concentrations of Metabolite GSK2391220 Day 57, 6 hours, n=31	41.432 Nanograms per milliliter Standard Deviation 24.2976	—
Plasma Concentrations of Metabolite GSK2391220 Day 57, 8 hours, n=31	33.689 Nanograms per milliliter Standard Deviation 20.3669	—
Plasma Concentrations of Metabolite GSK2391220 Day 57, 12 hours, n=31	25.771 Nanograms per milliliter Standard Deviation 17.8554	—
Plasma Concentrations of Metabolite GSK2391220 Day 57, 16 hours, n=31	21.481 Nanograms per milliliter Standard Deviation 15.6404	—
Plasma Concentrations of Metabolite GSK2391220 Day 57, 24 hours, n=32	14.836 Nanograms per milliliter Standard Deviation 11.2824	—

SECONDARY outcome

Timeframe: Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 12, 16 and 24 hours on Days 1 and 57

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

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

Outcome measures

Outcome measures
Measure	Daprodustat n=45 Participants 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.	Recombinant Human Erythropoietin 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.
Plasma Concentrations of Metabolite GSK2506104 Day 1, Predose, n=45	0.000 Nanograms per milliliter Standard Deviation 0.000	—
Plasma Concentrations of Metabolite GSK2506104 Day 1, 0.5 hours, n=43	9.337 Nanograms per milliliter Standard Deviation NA NA indicates SD could not be calculated due to the high proportion of NQ values (\>30% of values were imputed) which affected the SD.	—
Plasma Concentrations of Metabolite GSK2506104 Day 1, 1 hour, n=43	13.263 Nanograms per milliliter Standard Deviation 20.5510	—
Plasma Concentrations of Metabolite GSK2506104 Day 1, 2 hours, n=43	28.986 Nanograms per milliliter Standard Deviation 28.4324	—
Plasma Concentrations of Metabolite GSK2506104 Day 1, 3 hours, n=44	32.623 Nanograms per milliliter Standard Deviation 29.1622	—
Plasma Concentrations of Metabolite GSK2506104 Day 1, 4 hours, n=43	34.266 Nanograms per milliliter Standard Deviation 27.5021	—
Plasma Concentrations of Metabolite GSK2506104 Day 1, 6 hours, n=43	37.250 Nanograms per milliliter Standard Deviation 21.9404	—
Plasma Concentrations of Metabolite GSK2506104 Day 1, 8 hours, n=42	39.463 Nanograms per milliliter Standard Deviation 17.2013	—
Plasma Concentrations of Metabolite GSK2506104 Day 1, 12 hours, n=40	33.822 Nanograms per milliliter Standard Deviation 16.6962	—
Plasma Concentrations of Metabolite GSK2506104 Day 1, 16 hours, n=42	31.224 Nanograms per milliliter Standard Deviation 16.3048	—
Plasma Concentrations of Metabolite GSK2506104 Day 1, 24 hours, n=42	24.268 Nanograms per milliliter Standard Deviation 14.2298	—
Plasma Concentrations of Metabolite GSK2506104 Day 57, Predose, n=31	4.133 Nanograms per milliliter Standard Deviation 4.5315	—
Plasma Concentrations of Metabolite GSK2506104 Day 57, 0.5 hours, n=31	10.759 Nanograms per milliliter Standard Deviation 11.6369	—
Plasma Concentrations of Metabolite GSK2506104 Day 57, 1 hour, n=31	12.902 Nanograms per milliliter Standard Deviation 12.5068	—
Plasma Concentrations of Metabolite GSK2506104 Day 57, 2 hours, n=30	23.391 Nanograms per milliliter Standard Deviation 20.1627	—
Plasma Concentrations of Metabolite GSK2506104 Day 57, 3 hours, n=31	33.561 Nanograms per milliliter Standard Deviation 26.4516	—
Plasma Concentrations of Metabolite GSK2506104 Day 57, 4 hours, n=32	41.089 Nanograms per milliliter Standard Deviation 28.8815	—
Plasma Concentrations of Metabolite GSK2506104 Day 57, 6 hours, n=31	47.511 Nanograms per milliliter Standard Deviation 25.5686	—
Plasma Concentrations of Metabolite GSK2506104 Day 57, 8 hours, n=31	43.646 Nanograms per milliliter Standard Deviation 22.0075	—
Plasma Concentrations of Metabolite GSK2506104 Day 57, 12 hours, n=31	39.685 Nanograms per milliliter Standard Deviation 23.4732	—
Plasma Concentrations of Metabolite GSK2506104 Day 57, 16 hours, n=31	36.234 Nanograms per milliliter Standard Deviation 22.1830	—
Plasma Concentrations of Metabolite GSK2506104 Day 57, 24 hours, n=32	27.808 Nanograms per milliliter Standard Deviation 14.8739	—

SECONDARY outcome

Timeframe: Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 12, 16 and 24 hours on Days 1 and 57

