Trial Outcomes & Findings for Anemia Studies in Chronic Kidney Disease (CKD): Erythropoiesis Via a Novel Prolyl Hydroxylase Inhibitor (PHI) Daprodustat-Three-times Weekly Dosing in Dialysis (ASCEND-TD) (NCT NCT03400033)

Last Updated: 2021-07-12

Results Overview

Blood samples were collected from participants for hemoglobin measurements. Hemoglobin during the evaluation period was defined as the mean of all available post-randomization hemoglobin values (on and off-treatment) during the evaluation period (Week 28 to Week 52). For the primary analysis, the missing post-Baseline hemoglobin values were imputed using pre-specified multiple imputations. Baseline value was the latest non-missing pre-dose assessment on or before the randomization date, including those from unscheduled visits. Change from Baseline was defined as the average of post-randomization values during the evaluation period minus Baseline value. Analysis was performed using the Analysis of Covariance (ANCOVA) model with terms for treatment, Baseline hemoglobin, and region.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

407 participants

Primary outcome timeframe

Baseline (Pre-dose on Day 1) and evaluation period (Week 28 to Week 52)

Results posted on

2021-07-12

Participant Flow

This was a multicenter study conducted at 90 centers in 13 countries. Participants were randomized to receive either Daprodustat or Epoetin alfa.

A total of 595 participants were screened, of which 188 were screen failures. A total of 407 participants were enrolled in the study.

Participant milestones

Participant milestones
Measure	Daprodustat Participants received daprodustat tablets with titrated dose levels ranging from 2, 4, 8, 12, 16, 20, 24, 32 and 48 milligrams (mg) orally three-times weekly up to 52 weeks. Study treatment was dose-titrated to achieve and maintain hemoglobin in the target range (10 to 11 grams per deciliter \[g/dL\]). In order to maintain the study blind, participants also received saline intravenous (IV) injection once weekly or three-times weekly depending on dose level, up to 52 weeks as an inactive treatment for the IV formulation. All participants were followed up at 4 to 6 weeks after last dose.	Epoetin Alfa Participants received epoetin alfa with titrated dose levels ranging from 1500 Units to 60,000 Units total weekly dose and administered as IV injection once weekly or three-times weekly depending on dose level up to 52 weeks. Study treatment was dose-titrated to achieve and maintain hemoglobin in the target range (10 to 11 g/dL). In order to maintain the study blind, participants also received placebo tablets matching to daprodustat orally three-times weekly up to 52 weeks as an inactive treatment for the tablet formulation. All participants were followed up at 4 to 6 weeks after last dose.
Overall Study STARTED	270	137
Overall Study COMPLETED	269	135
Overall Study NOT COMPLETED	1	2

Reasons for withdrawal

Reasons for withdrawal
Measure	Daprodustat Participants received daprodustat tablets with titrated dose levels ranging from 2, 4, 8, 12, 16, 20, 24, 32 and 48 milligrams (mg) orally three-times weekly up to 52 weeks. Study treatment was dose-titrated to achieve and maintain hemoglobin in the target range (10 to 11 grams per deciliter \[g/dL\]). In order to maintain the study blind, participants also received saline intravenous (IV) injection once weekly or three-times weekly depending on dose level, up to 52 weeks as an inactive treatment for the IV formulation. All participants were followed up at 4 to 6 weeks after last dose.	Epoetin Alfa Participants received epoetin alfa with titrated dose levels ranging from 1500 Units to 60,000 Units total weekly dose and administered as IV injection once weekly or three-times weekly depending on dose level up to 52 weeks. Study treatment was dose-titrated to achieve and maintain hemoglobin in the target range (10 to 11 g/dL). In order to maintain the study blind, participants also received placebo tablets matching to daprodustat orally three-times weekly up to 52 weeks as an inactive treatment for the tablet formulation. All participants were followed up at 4 to 6 weeks after last dose.
Overall Study Withdrawal by Subject	1	2

Baseline Characteristics

Anemia Studies in Chronic Kidney Disease (CKD): Erythropoiesis Via a Novel Prolyl Hydroxylase Inhibitor (PHI) Daprodustat-Three-times Weekly Dosing in Dialysis (ASCEND-TD)

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Daprodustat n=270 Participants Participants received daprodustat tablets with titrated dose levels ranging from 2, 4, 8, 12, 16, 20, 24, 32 and 48 milligrams (mg) orally three-times weekly up to 52 weeks. Study treatment was dose-titrated to achieve and maintain hemoglobin in the target range (10 to 11 grams per deciliter \[g/dL\]). In order to maintain the study blind, participants also received saline intravenous (IV) injection once weekly or three-times weekly depending on dose level, up to 52 weeks as an inactive treatment for the IV formulation. All participants were followed up at 4 to 6 weeks after last dose.	Epoetin Alfa n=137 Participants Participants received epoetin alfa with titrated dose levels ranging from 1500 Units to 60,000 Units total weekly dose and administered as IV injection once weekly or three-times weekly depending on dose level up to 52 weeks. Study treatment was dose-titrated to achieve and maintain hemoglobin in the target range (10 to 11 g/dL). In order to maintain the study blind, participants also received placebo tablets matching to daprodustat orally three-times weekly up to 52 weeks as an inactive treatment for the tablet formulation. All participants were followed up at 4 to 6 weeks after last dose.	Total n=407 Participants Total of all reporting groups
Age, Customized 19-64 Years	167 Participants n=5 Participants	96 Participants n=7 Participants	263 Participants n=5 Participants
Age, Customized >= 65 Years	103 Participants n=5 Participants	41 Participants n=7 Participants	144 Participants n=5 Participants
Sex: Female, Male Female	121 Participants n=5 Participants	56 Participants n=7 Participants	177 Participants n=5 Participants
Sex: Female, Male Male	149 Participants n=5 Participants	81 Participants n=7 Participants	230 Participants n=5 Participants
Race/Ethnicity, Customized BLACK OR AFRICAN AMERICAN	49 Participants n=5 Participants	32 Participants n=7 Participants	81 Participants n=5 Participants
Race/Ethnicity, Customized AMERICAN INDIAN OR ALASKAN NATIVE	1 Participants n=5 Participants	1 Participants n=7 Participants	2 Participants n=5 Participants
Race/Ethnicity, Customized ASIAN - CENTRAL/SOUTH ASIAN HERITAGE	1 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants
Race/Ethnicity, Customized ASIAN - EAST ASIAN HERITAGE	16 Participants n=5 Participants	9 Participants n=7 Participants	25 Participants n=5 Participants
Race/Ethnicity, Customized ASIAN - SOUTH EAST ASIAN HERITAGE	3 Participants n=5 Participants	0 Participants n=7 Participants	3 Participants n=5 Participants
Race/Ethnicity, Customized NATIVE HAWAIIAN OR OTHER PACIFIC ISLANDER	1 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants
Race/Ethnicity, Customized WHITE - ARABIC/NORTH AFRICAN HERITAGE	1 Participants n=5 Participants	4 Participants n=7 Participants	5 Participants n=5 Participants
Race/Ethnicity, Customized WHITE - WHITE/CAUCASIAN/EUROPEAN HERITAGE	193 Participants n=5 Participants	90 Participants n=7 Participants	283 Participants n=5 Participants
Race/Ethnicity, Customized MIXED WHITE RACE	1 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants
Race/Ethnicity, Customized MIXED RACE	1 Participants n=5 Participants	1 Participants n=7 Participants	2 Participants n=5 Participants
Race/Ethnicity, Customized UNKNOWN	3 Participants n=5 Participants	0 Participants n=7 Participants	3 Participants n=5 Participants

PRIMARY outcome

Timeframe: Baseline (Pre-dose on Day 1) and evaluation period (Week 28 to Week 52)

Population: All Randomized (Intent-to-treat \[ITT\]) Population comprised of all randomized participants. Any participant who received a treatment randomization number was considered to have been randomized.

