Trial Outcomes & Findings for Anemia Studies in Chronic Kidney Disease: Erythropoiesis Via a Novel Prolyl Hydroxylase Inhibitor Daprodustat-Dialysis (ASCEND-D) (NCT NCT02879305)

Last Updated: 2021-12-03

Results Overview

Time to MACE defined as the time to first occurrence of Clinical Events Committee (CEC) adjudicated MACE (composite of all-cause mortality, non-fatal myocardial infarction \[MI\] and non-fatal stroke) was analyzed using a Cox proportional hazards regression model with treatment group, dialysis type and region as covariates. Time to the first occurrence was computed as (event date minus randomization date) plus (+) 1. The incidence rate per 100 person years calculated as (100 multiplied by \[\*\] number of participants with at least 1 event) divided by \[/\] first event person-years) is presented along with 95 percent (%) confidence interval (CI). First event person years=(cumulative total time to first event for participants who have the event + cumulative total of censored time for participants without the event)/365.25, based on the CV follow-up time period.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

2964 participants

Primary outcome timeframe

Up to 3.9 person-years for CV follow-up time period

Results posted on

2021-12-03

Participant Flow

This was a randomized, open-label (sponsor blind), active-controlled, parallel-group, event-driven study conducted at 431 centers in 35 countries. Participants were randomized to receive daprodustat and recombinant human erythropoietin (rhEPO) (epoetin alfa or darbepoetin alfa).

A total of 2964 participants were randomized in the study.

Participant milestones

Participant milestones
Measure	Daprodustat Participants received placebo tablets orally once daily in run-in period from Week -4 up to randomization (Day 1) and subsequently received daprodustat tablets at dose levels of 1, 2, 4, 6, 8, 10, 12, 16 and 24 milligrams (mg) orally once daily until the required number of major adverse cardiovascular event (MACE) occurred, at approximately 45.1 months of randomized treatment. Study treatment was dose-titrated to achieve and maintain hemoglobin in the target range (10 to 11 grams per deciliter \[g/dL\]).	rhEPO Participants received placebo tablets orally once daily in run-in period from Week -4 up to randomization (Day 1) and subsequently received treatment with rhEPO. Participants on hemodialysis received epoetin alfa as intravenous (IV) injection once weekly or three-times weekly with total weekly dose levels ranging from 1500 to 60,000 Units. Participants on peritoneal dialysis received subcutaneous (SC) injection of darbepoetin alfa every 1, 2, or 4 weeks with 4-weekly total dose levels ranging from 20 to 400 microgram (mcg). Darbepoetin could be given by IV injection for peritoneal dialysis participants switching to hemodialysis. Study treatment was dose-titrated to achieve and maintain hemoglobin in the target range (10 to 11 g/dL) and administered until the required number of MACE events occurred, at approximately 45.1 months of randomized treatment.
Overall Study STARTED	1487	1477
Overall Study COMPLETED	1370	1366
Overall Study NOT COMPLETED	117	111

Reasons for withdrawal

Reasons for withdrawal
Measure	Daprodustat Participants received placebo tablets orally once daily in run-in period from Week -4 up to randomization (Day 1) and subsequently received daprodustat tablets at dose levels of 1, 2, 4, 6, 8, 10, 12, 16 and 24 milligrams (mg) orally once daily until the required number of major adverse cardiovascular event (MACE) occurred, at approximately 45.1 months of randomized treatment. Study treatment was dose-titrated to achieve and maintain hemoglobin in the target range (10 to 11 grams per deciliter \[g/dL\]).	rhEPO Participants received placebo tablets orally once daily in run-in period from Week -4 up to randomization (Day 1) and subsequently received treatment with rhEPO. Participants on hemodialysis received epoetin alfa as intravenous (IV) injection once weekly or three-times weekly with total weekly dose levels ranging from 1500 to 60,000 Units. Participants on peritoneal dialysis received subcutaneous (SC) injection of darbepoetin alfa every 1, 2, or 4 weeks with 4-weekly total dose levels ranging from 20 to 400 microgram (mcg). Darbepoetin could be given by IV injection for peritoneal dialysis participants switching to hemodialysis. Study treatment was dose-titrated to achieve and maintain hemoglobin in the target range (10 to 11 g/dL) and administered until the required number of MACE events occurred, at approximately 45.1 months of randomized treatment.
Overall Study Investigator Site Closed	55	57
Overall Study Withdrawal by Subject	44	42
Overall Study Lost to Follow-up	17	12
Overall Study Other	1	0

Baseline Characteristics

Anemia Studies in Chronic Kidney Disease: Erythropoiesis Via a Novel Prolyl Hydroxylase Inhibitor Daprodustat-Dialysis (ASCEND-D)

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Daprodustat n=1487 Participants Participants received placebo tablets orally once daily in run-in period from Week -4 up to randomization (Day 1) and subsequently received daprodustat tablets at dose levels of 1, 2, 4, 6, 8, 10, 12, 16 and 24 milligrams (mg) orally once daily until the required number of major adverse cardiovascular event (MACE) occurred, at approximately 45.1 months of randomized treatment. Study treatment was dose-titrated to achieve and maintain hemoglobin in the target range (10 to 11 grams per deciliter \[g/dL\]).	rhEPO n=1477 Participants Participants received placebo tablets orally once daily in run-in period from Week -4 up to randomization (Day 1) and subsequently received treatment with rhEPO. Participants on hemodialysis received epoetin alfa as intravenous (IV) injection once weekly or three-times weekly with total weekly dose levels ranging from 1500 to 60,000 Units. Participants on peritoneal dialysis received subcutaneous (SC) injection of darbepoetin alfa every 1, 2, or 4 weeks with 4-weekly total dose levels ranging from 20 to 400 microgram (mcg). Darbepoetin could be given by IV injection for peritoneal dialysis participants switching to hemodialysis. Study treatment was dose-titrated to achieve and maintain hemoglobin in the target range (10 to 11 g/dL) and administered until the required number of MACE events occurred, at approximately 45.1 months of randomized treatment.	Total n=2964 Participants Total of all reporting groups
Age, Continuous	57.2 Years STANDARD_DEVIATION 14.29 • n=5 Participants	57.3 Years STANDARD_DEVIATION 14.65 • n=7 Participants	57.2 Years STANDARD_DEVIATION 14.47 • n=5 Participants
Sex: Female, Male Female	636 Participants n=5 Participants	630 Participants n=7 Participants	1266 Participants n=5 Participants
Sex: Female, Male Male	851 Participants n=5 Participants	847 Participants n=7 Participants	1698 Participants n=5 Participants
Race/Ethnicity, Customized American Indian or Alaskan Native	19 Participants n=5 Participants	32 Participants n=7 Participants	51 Participants n=5 Participants
Race/Ethnicity, Customized Asian - Central/South Asian Heritage	36 Participants n=5 Participants	46 Participants n=7 Participants	82 Participants n=5 Participants
Race/Ethnicity, Customized Asian - East Asian Heritage	97 Participants n=5 Participants	86 Participants n=7 Participants	183 Participants n=5 Participants
Race/Ethnicity, Customized Asian - Japanese Heritage	3 Participants n=5 Participants	3 Participants n=7 Participants	6 Participants n=5 Participants
Race/Ethnicity, Customized Asian - South East Asian Heritage	40 Participants n=5 Participants	45 Participants n=7 Participants	85 Participants n=5 Participants
Race/Ethnicity, Customized Black or African American	228 Participants n=5 Participants	233 Participants n=7 Participants	461 Participants n=5 Participants
Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander	26 Participants n=5 Participants	25 Participants n=7 Participants	51 Participants n=5 Participants
Race/Ethnicity, Customized White - Arabic/North African Heritage	8 Participants n=5 Participants	14 Participants n=7 Participants	22 Participants n=5 Participants
Race/Ethnicity, Customized White - White/Caucasian/European Heritage	987 Participants n=5 Participants	968 Participants n=7 Participants	1955 Participants n=5 Participants
Race/Ethnicity, Customized Mixed Asian Race	0 Participants n=5 Participants	1 Participants n=7 Participants	1 Participants n=5 Participants
Race/Ethnicity, Customized Mixed Race	43 Participants n=5 Participants	24 Participants n=7 Participants	67 Participants n=5 Participants

PRIMARY outcome

Timeframe: Up to 3.9 person-years for CV follow-up time period

Population: All Randomized (Intent-to-treat \[ITT\]) Population comprised of all randomized participants. Participants were analyzed according to the treatment to which they were randomized.

Outcome measures

Outcome measures
Measure	Daprodustat n=1487 Participants Participants received placebo tablets orally once daily in run-in period from Week -4 up to randomization (Day 1) and subsequently received daprodustat tablets at dose levels of 1, 2, 4, 6, 8, 10, 12, 16 and 24 milligrams (mg) orally once daily until the required number of major adverse cardiovascular event (MACE) occurred, at approximately 45.1 months of randomized treatment. Study treatment was dose-titrated to achieve and maintain hemoglobin in the target range (10 to 11 grams per deciliter \[g/dL\]).	rhEPO n=1477 Participants Participants received placebo tablets orally once daily in run-in period from Week -4 up to randomization (Day 1) and subsequently received treatment with rhEPO. Participants on hemodialysis received epoetin alfa as intravenous (IV) injection once weekly or three-times weekly with total weekly dose levels ranging from 1500 to 60,000 Units. Participants on peritoneal dialysis received subcutaneous (SC) injection of darbepoetin alfa every 1, 2, or 4 weeks with 4-weekly total dose levels ranging from 20 to 400 microgram (mcg). Darbepoetin could be given by IV injection for peritoneal dialysis participants switching to hemodialysis. Study treatment was dose-titrated to achieve and maintain hemoglobin in the target range (10 to 11 g/dL) and administered until the required number of MACE events occurred, at approximately 45.1 months of randomized treatment.
Time to First Occurrence of Adjudicated Major Adverse Cardiovascular Event (MACE) During Cardiovascular (CV) Events Follow-up Time Period: Non-inferiority Analysis	11.07 Events per 100 person years Interval 9.98 to 12.26	11.86 Events per 100 person years Interval 10.72 to 13.09

PRIMARY outcome

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

Population: All Randomized (ITT) Population.

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, missing post-Baseline hemoglobin values were imputed using pre-specified multiple imputation methods. Change from Baseline was defined as post-Baseline value minus Baseline value. Baseline was defined as the latest non-missing pre-dose assessment on or before the randomization date.

Outcome measures

Outcome measures
Measure	Daprodustat n=1487 Participants Participants received placebo tablets orally once daily in run-in period from Week -4 up to randomization (Day 1) and subsequently received daprodustat tablets at dose levels of 1, 2, 4, 6, 8, 10, 12, 16 and 24 milligrams (mg) orally once daily until the required number of major adverse cardiovascular event (MACE) occurred, at approximately 45.1 months of randomized treatment. Study treatment was dose-titrated to achieve and maintain hemoglobin in the target range (10 to 11 grams per deciliter \[g/dL\]).	rhEPO n=1477 Participants Participants received placebo tablets orally once daily in run-in period from Week -4 up to randomization (Day 1) and subsequently received treatment with rhEPO. Participants on hemodialysis received epoetin alfa as intravenous (IV) injection once weekly or three-times weekly with total weekly dose levels ranging from 1500 to 60,000 Units. Participants on peritoneal dialysis received subcutaneous (SC) injection of darbepoetin alfa every 1, 2, or 4 weeks with 4-weekly total dose levels ranging from 20 to 400 microgram (mcg). Darbepoetin could be given by IV injection for peritoneal dialysis participants switching to hemodialysis. Study treatment was dose-titrated to achieve and maintain hemoglobin in the target range (10 to 11 g/dL) and administered until the required number of MACE events occurred, at approximately 45.1 months of randomized treatment.
Mean Change From Baseline in Hemoglobin (Hgb) Levels During Evaluation Period (Week 28 to Week 52)	0.28 Grams per deciliter Standard Error 0.022	0.10 Grams per deciliter Standard Error 0.022

SECONDARY outcome

Timeframe: Up to 3.9 person-years for CV follow-up time period

Population: All Randomized (ITT) Population.