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

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

Outcome measures

Outcome measures
Measure	Daprodustat n=45 Participants 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.	Recombinant Human Erythropoietin 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.
Plasma Concentrations of Metabolite GSK2487818 Day 1, 2 hours, n=43	25.204 Nanograms per milliliter Standard Deviation 24.8233	—
Plasma Concentrations of Metabolite GSK2487818 Day 1, 3 hours, n=44	23.632 Nanograms per milliliter Standard Deviation 21.0661	—
Plasma Concentrations of Metabolite GSK2487818 Day 1, 4 hours, n=43	20.726 Nanograms per milliliter Standard Deviation 17.9713	—
Plasma Concentrations of Metabolite GSK2487818 Day 1, 6 hours, n=43	15.509 Nanograms per milliliter Standard Deviation 10.4545	—
Plasma Concentrations of Metabolite GSK2487818 Day 1, 8 hours, n=42	11.654 Nanograms per milliliter Standard Deviation 9.1747	—
Plasma Concentrations of Metabolite GSK2487818 Day 1, 12 hours, n=39	5.673 Nanograms per milliliter Standard Deviation 6.4670	—
Plasma Concentrations of Metabolite GSK2487818 Day 1, 16 hours, n=43	3.298 Nanograms per milliliter Standard Deviation 4.6779	—
Plasma Concentrations of Metabolite GSK2487818 Day 1, 24 hours, n=43	1.379 Nanograms per milliliter Standard Deviation 2.1969	—
Plasma Concentrations of Metabolite GSK2487818 Day 57, Predose, n=31	1.503 Nanograms per milliliter Standard Deviation NA NA indicates SD could not be calculated due to the high proportion of NQ values (\>30% of values were imputed) which affected the SD.	—
Plasma Concentrations of Metabolite GSK2487818 Day 1, Predose, n=45	0.000 Nanograms per milliliter Standard Deviation 0.000	—
Plasma Concentrations of Metabolite GSK2487818 Day 1, 0.5 hours, n=43	8.624 Nanograms per milliliter Standard Deviation NA NA indicates SD could not be calculated due to the high proportion of NQ values (\>30% of values were imputed) which affected the SD.	—
Plasma Concentrations of Metabolite GSK2487818 Day 1, 1 hour, n=43	13.181 Nanograms per milliliter Standard Deviation 19.2280	—
Plasma Concentrations of Metabolite GSK2487818 Day 57, 0.5 hours, n=31	7.760 Nanograms per milliliter Standard Deviation 12.2768	—
Plasma Concentrations of Metabolite GSK2487818 Day 57, 1 hour, n=31	10.507 Nanograms per milliliter Standard Deviation 13.6474	—
Plasma Concentrations of Metabolite GSK2487818 Day 57, 2 hours, n=30	20.254 Nanograms per milliliter Standard Deviation 20.1125	—
Plasma Concentrations of Metabolite GSK2487818 Day 57, 3 hours, n=30	25.092 Nanograms per milliliter Standard Deviation 20.7688	—
Plasma Concentrations of Metabolite GSK2487818 Day 57, 4 hours, n=32	24.865 Nanograms per milliliter Standard Deviation 18.7941	—
Plasma Concentrations of Metabolite GSK2487818 Day 57, 6 hours, n=31	21.749 Nanograms per milliliter Standard Deviation 16.6572	—
Plasma Concentrations of Metabolite GSK2487818 Day 57, 8 hours, n=31	11.419 Nanograms per milliliter Standard Deviation 11.2821	—
Plasma Concentrations of Metabolite GSK2487818 Day 57, 12 hours, n=31	5.537 Nanograms per milliliter Standard Deviation 9.1160	—
Plasma Concentrations of Metabolite GSK2487818 Day 57, 16 hours, n=30	3.613 Nanograms per milliliter Standard Deviation 6.4974	—
Plasma Concentrations of Metabolite GSK2487818 Day 57, 24 hours, n=31	1.693 Nanograms per milliliter Standard Deviation 2.9455	—

SECONDARY outcome

Timeframe: Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 12, 16 and 24 hours on Days 1 and 57