Outcome measures

Outcome measures
Measure	Daprodustat n=270 Participants Participants received daprodustat tablets with titrated dose levels ranging from 2, 4, 8, 12, 16, 20, 24, 32 and 48 milligrams (mg) orally three-times weekly up to 52 weeks. Study treatment was dose-titrated to achieve and maintain hemoglobin in the target range (10 to 11 grams per deciliter \[g/dL\]). In order to maintain the study blind, participants also received saline intravenous (IV) injection once weekly or three-times weekly depending on dose level, up to 52 weeks as an inactive treatment for the IV formulation. All participants were followed up at 4 to 6 weeks after last dose.	Epoetin Alfa n=137 Participants Participants received epoetin alfa with titrated dose levels ranging from 1500 Units to 60,000 Units total weekly dose and administered as IV injection once weekly or three-times weekly depending on dose level up to 52 weeks. Study treatment was dose-titrated to achieve and maintain hemoglobin in the target range (10 to 11 g/dL). In order to maintain the study blind, participants also received placebo tablets matching to daprodustat orally three-times weekly up to 52 weeks as an inactive treatment for the tablet formulation. All participants were followed up at 4 to 6 weeks after last dose.	Daprodustat 8 mg Participants received daprodustat tablets 8 mg orally three-times weekly at the time of the pharmacokinetic visit.	Daprodustat 12 mg Participants received daprodustat tablets 12 mg orally three-times weekly at the time of the pharmacokinetic visit.	Daprodustat 16 mg Participants received daprodustat tablets 16 mg orally three-times weekly at the time of the pharmacokinetic visit.	Daprodustat 20 mg Participants received daprodustat tablets 20 mg orally three-times weekly at the time of the pharmacokinetic visit.	Daprodustat 24 mg Participants received daprodustat tablets 24 mg orally three-times weekly at the time of the pharmacokinetic visit.	Daprodustat 32 mg Participants received daprodustat tablets 32 mg orally three-times weekly at the time of the pharmacokinetic visit.	Daprodustat 48 mg Participants received daprodustat tablets 48 mg orally three-times weekly at the time of the pharmacokinetic visit.
Mean Change From Baseline in Hemoglobin Levels Over the Evaluation Period (Week 28 to Week 52)	-0.04 Grams per deciliter (g/dL) Standard Error 0.045	0.02 Grams per deciliter (g/dL) Standard Error 0.066	—	—	—	—	—	—	—

SECONDARY outcome

Timeframe: Day 1 to Week 52

Population: All Randomized (ITT) Population. Only those participants with data available at specified time points were analyzed.

Average monthly IV iron dose (mg) per participant during Day 1 to Week 52 was determined by calculating the total IV iron dose per participant from Day 1 to Week 52 while the participant was on study treatment and dividing by (the number of days the participant was on study treatment divided by 30.4375 days). Analysis was performed using the ANCOVA model with terms for treatment, Baseline monthly IV iron dose, and region.

Outcome measures

Outcome measures
Measure	Daprodustat n=270 Participants Participants received daprodustat tablets with titrated dose levels ranging from 2, 4, 8, 12, 16, 20, 24, 32 and 48 milligrams (mg) orally three-times weekly up to 52 weeks. Study treatment was dose-titrated to achieve and maintain hemoglobin in the target range (10 to 11 grams per deciliter \[g/dL\]). In order to maintain the study blind, participants also received saline intravenous (IV) injection once weekly or three-times weekly depending on dose level, up to 52 weeks as an inactive treatment for the IV formulation. All participants were followed up at 4 to 6 weeks after last dose.	Epoetin Alfa n=136 Participants Participants received epoetin alfa with titrated dose levels ranging from 1500 Units to 60,000 Units total weekly dose and administered as IV injection once weekly or three-times weekly depending on dose level up to 52 weeks. Study treatment was dose-titrated to achieve and maintain hemoglobin in the target range (10 to 11 g/dL). In order to maintain the study blind, participants also received placebo tablets matching to daprodustat orally three-times weekly up to 52 weeks as an inactive treatment for the tablet formulation. All participants were followed up at 4 to 6 weeks after last dose.	Daprodustat 8 mg Participants received daprodustat tablets 8 mg orally three-times weekly at the time of the pharmacokinetic visit.	Daprodustat 12 mg Participants received daprodustat tablets 12 mg orally three-times weekly at the time of the pharmacokinetic visit.	Daprodustat 16 mg Participants received daprodustat tablets 16 mg orally three-times weekly at the time of the pharmacokinetic visit.	Daprodustat 20 mg Participants received daprodustat tablets 20 mg orally three-times weekly at the time of the pharmacokinetic visit.	Daprodustat 24 mg Participants received daprodustat tablets 24 mg orally three-times weekly at the time of the pharmacokinetic visit.	Daprodustat 32 mg Participants received daprodustat tablets 32 mg orally three-times weekly at the time of the pharmacokinetic visit.	Daprodustat 48 mg Participants received daprodustat tablets 48 mg orally three-times weekly at the time of the pharmacokinetic visit.
Mean Average Monthly On-treatment Intravenous (IV) Iron Dose Per Participant	98.11 Milligrams Standard Error 11.049	106.23 Milligrams Standard Error 15.569	—	—	—	—	—	—	—

SECONDARY outcome

Timeframe: Baseline (Pre-dose on Day 1) and Week 52

Population: All Randomized (ITT) Population. Only those participants with data available at specified time points were analyzed.

Blood samples were collected from participants for hemoglobin measurements. Baseline value was the latest non-missing pre-dose assessment on or before the randomization date, including those from unscheduled visits. Change from Baseline was defined as the post-randomization visit value minus Baseline value. Analysis was performed using a mixed model repeated measures (MMRM) model fitted to hemoglobin data collected after Baseline up to Week 52, excluding values collected during the stabilization period (Day 1 to Week 28). The model included factors for treatment, time, region, Baseline hemoglobin and Baseline hemoglobin by time and treatment by time interaction terms.

Outcome measures

Outcome measures
Measure	Daprodustat n=252 Participants Participants received daprodustat tablets with titrated dose levels ranging from 2, 4, 8, 12, 16, 20, 24, 32 and 48 milligrams (mg) orally three-times weekly up to 52 weeks. Study treatment was dose-titrated to achieve and maintain hemoglobin in the target range (10 to 11 grams per deciliter \[g/dL\]). In order to maintain the study blind, participants also received saline intravenous (IV) injection once weekly or three-times weekly depending on dose level, up to 52 weeks as an inactive treatment for the IV formulation. All participants were followed up at 4 to 6 weeks after last dose.	Epoetin Alfa n=128 Participants Participants received epoetin alfa with titrated dose levels ranging from 1500 Units to 60,000 Units total weekly dose and administered as IV injection once weekly or three-times weekly depending on dose level up to 52 weeks. Study treatment was dose-titrated to achieve and maintain hemoglobin in the target range (10 to 11 g/dL). In order to maintain the study blind, participants also received placebo tablets matching to daprodustat orally three-times weekly up to 52 weeks as an inactive treatment for the tablet formulation. All participants were followed up at 4 to 6 weeks after last dose.	Daprodustat 8 mg Participants received daprodustat tablets 8 mg orally three-times weekly at the time of the pharmacokinetic visit.	Daprodustat 12 mg Participants received daprodustat tablets 12 mg orally three-times weekly at the time of the pharmacokinetic visit.	Daprodustat 16 mg Participants received daprodustat tablets 16 mg orally three-times weekly at the time of the pharmacokinetic visit.	Daprodustat 20 mg Participants received daprodustat tablets 20 mg orally three-times weekly at the time of the pharmacokinetic visit.	Daprodustat 24 mg Participants received daprodustat tablets 24 mg orally three-times weekly at the time of the pharmacokinetic visit.	Daprodustat 32 mg Participants received daprodustat tablets 32 mg orally three-times weekly at the time of the pharmacokinetic visit.	Daprodustat 48 mg Participants received daprodustat tablets 48 mg orally three-times weekly at the time of the pharmacokinetic visit.
Change From Baseline in Hemoglobin Levels at Week 52	-0.03 Grams per deciliter Standard Error 0.069	0.11 Grams per deciliter Standard Error 0.098	—	—	—	—	—	—	—

SECONDARY outcome

Timeframe: Week 28 to Week 52

Population: All Randomized (ITT) Population. Only those participants with at least one evaluable hemoglobin value during the evaluation period were analyzed.

Participants received treatment during the study to achieve or maintain hemoglobin level in the target range. Percentage of time for which hemoglobin level was maintained within the analysis range (10 to 11.5 grams/deciliter) has been presented.