Time to MACE defined as the time to first occurrence of CEC adjudicated MACE was analyzed using a Cox proportional hazards regression model with treatment group, dialysis type and region as covariate. Time to the first occurrence was computed as (event date minus randomization date) + 1. The incidence rate per 100 person years calculated as (100\*number of participants with at least 1 event)/first event person-years) is presented along with 95% CI. First event person years=(cumulative total time to first event for participants who have the event + cumulative total of censored time for participants without the event)/365.25, based on the CV follow-up time period. This endpoint was adjusted for multiplicity using the Holm-Bonferonni method.

Outcome measures

Outcome measures
Measure	Daprodustat n=1487 Participants Participants received placebo tablets orally once daily in run-in period from Week -4 up to randomization (Day 1) and subsequently received daprodustat tablets at dose levels of 1, 2, 4, 6, 8, 10, 12, 16 and 24 milligrams (mg) orally once daily until the required number of major adverse cardiovascular event (MACE) occurred, at approximately 45.1 months of randomized treatment. Study treatment was dose-titrated to achieve and maintain hemoglobin in the target range (10 to 11 grams per deciliter \[g/dL\]).	rhEPO n=1477 Participants Participants received placebo tablets orally once daily in run-in period from Week -4 up to randomization (Day 1) and subsequently received treatment with rhEPO. Participants on hemodialysis received epoetin alfa as intravenous (IV) injection once weekly or three-times weekly with total weekly dose levels ranging from 1500 to 60,000 Units. Participants on peritoneal dialysis received subcutaneous (SC) injection of darbepoetin alfa every 1, 2, or 4 weeks with 4-weekly total dose levels ranging from 20 to 400 microgram (mcg). Darbepoetin could be given by IV injection for peritoneal dialysis participants switching to hemodialysis. Study treatment was dose-titrated to achieve and maintain hemoglobin in the target range (10 to 11 g/dL) and administered until the required number of MACE events occurred, at approximately 45.1 months of randomized treatment.
Time to First Occurrence of Adjudicated MACE During CV Events Follow-up Time Period: Superiority Analysis	11.07 Events per 100 person years Interval 9.98 to 12.26	11.86 Events per 100 person years Interval 10.72 to 13.09

SECONDARY outcome

Timeframe: Up to 3.9 person-years for CV follow-up time period

Population: All Randomized (ITT) Population.

Time to first occurrence of adjudicated MACE or thromboembolic event (vascular access thrombosis, symptomatic deep vein thrombosis or symptomatic pulmonary embolism) was analyzed using a Cox proportional hazards regression model with with treatment group, dialysis type and region as covariates. Time to the first occurrence was computed as (event date minus randomization date) + 1. The incidence rate per 100 person years calculated as (100\*number of participants with at least 1 event)/first event person-years) is presented along with 95% CI. First event person years=(cumulative total time to first event for participants who have the event + cumulative total of censored time for participants without the event)/365.25, based on the CV follow-up time period. This endpoint was adjusted for multiplicity using the Holm-Bonferonni method.

Outcome measures

Outcome measures
Measure	Daprodustat n=1487 Participants Participants received placebo tablets orally once daily in run-in period from Week -4 up to randomization (Day 1) and subsequently received daprodustat tablets at dose levels of 1, 2, 4, 6, 8, 10, 12, 16 and 24 milligrams (mg) orally once daily until the required number of major adverse cardiovascular event (MACE) occurred, at approximately 45.1 months of randomized treatment. Study treatment was dose-titrated to achieve and maintain hemoglobin in the target range (10 to 11 grams per deciliter \[g/dL\]).	rhEPO n=1477 Participants Participants received placebo tablets orally once daily in run-in period from Week -4 up to randomization (Day 1) and subsequently received treatment with rhEPO. Participants on hemodialysis received epoetin alfa as intravenous (IV) injection once weekly or three-times weekly with total weekly dose levels ranging from 1500 to 60,000 Units. Participants on peritoneal dialysis received subcutaneous (SC) injection of darbepoetin alfa every 1, 2, or 4 weeks with 4-weekly total dose levels ranging from 20 to 400 microgram (mcg). Darbepoetin could be given by IV injection for peritoneal dialysis participants switching to hemodialysis. Study treatment was dose-titrated to achieve and maintain hemoglobin in the target range (10 to 11 g/dL) and administered until the required number of MACE events occurred, at approximately 45.1 months of randomized treatment.
Time to First Occurrence of Adjudicated MACE or Thromboembolic Event During CV Events Follow-up Time Period	15.84 Events per 100 person years Interval 14.48 to 17.3	17.85 Events per 100 person years Interval 16.38 to 19.42

SECONDARY outcome

Timeframe: Up to 3.9 person-years for CV follow-up time period

Population: All Randomized (ITT) Population.

Time to first occurrence of adjudicated MACE or hospitalization for heart failure was analyzed using a Cox proportional hazards regression model with treatment group, dialysis type and region as covariates. Time to the first occurrence was computed as (event date minus randomization date) + 1. The incidence rate per 100 person years calculated as (100\*number of participants with at least 1 event)/first event person-years) is presented along with 95% CI. First event person years=(cumulative total time to first event for participants who have the event + cumulative total of censored time for participants without the event)/365.25, based on the CV follow-up time period. This endpoint was adjusted for multiplicity using the Holm-Bonferonni method.

Outcome measures

Outcome measures
Measure	Daprodustat n=1487 Participants Participants received placebo tablets orally once daily in run-in period from Week -4 up to randomization (Day 1) and subsequently received daprodustat tablets at dose levels of 1, 2, 4, 6, 8, 10, 12, 16 and 24 milligrams (mg) orally once daily until the required number of major adverse cardiovascular event (MACE) occurred, at approximately 45.1 months of randomized treatment. Study treatment was dose-titrated to achieve and maintain hemoglobin in the target range (10 to 11 grams per deciliter \[g/dL\]).	rhEPO n=1477 Participants Participants received placebo tablets orally once daily in run-in period from Week -4 up to randomization (Day 1) and subsequently received treatment with rhEPO. Participants on hemodialysis received epoetin alfa as intravenous (IV) injection once weekly or three-times weekly with total weekly dose levels ranging from 1500 to 60,000 Units. Participants on peritoneal dialysis received subcutaneous (SC) injection of darbepoetin alfa every 1, 2, or 4 weeks with 4-weekly total dose levels ranging from 20 to 400 microgram (mcg). Darbepoetin could be given by IV injection for peritoneal dialysis participants switching to hemodialysis. Study treatment was dose-titrated to achieve and maintain hemoglobin in the target range (10 to 11 g/dL) and administered until the required number of MACE events occurred, at approximately 45.1 months of randomized treatment.
Time to First Occurrence of Adjudicated MACE or Hospitalization for Heart Failure During CV Events Follow-up Time Period	12.98 Events per 100 person years Interval 11.77 to 14.27	13.38 Events per 100 person years Interval 12.15 to 14.7

SECONDARY outcome

Timeframe: Day 1 to Week 52

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

Average monthly IV iron dose (milligrams) per participant from Day 1 to Week 52 was determined by calculating the total IV iron dose per participant from treatment start date + 1 to the earliest of (Week 52 visit date, first blood (red blood cell \[RBC\] or whole blood) transfusion date, and treatment stop date + 1 day) which corresponds to the time while the participant was on randomized treatment and before receiving a blood transfusion. This total IV iron dose was divided by (the number of days from treatment start date + 1 to the earliest of (Week 52 visit date, first blood transfusion date (RBC or whole blood), and treatment stop date +1) / 30.4375 days). This endpoint was adjusted for multiplicity using the Holm-Bonferonni method.

Outcome measures

Outcome measures
Measure	Daprodustat n=1482 Participants Participants received placebo tablets orally once daily in run-in period from Week -4 up to randomization (Day 1) and subsequently received daprodustat tablets at dose levels of 1, 2, 4, 6, 8, 10, 12, 16 and 24 milligrams (mg) orally once daily until the required number of major adverse cardiovascular event (MACE) occurred, at approximately 45.1 months of randomized treatment. Study treatment was dose-titrated to achieve and maintain hemoglobin in the target range (10 to 11 grams per deciliter \[g/dL\]).	rhEPO n=1472 Participants Participants received placebo tablets orally once daily in run-in period from Week -4 up to randomization (Day 1) and subsequently received treatment with rhEPO. Participants on hemodialysis received epoetin alfa as intravenous (IV) injection once weekly or three-times weekly with total weekly dose levels ranging from 1500 to 60,000 Units. Participants on peritoneal dialysis received subcutaneous (SC) injection of darbepoetin alfa every 1, 2, or 4 weeks with 4-weekly total dose levels ranging from 20 to 400 microgram (mcg). Darbepoetin could be given by IV injection for peritoneal dialysis participants switching to hemodialysis. Study treatment was dose-titrated to achieve and maintain hemoglobin in the target range (10 to 11 g/dL) and administered until the required number of MACE events occurred, at approximately 45.1 months of randomized treatment.
Mean Average Monthly On-treatment IV Iron Dose Per Participant	90.8 Milligrams Standard Error 3.34	99.9 Milligrams Standard Error 3.35

SECONDARY outcome

Timeframe: Up to 3.9 person-years for vital status follow-up time period

Population: All Randomized (ITT) Population.

Time to first occurrence of adjudicated all-cause mortality was analyzed using a Cox proportional hazards regression model with treatment group, dialysis type and region as covariates. Time to the first occurrence was computed as (event date minus randomization date) + 1. The incidence rate per 100 person years calculated as (100\*number of participants with at least 1 event)/first event person-years) is presented along with 95% CI. First event person years=(cumulative total time to first event for participants who have the event + cumulative total of censored time for participants without the event)/365.25, based on the vital status for follow-up time period.

Outcome measures

Outcome measures
Measure	Daprodustat n=1487 Participants Participants received placebo tablets orally once daily in run-in period from Week -4 up to randomization (Day 1) and subsequently received daprodustat tablets at dose levels of 1, 2, 4, 6, 8, 10, 12, 16 and 24 milligrams (mg) orally once daily until the required number of major adverse cardiovascular event (MACE) occurred, at approximately 45.1 months of randomized treatment. Study treatment was dose-titrated to achieve and maintain hemoglobin in the target range (10 to 11 grams per deciliter \[g/dL\]).	rhEPO n=1477 Participants Participants received placebo tablets orally once daily in run-in period from Week -4 up to randomization (Day 1) and subsequently received treatment with rhEPO. Participants on hemodialysis received epoetin alfa as intravenous (IV) injection once weekly or three-times weekly with total weekly dose levels ranging from 1500 to 60,000 Units. Participants on peritoneal dialysis received subcutaneous (SC) injection of darbepoetin alfa every 1, 2, or 4 weeks with 4-weekly total dose levels ranging from 20 to 400 microgram (mcg). Darbepoetin could be given by IV injection for peritoneal dialysis participants switching to hemodialysis. Study treatment was dose-titrated to achieve and maintain hemoglobin in the target range (10 to 11 g/dL) and administered until the required number of MACE events occurred, at approximately 45.1 months of randomized treatment.
Time to First Occurrence of Adjudicated All-Cause Mortality During Vital Status for Follow-up Time Period	8.32 Events per 100 person years Interval 7.39 to 9.32	8.59 Events per 100 person years Interval 7.65 to 9.62

SECONDARY outcome

Timeframe: Up to 3.9 person-years for CV follow-up time period

Population: All Randomized (ITT) Population.