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

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

Outcome measures

Outcome measures
Measure	Daprodustat n=45 Participants 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.	Recombinant Human Erythropoietin 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.
Plasma Concentrations of Metabolite GSK2506102 Day 1, Predose, n=45	0.000 Nanograms per milliliter Standard Deviation 0.000	—
Plasma Concentrations of Metabolite GSK2506102 Day 1, 0.5 hours, n=43	1.862 Nanograms per milliliter Standard Deviation NA NA indicates SD could not be calculated due to the high proportion of NQ values (\>30% of values were imputed) which affected the SD.	—
Plasma Concentrations of Metabolite GSK2506102 Day 1, 1 hour, n=44	2.575 Nanograms per milliliter Standard Deviation NA NA indicates SD could not be calculated due to the high proportion of NQ values (\>30% of values were imputed) which affected the SD.	—
Plasma Concentrations of Metabolite GSK2506102 Day 1, 2 hours, n=43	5.999 Nanograms per milliliter Standard Deviation 5.9281	—
Plasma Concentrations of Metabolite GSK2506102 Day 1, 3 hours, n=44	7.047 Nanograms per milliliter Standard Deviation 6.3772	—
Plasma Concentrations of Metabolite GSK2506102 Day 1, 4 hours, n=43	7.554 Nanograms per milliliter Standard Deviation 6.0767	—
Plasma Concentrations of Metabolite GSK2506102 Day 1, 6 hours, n=43	8.564 Nanograms per milliliter Standard Deviation 5.0888	—
Plasma Concentrations of Metabolite GSK2506102 Day 1, 8 hours, n=42	9.379 Nanograms per milliliter Standard Deviation 3.9554	—
Plasma Concentrations of Metabolite GSK2506102 Day 1, 12 hours, n=40	8.658 Nanograms per milliliter Standard Deviation 3.6930	—
Plasma Concentrations of Metabolite GSK2506102 Day 1, 16 hours, n=42	8.225 Nanograms per milliliter Standard Deviation 3.7400	—
Plasma Concentrations of Metabolite GSK2506102 Day 1, 24 hours, n=42	7.024 Nanograms per milliliter Standard Deviation 3.5347	—
Plasma Concentrations of Metabolite GSK2506102 Day 57, Predose, n=31	1.126 Nanograms per milliliter Standard Deviation 1.0181	—
Plasma Concentrations of Metabolite GSK2506102 Day 57, 0.5 hours, n=30	2.472 Nanograms per milliliter Standard Deviation 2.2298	—
Plasma Concentrations of Metabolite GSK2506102 Day 57, 1 hour, n=31	2.890 Nanograms per milliliter Standard Deviation 2.4847	—
Plasma Concentrations of Metabolite GSK2506102 Day 57, 2 hours, n=30	5.082 Nanograms per milliliter Standard Deviation 4.1937	—
Plasma Concentrations of Metabolite GSK2506102 Day 57, 3 hours, n=31	7.688 Nanograms per milliliter Standard Deviation 5.7677	—
Plasma Concentrations of Metabolite GSK2506102 Day 57, 4 hours, n=32	9.474 Nanograms per milliliter Standard Deviation 6.3929	—
Plasma Concentrations of Metabolite GSK2506102 Day 57, 6 hours, n=30	11.507 Nanograms per milliliter Standard Deviation 5.3600	—
Plasma Concentrations of Metabolite GSK2506102 Day 57, 8 hours, n=31	10.945 Nanograms per milliliter Standard Deviation 4.9425	—
Plasma Concentrations of Metabolite GSK2506102 Day 57, 12 hours, n=31	10.286 Nanograms per milliliter Standard Deviation 5.1703	—
Plasma Concentrations of Metabolite GSK2506102 Day 57, 16 hours, n=31	9.735 Nanograms per milliliter Standard Deviation 5.1306	—
Plasma Concentrations of Metabolite GSK2506102 Day 57, 24 hours, n=32	8.449 Nanograms per milliliter Standard Deviation 3.7371	—

SECONDARY outcome

Timeframe: Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 12, 16 and 24 hours on Days 1 and 57

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

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

Outcome measures

Outcome measures
Measure	Daprodustat n=45 Participants 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.	Recombinant Human Erythropoietin 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.
Plasma Concentrations of Metabolite GSK2531398 Day 1, Predose, n=45	0.000 Nanograms per milliliter Standard Deviation 0.000	—
Plasma Concentrations of Metabolite GSK2531398 Day 1, 0.5 hours, n=43	4.409 Nanograms per milliliter Standard Deviation NA NA indicates SD could not be calculated due to the high proportion of NQ values (\>30% of values were imputed) which affected the SD.	—
Plasma Concentrations of Metabolite GSK2531398 Day 1, 1 hour, n=44	6.139 Nanograms per milliliter Standard Deviation NA NA indicates SD could not be calculated due to the high proportion of NQ values (\>30% of values were imputed) which affected the SD.	—
Plasma Concentrations of Metabolite GSK2531398 Day 1, 2 hours, n=43	13.779 Nanograms per milliliter Standard Deviation 13.5109	—
Plasma Concentrations of Metabolite GSK2531398 Day 1, 3 hours, n=44	15.087 Nanograms per milliliter Standard Deviation 13.4427	—
Plasma Concentrations of Metabolite GSK2531398 Day 1, 4 hours, n=43	14.881 Nanograms per milliliter Standard Deviation 12.5678	—
Plasma Concentrations of Metabolite GSK2531398 Day 1, 6 hours, n=43	14.907 Nanograms per milliliter Standard Deviation 9.6957	—
Plasma Concentrations of Metabolite GSK2531398 Day 1, 8 hours, n=42	13.930 Nanograms per milliliter Standard Deviation 7.4098	—
Plasma Concentrations of Metabolite GSK2531398 Day 1, 12 hours, n=40	9.784 Nanograms per milliliter Standard Deviation 6.6328	—
Plasma Concentrations of Metabolite GSK2531398 Day 1, 16 hours, n=42	7.751 Nanograms per milliliter Standard Deviation 5.9158	—
Plasma Concentrations of Metabolite GSK2531398 Day 1, 24 hours, n=42	4.687 Nanograms per milliliter Standard Deviation 4.1099	—
Plasma Concentrations of Metabolite GSK2531398 Day 57, Predose, n=31	1.246 Nanograms per milliliter Standard Deviation 1.9695	—
Plasma Concentrations of Metabolite GSK2531398 Day 57, 0.5 hours, n=30	4.482 Nanograms per milliliter Standard Deviation 5.7104	—
Plasma Concentrations of Metabolite GSK2531398 Day 57, 1 hour, n=31	5.406 Nanograms per milliliter Standard Deviation 5.8321	—
Plasma Concentrations of Metabolite GSK2531398 Day 57, 2 hours, n=30	10.580 Nanograms per milliliter Standard Deviation 10.1185	—
Plasma Concentrations of Metabolite GSK2531398 Day 57, 3 hours, n=31	15.191 Nanograms per milliliter Standard Deviation 12.9991	—
Plasma Concentrations of Metabolite GSK2531398 Day 57, 4 hours, n=32	17.904 Nanograms per milliliter Standard Deviation 13.4024	—
Plasma Concentrations of Metabolite GSK2531398 Day 57, 6 hours, n=30	19.827 Nanograms per milliliter Standard Deviation 11.4600	—
Plasma Concentrations of Metabolite GSK2531398 Day 57, 8 hours, n=31	15.038 Nanograms per milliliter Standard Deviation 11.0475	—
Plasma Concentrations of Metabolite GSK2531398 Day 57, 12 hours, n=31	10.292 Nanograms per milliliter Standard Deviation 8.2309	—
Plasma Concentrations of Metabolite GSK2531398 Day 57, 16 hours, n=31	8.348 Nanograms per milliliter Standard Deviation 7.1590	—
Plasma Concentrations of Metabolite GSK2531398 Day 57, 24 hours, n=32	5.334 Nanograms per milliliter Standard Deviation 4.8807	—