Outcome measures

Outcome measures
Measure	Daprodustat n=215 Participants Participants received daprodustat tablets with titrated dose levels ranging from 2, 4, 8, 12, 16, 20, 24, 32 and 48 milligrams (mg) orally three-times weekly up to 52 weeks. Study treatment was dose-titrated to achieve and maintain hemoglobin in the target range (10 to 11 grams per deciliter \[g/dL\]). In order to maintain the study blind, participants also received saline intravenous (IV) injection once weekly or three-times weekly depending on dose level, up to 52 weeks as an inactive treatment for the IV formulation. All participants were followed up at 4 to 6 weeks after last dose.	Epoetin Alfa n=107 Participants Participants received epoetin alfa with titrated dose levels ranging from 1500 Units to 60,000 Units total weekly dose and administered as IV injection once weekly or three-times weekly depending on dose level up to 52 weeks. Study treatment was dose-titrated to achieve and maintain hemoglobin in the target range (10 to 11 g/dL). In order to maintain the study blind, participants also received placebo tablets matching to daprodustat orally three-times weekly up to 52 weeks as an inactive treatment for the tablet formulation. All participants were followed up at 4 to 6 weeks after last dose.	Daprodustat 8 mg Participants received daprodustat tablets 8 mg orally three-times weekly at the time of the pharmacokinetic visit.	Daprodustat 12 mg Participants received daprodustat tablets 12 mg orally three-times weekly at the time of the pharmacokinetic visit.	Daprodustat 16 mg Participants received daprodustat tablets 16 mg orally three-times weekly at the time of the pharmacokinetic visit.	Daprodustat 20 mg Participants received daprodustat tablets 20 mg orally three-times weekly at the time of the pharmacokinetic visit.	Daprodustat 24 mg Participants received daprodustat tablets 24 mg orally three-times weekly at the time of the pharmacokinetic visit.	Daprodustat 32 mg Participants received daprodustat tablets 32 mg orally three-times weekly at the time of the pharmacokinetic visit.	Daprodustat 48 mg Participants received daprodustat tablets 48 mg orally three-times weekly at the time of the pharmacokinetic visit.
Percentage of Time With Hemoglobin in the Analysis Range (10 to 11.5 Grams/Deciliter) Over Evaluation Period (Week 28 to Week 52)	70.83 Percentage of days Interval 50.98 to 91.07	61.76 Percentage of days Interval 29.69 to 85.19	—	—	—	—	—	—	—

SECONDARY outcome

Timeframe: Week 28 to Week 52

Population: All Randomized (ITT) Population. Only those participants with at least one evaluable hemoglobin value during the evaluation period were analyzed.

Mean hemoglobin during the evaluation period was defined as the mean of all evaluable hemoglobin values during the evaluation period (Week 28 to Week 52) including any evaluable unscheduled hemoglobin values that were taken during this time period. Hemoglobin responders were defined as the number of participants with a mean hemoglobin during the evaluation period that falls within the hemoglobin analysis range of 10-11.5 grams/deciliter.

Outcome measures

Outcome measures
Measure	Daprodustat n=215 Participants Participants received daprodustat tablets with titrated dose levels ranging from 2, 4, 8, 12, 16, 20, 24, 32 and 48 milligrams (mg) orally three-times weekly up to 52 weeks. Study treatment was dose-titrated to achieve and maintain hemoglobin in the target range (10 to 11 grams per deciliter \[g/dL\]). In order to maintain the study blind, participants also received saline intravenous (IV) injection once weekly or three-times weekly depending on dose level, up to 52 weeks as an inactive treatment for the IV formulation. All participants were followed up at 4 to 6 weeks after last dose.	Epoetin Alfa n=107 Participants Participants received epoetin alfa with titrated dose levels ranging from 1500 Units to 60,000 Units total weekly dose and administered as IV injection once weekly or three-times weekly depending on dose level up to 52 weeks. Study treatment was dose-titrated to achieve and maintain hemoglobin in the target range (10 to 11 g/dL). In order to maintain the study blind, participants also received placebo tablets matching to daprodustat orally three-times weekly up to 52 weeks as an inactive treatment for the tablet formulation. All participants were followed up at 4 to 6 weeks after last dose.	Daprodustat 8 mg Participants received daprodustat tablets 8 mg orally three-times weekly at the time of the pharmacokinetic visit.	Daprodustat 12 mg Participants received daprodustat tablets 12 mg orally three-times weekly at the time of the pharmacokinetic visit.	Daprodustat 16 mg Participants received daprodustat tablets 16 mg orally three-times weekly at the time of the pharmacokinetic visit.	Daprodustat 20 mg Participants received daprodustat tablets 20 mg orally three-times weekly at the time of the pharmacokinetic visit.	Daprodustat 24 mg Participants received daprodustat tablets 24 mg orally three-times weekly at the time of the pharmacokinetic visit.	Daprodustat 32 mg Participants received daprodustat tablets 32 mg orally three-times weekly at the time of the pharmacokinetic visit.	Daprodustat 48 mg Participants received daprodustat tablets 48 mg orally three-times weekly at the time of the pharmacokinetic visit.
Number of Hemoglobin Responders in the Hemoglobin Analysis Range (10 to 11.5 Grams/Deciliter) Over Evaluation Period (Week 28 to Week 52)	172 Participants	68 Participants	—	—	—	—	—	—	—

SECONDARY outcome

Timeframe: Up to Week 52

Population: All Randomized (ITT) Population

Percentage of participants permanently stopping study treatment due to meeting rescue criteria has been presented.

Outcome measures

Outcome measures
Measure	Daprodustat n=270 Participants Participants received daprodustat tablets with titrated dose levels ranging from 2, 4, 8, 12, 16, 20, 24, 32 and 48 milligrams (mg) orally three-times weekly up to 52 weeks. Study treatment was dose-titrated to achieve and maintain hemoglobin in the target range (10 to 11 grams per deciliter \[g/dL\]). In order to maintain the study blind, participants also received saline intravenous (IV) injection once weekly or three-times weekly depending on dose level, up to 52 weeks as an inactive treatment for the IV formulation. All participants were followed up at 4 to 6 weeks after last dose.	Epoetin Alfa n=137 Participants Participants received epoetin alfa with titrated dose levels ranging from 1500 Units to 60,000 Units total weekly dose and administered as IV injection once weekly or three-times weekly depending on dose level up to 52 weeks. Study treatment was dose-titrated to achieve and maintain hemoglobin in the target range (10 to 11 g/dL). In order to maintain the study blind, participants also received placebo tablets matching to daprodustat orally three-times weekly up to 52 weeks as an inactive treatment for the tablet formulation. All participants were followed up at 4 to 6 weeks after last dose.	Daprodustat 8 mg Participants received daprodustat tablets 8 mg orally three-times weekly at the time of the pharmacokinetic visit.	Daprodustat 12 mg Participants received daprodustat tablets 12 mg orally three-times weekly at the time of the pharmacokinetic visit.	Daprodustat 16 mg Participants received daprodustat tablets 16 mg orally three-times weekly at the time of the pharmacokinetic visit.	Daprodustat 20 mg Participants received daprodustat tablets 20 mg orally three-times weekly at the time of the pharmacokinetic visit.	Daprodustat 24 mg Participants received daprodustat tablets 24 mg orally three-times weekly at the time of the pharmacokinetic visit.	Daprodustat 32 mg Participants received daprodustat tablets 32 mg orally three-times weekly at the time of the pharmacokinetic visit.	Daprodustat 48 mg Participants received daprodustat tablets 48 mg orally three-times weekly at the time of the pharmacokinetic visit.
Percentage of Participants Permanently Stopping Study Treatment Due to Meeting Rescue Criteria	2.2 Percentage of participants	2.2 Percentage of participants	—	—	—	—	—	—	—

SECONDARY outcome

Timeframe: Baseline (Week -4 ) and Week 52

Population: All Randomized (ITT) Population. Only those participants with data available at specified time points were analyzed.

Measurements for SBP, DBP and MAP were taken with the participant in a semi-supine or seated position in the dialysis chair after at least a 5-minute rest period. MAP is the average BP in an individual's arteries during a single cardiac cycle. Baseline value was the latest non-missing pre-dose assessment on or before the randomization date, including those from unscheduled visits. Change from Baseline was defined as the on-treatment visit value minus Baseline value. Analysis was performed using MMRM model with treatment group, time, region, Baseline value, Baseline value\*time, treatment group\*time as variables.