Time to first occurrence of adjudicated CV mortality was analyzed using a Cox proportional hazards regression model with treatment group, dialysis type and region as covariates. Time to the first occurrence was computed as (event date minus randomization date) + 1. The incidence rate per 100 person years calculated as (100\*number of participants with at least 1 event)/first event person-years) is presented along with 95% CI. First event person years=(cumulative total time to first event for participants who have the event + cumulative total of censored time for participants without the event)/365.25, based on the CV follow-up time period.

Outcome measures

Outcome measures
Measure	Daprodustat n=1487 Participants Participants received placebo tablets orally once daily in run-in period from Week -4 up to randomization (Day 1) and subsequently received daprodustat tablets at dose levels of 1, 2, 4, 6, 8, 10, 12, 16 and 24 milligrams (mg) orally once daily until the required number of major adverse cardiovascular event (MACE) occurred, at approximately 45.1 months of randomized treatment. Study treatment was dose-titrated to achieve and maintain hemoglobin in the target range (10 to 11 grams per deciliter \[g/dL\]).	rhEPO n=1477 Participants Participants received placebo tablets orally once daily in run-in period from Week -4 up to randomization (Day 1) and subsequently received treatment with rhEPO. Participants on hemodialysis received epoetin alfa as intravenous (IV) injection once weekly or three-times weekly with total weekly dose levels ranging from 1500 to 60,000 Units. Participants on peritoneal dialysis received subcutaneous (SC) injection of darbepoetin alfa every 1, 2, or 4 weeks with 4-weekly total dose levels ranging from 20 to 400 microgram (mcg). Darbepoetin could be given by IV injection for peritoneal dialysis participants switching to hemodialysis. Study treatment was dose-titrated to achieve and maintain hemoglobin in the target range (10 to 11 g/dL) and administered until the required number of MACE events occurred, at approximately 45.1 months of randomized treatment.
Time to First Occurrence of Adjudicated CV Mortality During CV Events Follow-up Time Period	3.31 Events per 100 person years Interval 2.74 to 3.97	3.46 Events per 100 person years Interval 2.88 to 4.14

SECONDARY outcome

Timeframe: Up to 3.9 person-years for CV follow-up time period

Population: All Randomized (ITT) Population.

Time to first occurrence of adjudicated MI (fatal and non-fatal) was analyzed using a Cox proportional hazards regression model with treatment group, dialysis type and region as covariates. Time to the first occurrence was computed as (event date minus randomization date) + 1. The incidence rate per 100 person years calculated as (100\*number of participants with at least 1 event)/first event person-years) is presented along with 95% CI. First event person years=(cumulative total time to first event for participants who have the event + cumulative total of censored time for participants without the event)/365.25, based on the CV follow-up time period.

Outcome measures

Outcome measures
Measure	Daprodustat n=1487 Participants Participants received placebo tablets orally once daily in run-in period from Week -4 up to randomization (Day 1) and subsequently received daprodustat tablets at dose levels of 1, 2, 4, 6, 8, 10, 12, 16 and 24 milligrams (mg) orally once daily until the required number of major adverse cardiovascular event (MACE) occurred, at approximately 45.1 months of randomized treatment. Study treatment was dose-titrated to achieve and maintain hemoglobin in the target range (10 to 11 grams per deciliter \[g/dL\]).	rhEPO n=1477 Participants Participants received placebo tablets orally once daily in run-in period from Week -4 up to randomization (Day 1) and subsequently received treatment with rhEPO. Participants on hemodialysis received epoetin alfa as intravenous (IV) injection once weekly or three-times weekly with total weekly dose levels ranging from 1500 to 60,000 Units. Participants on peritoneal dialysis received subcutaneous (SC) injection of darbepoetin alfa every 1, 2, or 4 weeks with 4-weekly total dose levels ranging from 20 to 400 microgram (mcg). Darbepoetin could be given by IV injection for peritoneal dialysis participants switching to hemodialysis. Study treatment was dose-titrated to achieve and maintain hemoglobin in the target range (10 to 11 g/dL) and administered until the required number of MACE events occurred, at approximately 45.1 months of randomized treatment.
Time to First Occurrence of Adjudicated Myocardial Infarction (MI) (Fatal and Non-Fatal) During CV Events Follow-up Time Period	3.34 Events per 100 person years Interval 2.76 to 4.01	4.08 Events per 100 person years Interval 3.43 to 4.83

SECONDARY outcome

Timeframe: Up to 3.9 person-years for CV follow-up time period

Population: All Randomized (ITT) Population.

Time to first occurrence of adjudicated stroke (fatal and non-fatal) was analyzed using a Cox proportional hazards regression model with treatment group, dialysis type and region as covariates. Time to the first occurrence was computed as (event date minus randomization date) + 1. The incidence rate per 100 person years calculated as (100\*number of participants with at least 1 event)/first event person-years) is presented along with 95% CI. First event person years=(cumulative total time to first event for participants who have the event + cumulative total of censored time for participants without the event)/365.25, based on the CV follow-up time period.

Outcome measures

Outcome measures
Measure	Daprodustat n=1487 Participants Participants received placebo tablets orally once daily in run-in period from Week -4 up to randomization (Day 1) and subsequently received daprodustat tablets at dose levels of 1, 2, 4, 6, 8, 10, 12, 16 and 24 milligrams (mg) orally once daily until the required number of major adverse cardiovascular event (MACE) occurred, at approximately 45.1 months of randomized treatment. Study treatment was dose-titrated to achieve and maintain hemoglobin in the target range (10 to 11 grams per deciliter \[g/dL\]).	rhEPO n=1477 Participants Participants received placebo tablets orally once daily in run-in period from Week -4 up to randomization (Day 1) and subsequently received treatment with rhEPO. Participants on hemodialysis received epoetin alfa as intravenous (IV) injection once weekly or three-times weekly with total weekly dose levels ranging from 1500 to 60,000 Units. Participants on peritoneal dialysis received subcutaneous (SC) injection of darbepoetin alfa every 1, 2, or 4 weeks with 4-weekly total dose levels ranging from 20 to 400 microgram (mcg). Darbepoetin could be given by IV injection for peritoneal dialysis participants switching to hemodialysis. Study treatment was dose-titrated to achieve and maintain hemoglobin in the target range (10 to 11 g/dL) and administered until the required number of MACE events occurred, at approximately 45.1 months of randomized treatment.
Time to First Occurrence of Adjudicated Stroke (Fatal and Non-Fatal) During CV Events Follow-up Time Period	1.23 Events per 100 person years Interval 0.89 to 1.66	1.48 Events per 100 person years Interval 1.1 to 1.94

SECONDARY outcome

Timeframe: Up to 3.9 person-years for CV follow-up time period

Population: All Randomized (ITT) Population.

Number of participants with adjudicated MACE or hospitalization for heart failure (recurrent events analysis) is presented, categorized by number of occurrences of adjudicated MACE or hospitalization for heart failure per participant.

Outcome measures

Outcome measures
Measure	Daprodustat n=1487 Participants Participants received placebo tablets orally once daily in run-in period from Week -4 up to randomization (Day 1) and subsequently received daprodustat tablets at dose levels of 1, 2, 4, 6, 8, 10, 12, 16 and 24 milligrams (mg) orally once daily until the required number of major adverse cardiovascular event (MACE) occurred, at approximately 45.1 months of randomized treatment. Study treatment was dose-titrated to achieve and maintain hemoglobin in the target range (10 to 11 grams per deciliter \[g/dL\]).	rhEPO n=1477 Participants Participants received placebo tablets orally once daily in run-in period from Week -4 up to randomization (Day 1) and subsequently received treatment with rhEPO. Participants on hemodialysis received epoetin alfa as intravenous (IV) injection once weekly or three-times weekly with total weekly dose levels ranging from 1500 to 60,000 Units. Participants on peritoneal dialysis received subcutaneous (SC) injection of darbepoetin alfa every 1, 2, or 4 weeks with 4-weekly total dose levels ranging from 20 to 400 microgram (mcg). Darbepoetin could be given by IV injection for peritoneal dialysis participants switching to hemodialysis. Study treatment was dose-titrated to achieve and maintain hemoglobin in the target range (10 to 11 g/dL) and administered until the required number of MACE events occurred, at approximately 45.1 months of randomized treatment.
Number of Participants With Adjudicated MACE or Hospitalization for Heart Failure (Recurrent Events Analysis) Occurrences per participant: 0	1062 Participants	1044 Participants
Number of Participants With Adjudicated MACE or Hospitalization for Heart Failure (Recurrent Events Analysis) Occurrences per participant: 1	315 Participants	300 Participants
Number of Participants With Adjudicated MACE or Hospitalization for Heart Failure (Recurrent Events Analysis) Occurrences per participant: 2	72 Participants	88 Participants
Number of Participants With Adjudicated MACE or Hospitalization for Heart Failure (Recurrent Events Analysis) Occurrences per participant: 3	25 Participants	22 Participants
Number of Participants With Adjudicated MACE or Hospitalization for Heart Failure (Recurrent Events Analysis) Occurrences per participant: 4	3 Participants	11 Participants
Number of Participants With Adjudicated MACE or Hospitalization for Heart Failure (Recurrent Events Analysis) Occurrences per participant: 5	4 Participants	4 Participants
Number of Participants With Adjudicated MACE or Hospitalization for Heart Failure (Recurrent Events Analysis) Occurrences per participant: 6	4 Participants	3 Participants
Number of Participants With Adjudicated MACE or Hospitalization for Heart Failure (Recurrent Events Analysis) Occurrences per participant: 7	0 Participants	2 Participants
Number of Participants With Adjudicated MACE or Hospitalization for Heart Failure (Recurrent Events Analysis) Occurrences per participant: 9	1 Participants	1 Participants
Number of Participants With Adjudicated MACE or Hospitalization for Heart Failure (Recurrent Events Analysis) Occurrences per participant: 10	1 Participants	1 Participants
Number of Participants With Adjudicated MACE or Hospitalization for Heart Failure (Recurrent Events Analysis) Occurrences per participant: 8	0 Participants	1 Participants

SECONDARY outcome

Timeframe: Up to 3.9 person-years for CV follow-up time period

Population: All Randomized (ITT) Population.

Time to first occurrence of adjudicated CV mortality or non-fatal MI was analyzed using a Cox proportional hazards regression model with treatment group, dialysis type and region as covariates. Time to the first occurrence was computed as (event date minus randomization date) + 1. The incidence rate per 100 person years calculated as (100\*number of participants with at least 1 event)/first event person-years) is presented along with 95% CI. First event person years=(cumulative total time to first event for participants who have the event + cumulative total of censored time for participants without the event)/365.25, based on the CV follow-up time period.

Outcome measures

Outcome measures
Measure	Daprodustat n=1487 Participants Participants received placebo tablets orally once daily in run-in period from Week -4 up to randomization (Day 1) and subsequently received daprodustat tablets at dose levels of 1, 2, 4, 6, 8, 10, 12, 16 and 24 milligrams (mg) orally once daily until the required number of major adverse cardiovascular event (MACE) occurred, at approximately 45.1 months of randomized treatment. Study treatment was dose-titrated to achieve and maintain hemoglobin in the target range (10 to 11 grams per deciliter \[g/dL\]).	rhEPO n=1477 Participants Participants received placebo tablets orally once daily in run-in period from Week -4 up to randomization (Day 1) and subsequently received treatment with rhEPO. Participants on hemodialysis received epoetin alfa as intravenous (IV) injection once weekly or three-times weekly with total weekly dose levels ranging from 1500 to 60,000 Units. Participants on peritoneal dialysis received subcutaneous (SC) injection of darbepoetin alfa every 1, 2, or 4 weeks with 4-weekly total dose levels ranging from 20 to 400 microgram (mcg). Darbepoetin could be given by IV injection for peritoneal dialysis participants switching to hemodialysis. Study treatment was dose-titrated to achieve and maintain hemoglobin in the target range (10 to 11 g/dL) and administered until the required number of MACE events occurred, at approximately 45.1 months of randomized treatment.
Time to First Occurrence of Adjudicated CV Mortality or Non-Fatal MI During CV Events Follow-up Time Period	5.98 Events per 100 person years Interval 5.18 to 6.86	6.79 Events per 100 person years Interval 5.94 to 7.73

SECONDARY outcome

Timeframe: Up to 3.9 person-years for CV follow-up time period

Population: All Randomized (ITT) Population.