SECONDARY outcome

Timeframe: Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 12, 16 and 24 hours on Days 1 and 57

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

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

Outcome measures

Outcome measures
Measure	Daprodustat n=45 Participants 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.	Recombinant Human Erythropoietin 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.
Plasma Concentrations of Metabolite GSK2531401 Day 1, Predose, n=45	0.000 Nanograms per milliliter Standard Deviation 0.000	—
Plasma Concentrations of Metabolite GSK2531401 Day 1, 0.5 hours, n=43	2.927 Nanograms per milliliter Standard Deviation NA NA indicates SD could not be calculated due to the high proportion of NQ values (\>30% of values were imputed) which affected the SD.	—
Plasma Concentrations of Metabolite GSK2531401 Day 1, 1 hour, n=44	4.134 Nanograms per milliliter Standard Deviation NA NA indicates SD could not be calculated due to the high proportion of NQ values (\>30% of values were imputed) which affected the SD.	—
Plasma Concentrations of Metabolite GSK2531401 Day 1, 2 hours, n=43	11.013 Nanograms per milliliter Standard Deviation 11.9279	—
Plasma Concentrations of Metabolite GSK2531401 Day 1, 3 hours, n=44	13.752 Nanograms per milliliter Standard Deviation 14.0238	—
Plasma Concentrations of Metabolite GSK2531401 Day 1, 4 hours, n=43	15.497 Nanograms per milliliter Standard Deviation 14.6142	—
Plasma Concentrations of Metabolite GSK2531401 Day 1, 6 hours, n=43	18.302 Nanograms per milliliter Standard Deviation 13.9244	—
Plasma Concentrations of Metabolite GSK2531401 Day 1, 8 hours, n=42	21.139 Nanograms per milliliter Standard Deviation 13.2221	—
Plasma Concentrations of Metabolite GSK2531401 Day 1, 12 hours, n=40	20.174 Nanograms per milliliter Standard Deviation 11.6828	—
Plasma Concentrations of Metabolite GSK2531401 Day 1, 16 hours, n=42	20.127 Nanograms per milliliter Standard Deviation 12.1374	—
Plasma Concentrations of Metabolite GSK2531401 Day 1, 24 hours, n=42	18.143 Nanograms per milliliter Standard Deviation 11.6065	—
Plasma Concentrations of Metabolite GSK2531401 Day 57, Predose, n=31	2.448 Nanograms per milliliter Standard Deviation 2.0199	—
Plasma Concentrations of Metabolite GSK2531401 Day 57, 0.5 hours, n=31	4.486 Nanograms per milliliter Standard Deviation 3.9244	—
Plasma Concentrations of Metabolite GSK2531401 Day 57, 1 hour, n=31	5.480 Nanograms per milliliter Standard Deviation 5.0425	—
Plasma Concentrations of Metabolite GSK2531401 Day 57, 2 hours, n=30	9.015 Nanograms per milliliter Standard Deviation 8.4201	—
Plasma Concentrations of Metabolite GSK2531401 Day 57, 3 hours, n=31	14.027 Nanograms per milliliter Standard Deviation 12.7046	—
Plasma Concentrations of Metabolite GSK2531401 Day 57, 4 hours, n=32	17.722 Nanograms per milliliter Standard Deviation 14.2802	—
Plasma Concentrations of Metabolite GSK2531401 Day 57, 6 hours, n=30	24.285 Nanograms per milliliter Standard Deviation 15.7868	—
Plasma Concentrations of Metabolite GSK2531401 Day 57, 8 hours, n=31	25.557 Nanograms per milliliter Standard Deviation 16.2248	—
Plasma Concentrations of Metabolite GSK2531401 Day 57, 12 hours, n=31	25.288 Nanograms per milliliter Standard Deviation 15.7597	—
Plasma Concentrations of Metabolite GSK2531401 Day 57, 16 hours, n=31	24.881 Nanograms per milliliter Standard Deviation 15.3688	—
Plasma Concentrations of Metabolite GSK2531401 Day 57, 24 hours, n=32	21.914 Nanograms per milliliter Standard Deviation 12.9806	—