Outcome measures

Outcome measures
Measure	Daprodustat n=266 Participants Participants received daprodustat tablets with titrated dose levels ranging from 2, 4, 8, 12, 16, 20, 24, 32 and 48 milligrams (mg) orally three-times weekly up to 52 weeks. Study treatment was dose-titrated to achieve and maintain hemoglobin in the target range (10 to 11 grams per deciliter \[g/dL\]). In order to maintain the study blind, participants also received saline intravenous (IV) injection once weekly or three-times weekly depending on dose level, up to 52 weeks as an inactive treatment for the IV formulation. All participants were followed up at 4 to 6 weeks after last dose.	Epoetin Alfa n=133 Participants Participants received epoetin alfa with titrated dose levels ranging from 1500 Units to 60,000 Units total weekly dose and administered as IV injection once weekly or three-times weekly depending on dose level up to 52 weeks. Study treatment was dose-titrated to achieve and maintain hemoglobin in the target range (10 to 11 g/dL). In order to maintain the study blind, participants also received placebo tablets matching to daprodustat orally three-times weekly up to 52 weeks as an inactive treatment for the tablet formulation. All participants were followed up at 4 to 6 weeks after last dose.	Daprodustat 8 mg Participants received daprodustat tablets 8 mg orally three-times weekly at the time of the pharmacokinetic visit.	Daprodustat 12 mg Participants received daprodustat tablets 12 mg orally three-times weekly at the time of the pharmacokinetic visit.	Daprodustat 16 mg Participants received daprodustat tablets 16 mg orally three-times weekly at the time of the pharmacokinetic visit.	Daprodustat 20 mg Participants received daprodustat tablets 20 mg orally three-times weekly at the time of the pharmacokinetic visit.	Daprodustat 24 mg Participants received daprodustat tablets 24 mg orally three-times weekly at the time of the pharmacokinetic visit.	Daprodustat 32 mg Participants received daprodustat tablets 32 mg orally three-times weekly at the time of the pharmacokinetic visit.	Daprodustat 48 mg Participants received daprodustat tablets 48 mg orally three-times weekly at the time of the pharmacokinetic visit.
Change From Baseline in Systolic Blood Pressure (SBP), Diastolic Blood Pressure (DBP) and Mean Arterial Pressure (MAP) at Week 52 DBP	-2.52 Millimeter of mercury (mmHg) Standard Error 0.764	-0.29 Millimeter of mercury (mmHg) Standard Error 1.176	—	—	—	—	—	—	—
Change From Baseline in Systolic Blood Pressure (SBP), Diastolic Blood Pressure (DBP) and Mean Arterial Pressure (MAP) at Week 52 SBP	-3.18 Millimeter of mercury (mmHg) Standard Error 1.470	0.55 Millimeter of mercury (mmHg) Standard Error 2.252	—	—	—	—	—	—	—
Change From Baseline in Systolic Blood Pressure (SBP), Diastolic Blood Pressure (DBP) and Mean Arterial Pressure (MAP) at Week 52 MAP	-2.72 Millimeter of mercury (mmHg) Standard Error 0.907	-0.12 Millimeter of mercury (mmHg) Standard Error 1.389	—	—	—	—	—	—	—

SECONDARY outcome

Timeframe: Baseline (Week -4) and end of treatment (last on-treatment value until Week 52)

Population: All Randomized (ITT) Population. Only those participants with data available at specified time points were analyzed.

Measurements for SBP, DBP and MAP were taken with the participant in a semi-supine or seated position in the dialysis chair after at least a 5-minute rest period. MAP is the average BP in an individual's arteries during a single cardiac cycle. Baseline value was the latest non-missing pre-dose assessment on or before the randomization date, including those from unscheduled visits. Change from Baseline was defined as the last on-treatment visit value minus Baseline value. Analysis was performed using ANCOVA model with terms for treatment group, region and Baseline value. Adjusted mean and standard error have been presented.

Outcome measures

Outcome measures
Measure	Daprodustat n=270 Participants Participants received daprodustat tablets with titrated dose levels ranging from 2, 4, 8, 12, 16, 20, 24, 32 and 48 milligrams (mg) orally three-times weekly up to 52 weeks. Study treatment was dose-titrated to achieve and maintain hemoglobin in the target range (10 to 11 grams per deciliter \[g/dL\]). In order to maintain the study blind, participants also received saline intravenous (IV) injection once weekly or three-times weekly depending on dose level, up to 52 weeks as an inactive treatment for the IV formulation. All participants were followed up at 4 to 6 weeks after last dose.	Epoetin Alfa n=136 Participants Participants received epoetin alfa with titrated dose levels ranging from 1500 Units to 60,000 Units total weekly dose and administered as IV injection once weekly or three-times weekly depending on dose level up to 52 weeks. Study treatment was dose-titrated to achieve and maintain hemoglobin in the target range (10 to 11 g/dL). In order to maintain the study blind, participants also received placebo tablets matching to daprodustat orally three-times weekly up to 52 weeks as an inactive treatment for the tablet formulation. All participants were followed up at 4 to 6 weeks after last dose.	Daprodustat 8 mg Participants received daprodustat tablets 8 mg orally three-times weekly at the time of the pharmacokinetic visit.	Daprodustat 12 mg Participants received daprodustat tablets 12 mg orally three-times weekly at the time of the pharmacokinetic visit.	Daprodustat 16 mg Participants received daprodustat tablets 16 mg orally three-times weekly at the time of the pharmacokinetic visit.	Daprodustat 20 mg Participants received daprodustat tablets 20 mg orally three-times weekly at the time of the pharmacokinetic visit.	Daprodustat 24 mg Participants received daprodustat tablets 24 mg orally three-times weekly at the time of the pharmacokinetic visit.	Daprodustat 32 mg Participants received daprodustat tablets 32 mg orally three-times weekly at the time of the pharmacokinetic visit.	Daprodustat 48 mg Participants received daprodustat tablets 48 mg orally three-times weekly at the time of the pharmacokinetic visit.
Change From Baseline in SBP, DBP and MAP at End of Treatment SBP	-1.4 Millimeter of mercury (mmHg) Standard Error 1.24	-0.9 Millimeter of mercury (mmHg) Standard Error 1.75	—	—	—	—	—	—	—
Change From Baseline in SBP, DBP and MAP at End of Treatment DBP	-1.8 Millimeter of mercury (mmHg) Standard Error 0.66	-0.8 Millimeter of mercury (mmHg) Standard Error 0.93	—	—	—	—	—	—	—
Change From Baseline in SBP, DBP and MAP at End of Treatment MAP	-1.7 Millimeter of mercury (mmHg) Standard Error 0.78	-0.8 Millimeter of mercury (mmHg) Standard Error 1.09	—	—	—	—	—	—	—

SECONDARY outcome

Timeframe: Up to 52 weeks

Population: All Randomized (ITT) Population. Only those participants with data available at specified time points were analyzed.

BP exacerbation event is defined (based on post-dialysis BP) as SBP \>=25 mmHg increased from Baseline or SBP \>=180 mmHg; or DBP \>=15 mmHg increased from Baseline or DBP \>=110 mmHg. The BP exacerbation events per 100 participant years was estimated using the Negative Binomial Model.

Outcome measures

Outcome measures
Measure	Daprodustat n=270 Participants Participants received daprodustat tablets with titrated dose levels ranging from 2, 4, 8, 12, 16, 20, 24, 32 and 48 milligrams (mg) orally three-times weekly up to 52 weeks. Study treatment was dose-titrated to achieve and maintain hemoglobin in the target range (10 to 11 grams per deciliter \[g/dL\]). In order to maintain the study blind, participants also received saline intravenous (IV) injection once weekly or three-times weekly depending on dose level, up to 52 weeks as an inactive treatment for the IV formulation. All participants were followed up at 4 to 6 weeks after last dose.	Epoetin Alfa n=136 Participants Participants received epoetin alfa with titrated dose levels ranging from 1500 Units to 60,000 Units total weekly dose and administered as IV injection once weekly or three-times weekly depending on dose level up to 52 weeks. Study treatment was dose-titrated to achieve and maintain hemoglobin in the target range (10 to 11 g/dL). In order to maintain the study blind, participants also received placebo tablets matching to daprodustat orally three-times weekly up to 52 weeks as an inactive treatment for the tablet formulation. All participants were followed up at 4 to 6 weeks after last dose.	Daprodustat 8 mg Participants received daprodustat tablets 8 mg orally three-times weekly at the time of the pharmacokinetic visit.	Daprodustat 12 mg Participants received daprodustat tablets 12 mg orally three-times weekly at the time of the pharmacokinetic visit.	Daprodustat 16 mg Participants received daprodustat tablets 16 mg orally three-times weekly at the time of the pharmacokinetic visit.	Daprodustat 20 mg Participants received daprodustat tablets 20 mg orally three-times weekly at the time of the pharmacokinetic visit.	Daprodustat 24 mg Participants received daprodustat tablets 24 mg orally three-times weekly at the time of the pharmacokinetic visit.	Daprodustat 32 mg Participants received daprodustat tablets 32 mg orally three-times weekly at the time of the pharmacokinetic visit.	Daprodustat 48 mg Participants received daprodustat tablets 48 mg orally three-times weekly at the time of the pharmacokinetic visit.
Blood Pressure (BP) Exacerbation Event Rate Per 100 Participant Years	250.45 Events per 100 participant years Interval 210.69 to 297.72	356.91 Events per 100 participant years Interval 280.95 to 453.41	—	—	—	—	—	—	—

SECONDARY outcome

Timeframe: Up to 52 weeks

Population: All Randomized (ITT) Population. Only those participants with data available at specified time points were analyzed.

BP exacerbation (based on post-dialysis BP) is defined as: SBP \>= 25 mmHg increased from Baseline or SBP \>=180mmHg; or DBP \>=15 mmHg increase from Baseline or DBP \>=110 mmHg. Number of participants with at least 1 BP exacerbation event have been reported.