All-cause hospitalization events were hospital admissions recorded on the Hospitalization electronic case report form (eCRF) with a hospitalization duration \>=24 hours. Time to first occurrence of all-cause hospitalization was analyzed using a Cox proportional hazards regression model with treatment group, dialysis type and region as covariates. Time to the first occurrence was computed as (event date minus randomization date) + 1. The incidence rate per 100 person years calculated as (100\*number of participants with at least 1 event)/first event person-years) is presented along with 95% CI. First event person years=(cumulative total time to first event for participants who have the event + cumulative total of censored time for participants without the event)/365.25, based on the CV follow-up time period.

Outcome measures

Outcome measures
Measure	Daprodustat n=1487 Participants Participants received placebo tablets orally once daily in run-in period from Week -4 up to randomization (Day 1) and subsequently received daprodustat tablets at dose levels of 1, 2, 4, 6, 8, 10, 12, 16 and 24 milligrams (mg) orally once daily until the required number of major adverse cardiovascular event (MACE) occurred, at approximately 45.1 months of randomized treatment. Study treatment was dose-titrated to achieve and maintain hemoglobin in the target range (10 to 11 grams per deciliter \[g/dL\]).	rhEPO n=1477 Participants Participants received placebo tablets orally once daily in run-in period from Week -4 up to randomization (Day 1) and subsequently received treatment with rhEPO. Participants on hemodialysis received epoetin alfa as intravenous (IV) injection once weekly or three-times weekly with total weekly dose levels ranging from 1500 to 60,000 Units. Participants on peritoneal dialysis received subcutaneous (SC) injection of darbepoetin alfa every 1, 2, or 4 weeks with 4-weekly total dose levels ranging from 20 to 400 microgram (mcg). Darbepoetin could be given by IV injection for peritoneal dialysis participants switching to hemodialysis. Study treatment was dose-titrated to achieve and maintain hemoglobin in the target range (10 to 11 g/dL) and administered until the required number of MACE events occurred, at approximately 45.1 months of randomized treatment.
Time to First Occurrence of All-Cause Hospitalization During CV Events Follow-up Time Period	43.92 Events per 100 person years Interval 41.18 to 46.81	46.03 Events per 100 person years Interval 43.17 to 49.04

SECONDARY outcome

Timeframe: Up to 3.9 person-years for CV follow-up time period

Population: All Randomized (ITT) Population.

All-cause hospital re-admissions within 30days are defined as hospital admissions recorded on hospitalization eCRF with hospitalization duration of \>=24 hours and admission date within 30days following previous discharge date of all-cause hospitalization event, where previous hospitalization was \>=24 hours. Time to first occurrence of all-cause hospital re-admission within 30days was analyzed using Cox proportional hazards regression model with treatment group, dialysis type and region as covariates. Time to the first occurrence was computed as (event date minus randomization date)+1. Incidence rate per 100person years calculated as(100\*number of participants with at least 1 event)/first event person-years) is presented along with 95% CI. First event person years=(cumulative total time to first event for participants who have the event+cumulative total of censored time for participants without the event)/365.25, based on the CV follow-up time period.

Outcome measures

Outcome measures
Measure	Daprodustat n=1487 Participants Participants received placebo tablets orally once daily in run-in period from Week -4 up to randomization (Day 1) and subsequently received daprodustat tablets at dose levels of 1, 2, 4, 6, 8, 10, 12, 16 and 24 milligrams (mg) orally once daily until the required number of major adverse cardiovascular event (MACE) occurred, at approximately 45.1 months of randomized treatment. Study treatment was dose-titrated to achieve and maintain hemoglobin in the target range (10 to 11 grams per deciliter \[g/dL\]).	rhEPO n=1477 Participants Participants received placebo tablets orally once daily in run-in period from Week -4 up to randomization (Day 1) and subsequently received treatment with rhEPO. Participants on hemodialysis received epoetin alfa as intravenous (IV) injection once weekly or three-times weekly with total weekly dose levels ranging from 1500 to 60,000 Units. Participants on peritoneal dialysis received subcutaneous (SC) injection of darbepoetin alfa every 1, 2, or 4 weeks with 4-weekly total dose levels ranging from 20 to 400 microgram (mcg). Darbepoetin could be given by IV injection for peritoneal dialysis participants switching to hemodialysis. Study treatment was dose-titrated to achieve and maintain hemoglobin in the target range (10 to 11 g/dL) and administered until the required number of MACE events occurred, at approximately 45.1 months of randomized treatment.
Time to First Occurrence of All-Cause Hospital Re-admission Within 30 Days During CV Events Follow-up Time Period	8.86 Events per 100 person years Interval 7.85 to 9.95	9.67 Events per 100 person years Interval 8.62 to 10.82

SECONDARY outcome

Timeframe: Up to 3.9 person-years for CV follow-up time period

Population: All Randomized (ITT) Population.

Time to first occurrence of adjudicated MACE or hospitalization for heart failure or thromboembolic events were analyzed using a Cox proportional hazards regression model with treatment group, dialysis type and region as covariates. Time to the first occurrence was computed as (event date minus randomization date) + 1. The incidence rate per 100 person years calculated as (100\*number of participants with at least 1 event)/first event person-years) is presented along with 95% CI. First event person years=(cumulative total time to first event for participants who have the event + cumulative total of censored time for participants without the event)/365.25, based on the CV follow-up time period.

Outcome measures

Outcome measures
Measure	Daprodustat n=1487 Participants Participants received placebo tablets orally once daily in run-in period from Week -4 up to randomization (Day 1) and subsequently received daprodustat tablets at dose levels of 1, 2, 4, 6, 8, 10, 12, 16 and 24 milligrams (mg) orally once daily until the required number of major adverse cardiovascular event (MACE) occurred, at approximately 45.1 months of randomized treatment. Study treatment was dose-titrated to achieve and maintain hemoglobin in the target range (10 to 11 grams per deciliter \[g/dL\]).	rhEPO n=1477 Participants Participants received placebo tablets orally once daily in run-in period from Week -4 up to randomization (Day 1) and subsequently received treatment with rhEPO. Participants on hemodialysis received epoetin alfa as intravenous (IV) injection once weekly or three-times weekly with total weekly dose levels ranging from 1500 to 60,000 Units. Participants on peritoneal dialysis received subcutaneous (SC) injection of darbepoetin alfa every 1, 2, or 4 weeks with 4-weekly total dose levels ranging from 20 to 400 microgram (mcg). Darbepoetin could be given by IV injection for peritoneal dialysis participants switching to hemodialysis. Study treatment was dose-titrated to achieve and maintain hemoglobin in the target range (10 to 11 g/dL) and administered until the required number of MACE events occurred, at approximately 45.1 months of randomized treatment.
Time to First Occurrence of Adjudicated MACE or Hospitalization for Heart Failure or Thromboembolic Events During CV Events Follow-up Time Period	17.74 Events per 100 person years Interval 16.28 to 19.3	19.50 Events per 100 person years Interval 17.94 to 21.16

SECONDARY outcome

Timeframe: Up to 3.9 person-years for CV follow-up time period

Population: All Randomized (ITT) Population.

Time to first occurrence of adjudicated hospitalization for heart failure was analyzed using a Cox proportional hazards regression model with treatment group, dialysis type and region as covariates. Time to the first occurrence was computed as (event date minus randomization date) + 1. The incidence rate per 100 person years calculated as (100\*number of participants with at least 1 event)/first event person-years) is presented along with 95% CI. First event person years=(cumulative total time to first event for participants who have the event + cumulative total of censored time for participants without the event)/365.25, based on the CV follow-up time period.

Outcome measures

Outcome measures
Measure	Daprodustat n=1487 Participants Participants received placebo tablets orally once daily in run-in period from Week -4 up to randomization (Day 1) and subsequently received daprodustat tablets at dose levels of 1, 2, 4, 6, 8, 10, 12, 16 and 24 milligrams (mg) orally once daily until the required number of major adverse cardiovascular event (MACE) occurred, at approximately 45.1 months of randomized treatment. Study treatment was dose-titrated to achieve and maintain hemoglobin in the target range (10 to 11 grams per deciliter \[g/dL\]).	rhEPO n=1477 Participants Participants received placebo tablets orally once daily in run-in period from Week -4 up to randomization (Day 1) and subsequently received treatment with rhEPO. Participants on hemodialysis received epoetin alfa as intravenous (IV) injection once weekly or three-times weekly with total weekly dose levels ranging from 1500 to 60,000 Units. Participants on peritoneal dialysis received subcutaneous (SC) injection of darbepoetin alfa every 1, 2, or 4 weeks with 4-weekly total dose levels ranging from 20 to 400 microgram (mcg). Darbepoetin could be given by IV injection for peritoneal dialysis participants switching to hemodialysis. Study treatment was dose-titrated to achieve and maintain hemoglobin in the target range (10 to 11 g/dL) and administered until the required number of MACE events occurred, at approximately 45.1 months of randomized treatment.
Time to First Occurrence of Adjudicated Hospitalization for Heart Failure During CV Events Follow-up Time Period	3.30 Events per 100 person years Interval 2.72 to 3.97	3.01 Events per 100 person years Interval 2.45 to 3.65

SECONDARY outcome

Timeframe: Up to 3.9 person-years for CV follow-up time period

Population: All Randomized (ITT) Population.

Time to first occurrence of adjudicated thromboembolic events were analyzed using a Cox proportional hazards regression model with treatment group, dialysis type and region as covariates. Time to the first occurrence was computed as (event date minus randomization date) + 1. The incidence rate per 100 person years calculated as (100\*number of participants with at least 1 event)/first event person-years) is presented along with 95% CI. First event person years=(cumulative total time to first event for participants who have the event + cumulative total of censored time for participants without the event)/365.25, based on the CV follow-up time period.

Outcome measures

Outcome measures
Measure	Daprodustat n=1487 Participants Participants received placebo tablets orally once daily in run-in period from Week -4 up to randomization (Day 1) and subsequently received daprodustat tablets at dose levels of 1, 2, 4, 6, 8, 10, 12, 16 and 24 milligrams (mg) orally once daily until the required number of major adverse cardiovascular event (MACE) occurred, at approximately 45.1 months of randomized treatment. Study treatment was dose-titrated to achieve and maintain hemoglobin in the target range (10 to 11 grams per deciliter \[g/dL\]).	rhEPO n=1477 Participants Participants received placebo tablets orally once daily in run-in period from Week -4 up to randomization (Day 1) and subsequently received treatment with rhEPO. Participants on hemodialysis received epoetin alfa as intravenous (IV) injection once weekly or three-times weekly with total weekly dose levels ranging from 1500 to 60,000 Units. Participants on peritoneal dialysis received subcutaneous (SC) injection of darbepoetin alfa every 1, 2, or 4 weeks with 4-weekly total dose levels ranging from 20 to 400 microgram (mcg). Darbepoetin could be given by IV injection for peritoneal dialysis participants switching to hemodialysis. Study treatment was dose-titrated to achieve and maintain hemoglobin in the target range (10 to 11 g/dL) and administered until the required number of MACE events occurred, at approximately 45.1 months of randomized treatment.
Time to First Occurrence of Adjudicated Thromboembolic Events During CV Events Follow-up Time Period	5.66 Events per 100 person years Interval 4.87 to 6.54	6.75 Events per 100 person years Interval 5.88 to 7.72

SECONDARY outcome

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

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

Blood samples were collected from participants for hemoglobin measurements. Change from Baseline was defined as post-Baseline value minus Baseline value. Baseline was defined as the latest non-missing pre-dose assessment on or before the randomization date. Analysis was performed using mixed model repeated measures (MMRM) model fitted from Baseline up to Week 52, excluding values collected during the stabilization period, with factors for treatment, time, dialysis type, region, Baseline hemoglobin and Baseline hemoglobin by time and treatment by time interactions.