SECONDARY outcome

Timeframe: Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 12, 16 and 24 hours on Days 1 and 57

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

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.

Outcome measures

Outcome measures
Measure	Daprodustat n=44 Participants 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.	Recombinant Human Erythropoietin 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.
Maximum Plasma Concentration (Cmax) of Daprodustat, GSK2391220, GSK2487818, GSK2506102, GSK2506104, GSK2531398 and GSK2531401 Daprodustat, Day 1, n=44	218.841 Nanograms per milliliter Geometric Coefficient of Variation 187.869	—
Maximum Plasma Concentration (Cmax) of Daprodustat, GSK2391220, GSK2487818, GSK2506102, GSK2506104, GSK2531398 and GSK2531401 Daprodustat, Day 57, n=32	163.795 Nanograms per milliliter Geometric Coefficient of Variation 330.249	—
Maximum Plasma Concentration (Cmax) of Daprodustat, GSK2391220, GSK2487818, GSK2506102, GSK2506104, GSK2531398 and GSK2531401 GSK2391220, Day 1, n=44	39.506 Nanograms per milliliter Geometric Coefficient of Variation 66.816	—
Maximum Plasma Concentration (Cmax) of Daprodustat, GSK2391220, GSK2487818, GSK2506102, GSK2506104, GSK2531398 and GSK2531401 GSK2391220, Day 57, n=32	44.703 Nanograms per milliliter Geometric Coefficient of Variation 57.029	—
Maximum Plasma Concentration (Cmax) of Daprodustat, GSK2391220, GSK2487818, GSK2506102, GSK2506104, GSK2531398 and GSK2531401 GSK2487818, Day 1, n=44	26.678 Nanograms per milliliter Geometric Coefficient of Variation 79.992	—
Maximum Plasma Concentration (Cmax) of Daprodustat, GSK2391220, GSK2487818, GSK2506102, GSK2506104, GSK2531398 and GSK2531401 GSK2487818, Day 57, n=32	24.846 Nanograms per milliliter Geometric Coefficient of Variation 117.570	—
Maximum Plasma Concentration (Cmax) of Daprodustat, GSK2391220, GSK2487818, GSK2506102, GSK2506104, GSK2531398 and GSK2531401 GSK2506102, Day 1, n=44	9.933 Nanograms per milliliter Geometric Coefficient of Variation 62.188	—
Maximum Plasma Concentration (Cmax) of Daprodustat, GSK2391220, GSK2487818, GSK2506102, GSK2506104, GSK2531398 and GSK2531401 GSK2506102, Day 57, n=32	12.114 Nanograms per milliliter Geometric Coefficient of Variation 46.563	—
Maximum Plasma Concentration (Cmax) of Daprodustat, GSK2391220, GSK2487818, GSK2506102, GSK2506104, GSK2531398 and GSK2531401 GSK2506104, Day 1, n=44	43.169 Nanograms per milliliter Geometric Coefficient of Variation 61.558	—
Maximum Plasma Concentration (Cmax) of Daprodustat, GSK2391220, GSK2487818, GSK2506102, GSK2506104, GSK2531398 and GSK2531401 GSK2506104, Day 57, n=32	51.643 Nanograms per milliliter Geometric Coefficient of Variation 48.087	—
Maximum Plasma Concentration (Cmax) of Daprodustat, GSK2391220, GSK2487818, GSK2506102, GSK2506104, GSK2531398 and GSK2531401 GSK2531398, Day 1, n=44	18.454 Nanograms per milliliter Geometric Coefficient of Variation 67.277	—
Maximum Plasma Concentration (Cmax) of Daprodustat, GSK2391220, GSK2487818, GSK2506102, GSK2506104, GSK2531398 and GSK2531401 GSK2531398, Day 57, n=32	20.362 Nanograms per milliliter Geometric Coefficient of Variation 67.040	—
Maximum Plasma Concentration (Cmax) of Daprodustat, GSK2391220, GSK2487818, GSK2506102, GSK2506104, GSK2531398 and GSK2531401 GSK2531401, Day 1, n=44	18.335 Nanograms per milliliter Geometric Coefficient of Variation 96.906	—
Maximum Plasma Concentration (Cmax) of Daprodustat, GSK2391220, GSK2487818, GSK2506102, GSK2506104, GSK2531398 and GSK2531401 GSK2531401, Day 57, n=32	23.337 Nanograms per milliliter Geometric Coefficient of Variation 75.801	—