Outcome measures

Outcome measures
Measure	Daprodustat n=270 Participants Participants received daprodustat tablets with titrated dose levels ranging from 2, 4, 8, 12, 16, 20, 24, 32 and 48 milligrams (mg) orally three-times weekly up to 52 weeks. Study treatment was dose-titrated to achieve and maintain hemoglobin in the target range (10 to 11 grams per deciliter \[g/dL\]). In order to maintain the study blind, participants also received saline intravenous (IV) injection once weekly or three-times weekly depending on dose level, up to 52 weeks as an inactive treatment for the IV formulation. All participants were followed up at 4 to 6 weeks after last dose.	Epoetin Alfa n=136 Participants Participants received epoetin alfa with titrated dose levels ranging from 1500 Units to 60,000 Units total weekly dose and administered as IV injection once weekly or three-times weekly depending on dose level up to 52 weeks. Study treatment was dose-titrated to achieve and maintain hemoglobin in the target range (10 to 11 g/dL). In order to maintain the study blind, participants also received placebo tablets matching to daprodustat orally three-times weekly up to 52 weeks as an inactive treatment for the tablet formulation. All participants were followed up at 4 to 6 weeks after last dose.	Daprodustat 8 mg Participants received daprodustat tablets 8 mg orally three-times weekly at the time of the pharmacokinetic visit.	Daprodustat 12 mg Participants received daprodustat tablets 12 mg orally three-times weekly at the time of the pharmacokinetic visit.	Daprodustat 16 mg Participants received daprodustat tablets 16 mg orally three-times weekly at the time of the pharmacokinetic visit.	Daprodustat 20 mg Participants received daprodustat tablets 20 mg orally three-times weekly at the time of the pharmacokinetic visit.	Daprodustat 24 mg Participants received daprodustat tablets 24 mg orally three-times weekly at the time of the pharmacokinetic visit.	Daprodustat 32 mg Participants received daprodustat tablets 32 mg orally three-times weekly at the time of the pharmacokinetic visit.	Daprodustat 48 mg Participants received daprodustat tablets 48 mg orally three-times weekly at the time of the pharmacokinetic visit.
Number of Participants With at Least One BP Exacerbation Event During the Study	151 Participants	91 Participants	—	—	—	—	—	—	—

SECONDARY outcome

Timeframe: Baseline (Pre-dose on Day 1) and Weeks 8, 12, 28, 52

Population: All Randomized (ITT) Population. Only those participants with data available at specified time points were analyzed (represented as n=X in the category titles).

The PGI-S is a 1-item questionnaire designed to assess participant's impression of disease severity of their anemia of Chronic kidney disease (CKD). It is measured on a 5-point disease severity scale ranging from 0 (absent) to 4 (very severe), higher score indicates more disease severity. Baseline value was the latest non-missing pre-dose assessment on or before the randomization date, including those from unscheduled visits. Change from Baseline in on-treatment PGI-S scores was defined as the on-treatment visit value minus Baseline value. Analysis was performed using MMRM model fitted from Baseline up to Week 52 with factors for treatment, time, region, Baseline value and Baseline value by time and treatment by time interactions.

Outcome measures

Outcome measures
Measure	Daprodustat n=270 Participants Participants received daprodustat tablets with titrated dose levels ranging from 2, 4, 8, 12, 16, 20, 24, 32 and 48 milligrams (mg) orally three-times weekly up to 52 weeks. Study treatment was dose-titrated to achieve and maintain hemoglobin in the target range (10 to 11 grams per deciliter \[g/dL\]). In order to maintain the study blind, participants also received saline intravenous (IV) injection once weekly or three-times weekly depending on dose level, up to 52 weeks as an inactive treatment for the IV formulation. All participants were followed up at 4 to 6 weeks after last dose.	Epoetin Alfa n=137 Participants Participants received epoetin alfa with titrated dose levels ranging from 1500 Units to 60,000 Units total weekly dose and administered as IV injection once weekly or three-times weekly depending on dose level up to 52 weeks. Study treatment was dose-titrated to achieve and maintain hemoglobin in the target range (10 to 11 g/dL). In order to maintain the study blind, participants also received placebo tablets matching to daprodustat orally three-times weekly up to 52 weeks as an inactive treatment for the tablet formulation. All participants were followed up at 4 to 6 weeks after last dose.	Daprodustat 8 mg Participants received daprodustat tablets 8 mg orally three-times weekly at the time of the pharmacokinetic visit.	Daprodustat 12 mg Participants received daprodustat tablets 12 mg orally three-times weekly at the time of the pharmacokinetic visit.	Daprodustat 16 mg Participants received daprodustat tablets 16 mg orally three-times weekly at the time of the pharmacokinetic visit.	Daprodustat 20 mg Participants received daprodustat tablets 20 mg orally three-times weekly at the time of the pharmacokinetic visit.	Daprodustat 24 mg Participants received daprodustat tablets 24 mg orally three-times weekly at the time of the pharmacokinetic visit.	Daprodustat 32 mg Participants received daprodustat tablets 32 mg orally three-times weekly at the time of the pharmacokinetic visit.	Daprodustat 48 mg Participants received daprodustat tablets 48 mg orally three-times weekly at the time of the pharmacokinetic visit.
Change From Baseline at Weeks 8, 12, 28 and 52 in Patient Global Impression of Severity (PGI-S) Week 8; n=248, 126	-0.10 Scores on a scale Standard Error 0.048	0.05 Scores on a scale Standard Error 0.068	—	—	—	—	—	—	—
Change From Baseline at Weeks 8, 12, 28 and 52 in Patient Global Impression of Severity (PGI-S) Week 12; n=243, 120	-0.13 Scores on a scale Standard Error 0.050	-0.01 Scores on a scale Standard Error 0.071	—	—	—	—	—	—	—
Change From Baseline at Weeks 8, 12, 28 and 52 in Patient Global Impression of Severity (PGI-S) Week 28; n=211, 106	-0.07 Scores on a scale Standard Error 0.054	0.03 Scores on a scale Standard Error 0.077	—	—	—	—	—	—	—
Change From Baseline at Weeks 8, 12, 28 and 52 in Patient Global Impression of Severity (PGI-S) Week 52; n=170, 85	-0.11 Scores on a scale Standard Error 0.063	0.04 Scores on a scale Standard Error 0.088	—	—	—	—	—	—	—

SECONDARY outcome

Timeframe: Pre-dose on Day 1; Pre-dose and at 0.5, 1, 2, 3 hours post-dose on any one post-Baseline visit day between Week 8 and Week 52

Population: Pharmacokinetic Population comprised of all randomized participants for whom a post-Baseline pharmacokinetic sample was obtained and analyzed. Only those participants with data available at specified time points were analyzed (represented as n=X in the category titles).

Blood samples were collected at indicated time points for pharmacokinetic analysis of daprodustat (GSK1278863) and its metabolites: GSK2391220 (M2), GSK2487818 (M4), GSK2506102 (M5), GSK2506104 (M3), GSK2531398 (M6) and GSK2531401 (M13).