Outcome measures

Outcome measures
Measure	Daprodustat n=1358 Participants Participants received placebo tablets orally once daily in run-in period from Week -4 up to randomization (Day 1) and subsequently received daprodustat tablets at dose levels of 1, 2, 4, 6, 8, 10, 12, 16 and 24 milligrams (mg) orally once daily until the required number of major adverse cardiovascular event (MACE) occurred, at approximately 45.1 months of randomized treatment. Study treatment was dose-titrated to achieve and maintain hemoglobin in the target range (10 to 11 grams per deciliter \[g/dL\]).	rhEPO n=1347 Participants Participants received placebo tablets orally once daily in run-in period from Week -4 up to randomization (Day 1) and subsequently received treatment with rhEPO. Participants on hemodialysis received epoetin alfa as intravenous (IV) injection once weekly or three-times weekly with total weekly dose levels ranging from 1500 to 60,000 Units. Participants on peritoneal dialysis received subcutaneous (SC) injection of darbepoetin alfa every 1, 2, or 4 weeks with 4-weekly total dose levels ranging from 20 to 400 microgram (mcg). Darbepoetin could be given by IV injection for peritoneal dialysis participants switching to hemodialysis. Study treatment was dose-titrated to achieve and maintain hemoglobin in the target range (10 to 11 g/dL) and administered until the required number of MACE events occurred, at approximately 45.1 months of randomized treatment.
Change From Baseline in Post-randomization Hemoglobin Levels at Week 52	0.26 Grams per deciliter Standard Error 0.032	0.14 Grams per deciliter Standard Error 0.032

SECONDARY outcome

Timeframe: Week 28 to Week 52

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

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

Outcome measures

Outcome measures
Measure	Daprodustat n=1238 Participants Participants received placebo tablets orally once daily in run-in period from Week -4 up to randomization (Day 1) and subsequently received daprodustat tablets at dose levels of 1, 2, 4, 6, 8, 10, 12, 16 and 24 milligrams (mg) orally once daily until the required number of major adverse cardiovascular event (MACE) occurred, at approximately 45.1 months of randomized treatment. Study treatment was dose-titrated to achieve and maintain hemoglobin in the target range (10 to 11 grams per deciliter \[g/dL\]).	rhEPO n=1247 Participants Participants received placebo tablets orally once daily in run-in period from Week -4 up to randomization (Day 1) and subsequently received treatment with rhEPO. Participants on hemodialysis received epoetin alfa as intravenous (IV) injection once weekly or three-times weekly with total weekly dose levels ranging from 1500 to 60,000 Units. Participants on peritoneal dialysis received subcutaneous (SC) injection of darbepoetin alfa every 1, 2, or 4 weeks with 4-weekly total dose levels ranging from 20 to 400 microgram (mcg). Darbepoetin could be given by IV injection for peritoneal dialysis participants switching to hemodialysis. Study treatment was dose-titrated to achieve and maintain hemoglobin in the target range (10 to 11 g/dL) and administered until the required number of MACE events occurred, at approximately 45.1 months of randomized treatment.
Number of Hgb Responders in the Hgb Analysis Range (10 to 11.5 Grams/Deciliter) During Evaluation Period (Week 28 to Week 52)	903 Participants	866 Participants

SECONDARY outcome

Timeframe: Week 28 to Week 52

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

Percentage of days for which a participant's Hgb was within the analysis range of 10-11.5 g/dL (both inclusive) during the evaluation period (Week 28 to Week 52), including any unscheduled evaluable Hgb values that were taken during this time period was calculated. Percentage of time in the analysis range during evaluation period is calculated as time in range during the evaluation period / \[Earlier of (Date of the last evaluable Hgb value, Week 52 visit date) - Later of (Date of the first evaluable Hgb value that between Week 16 and Week 52 inclusive, Week 28 visit date)\].

Outcome measures

Outcome measures
Measure	Daprodustat n=1202 Participants Participants received placebo tablets orally once daily in run-in period from Week -4 up to randomization (Day 1) and subsequently received daprodustat tablets at dose levels of 1, 2, 4, 6, 8, 10, 12, 16 and 24 milligrams (mg) orally once daily until the required number of major adverse cardiovascular event (MACE) occurred, at approximately 45.1 months of randomized treatment. Study treatment was dose-titrated to achieve and maintain hemoglobin in the target range (10 to 11 grams per deciliter \[g/dL\]).	rhEPO n=1224 Participants Participants received placebo tablets orally once daily in run-in period from Week -4 up to randomization (Day 1) and subsequently received treatment with rhEPO. Participants on hemodialysis received epoetin alfa as intravenous (IV) injection once weekly or three-times weekly with total weekly dose levels ranging from 1500 to 60,000 Units. Participants on peritoneal dialysis received subcutaneous (SC) injection of darbepoetin alfa every 1, 2, or 4 weeks with 4-weekly total dose levels ranging from 20 to 400 microgram (mcg). Darbepoetin could be given by IV injection for peritoneal dialysis participants switching to hemodialysis. Study treatment was dose-titrated to achieve and maintain hemoglobin in the target range (10 to 11 g/dL) and administered until the required number of MACE events occurred, at approximately 45.1 months of randomized treatment.
Percentage of Time With Hemoglobin in the Analysis Range (10 to 11.5 Grams/Deciliter) During Evaluation Period (Week 28 to Week 52): Non-inferiority Analysis	60.9 Percentage of days Interval 0.0 to 100.0	59.4 Percentage of days Interval 0.0 to 100.0

SECONDARY outcome

Timeframe: Week 28 to Week 52

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

Outcome measures

Outcome measures
Measure	Daprodustat n=1202 Participants Participants received placebo tablets orally once daily in run-in period from Week -4 up to randomization (Day 1) and subsequently received daprodustat tablets at dose levels of 1, 2, 4, 6, 8, 10, 12, 16 and 24 milligrams (mg) orally once daily until the required number of major adverse cardiovascular event (MACE) occurred, at approximately 45.1 months of randomized treatment. Study treatment was dose-titrated to achieve and maintain hemoglobin in the target range (10 to 11 grams per deciliter \[g/dL\]).	rhEPO n=1224 Participants Participants received placebo tablets orally once daily in run-in period from Week -4 up to randomization (Day 1) and subsequently received treatment with rhEPO. Participants on hemodialysis received epoetin alfa as intravenous (IV) injection once weekly or three-times weekly with total weekly dose levels ranging from 1500 to 60,000 Units. Participants on peritoneal dialysis received subcutaneous (SC) injection of darbepoetin alfa every 1, 2, or 4 weeks with 4-weekly total dose levels ranging from 20 to 400 microgram (mcg). Darbepoetin could be given by IV injection for peritoneal dialysis participants switching to hemodialysis. Study treatment was dose-titrated to achieve and maintain hemoglobin in the target range (10 to 11 g/dL) and administered until the required number of MACE events occurred, at approximately 45.1 months of randomized treatment.
Percentage of Time With Hemoglobin in the Analysis Range (10 to 11.5 Grams/Deciliter) During Evaluation Period (Week 28 to Week 52): Superiority Analysis	60.9 Percentage of days Interval 0.0 to 100.0	59.4 Percentage of days Interval 0.0 to 100.0

SECONDARY outcome

Timeframe: Week 28 to end of study (3.9 person-years for follow-up time period)

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

Percentage of days for which a participant's Hgb was within the analysis range of 10-11.5 g/dL (both inclusive) during the maintenance period (Week 28 to end of study), including any unscheduled evaluable Hgb values that were taken during this time period was calculated. Percentage of time in the analysis range during maintenance period is calculated as time in range during the maintenance period / \[Earlier of (Date of the last evaluable Hgb value, End of study date)- Later of (Date of the first evaluable Hgb value that is on or after week 16, Week 28 visit date)\].

Outcome measures

Outcome measures
Measure	Daprodustat n=1203 Participants Participants received placebo tablets orally once daily in run-in period from Week -4 up to randomization (Day 1) and subsequently received daprodustat tablets at dose levels of 1, 2, 4, 6, 8, 10, 12, 16 and 24 milligrams (mg) orally once daily until the required number of major adverse cardiovascular event (MACE) occurred, at approximately 45.1 months of randomized treatment. Study treatment was dose-titrated to achieve and maintain hemoglobin in the target range (10 to 11 grams per deciliter \[g/dL\]).	rhEPO n=1224 Participants Participants received placebo tablets orally once daily in run-in period from Week -4 up to randomization (Day 1) and subsequently received treatment with rhEPO. Participants on hemodialysis received epoetin alfa as intravenous (IV) injection once weekly or three-times weekly with total weekly dose levels ranging from 1500 to 60,000 Units. Participants on peritoneal dialysis received subcutaneous (SC) injection of darbepoetin alfa every 1, 2, or 4 weeks with 4-weekly total dose levels ranging from 20 to 400 microgram (mcg). Darbepoetin could be given by IV injection for peritoneal dialysis participants switching to hemodialysis. Study treatment was dose-titrated to achieve and maintain hemoglobin in the target range (10 to 11 g/dL) and administered until the required number of MACE events occurred, at approximately 45.1 months of randomized treatment.
Percentage of Time With Hemoglobin in the Analysis Range (10 to 11.5 Grams/Deciliter) During Maintenance Period (Week 28 to End of Study): Non-inferiority Analysis	60.9 Percentage of days Interval 0.0 to 100.0	57.7 Percentage of days Interval 0.0 to 100.0

SECONDARY outcome

Timeframe: Week 28 to end of study (3.9 person-years for follow-up time period)

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

Outcome measures

Outcome measures
Measure	Daprodustat n=1203 Participants Participants received placebo tablets orally once daily in run-in period from Week -4 up to randomization (Day 1) and subsequently received daprodustat tablets at dose levels of 1, 2, 4, 6, 8, 10, 12, 16 and 24 milligrams (mg) orally once daily until the required number of major adverse cardiovascular event (MACE) occurred, at approximately 45.1 months of randomized treatment. Study treatment was dose-titrated to achieve and maintain hemoglobin in the target range (10 to 11 grams per deciliter \[g/dL\]).	rhEPO n=1224 Participants Participants received placebo tablets orally once daily in run-in period from Week -4 up to randomization (Day 1) and subsequently received treatment with rhEPO. Participants on hemodialysis received epoetin alfa as intravenous (IV) injection once weekly or three-times weekly with total weekly dose levels ranging from 1500 to 60,000 Units. Participants on peritoneal dialysis received subcutaneous (SC) injection of darbepoetin alfa every 1, 2, or 4 weeks with 4-weekly total dose levels ranging from 20 to 400 microgram (mcg). Darbepoetin could be given by IV injection for peritoneal dialysis participants switching to hemodialysis. Study treatment was dose-titrated to achieve and maintain hemoglobin in the target range (10 to 11 g/dL) and administered until the required number of MACE events occurred, at approximately 45.1 months of randomized treatment.
Percentage of Time With Hemoglobin in the Analysis Range (10 to 11.5 Grams/Deciliter) During Maintenance Period (Week 28 to End of Study): Superiority Analysis	60.9 Percentage of days Interval 0.0 to 100.0	57.7 Percentage of days Interval 0.0 to 100.0

SECONDARY outcome

Timeframe: Baseline (Week -4) and Week 52

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

SBP, DBP and MAP were measured in a semi-supine or seated position in the dialysis chair after at least a 5-minutes of rest. MAP is the average BP in an individual's arteries during a single cardiac cycle. Change from Baseline was calculated as on-treatment visit value minus Baseline value. Baseline was defined as the latest non-missing pre-dose assessment on or before the randomization date. Analysis was performed using MMRM model with treatment group + time + dialysis type + region + Baseline value + Baseline value\*time + treatment group\*time, using an unstructured covariance matrix. Data for post-dialysis BP measurements have been presented.