SECONDARY outcome

Timeframe: Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 12, 16 and 24 hours on Days 1 and 57

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

Outcome measures

Outcome measures
Measure	Daprodustat n=44 Participants 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.	Recombinant Human Erythropoietin 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.
Time of Occurrence of Cmax (Tmax) of Daprodustat, GSK2391220, GSK2487818, GSK2506102, GSK2506104, GSK2531398 and GSK2531401 Daprodustat, Day 1, n=44	2.000 Hours Interval 0.38 to 8.0	—
Time of Occurrence of Cmax (Tmax) of Daprodustat, GSK2391220, GSK2487818, GSK2506102, GSK2506104, GSK2531398 and GSK2531401 Daprodustat, Day 57, n=32	2.000 Hours Interval 0.5 to 12.0	—
Time of Occurrence of Cmax (Tmax) of Daprodustat, GSK2391220, GSK2487818, GSK2506102, GSK2506104, GSK2531398 and GSK2531401 GSK2391220, Day 1, n=44	4.160 Hours Interval 0.5 to 16.0	—
Time of Occurrence of Cmax (Tmax) of Daprodustat, GSK2391220, GSK2487818, GSK2506102, GSK2506104, GSK2531398 and GSK2531401 GSK2391220, Day 57, n=32	4.000 Hours Interval 0.5 to 16.0	—
Time of Occurrence of Cmax (Tmax) of Daprodustat, GSK2391220, GSK2487818, GSK2506102, GSK2506104, GSK2531398 and GSK2531401 GSK2487818, Day 1, n=44	3.090 Hours Interval 0.5 to 12.0	—
Time of Occurrence of Cmax (Tmax) of Daprodustat, GSK2391220, GSK2487818, GSK2506102, GSK2506104, GSK2531398 and GSK2531401 GSK2487818, Day 57, n=32	4.000 Hours Interval 0.5 to 12.0	—
Time of Occurrence of Cmax (Tmax) of Daprodustat, GSK2391220, GSK2487818, GSK2506102, GSK2506104, GSK2531398 and GSK2531401 GSK2506102, Day 1, n=44	6.000 Hours Interval 0.5 to 24.0	—
Time of Occurrence of Cmax (Tmax) of Daprodustat, GSK2391220, GSK2487818, GSK2506102, GSK2506104, GSK2531398 and GSK2531401 GSK2506102, Day 57, n=32	6.000 Hours Interval 2.0 to 24.0	—
Time of Occurrence of Cmax (Tmax) of Daprodustat, GSK2391220, GSK2487818, GSK2506102, GSK2506104, GSK2531398 and GSK2531401 GSK2506104, Day 1, n=44	6.000 Hours Interval 0.5 to 16.3	—
Time of Occurrence of Cmax (Tmax) of Daprodustat, GSK2391220, GSK2487818, GSK2506102, GSK2506104, GSK2531398 and GSK2531401 GSK2506104, Day 57, n=32	5.990 Hours Interval 0.5 to 24.0	—
Time of Occurrence of Cmax (Tmax) of Daprodustat, GSK2391220, GSK2487818, GSK2506102, GSK2506104, GSK2531398 and GSK2531401 GSK2531398, Day 1, n=44	4.160 Hours Interval 0.5 to 24.0	—
Time of Occurrence of Cmax (Tmax) of Daprodustat, GSK2391220, GSK2487818, GSK2506102, GSK2506104, GSK2531398 and GSK2531401 GSK2531398, Day 57, n=32	4.000 Hours Interval 0.5 to 16.0	—
Time of Occurrence of Cmax (Tmax) of Daprodustat, GSK2391220, GSK2487818, GSK2506102, GSK2506104, GSK2531398 and GSK2531401 GSK2531401, Day 1, n=44	8.015 Hours Interval 1.0 to 24.5	—
Time of Occurrence of Cmax (Tmax) of Daprodustat, GSK2391220, GSK2487818, GSK2506102, GSK2506104, GSK2531398 and GSK2531401 GSK2531401, Day 57, n=32	8.000 Hours Interval 3.0 to 24.0	—

SECONDARY outcome

Timeframe: Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 12, 16 and 24 hours on Days 1 and 57