Outcome measures

Outcome measures
Measure	Daprodustat n=8 Participants Participants received daprodustat tablets with titrated dose levels ranging from 2, 4, 8, 12, 16, 20, 24, 32 and 48 milligrams (mg) orally three-times weekly up to 52 weeks. Study treatment was dose-titrated to achieve and maintain hemoglobin in the target range (10 to 11 grams per deciliter \[g/dL\]). In order to maintain the study blind, participants also received saline intravenous (IV) injection once weekly or three-times weekly depending on dose level, up to 52 weeks as an inactive treatment for the IV formulation. All participants were followed up at 4 to 6 weeks after last dose.	Epoetin Alfa n=20 Participants Participants received epoetin alfa with titrated dose levels ranging from 1500 Units to 60,000 Units total weekly dose and administered as IV injection once weekly or three-times weekly depending on dose level up to 52 weeks. Study treatment was dose-titrated to achieve and maintain hemoglobin in the target range (10 to 11 g/dL). In order to maintain the study blind, participants also received placebo tablets matching to daprodustat orally three-times weekly up to 52 weeks as an inactive treatment for the tablet formulation. All participants were followed up at 4 to 6 weeks after last dose.	Daprodustat 8 mg n=51 Participants Participants received daprodustat tablets 8 mg orally three-times weekly at the time of the pharmacokinetic visit.	Daprodustat 12 mg n=59 Participants Participants received daprodustat tablets 12 mg orally three-times weekly at the time of the pharmacokinetic visit.	Daprodustat 16 mg n=45 Participants Participants received daprodustat tablets 16 mg orally three-times weekly at the time of the pharmacokinetic visit.	Daprodustat 20 mg n=28 Participants Participants received daprodustat tablets 20 mg orally three-times weekly at the time of the pharmacokinetic visit.	Daprodustat 24 mg n=16 Participants Participants received daprodustat tablets 24 mg orally three-times weekly at the time of the pharmacokinetic visit.	Daprodustat 32 mg n=3 Participants Participants received daprodustat tablets 32 mg orally three-times weekly at the time of the pharmacokinetic visit.	Daprodustat 48 mg n=3 Participants Participants received daprodustat tablets 48 mg orally three-times weekly at the time of the pharmacokinetic visit.
Pre-dose Trough Concentration (Ctau) of Daprodustat (GSK1278863) and Its Metabolites GSK2391220 (M2), GSK2487818 (M4), GSK2506102 (M5), GSK2506104 (M3), GSK2531398 (M6) and GSK2531401 (M13) GSK2506102; n=4, 17, 45, 59, 43, 27, 16, 3, 3	0.9951 Nanograms per milliliter Geometric Coefficient of Variation 122.94	0.8372 Nanograms per milliliter Geometric Coefficient of Variation 121.27	0.9634 Nanograms per milliliter Geometric Coefficient of Variation 95.99	1.5100 Nanograms per milliliter Geometric Coefficient of Variation 105.50	1.5480 Nanograms per milliliter Geometric Coefficient of Variation 122.95	1.6555 Nanograms per milliliter Geometric Coefficient of Variation 133.94	3.2099 Nanograms per milliliter Geometric Coefficient of Variation 67.36	1.6892 Nanograms per milliliter Geometric Coefficient of Variation 30.44	1.8595 Nanograms per milliliter Geometric Coefficient of Variation 48.36
Pre-dose Trough Concentration (Ctau) of Daprodustat (GSK1278863) and Its Metabolites GSK2391220 (M2), GSK2487818 (M4), GSK2506102 (M5), GSK2506104 (M3), GSK2531398 (M6) and GSK2531401 (M13) GSK2531401; n=6, 17, 45, 59, 44, 27, 16, 3, 3	1.4466 Nanograms per milliliter Geometric Coefficient of Variation 190.80	3.5579 Nanograms per milliliter Geometric Coefficient of Variation 102.68	4.0910 Nanograms per milliliter Geometric Coefficient of Variation 148.03	6.8137 Nanograms per milliliter Geometric Coefficient of Variation 102.34	5.6037 Nanograms per milliliter Geometric Coefficient of Variation 130.97	8.4611 Nanograms per milliliter Geometric Coefficient of Variation 128.74	11.7372 Nanograms per milliliter Geometric Coefficient of Variation 65.37	6.0453 Nanograms per milliliter Geometric Coefficient of Variation 140.63	16.2584 Nanograms per milliliter Geometric Coefficient of Variation 41.06
Pre-dose Trough Concentration (Ctau) of Daprodustat (GSK1278863) and Its Metabolites GSK2391220 (M2), GSK2487818 (M4), GSK2506102 (M5), GSK2506104 (M3), GSK2531398 (M6) and GSK2531401 (M13) Daprodustat; n=1, 2, 10, 18, 14, 9, 6, 3, 2	6.2400 Nanograms per milliliter Geometric Coefficient of Variation NA NA indicates that data was not available as geometric coefficient of variation could not be calculated for single participant.	1.1207 Nanograms per milliliter Geometric Coefficient of Variation 494.71	0.1786 Nanograms per milliliter Geometric Coefficient of Variation 77.35	0.3727 Nanograms per milliliter Geometric Coefficient of Variation 277.88	0.3443 Nanograms per milliliter Geometric Coefficient of Variation 100.78	0.3871 Nanograms per milliliter Geometric Coefficient of Variation 161.05	0.1621 Nanograms per milliliter Geometric Coefficient of Variation 42.17	0.2768 Nanograms per milliliter Geometric Coefficient of Variation 140.82	0.3486 Nanograms per milliliter Geometric Coefficient of Variation 68.34
Pre-dose Trough Concentration (Ctau) of Daprodustat (GSK1278863) and Its Metabolites GSK2391220 (M2), GSK2487818 (M4), GSK2506102 (M5), GSK2506104 (M3), GSK2531398 (M6) and GSK2531401 (M13) GSK2391220; n=4, 17,42, 57, 40, 25, 16, 3, 3	0.8623 Nanograms per milliliter Geometric Coefficient of Variation 241.17	0.5893 Nanograms per milliliter Geometric Coefficient of Variation 255.59	0.6341 Nanograms per milliliter Geometric Coefficient of Variation 123.92	1.1572 Nanograms per milliliter Geometric Coefficient of Variation 184.51	1.1654 Nanograms per milliliter Geometric Coefficient of Variation 191.57	1.1792 Nanograms per milliliter Geometric Coefficient of Variation 168.59	1.4987 Nanograms per milliliter Geometric Coefficient of Variation 136.35	1.6974 Nanograms per milliliter Geometric Coefficient of Variation 6.82	1.3531 Nanograms per milliliter Geometric Coefficient of Variation 19.28
Pre-dose Trough Concentration (Ctau) of Daprodustat (GSK1278863) and Its Metabolites GSK2391220 (M2), GSK2487818 (M4), GSK2506102 (M5), GSK2506104 (M3), GSK2531398 (M6) and GSK2531401 (M13) GSK2487818; n=1, 4, 5, 20, 14, 7, 4, 3, 2	0.3620 Nanograms per milliliter Geometric Coefficient of Variation NA NA indicates that data was not available as geometric coefficient of variation could not be calculated for single participant.	0.2867 Nanograms per milliliter Geometric Coefficient of Variation 111.67	0.1594 Nanograms per milliliter Geometric Coefficient of Variation 16.91	0.2996 Nanograms per milliliter Geometric Coefficient of Variation 105.55	0.3027 Nanograms per milliliter Geometric Coefficient of Variation 69.12	0.2868 Nanograms per milliliter Geometric Coefficient of Variation 109.23	0.2585 Nanograms per milliliter Geometric Coefficient of Variation 30.72	0.2414 Nanograms per milliliter Geometric Coefficient of Variation 29.66	0.2111 Nanograms per milliliter Geometric Coefficient of Variation 80.56
Pre-dose Trough Concentration (Ctau) of Daprodustat (GSK1278863) and Its Metabolites GSK2391220 (M2), GSK2487818 (M4), GSK2506102 (M5), GSK2506104 (M3), GSK2531398 (M6) and GSK2531401 (M13) GSK2506104; n=6, 17, 45, 59, 43, 27, 16, 3, 3	0.9750 Nanograms per milliliter Geometric Coefficient of Variation 408.49	1.9588 Nanograms per milliliter Geometric Coefficient of Variation 163.27	2.0381 Nanograms per milliliter Geometric Coefficient of Variation 124.74	3.5141 Nanograms per milliliter Geometric Coefficient of Variation 136.72	3.3872 Nanograms per milliliter Geometric Coefficient of Variation 182.27	3.6000 Nanograms per milliliter Geometric Coefficient of Variation 173.62	6.5730 Nanograms per milliliter Geometric Coefficient of Variation 99.82	4.2068 Nanograms per milliliter Geometric Coefficient of Variation 15.44	4.1894 Nanograms per milliliter Geometric Coefficient of Variation 23.78
Pre-dose Trough Concentration (Ctau) of Daprodustat (GSK1278863) and Its Metabolites GSK2391220 (M2), GSK2487818 (M4), GSK2506102 (M5), GSK2506104 (M3), GSK2531398 (M6) and GSK2531401 (M13) GSK2531398; n=2, 7, 22, 41, 33, 20, 15, 3, 3	1.1778 Nanograms per milliliter Geometric Coefficient of Variation 20.55	0.6069 Nanograms per milliliter Geometric Coefficient of Variation 271.48	0.2362 Nanograms per milliliter Geometric Coefficient of Variation 76.76	0.4444 Nanograms per milliliter Geometric Coefficient of Variation 144.99	0.3917 Nanograms per milliliter Geometric Coefficient of Variation 169.77	0.3728 Nanograms per milliliter Geometric Coefficient of Variation 197.51	0.3992 Nanograms per milliliter Geometric Coefficient of Variation 153.15	0.3963 Nanograms per milliliter Geometric Coefficient of Variation 16.52	0.2280 Nanograms per milliliter Geometric Coefficient of Variation 56.68

SECONDARY outcome

Timeframe: Pre-dose on Day 1; Pre-dose and at 0.5, 1, 2, 3 hours post-dose on any one post-Baseline visit day between Week 8 and Week 52