Outcome measures

Outcome measures
Measure	Daprodustat n=1455 Participants Participants received placebo tablets orally once daily in run-in period from Week -4 up to randomization (Day 1) and subsequently received daprodustat tablets at dose levels of 1, 2, 4, 6, 8, 10, 12, 16 and 24 milligrams (mg) orally once daily until the required number of major adverse cardiovascular event (MACE) occurred, at approximately 45.1 months of randomized treatment. Study treatment was dose-titrated to achieve and maintain hemoglobin in the target range (10 to 11 grams per deciliter \[g/dL\]).	rhEPO n=1442 Participants Participants received placebo tablets orally once daily in run-in period from Week -4 up to randomization (Day 1) and subsequently received treatment with rhEPO. Participants on hemodialysis received epoetin alfa as intravenous (IV) injection once weekly or three-times weekly with total weekly dose levels ranging from 1500 to 60,000 Units. Participants on peritoneal dialysis received subcutaneous (SC) injection of darbepoetin alfa every 1, 2, or 4 weeks with 4-weekly total dose levels ranging from 20 to 400 microgram (mcg). Darbepoetin could be given by IV injection for peritoneal dialysis participants switching to hemodialysis. Study treatment was dose-titrated to achieve and maintain hemoglobin in the target range (10 to 11 g/dL) and administered until the required number of MACE events occurred, at approximately 45.1 months of randomized treatment.
Change From Baseline in Systolic Blood Pressure (SBP), Diastolic Blood Pressure (DBP) and Mean Arterial Blood Pressure (MAP) at Week 52 SBP	-0.61 Millimeter of mercury Standard Error 0.582	-0.93 Millimeter of mercury Standard Error 0.578
Change From Baseline in Systolic Blood Pressure (SBP), Diastolic Blood Pressure (DBP) and Mean Arterial Blood Pressure (MAP) at Week 52 DBP	-1.04 Millimeter of mercury Standard Error 0.326	-0.58 Millimeter of mercury Standard Error 0.324
Change From Baseline in Systolic Blood Pressure (SBP), Diastolic Blood Pressure (DBP) and Mean Arterial Blood Pressure (MAP) at Week 52 MAP	-0.89 Millimeter of mercury Standard Error 0.370	-0.71 Millimeter of mercury Standard Error 0.368

SECONDARY outcome

Timeframe: Baseline (Week -4) and 45.1 months

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

SBP, DBP and MAP were measured in a semi-supine or seated position in the dialysis chair after at least a 5-minutes of rest. MAP is an average BP in an individual's arteries during a single cardiac cycle. Change from Baseline was calculated as on-treatment visit value minus Baseline value. Baseline was defined as the latest non-missing pre-dose assessment on or before the randomization date. This analysis was carried out by using ANCOVA model with terms for treatment group, dialysis type, region and Baseline value. Data for post-dialysis BP measurements have been presented.

Outcome measures

Outcome measures
Measure	Daprodustat n=1468 Participants Participants received placebo tablets orally once daily in run-in period from Week -4 up to randomization (Day 1) and subsequently received daprodustat tablets at dose levels of 1, 2, 4, 6, 8, 10, 12, 16 and 24 milligrams (mg) orally once daily until the required number of major adverse cardiovascular event (MACE) occurred, at approximately 45.1 months of randomized treatment. Study treatment was dose-titrated to achieve and maintain hemoglobin in the target range (10 to 11 grams per deciliter \[g/dL\]).	rhEPO n=1454 Participants Participants received placebo tablets orally once daily in run-in period from Week -4 up to randomization (Day 1) and subsequently received treatment with rhEPO. Participants on hemodialysis received epoetin alfa as intravenous (IV) injection once weekly or three-times weekly with total weekly dose levels ranging from 1500 to 60,000 Units. Participants on peritoneal dialysis received subcutaneous (SC) injection of darbepoetin alfa every 1, 2, or 4 weeks with 4-weekly total dose levels ranging from 20 to 400 microgram (mcg). Darbepoetin could be given by IV injection for peritoneal dialysis participants switching to hemodialysis. Study treatment was dose-titrated to achieve and maintain hemoglobin in the target range (10 to 11 g/dL) and administered until the required number of MACE events occurred, at approximately 45.1 months of randomized treatment.
Change From Baseline in SBP, DBP, MAP at End of Treatment SBP	-0.43 Millimeter of mercury Standard Error 0.554	-0.43 Millimeter of mercury Standard Error 0.557
Change From Baseline in SBP, DBP, MAP at End of Treatment DBP	-0.92 Millimeter of mercury Standard Error 0.310	-1.37 Millimeter of mercury Standard Error 0.312
Change From Baseline in SBP, DBP, MAP at End of Treatment MAP	-0.75 Millimeter of mercury Standard Error 0.350	-1.06 Millimeter of mercury Standard Error 0.351

SECONDARY outcome

Timeframe: Day 1 to end of study (3.9 person-years for follow-up time period)

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

BP exacerbation was defined (based on post-dialysis) as: SBP \>= 25 millimeter of mercury (mmHg) increased from Baseline or SBP \>=180 mmHg; 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 with treatment, dialysis type and region as covariates and the logarithm of time on-treatment as an offset variable. Data for post-dialysis BP measurements have been presented.

Outcome measures

Outcome measures
Measure	Daprodustat n=1470 Participants Participants received placebo tablets orally once daily in run-in period from Week -4 up to randomization (Day 1) and subsequently received daprodustat tablets at dose levels of 1, 2, 4, 6, 8, 10, 12, 16 and 24 milligrams (mg) orally once daily until the required number of major adverse cardiovascular event (MACE) occurred, at approximately 45.1 months of randomized treatment. Study treatment was dose-titrated to achieve and maintain hemoglobin in the target range (10 to 11 grams per deciliter \[g/dL\]).	rhEPO n=1458 Participants Participants received placebo tablets orally once daily in run-in period from Week -4 up to randomization (Day 1) and subsequently received treatment with rhEPO. Participants on hemodialysis received epoetin alfa as intravenous (IV) injection once weekly or three-times weekly with total weekly dose levels ranging from 1500 to 60,000 Units. Participants on peritoneal dialysis received subcutaneous (SC) injection of darbepoetin alfa every 1, 2, or 4 weeks with 4-weekly total dose levels ranging from 20 to 400 microgram (mcg). Darbepoetin could be given by IV injection for peritoneal dialysis participants switching to hemodialysis. Study treatment was dose-titrated to achieve and maintain hemoglobin in the target range (10 to 11 g/dL) and administered until the required number of MACE events occurred, at approximately 45.1 months of randomized treatment.
Blood Pressure (BP) Exacerbation Event Rate Per 100 Participant Years	207.13 Events per 100 participant years Interval 188.83 to 227.21	206.38 Events per 100 participant years Interval 187.88 to 226.71

SECONDARY outcome

Timeframe: Day 1 to end of study (3.9 person-years for follow-up time period)

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

BP exacerbation was defined as: SBP \>= 25 mmHg increased from Baseline or SBP \>=180 mmHg; DBP \>=15 mmHg increased from Baseline or DBP \>=110 mmHg. Number of participants with at least one BP exacerbation event is presented.

Outcome measures

Outcome measures
Measure	Daprodustat n=1480 Participants Participants received placebo tablets orally once daily in run-in period from Week -4 up to randomization (Day 1) and subsequently received daprodustat tablets at dose levels of 1, 2, 4, 6, 8, 10, 12, 16 and 24 milligrams (mg) orally once daily until the required number of major adverse cardiovascular event (MACE) occurred, at approximately 45.1 months of randomized treatment. Study treatment was dose-titrated to achieve and maintain hemoglobin in the target range (10 to 11 grams per deciliter \[g/dL\]).	rhEPO n=1470 Participants Participants received placebo tablets orally once daily in run-in period from Week -4 up to randomization (Day 1) and subsequently received treatment with rhEPO. Participants on hemodialysis received epoetin alfa as intravenous (IV) injection once weekly or three-times weekly with total weekly dose levels ranging from 1500 to 60,000 Units. Participants on peritoneal dialysis received subcutaneous (SC) injection of darbepoetin alfa every 1, 2, or 4 weeks with 4-weekly total dose levels ranging from 20 to 400 microgram (mcg). Darbepoetin could be given by IV injection for peritoneal dialysis participants switching to hemodialysis. Study treatment was dose-titrated to achieve and maintain hemoglobin in the target range (10 to 11 g/dL) and administered until the required number of MACE events occurred, at approximately 45.1 months of randomized treatment.
Number of Participants With at Least One BP Exacerbation Event During Study	1191 Participants	1186 Participants

SECONDARY outcome

Timeframe: Day 1 to 45.1 months

Population: All Randomized (ITT) Population.

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

Outcome measures

Outcome measures
Measure	Daprodustat n=1487 Participants Participants received placebo tablets orally once daily in run-in period from Week -4 up to randomization (Day 1) and subsequently received daprodustat tablets at dose levels of 1, 2, 4, 6, 8, 10, 12, 16 and 24 milligrams (mg) orally once daily until the required number of major adverse cardiovascular event (MACE) occurred, at approximately 45.1 months of randomized treatment. Study treatment was dose-titrated to achieve and maintain hemoglobin in the target range (10 to 11 grams per deciliter \[g/dL\]).	rhEPO n=1477 Participants Participants received placebo tablets orally once daily in run-in period from Week -4 up to randomization (Day 1) and subsequently received treatment with rhEPO. Participants on hemodialysis received epoetin alfa as intravenous (IV) injection once weekly or three-times weekly with total weekly dose levels ranging from 1500 to 60,000 Units. Participants on peritoneal dialysis received subcutaneous (SC) injection of darbepoetin alfa every 1, 2, or 4 weeks with 4-weekly total dose levels ranging from 20 to 400 microgram (mcg). Darbepoetin could be given by IV injection for peritoneal dialysis participants switching to hemodialysis. Study treatment was dose-titrated to achieve and maintain hemoglobin in the target range (10 to 11 g/dL) and administered until the required number of MACE events occurred, at approximately 45.1 months of randomized treatment.
Percentage of Participants Permanently Stopping Randomized Treatment Due to Meeting Rescue Criteria	3.6 Percentage of participants	3.6 Percentage of participants

SECONDARY outcome

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

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

The SF-36 acute version 2 is a 36-item generic quality of life instrument designed to measure a participant's level of performance in the following 8 health domains: physical functioning, role-physical (role limitations caused by physical problems), social functioning, bodily pain, mental health, role-emotional (role limitations caused by emotional problems), vitality and general health. Each domain is scored from 0 (poorer health) to 100 (better health). The PCS is an average score derived from 4 domains (physical functioning, role-physical, bodily pain and general health) representing overall physical health. PCS ranges from 0 to 100; higher scores represent better health. Change from Baseline was calculated as on-treatment visit value minus Baseline value. Baseline was defined as the latest non-missing pre-dose assessment on or before the randomization date.