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

Outcome measures

Outcome measures
Measure	Daprodustat n=44 Participants 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.	Recombinant Human Erythropoietin 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.
Terminal Phase Half-life (t1/2) of Daprodustat, GSK2391220, GSK2487818, GSK2506102, GSK2506104, GSK2531398 and GSK2531401 Daprodustat, Day 1, n=22	3.031 Hours Geometric Coefficient of Variation 40.320	—
Terminal Phase Half-life (t1/2) of Daprodustat, GSK2391220, GSK2487818, GSK2506102, GSK2506104, GSK2531398 and GSK2531401 Daprodustat, Day 57, n=10	3.635 Hours Geometric Coefficient of Variation 26.884	—
Terminal Phase Half-life (t1/2) of Daprodustat, GSK2391220, GSK2487818, GSK2506102, GSK2506104, GSK2531398 and GSK2531401 GSK2391220, Day 1, n=9	6.820 Hours Geometric Coefficient of Variation 22.096	—
Terminal Phase Half-life (t1/2) of Daprodustat, GSK2391220, GSK2487818, GSK2506102, GSK2506104, GSK2531398 and GSK2531401 GSK2391220, Day 57, n=4	7.447 Hours Geometric Coefficient of Variation 7.539	—
Terminal Phase Half-life (t1/2) of Daprodustat, GSK2391220, GSK2487818, GSK2506102, GSK2506104, GSK2531398 and GSK2531401 GSK2487818, Day 1, n=20	3.388 Hours Geometric Coefficient of Variation 22.165	—
Terminal Phase Half-life (t1/2) of Daprodustat, GSK2391220, GSK2487818, GSK2506102, GSK2506104, GSK2531398 and GSK2531401 GSK2487818, Day 57, n=13	3.524 Hours Geometric Coefficient of Variation 32.634	—
Terminal Phase Half-life (t1/2) of Daprodustat, GSK2391220, GSK2487818, GSK2506102, GSK2506104, GSK2531398 and GSK2531401 GSK2506102, Day 1, n=1	8.530 Hours Geometric Coefficient of Variation NA NA indicates geometric coefficient of variation could not be calculated for single participant.	—
Terminal Phase Half-life (t1/2) of Daprodustat, GSK2391220, GSK2487818, GSK2506102, GSK2506104, GSK2531398 and GSK2531401 GSK2506102, Day 57, n=32	NA Hours Geometric Coefficient of Variation NA NA indicates data were not analyzed for t1/2 as there were not enough data points collected for a terminal slope required to calculate t1/2.	—
Terminal Phase Half-life (t1/2) of Daprodustat, GSK2391220, GSK2487818, GSK2506102, GSK2506104, GSK2531398 and GSK2531401 GSK2506104, Day 1, n=1	6.150 Hours Geometric Coefficient of Variation NA NA indicates geometric coefficient of variation could not be calculated for single participant.	—
Terminal Phase Half-life (t1/2) of Daprodustat, GSK2391220, GSK2487818, GSK2506102, GSK2506104, GSK2531398 and GSK2531401 GSK2506104, Day 57, n=32	NA Hours Geometric Coefficient of Variation NA NA indicates data were not analyzed for t1/2 as there were not enough data points collected for a terminal slope required to calculate t1/2.	—
Terminal Phase Half-life (t1/2) of Daprodustat, GSK2391220, GSK2487818, GSK2506102, GSK2506104, GSK2531398 and GSK2531401 GSK2531398, Day 1, n=11	5.582 Hours Geometric Coefficient of Variation 22.955	—
Terminal Phase Half-life (t1/2) of Daprodustat, GSK2391220, GSK2487818, GSK2506102, GSK2506104, GSK2531398 and GSK2531401 GSK2531398, Day 57, n=9	6.182 Hours Geometric Coefficient of Variation 14.307	—
Terminal Phase Half-life (t1/2) of Daprodustat, GSK2391220, GSK2487818, GSK2506102, GSK2506104, GSK2531398 and GSK2531401 GSK2531401, Day 1, n=44	NA Hours Geometric Coefficient of Variation NA NA indicates data were not analyzed for t1/2 as there were not enough data points collected for a terminal slope required to calculate t1/2.	—
Terminal Phase Half-life (t1/2) of Daprodustat, GSK2391220, GSK2487818, GSK2506102, GSK2506104, GSK2531398 and GSK2531401 GSK2531401, Day 57, n=32	NA Hours Geometric Coefficient of Variation NA NA indicates data were not analyzed for t1/2 as there were not enough data points collected for a terminal slope required to calculate t1/2.	—

SECONDARY outcome

Timeframe: Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 12, 16 and 24 hours on Days 1 and 57