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

Outcome measures

Outcome measures
Measure	Daprodustat n=8 Participants Participants received daprodustat tablets with titrated dose levels ranging from 2, 4, 8, 12, 16, 20, 24, 32 and 48 milligrams (mg) orally three-times weekly up to 52 weeks. Study treatment was dose-titrated to achieve and maintain hemoglobin in the target range (10 to 11 grams per deciliter \[g/dL\]). In order to maintain the study blind, participants also received saline intravenous (IV) injection once weekly or three-times weekly depending on dose level, up to 52 weeks as an inactive treatment for the IV formulation. All participants were followed up at 4 to 6 weeks after last dose.	Epoetin Alfa n=20 Participants Participants received epoetin alfa with titrated dose levels ranging from 1500 Units to 60,000 Units total weekly dose and administered as IV injection once weekly or three-times weekly depending on dose level up to 52 weeks. Study treatment was dose-titrated to achieve and maintain hemoglobin in the target range (10 to 11 g/dL). In order to maintain the study blind, participants also received placebo tablets matching to daprodustat orally three-times weekly up to 52 weeks as an inactive treatment for the tablet formulation. All participants were followed up at 4 to 6 weeks after last dose.	Daprodustat 8 mg n=51 Participants Participants received daprodustat tablets 8 mg orally three-times weekly at the time of the pharmacokinetic visit.	Daprodustat 12 mg n=59 Participants Participants received daprodustat tablets 12 mg orally three-times weekly at the time of the pharmacokinetic visit.	Daprodustat 16 mg n=45 Participants Participants received daprodustat tablets 16 mg orally three-times weekly at the time of the pharmacokinetic visit.	Daprodustat 20 mg n=28 Participants Participants received daprodustat tablets 20 mg orally three-times weekly at the time of the pharmacokinetic visit.	Daprodustat 24 mg n=16 Participants Participants received daprodustat tablets 24 mg orally three-times weekly at the time of the pharmacokinetic visit.	Daprodustat 32 mg n=3 Participants Participants received daprodustat tablets 32 mg orally three-times weekly at the time of the pharmacokinetic visit.	Daprodustat 48 mg n=3 Participants Participants received daprodustat tablets 48 mg orally three-times weekly at the time of the pharmacokinetic visit.
Maximum Observed Concentration (Cmax) of Daprodustat (GSK1278863) and Its Metabolites GSK2391220 (M2), GSK2487818 (M4), GSK2506102 (M5), GSK2506104 (M3), GSK2531398 (M6) and GSK2531401 (M13) GSK2391220; n=8, 19, 50, 59, 45, 28, 16, 3, 3	2.6298 Nanograms per milliliter Geometric Coefficient of Variation 60.93	4.0224 Nanograms per milliliter Geometric Coefficient of Variation 134.91	6.3826 Nanograms per milliliter Geometric Coefficient of Variation 198.78	8.9535 Nanograms per milliliter Geometric Coefficient of Variation 126.76	9.5131 Nanograms per milliliter Geometric Coefficient of Variation 167.92	11.8995 Nanograms per milliliter Geometric Coefficient of Variation 172.35	22.3378 Nanograms per milliliter Geometric Coefficient of Variation 95.60	9.3582 Nanograms per milliliter Geometric Coefficient of Variation 71.78	31.6698 Nanograms per milliliter Geometric Coefficient of Variation 84.08
Maximum Observed Concentration (Cmax) of Daprodustat (GSK1278863) and Its Metabolites GSK2391220 (M2), GSK2487818 (M4), GSK2506102 (M5), GSK2506104 (M3), GSK2531398 (M6) and GSK2531401 (M13) Daprodustat; n=8, 20, 49, 57, 45, 28, 16, 3, 3	44.5832 Nanograms per milliliter Geometric Coefficient of Variation 227.65	51.9261 Nanograms per milliliter Geometric Coefficient of Variation 227.59	113.4049 Nanograms per milliliter Geometric Coefficient of Variation 179.69	143.8790 Nanograms per milliliter Geometric Coefficient of Variation 233.09	126.6824 Nanograms per milliliter Geometric Coefficient of Variation 288.50	212.5087 Nanograms per milliliter Geometric Coefficient of Variation 152.47	290.3163 Nanograms per milliliter Geometric Coefficient of Variation 87.39	197.7071 Nanograms per milliliter Geometric Coefficient of Variation 36.53	310.1938 Nanograms per milliliter Geometric Coefficient of Variation 190.69
Maximum Observed Concentration (Cmax) of Daprodustat (GSK1278863) and Its Metabolites GSK2391220 (M2), GSK2487818 (M4), GSK2506102 (M5), GSK2506104 (M3), GSK2531398 (M6) and GSK2531401 (M13) GSK2487818; n=7, 18, 47, 56, 45, 28, 16, 3, 3	2.0320 Nanograms per milliliter Geometric Coefficient of Variation 73.45	3.2703 Nanograms per milliliter Geometric Coefficient of Variation 143.75	6.3474 Nanograms per milliliter Geometric Coefficient of Variation 175.79	8.0134 Nanograms per milliliter Geometric Coefficient of Variation 146.43	6.4276 Nanograms per milliliter Geometric Coefficient of Variation 278.04	9.6617 Nanograms per milliliter Geometric Coefficient of Variation 207.18	19.9693 Nanograms per milliliter Geometric Coefficient of Variation 94.09	8.4327 Nanograms per milliliter Geometric Coefficient of Variation 64.98	29.3042 Nanograms per milliliter Geometric Coefficient of Variation 72.06
Maximum Observed Concentration (Cmax) of Daprodustat (GSK1278863) and Its Metabolites GSK2391220 (M2), GSK2487818 (M4), GSK2506102 (M5), GSK2506104 (M3), GSK2531398 (M6) and GSK2531401 (M13) GSK2506102; n=8, 19, 51, 59, 45, 28, 16, 3, 3	0.8328 Nanograms per milliliter Geometric Coefficient of Variation 101.92	1.4018 Nanograms per milliliter Geometric Coefficient of Variation 84.93	2.0385 Nanograms per milliliter Geometric Coefficient of Variation 85.59	2.8357 Nanograms per milliliter Geometric Coefficient of Variation 68.15	3.2007 Nanograms per milliliter Geometric Coefficient of Variation 89.86	3.5712 Nanograms per milliliter Geometric Coefficient of Variation 96.48	6.4555 Nanograms per milliliter Geometric Coefficient of Variation 59.57	2.4981 Nanograms per milliliter Geometric Coefficient of Variation 71.38	7.1245 Nanograms per milliliter Geometric Coefficient of Variation 87.62
Maximum Observed Concentration (Cmax) of Daprodustat (GSK1278863) and Its Metabolites GSK2391220 (M2), GSK2487818 (M4), GSK2506102 (M5), GSK2506104 (M3), GSK2531398 (M6) and GSK2531401 (M13) GSK2506104; n=8, 19, 51, 59, 45, 28, 16, 3, 3	3.2020 Nanograms per milliliter Geometric Coefficient of Variation 81.23	5.2039 Nanograms per milliliter Geometric Coefficient of Variation 98.70	7.5220 Nanograms per milliliter Geometric Coefficient of Variation 131.81	10.8186 Nanograms per milliliter Geometric Coefficient of Variation 84.31	11.5783 Nanograms per milliliter Geometric Coefficient of Variation 130.74	13.8509 Nanograms per milliliter Geometric Coefficient of Variation 125.27	24.4926 Nanograms per milliliter Geometric Coefficient of Variation 84.96	9.5457 Nanograms per milliliter Geometric Coefficient of Variation 73.58	30.4034 Nanograms per milliliter Geometric Coefficient of Variation 79.13
Maximum Observed Concentration (Cmax) of Daprodustat (GSK1278863) and Its Metabolites GSK2391220 (M2), GSK2487818 (M4), GSK2506102 (M5), GSK2506104 (M3), GSK2531398 (M6) and GSK2531401 (M13) GSK2531398; n=8, 17, 46, 59, 45, 27, 16, 3, 3	1.2731 Nanograms per milliliter Geometric Coefficient of Variation 57.92	2.3676 Nanograms per milliliter Geometric Coefficient of Variation 84.23	3.7348 Nanograms per milliliter Geometric Coefficient of Variation 131.10	3.8017 Nanograms per milliliter Geometric Coefficient of Variation 177.36	4.0850 Nanograms per milliliter Geometric Coefficient of Variation 209.29	6.1029 Nanograms per milliliter Geometric Coefficient of Variation 137.40	10.7532 Nanograms per milliliter Geometric Coefficient of Variation 98.46	4.6296 Nanograms per milliliter Geometric Coefficient of Variation 72.00	14.7844 Nanograms per milliliter Geometric Coefficient of Variation 81.18
Maximum Observed Concentration (Cmax) of Daprodustat (GSK1278863) and Its Metabolites GSK2391220 (M2), GSK2487818 (M4), GSK2506102 (M5), GSK2506104 (M3), GSK2531398 (M6) and GSK2531401 (M13) GSK2531401; n=7, 19, 51, 59, 45, 28, 16, 3, 3	2.0473 Nanograms per milliliter Geometric Coefficient of Variation 100.05	4.0012 Nanograms per milliliter Geometric Coefficient of Variation 88.64	5.4631 Nanograms per milliliter Geometric Coefficient of Variation 120.63	8.8488 Nanograms per milliliter Geometric Coefficient of Variation 80.17	8.4814 Nanograms per milliliter Geometric Coefficient of Variation 93.83	10.7368 Nanograms per milliliter Geometric Coefficient of Variation 90.83	14.7926 Nanograms per milliliter Geometric Coefficient of Variation 59.24	7.1458 Nanograms per milliliter Geometric Coefficient of Variation 174.98	20.1044 Nanograms per milliliter Geometric Coefficient of Variation 67.56