Outcome measures

Outcome measures
Measure	Daprodustat n=990 Participants Participants received placebo tablets orally once daily in run-in period from Week -4 up to randomization (Day 1) and subsequently received daprodustat tablets at dose levels of 1, 2, 4, 6, 8, 10, 12, 16 and 24 milligrams (mg) orally once daily until the required number of major adverse cardiovascular event (MACE) occurred, at approximately 45.1 months of randomized treatment. Study treatment was dose-titrated to achieve and maintain hemoglobin in the target range (10 to 11 grams per deciliter \[g/dL\]).	rhEPO n=943 Participants Participants received placebo tablets orally once daily in run-in period from Week -4 up to randomization (Day 1) and subsequently received treatment with rhEPO. Participants on hemodialysis received epoetin alfa as intravenous (IV) injection once weekly or three-times weekly with total weekly dose levels ranging from 1500 to 60,000 Units. Participants on peritoneal dialysis received subcutaneous (SC) injection of darbepoetin alfa every 1, 2, or 4 weeks with 4-weekly total dose levels ranging from 20 to 400 microgram (mcg). Darbepoetin could be given by IV injection for peritoneal dialysis participants switching to hemodialysis. Study treatment was dose-titrated to achieve and maintain hemoglobin in the target range (10 to 11 g/dL) and administered until the required number of MACE events occurred, at approximately 45.1 months of randomized treatment.
Change From Baseline in On-Treatment Physical Component Score (PCS) Using Short Form (SF)-36 Health-related Quality of Life (HRQoL) Questionnaire at Weeks 8, 12, 28, 52 Week 8, n=982,936	0.30 Scores on a scale Standard Error 0.205	0.01 Scores on a scale Standard Error 0.210
Change From Baseline in On-Treatment Physical Component Score (PCS) Using Short Form (SF)-36 Health-related Quality of Life (HRQoL) Questionnaire at Weeks 8, 12, 28, 52 Week 12, n=990,943	0.33 Scores on a scale Standard Error 0.203	-0.27 Scores on a scale Standard Error 0.207
Change From Baseline in On-Treatment Physical Component Score (PCS) Using Short Form (SF)-36 Health-related Quality of Life (HRQoL) Questionnaire at Weeks 8, 12, 28, 52 Week 28, n=836,819	-0.23 Scores on a scale Standard Error 0.229	-0.57 Scores on a scale Standard Error 0.232
Change From Baseline in On-Treatment Physical Component Score (PCS) Using Short Form (SF)-36 Health-related Quality of Life (HRQoL) Questionnaire at Weeks 8, 12, 28, 52 Week 52, n=729,707	-0.52 Scores on a scale Standard Error 0.248	-1.05 Scores on a scale Standard Error 0.252

SECONDARY outcome

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

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

The SF-36 acute version 2 is a 36-item generic quality of life instrument designed to measure a participant's level of performance in the following 8 health domains: physical functioning, role-physical (role limitations caused by physical problems), social functioning, bodily pain, mental health, role-emotional (role limitations caused by emotional problems), vitality and general health. Each domain is scored from 0 (poorer health) to 100 (better health). MCS is an average score derived from 4 domains (vitality, social functioning, role-emotional and mental health) representing overall mental health. MCS ranges from 0 to 100; higher scores represent better health. Change from Baseline was calculated as on-treatment visit value minus Baseline value. Baseline was defined as the latest non-missing pre-dose assessment on or before the randomization date.

Outcome measures

Outcome measures
Measure	Daprodustat n=990 Participants Participants received placebo tablets orally once daily in run-in period from Week -4 up to randomization (Day 1) and subsequently received daprodustat tablets at dose levels of 1, 2, 4, 6, 8, 10, 12, 16 and 24 milligrams (mg) orally once daily until the required number of major adverse cardiovascular event (MACE) occurred, at approximately 45.1 months of randomized treatment. Study treatment was dose-titrated to achieve and maintain hemoglobin in the target range (10 to 11 grams per deciliter \[g/dL\]).	rhEPO n=943 Participants Participants received placebo tablets orally once daily in run-in period from Week -4 up to randomization (Day 1) and subsequently received treatment with rhEPO. Participants on hemodialysis received epoetin alfa as intravenous (IV) injection once weekly or three-times weekly with total weekly dose levels ranging from 1500 to 60,000 Units. Participants on peritoneal dialysis received subcutaneous (SC) injection of darbepoetin alfa every 1, 2, or 4 weeks with 4-weekly total dose levels ranging from 20 to 400 microgram (mcg). Darbepoetin could be given by IV injection for peritoneal dialysis participants switching to hemodialysis. Study treatment was dose-titrated to achieve and maintain hemoglobin in the target range (10 to 11 g/dL) and administered until the required number of MACE events occurred, at approximately 45.1 months of randomized treatment.
Change From Baseline in On-Treatment Mental Component Score (MCS) Using SF-36 HRQoL Questionnaire at Weeks 8, 12, 28, 52 Week 8, n=982,936	-0.38 Scores on a scale Standard Error 0.254	-0.21 Scores on a scale Standard Error 0.260
Change From Baseline in On-Treatment Mental Component Score (MCS) Using SF-36 HRQoL Questionnaire at Weeks 8, 12, 28, 52 Week 12, n=990,943	-0.55 Scores on a scale Standard Error 0.262	-0.72 Scores on a scale Standard Error 0.268
Change From Baseline in On-Treatment Mental Component Score (MCS) Using SF-36 HRQoL Questionnaire at Weeks 8, 12, 28, 52 Week 28, n=836,819	-1.25 Scores on a scale Standard Error 0.286	-1.23 Scores on a scale Standard Error 0.290
Change From Baseline in On-Treatment Mental Component Score (MCS) Using SF-36 HRQoL Questionnaire at Weeks 8, 12, 28, 52 Week 52, n=729,707	-1.63 Scores on a scale Standard Error 0.311	-1.03 Scores on a scale Standard Error 0.316

SECONDARY outcome

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

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

The SF-36 acute version 2 is a 36-item generic quality of life instrument designed to measure a participant's level of performance in the following 8 health domains: bodily pain, general health, mental health, role-emotional (role limitations caused by emotional problems), role-physical (role limitations caused by physical problems), social functioning (Social fun), physical functioning (Phy. fun) and vitality. Each domain is scored from 0 (poorer health) to 100 (better health). Each domain score ranges from 0 to 100, higher score indicates a better health state and better functioning. Change from Baseline was calculated as on-treatment visit value minus Baseline value. Baseline was defined as the latest non-missing pre-dose assessment on or before the randomization date.

Outcome measures

Outcome measures
Measure	Daprodustat n=990 Participants Participants received placebo tablets orally once daily in run-in period from Week -4 up to randomization (Day 1) and subsequently received daprodustat tablets at dose levels of 1, 2, 4, 6, 8, 10, 12, 16 and 24 milligrams (mg) orally once daily until the required number of major adverse cardiovascular event (MACE) occurred, at approximately 45.1 months of randomized treatment. Study treatment was dose-titrated to achieve and maintain hemoglobin in the target range (10 to 11 grams per deciliter \[g/dL\]).	rhEPO n=943 Participants Participants received placebo tablets orally once daily in run-in period from Week -4 up to randomization (Day 1) and subsequently received treatment with rhEPO. Participants on hemodialysis received epoetin alfa as intravenous (IV) injection once weekly or three-times weekly with total weekly dose levels ranging from 1500 to 60,000 Units. Participants on peritoneal dialysis received subcutaneous (SC) injection of darbepoetin alfa every 1, 2, or 4 weeks with 4-weekly total dose levels ranging from 20 to 400 microgram (mcg). Darbepoetin could be given by IV injection for peritoneal dialysis participants switching to hemodialysis. Study treatment was dose-titrated to achieve and maintain hemoglobin in the target range (10 to 11 g/dL) and administered until the required number of MACE events occurred, at approximately 45.1 months of randomized treatment.
Change From Baseline in On-Treatment SF-36 HRQoL Scores for Bodily Pain, General Health, Mental Health, Role-Emotional, Role-Physical, Social Functioning at Weeks 8, 12, 28, 52 Bodily pain: Week 8, n=982,936	-0.13 Scores on a scale Standard Error 0.265	0.12 Scores on a scale Standard Error 0.272
Change From Baseline in On-Treatment SF-36 HRQoL Scores for Bodily Pain, General Health, Mental Health, Role-Emotional, Role-Physical, Social Functioning at Weeks 8, 12, 28, 52 Bodily pain: Week 12, n=990,943	0.20 Scores on a scale Standard Error 0.267	-0.39 Scores on a scale Standard Error 0.274
Change From Baseline in On-Treatment SF-36 HRQoL Scores for Bodily Pain, General Health, Mental Health, Role-Emotional, Role-Physical, Social Functioning at Weeks 8, 12, 28, 52 Bodily pain: Week 28, n=836,819	-0.70 Scores on a scale Standard Error 0.297	-0.74 Scores on a scale Standard Error 0.301
Change From Baseline in On-Treatment SF-36 HRQoL Scores for Bodily Pain, General Health, Mental Health, Role-Emotional, Role-Physical, Social Functioning at Weeks 8, 12, 28, 52 Bodily pain: Week 52, n=729,707	-1.12 Scores on a scale Standard Error 0.313	-1.39 Scores on a scale Standard Error 0.318
Change From Baseline in On-Treatment SF-36 HRQoL Scores for Bodily Pain, General Health, Mental Health, Role-Emotional, Role-Physical, Social Functioning at Weeks 8, 12, 28, 52 General health: Week 8, n=982,936	-0.39 Scores on a scale Standard Error 0.208	-0.65 Scores on a scale Standard Error 0.213
Change From Baseline in On-Treatment SF-36 HRQoL Scores for Bodily Pain, General Health, Mental Health, Role-Emotional, Role-Physical, Social Functioning at Weeks 8, 12, 28, 52 General health: Week 12, n=990,943	-0.59 Scores on a scale Standard Error 0.210	-1.04 Scores on a scale Standard Error 0.215
Change From Baseline in On-Treatment SF-36 HRQoL Scores for Bodily Pain, General Health, Mental Health, Role-Emotional, Role-Physical, Social Functioning at Weeks 8, 12, 28, 52 General health: Week 28, n=836,819	-1.32 Scores on a scale Standard Error 0.232	-0.99 Scores on a scale Standard Error 0.235
Change From Baseline in On-Treatment SF-36 HRQoL Scores for Bodily Pain, General Health, Mental Health, Role-Emotional, Role-Physical, Social Functioning at Weeks 8, 12, 28, 52 General health: Week 52, n=729,707	-1.51 Scores on a scale Standard Error 0.251	-1.22 Scores on a scale Standard Error 0.255
Change From Baseline in On-Treatment SF-36 HRQoL Scores for Bodily Pain, General Health, Mental Health, Role-Emotional, Role-Physical, Social Functioning at Weeks 8, 12, 28, 52 Mental health: Week 8, n=982,936	-0.43 Scores on a scale Standard Error 0.238	-0.47 Scores on a scale Standard Error 0.244
Change From Baseline in On-Treatment SF-36 HRQoL Scores for Bodily Pain, General Health, Mental Health, Role-Emotional, Role-Physical, Social Functioning at Weeks 8, 12, 28, 52 Mental health: Week 12, n=990,943	-0.86 Scores on a scale Standard Error 0.247	-0.81 Scores on a scale Standard Error 0.253
Change From Baseline in On-Treatment SF-36 HRQoL Scores for Bodily Pain, General Health, Mental Health, Role-Emotional, Role-Physical, Social Functioning at Weeks 8, 12, 28, 52 Mental health: Week 28, n=836,819	-1.30 Scores on a scale Standard Error 0.267	-1.43 Scores on a scale Standard Error 0.270
Change From Baseline in On-Treatment SF-36 HRQoL Scores for Bodily Pain, General Health, Mental Health, Role-Emotional, Role-Physical, Social Functioning at Weeks 8, 12, 28, 52 Mental health: Week 52, n=729,707	-1.97 Scores on a scale Standard Error 0.296	-1.16 Scores on a scale Standard Error 0.301
Change From Baseline in On-Treatment SF-36 HRQoL Scores for Bodily Pain, General Health, Mental Health, Role-Emotional, Role-Physical, Social Functioning at Weeks 8, 12, 28, 52 Role-emotional: Week 8, n=982,936	-0.10 Scores on a scale Standard Error 0.310	-0.02 Scores on a scale Standard Error 0.317
Change From Baseline in On-Treatment SF-36 HRQoL Scores for Bodily Pain, General Health, Mental Health, Role-Emotional, Role-Physical, Social Functioning at Weeks 8, 12, 28, 52 Role-emotional: Week 12, n=990,943	-0.17 Scores on a scale Standard Error 0.311	-0.53 Scores on a scale Standard Error 0.318
Change From Baseline in On-Treatment SF-36 HRQoL Scores for Bodily Pain, General Health, Mental Health, Role-Emotional, Role-Physical, Social Functioning at Weeks 8, 12, 28, 52 Role-emotional: Week 28, n=836,819	-0.95 Scores on a scale Standard Error 0.335	-0.90 Scores on a scale Standard Error 0.339
Change From Baseline in On-Treatment SF-36 HRQoL Scores for Bodily Pain, General Health, Mental Health, Role-Emotional, Role-Physical, Social Functioning at Weeks 8, 12, 28, 52 Role-emotional: Week 52, n=729,707	-0.83 Scores on a scale Standard Error 0.358	-0.92 Scores on a scale Standard Error 0.363
Change From Baseline in On-Treatment SF-36 HRQoL Scores for Bodily Pain, General Health, Mental Health, Role-Emotional, Role-Physical, Social Functioning at Weeks 8, 12, 28, 52 Role-physical: Week 8, n=982,936	0.40 Scores on a scale Standard Error 0.241	0.32 Scores on a scale Standard Error 0.246
Change From Baseline in On-Treatment SF-36 HRQoL Scores for Bodily Pain, General Health, Mental Health, Role-Emotional, Role-Physical, Social Functioning at Weeks 8, 12, 28, 52 Role-physical: Week 12, n=990,943	0.48 Scores on a scale Standard Error 0.239	0.08 Scores on a scale Standard Error 0.245
Change From Baseline in On-Treatment SF-36 HRQoL Scores for Bodily Pain, General Health, Mental Health, Role-Emotional, Role-Physical, Social Functioning at Weeks 8, 12, 28, 52 Role-physical: Week 28, n=836,819	-0.10 Scores on a scale Standard Error 0.257	-0.39 Scores on a scale Standard Error 0.260
Change From Baseline in On-Treatment SF-36 HRQoL Scores for Bodily Pain, General Health, Mental Health, Role-Emotional, Role-Physical, Social Functioning at Weeks 8, 12, 28, 52 Role-physical: Week 52, n=729,707	-0.21 Scores on a scale Standard Error 0.285	-0.60 Scores on a scale Standard Error 0.289
Change From Baseline in On-Treatment SF-36 HRQoL Scores for Bodily Pain, General Health, Mental Health, Role-Emotional, Role-Physical, Social Functioning at Weeks 8, 12, 28, 52 Social functioning: Week 8, n=982,936	0.24 Scores on a scale Standard Error 0.241	0.38 Scores on a scale Standard Error 0.247
Change From Baseline in On-Treatment SF-36 HRQoL Scores for Bodily Pain, General Health, Mental Health, Role-Emotional, Role-Physical, Social Functioning at Weeks 8, 12, 28, 52 Social functioning: Week 12, n=990,943	0.25 Scores on a scale Standard Error 0.255	-0.44 Scores on a scale Standard Error 0.261
Change From Baseline in On-Treatment SF-36 HRQoL Scores for Bodily Pain, General Health, Mental Health, Role-Emotional, Role-Physical, Social Functioning at Weeks 8, 12, 28, 52 Social functioning: Week 28, n=836,819	-0.61 Scores on a scale Standard Error 0.280	-0.94 Scores on a scale Standard Error 0.283
Change From Baseline in On-Treatment SF-36 HRQoL Scores for Bodily Pain, General Health, Mental Health, Role-Emotional, Role-Physical, Social Functioning at Weeks 8, 12, 28, 52 Social functioning: Week 52, n=729,707	-1.12 Scores on a scale Standard Error 0.315	-1.14 Scores on a scale Standard Error 0.320