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

Outcome measures

Outcome measures
Measure	Daprodustat n=42 Participants 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.	Recombinant Human Erythropoietin 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.
Area Under Concentration-time Curve From Time Zero to 24 Hours (AUC[0-24]) of Daprodustat, GSK2391220, GSK2487818, GSK2506102, GSK2506104, GSK2531398 and GSK2531401 Daprodustat, Day 1, n=42	767.95 Hour*nanograms per milliliter Geometric Coefficient of Variation 125.63	—
Area Under Concentration-time Curve From Time Zero to 24 Hours (AUC[0-24]) of Daprodustat, GSK2391220, GSK2487818, GSK2506102, GSK2506104, GSK2531398 and GSK2531401 Daprodustat, Day 57, n=28	616.12 Hour*nanograms per milliliter Geometric Coefficient of Variation 168.05	—
Area Under Concentration-time Curve From Time Zero to 24 Hours (AUC[0-24]) of Daprodustat, GSK2391220, GSK2487818, GSK2506102, GSK2506104, GSK2531398 and GSK2531401 GSK2391220, Day 1, n=42	483.12 Hour*nanograms per milliliter Geometric Coefficient of Variation 60.42	—
Area Under Concentration-time Curve From Time Zero to 24 Hours (AUC[0-24]) of Daprodustat, GSK2391220, GSK2487818, GSK2506102, GSK2506104, GSK2531398 and GSK2531401 GSK2391220, Day 57, n=31	516.59 Hour*nanograms per milliliter Geometric Coefficient of Variation 61.78	—
Area Under Concentration-time Curve From Time Zero to 24 Hours (AUC[0-24]) of Daprodustat, GSK2391220, GSK2487818, GSK2506102, GSK2506104, GSK2531398 and GSK2531401 GSK2487818, Day 1, n=41	177.39 Hour*nanograms per milliliter Geometric Coefficient of Variation 66.83	—
Area Under Concentration-time Curve From Time Zero to 24 Hours (AUC[0-24]) of Daprodustat, GSK2391220, GSK2487818, GSK2506102, GSK2506104, GSK2531398 and GSK2531401 GSK2487818, Day 57, n=28	171.09 Hour*nanograms per milliliter Geometric Coefficient of Variation 93.41	—
Area Under Concentration-time Curve From Time Zero to 24 Hours (AUC[0-24]) of Daprodustat, GSK2391220, GSK2487818, GSK2506102, GSK2506104, GSK2531398 and GSK2531401 GSK2506102, Day 1, n=42	166.89 Hour*nanograms per milliliter Geometric Coefficient of Variation 52.93	—
Area Under Concentration-time Curve From Time Zero to 24 Hours (AUC[0-24]) of Daprodustat, GSK2391220, GSK2487818, GSK2506102, GSK2506104, GSK2531398 and GSK2531401 GSK2506102, Day 57, n=31	199.85 Hour*nanograms per milliliter Geometric Coefficient of Variation 44.33	—
Area Under Concentration-time Curve From Time Zero to 24 Hours (AUC[0-24]) of Daprodustat, GSK2391220, GSK2487818, GSK2506102, GSK2506104, GSK2531398 and GSK2531401 GSK2506104, Day 1, n=42	662.23 Hour*nanograms per milliliter Geometric Coefficient of Variation 54.48	—
Area Under Concentration-time Curve From Time Zero to 24 Hours (AUC[0-24]) of Daprodustat, GSK2391220, GSK2487818, GSK2506102, GSK2506104, GSK2531398 and GSK2531401 GSK2506104, Day 57, n=31	756.39 Hour*nanograms per milliliter Geometric Coefficient of Variation 50.29	—
Area Under Concentration-time Curve From Time Zero to 24 Hours (AUC[0-24]) of Daprodustat, GSK2391220, GSK2487818, GSK2506102, GSK2506104, GSK2531398 and GSK2531401 GSK2531398, Day 1, n=42	204.02 Hour*nanograms per milliliter Geometric Coefficient of Variation 59.48	—
Area Under Concentration-time Curve From Time Zero to 24 Hours (AUC[0-24]) of Daprodustat, GSK2391220, GSK2487818, GSK2506102, GSK2506104, GSK2531398 and GSK2531401 GSK2531398, Day 57, n=31	212.04 Hour*nanograms per milliliter Geometric Coefficient of Variation 66.63	—
Area Under Concentration-time Curve From Time Zero to 24 Hours (AUC[0-24]) of Daprodustat, GSK2391220, GSK2487818, GSK2506102, GSK2506104, GSK2531398 and GSK2531401 GSK2531401, Day 1, n=42	334.86 Hour*nanograms per milliliter Geometric Coefficient of Variation 93.49	—
Area Under Concentration-time Curve From Time Zero to 24 Hours (AUC[0-24]) of Daprodustat, GSK2391220, GSK2487818, GSK2506102, GSK2506104, GSK2531398 and GSK2531401 GSK2531401, Day 57, n=31	430.10 Hour*nanograms per milliliter Geometric Coefficient of Variation 73.53	—

OTHER_PRE_SPECIFIED outcome

Timeframe: Up to Week 10

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

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.

Outcome measures

Outcome measures
Measure	Daprodustat n=45 Participants 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.	Recombinant Human Erythropoietin n=43 Participants 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.
Number of Participants With Any Serious Adverse Events (SAEs)	10 Participants	5 Participants

OTHER_PRE_SPECIFIED outcome

Timeframe: Up to Week 8

Population: Safety Population.

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.

Outcome measures

Outcome measures
Measure	Daprodustat n=45 Participants 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.	Recombinant Human Erythropoietin n=43 Participants 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.
Number of Participants With Treatment Emergent Common (>=2%) Non-serious Adverse Events (Non-SAEs)	10 Participants	4 Participants

OTHER_PRE_SPECIFIED outcome

Timeframe: Up to Week 10

Population: ITT Population.

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.