Adverse Events

Daprodustat

Serious events: 80 serious events

Other events: 74 other events

Deaths: 18 deaths

Epoetin Alfa

Serious events: 47 serious events

Other events: 42 other events

Deaths: 10 deaths

Serious adverse events

Other adverse events

Other adverse events
Measure	Daprodustat n=270 participants at risk Participants received daprodustat tablets with titrated dose levels ranging from 2, 4, 8, 12, 16, 20, 24, 32 and 48 milligrams (mg) orally three-times weekly up to 52 weeks. Study treatment was dose-titrated to achieve and maintain hemoglobin in the target range (10 to 11 grams per deciliter \[g/dL\]). In order to maintain the study blind, participants also received saline intravenous (IV) injection once weekly or three-times weekly depending on dose level, up to 52 weeks as an inactive treatment for the IV formulation. All participants were followed up at 4 to 6 weeks after last dose.	Epoetin Alfa n=136 participants at risk Participants received epoetin alfa with titrated dose levels ranging from 1500 Units to 60,000 Units total weekly dose and administered as IV injection once weekly or three-times weekly depending on dose level up to 52 weeks. Study treatment was dose-titrated to achieve and maintain hemoglobin in the target range (10 to 11 g/dL). In order to maintain the study blind, participants also received placebo tablets matching to daprodustat orally three-times weekly up to 52 weeks as an inactive treatment for the tablet formulation. All participants were followed up at 4 to 6 weeks after last dose.
Gastrointestinal disorders Diarrhoea	8.5% 23/270 • Number of events 36 • Treatment emergent serious adverse events (SAEs) and non-serious adverse events (non-serious AEs) were collected up to 52 weeks. Safety Population was used to assess SAEs and non-serious AEs, which comprised of all randomized participants who have taken at least 1 dose of study treatment. One participant from Randomized (ITT) Population (N=407) did not receive study treatment, hence was not included in Safety Population (N=406).	10.3% 14/136 • Number of events 19 • Treatment emergent serious adverse events (SAEs) and non-serious adverse events (non-serious AEs) were collected up to 52 weeks. Safety Population was used to assess SAEs and non-serious AEs, which comprised of all randomized participants who have taken at least 1 dose of study treatment. One participant from Randomized (ITT) Population (N=407) did not receive study treatment, hence was not included in Safety Population (N=406).
Gastrointestinal disorders Vomiting	5.6% 15/270 • Number of events 16 • Treatment emergent serious adverse events (SAEs) and non-serious adverse events (non-serious AEs) were collected up to 52 weeks. Safety Population was used to assess SAEs and non-serious AEs, which comprised of all randomized participants who have taken at least 1 dose of study treatment. One participant from Randomized (ITT) Population (N=407) did not receive study treatment, hence was not included in Safety Population (N=406).	9.6% 13/136 • Number of events 15 • Treatment emergent serious adverse events (SAEs) and non-serious adverse events (non-serious AEs) were collected up to 52 weeks. Safety Population was used to assess SAEs and non-serious AEs, which comprised of all randomized participants who have taken at least 1 dose of study treatment. One participant from Randomized (ITT) Population (N=407) did not receive study treatment, hence was not included in Safety Population (N=406).
Gastrointestinal disorders Nausea	2.2% 6/270 • Number of events 8 • Treatment emergent serious adverse events (SAEs) and non-serious adverse events (non-serious AEs) were collected up to 52 weeks. Safety Population was used to assess SAEs and non-serious AEs, which comprised of all randomized participants who have taken at least 1 dose of study treatment. One participant from Randomized (ITT) Population (N=407) did not receive study treatment, hence was not included in Safety Population (N=406).	8.1% 11/136 • Number of events 21 • Treatment emergent serious adverse events (SAEs) and non-serious adverse events (non-serious AEs) were collected up to 52 weeks. Safety Population was used to assess SAEs and non-serious AEs, which comprised of all randomized participants who have taken at least 1 dose of study treatment. One participant from Randomized (ITT) Population (N=407) did not receive study treatment, hence was not included in Safety Population (N=406).
Gastrointestinal disorders Abdominal pain	2.6% 7/270 • Number of events 8 • Treatment emergent serious adverse events (SAEs) and non-serious adverse events (non-serious AEs) were collected up to 52 weeks. Safety Population was used to assess SAEs and non-serious AEs, which comprised of all randomized participants who have taken at least 1 dose of study treatment. One participant from Randomized (ITT) Population (N=407) did not receive study treatment, hence was not included in Safety Population (N=406).	6.6% 9/136 • Number of events 9 • Treatment emergent serious adverse events (SAEs) and non-serious adverse events (non-serious AEs) were collected up to 52 weeks. Safety Population was used to assess SAEs and non-serious AEs, which comprised of all randomized participants who have taken at least 1 dose of study treatment. One participant from Randomized (ITT) Population (N=407) did not receive study treatment, hence was not included in Safety Population (N=406).
Vascular disorders Hypertension	8.1% 22/270 • Number of events 35 • Treatment emergent serious adverse events (SAEs) and non-serious adverse events (non-serious AEs) were collected up to 52 weeks. Safety Population was used to assess SAEs and non-serious AEs, which comprised of all randomized participants who have taken at least 1 dose of study treatment. One participant from Randomized (ITT) Population (N=407) did not receive study treatment, hence was not included in Safety Population (N=406).	10.3% 14/136 • Number of events 19 • Treatment emergent serious adverse events (SAEs) and non-serious adverse events (non-serious AEs) were collected up to 52 weeks. Safety Population was used to assess SAEs and non-serious AEs, which comprised of all randomized participants who have taken at least 1 dose of study treatment. One participant from Randomized (ITT) Population (N=407) did not receive study treatment, hence was not included in Safety Population (N=406).
Vascular disorders Hypotension	4.4% 12/270 • Number of events 16 • Treatment emergent serious adverse events (SAEs) and non-serious adverse events (non-serious AEs) were collected up to 52 weeks. Safety Population was used to assess SAEs and non-serious AEs, which comprised of all randomized participants who have taken at least 1 dose of study treatment. One participant from Randomized (ITT) Population (N=407) did not receive study treatment, hence was not included in Safety Population (N=406).	6.6% 9/136 • Number of events 13 • Treatment emergent serious adverse events (SAEs) and non-serious adverse events (non-serious AEs) were collected up to 52 weeks. Safety Population was used to assess SAEs and non-serious AEs, which comprised of all randomized participants who have taken at least 1 dose of study treatment. One participant from Randomized (ITT) Population (N=407) did not receive study treatment, hence was not included in Safety Population (N=406).
General disorders Pyrexia	2.6% 7/270 • Number of events 9 • Treatment emergent serious adverse events (SAEs) and non-serious adverse events (non-serious AEs) were collected up to 52 weeks. Safety Population was used to assess SAEs and non-serious AEs, which comprised of all randomized participants who have taken at least 1 dose of study treatment. One participant from Randomized (ITT) Population (N=407) did not receive study treatment, hence was not included in Safety Population (N=406).	5.9% 8/136 • Number of events 9 • Treatment emergent serious adverse events (SAEs) and non-serious adverse events (non-serious AEs) were collected up to 52 weeks. Safety Population was used to assess SAEs and non-serious AEs, which comprised of all randomized participants who have taken at least 1 dose of study treatment. One participant from Randomized (ITT) Population (N=407) did not receive study treatment, hence was not included in Safety Population (N=406).
Nervous system disorders Headache	4.1% 11/270 • Number of events 13 • Treatment emergent serious adverse events (SAEs) and non-serious adverse events (non-serious AEs) were collected up to 52 weeks. Safety Population was used to assess SAEs and non-serious AEs, which comprised of all randomized participants who have taken at least 1 dose of study treatment. One participant from Randomized (ITT) Population (N=407) did not receive study treatment, hence was not included in Safety Population (N=406).	9.6% 13/136 • Number of events 26 • Treatment emergent serious adverse events (SAEs) and non-serious adverse events (non-serious AEs) were collected up to 52 weeks. Safety Population was used to assess SAEs and non-serious AEs, which comprised of all randomized participants who have taken at least 1 dose of study treatment. One participant from Randomized (ITT) Population (N=407) did not receive study treatment, hence was not included in Safety Population (N=406).

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