SECONDARY outcome

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

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

The SF-36 acute version 2 is a 36-item generic quality of life instrument designed to measure a participant's level of performance in the following 8 health domains: physical functioning, role-physical (role limitations caused by physical problems), social functioning, bodily pain, mental health, role-emotional (role limitations caused by emotional problems), vitality and general health. Each domain is scored from 0 (poorer health) to 100 (better health). Vitality score ranges from 0 to 100; higher scores represent better health. Change from Baseline was calculated as on-treatment visit value minus Baseline value. Baseline was defined as the latest non-missing pre-dose assessment on or before the randomization date.

Outcome measures

Outcome measures
Measure	Daprodustat n=990 Participants Participants received placebo tablets orally once daily in run-in period from Week -4 up to randomization (Day 1) and subsequently received daprodustat tablets at dose levels of 1, 2, 4, 6, 8, 10, 12, 16 and 24 milligrams (mg) orally once daily until the required number of major adverse cardiovascular event (MACE) occurred, at approximately 45.1 months of randomized treatment. Study treatment was dose-titrated to achieve and maintain hemoglobin in the target range (10 to 11 grams per deciliter \[g/dL\]).	rhEPO n=943 Participants Participants received placebo tablets orally once daily in run-in period from Week -4 up to randomization (Day 1) and subsequently received treatment with rhEPO. Participants on hemodialysis received epoetin alfa as intravenous (IV) injection once weekly or three-times weekly with total weekly dose levels ranging from 1500 to 60,000 Units. Participants on peritoneal dialysis received subcutaneous (SC) injection of darbepoetin alfa every 1, 2, or 4 weeks with 4-weekly total dose levels ranging from 20 to 400 microgram (mcg). Darbepoetin could be given by IV injection for peritoneal dialysis participants switching to hemodialysis. Study treatment was dose-titrated to achieve and maintain hemoglobin in the target range (10 to 11 g/dL) and administered until the required number of MACE events occurred, at approximately 45.1 months of randomized treatment.
Change From Baseline in On-Treatment Vitality Scores Using SF-36 HRQoL Questionnaire at Weeks 8, 12, 28, 52 Week 28, n=836,819	-0.79 Scores on a scale Standard Error 0.242	-1.03 Scores on a scale Standard Error 0.245
Change From Baseline in On-Treatment Vitality Scores Using SF-36 HRQoL Questionnaire at Weeks 8, 12, 28, 52 Week 52, n=729,707	-1.19 Scores on a scale Standard Error 0.268	-1.04 Scores on a scale Standard Error 0.272
Change From Baseline in On-Treatment Vitality Scores Using SF-36 HRQoL Questionnaire at Weeks 8, 12, 28, 52 Week 8, n=982,936	-0.23 Scores on a scale Standard Error 0.219	-0.26 Scores on a scale Standard Error 0.224
Change From Baseline in On-Treatment Vitality Scores Using SF-36 HRQoL Questionnaire at Weeks 8, 12, 28, 52 Week 12, n=990,943	-0.17 Scores on a scale Standard Error 0.227	-0.51 Scores on a scale Standard Error 0.232

SECONDARY outcome

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

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

The SF-36 acute version 2 is a 36-item generic quality of life instrument designed to measure a participant's level of performance in the following 8 health domains: physical functioning, role-physical (role limitations caused by physical problems), social functioning, bodily pain, mental health, role-emotional (role limitations caused by emotional problems), vitality and general health. Each domain is scored from 0 (poorer health) to 100 (better health). Physical functioning score ranges from 0 to 100; higher scores represent better health. Change from Baseline was calculated as on-treatment visit value minus (-) Baseline value. Baseline was defined as the latest non-missing pre-dose assessment on or before the randomization date.

Outcome measures

Outcome measures
Measure	Daprodustat n=990 Participants Participants received placebo tablets orally once daily in run-in period from Week -4 up to randomization (Day 1) and subsequently received daprodustat tablets at dose levels of 1, 2, 4, 6, 8, 10, 12, 16 and 24 milligrams (mg) orally once daily until the required number of major adverse cardiovascular event (MACE) occurred, at approximately 45.1 months of randomized treatment. Study treatment was dose-titrated to achieve and maintain hemoglobin in the target range (10 to 11 grams per deciliter \[g/dL\]).	rhEPO n=943 Participants Participants received placebo tablets orally once daily in run-in period from Week -4 up to randomization (Day 1) and subsequently received treatment with rhEPO. Participants on hemodialysis received epoetin alfa as intravenous (IV) injection once weekly or three-times weekly with total weekly dose levels ranging from 1500 to 60,000 Units. Participants on peritoneal dialysis received subcutaneous (SC) injection of darbepoetin alfa every 1, 2, or 4 weeks with 4-weekly total dose levels ranging from 20 to 400 microgram (mcg). Darbepoetin could be given by IV injection for peritoneal dialysis participants switching to hemodialysis. Study treatment was dose-titrated to achieve and maintain hemoglobin in the target range (10 to 11 g/dL) and administered until the required number of MACE events occurred, at approximately 45.1 months of randomized treatment.
Change From Baseline in On-Treatment Physical Functioning Domain Scores Using SF-36 HRQoL Questionnaire at Weeks 8, 12, 28, 52 Week 8, n=982,936	0.48 Scores on a scale Standard Error 0.237	-0.16 Scores on a scale Standard Error 0.243
Change From Baseline in On-Treatment Physical Functioning Domain Scores Using SF-36 HRQoL Questionnaire at Weeks 8, 12, 28, 52 Week 12, n=990,943	0.11 Scores on a scale Standard Error 0.240	-0.45 Scores on a scale Standard Error 0.246
Change From Baseline in On-Treatment Physical Functioning Domain Scores Using SF-36 HRQoL Questionnaire at Weeks 8, 12, 28, 52 Week 28, n=836,819	-0.20 Scores on a scale Standard Error 0.273	-0.97 Scores on a scale Standard Error 0.277
Change From Baseline in On-Treatment Physical Functioning Domain Scores Using SF-36 HRQoL Questionnaire at Weeks 8, 12, 28, 52 Week 52, n=729,707	-0.61 Scores on a scale Standard Error 0.291	-1.19 Scores on a scale Standard Error 0.296

SECONDARY outcome

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

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

EQ-5D-5L is self-assessment questionnaire,consisting of 5 items covering 5 dimensions (mobility,self care,usual activities,pain/discomfort and anxiety/depression). Each dimension is measured by 5-point Likert scale (1=no problems, 2=slight problems, 3=moderate problems, 4=severe problems and 5=extreme problems). Responses for 5 dimensions together formed a 5-figure description of health state (e.g.11111 indicates no problems in all 5 dimensions). Each of these 5 figure health states were converted to a single index score by applying country-specific value set formula that attaches weights to dimensions and levels. Range for EQ-5D-5L index score is -0.594 (worst health) to 1 (full health state). Change from Baseline was calculated as on-treatment visit value-Baseline value. Baseline was latest non-missing pre-dose assessment on or before randomization date.

Outcome measures

Outcome measures
Measure	Daprodustat n=333 Participants Participants received placebo tablets orally once daily in run-in period from Week -4 up to randomization (Day 1) and subsequently received daprodustat tablets at dose levels of 1, 2, 4, 6, 8, 10, 12, 16 and 24 milligrams (mg) orally once daily until the required number of major adverse cardiovascular event (MACE) occurred, at approximately 45.1 months of randomized treatment. Study treatment was dose-titrated to achieve and maintain hemoglobin in the target range (10 to 11 grams per deciliter \[g/dL\]).	rhEPO n=329 Participants Participants received placebo tablets orally once daily in run-in period from Week -4 up to randomization (Day 1) and subsequently received treatment with rhEPO. Participants on hemodialysis received epoetin alfa as intravenous (IV) injection once weekly or three-times weekly with total weekly dose levels ranging from 1500 to 60,000 Units. Participants on peritoneal dialysis received subcutaneous (SC) injection of darbepoetin alfa every 1, 2, or 4 weeks with 4-weekly total dose levels ranging from 20 to 400 microgram (mcg). Darbepoetin could be given by IV injection for peritoneal dialysis participants switching to hemodialysis. Study treatment was dose-titrated to achieve and maintain hemoglobin in the target range (10 to 11 g/dL) and administered until the required number of MACE events occurred, at approximately 45.1 months of randomized treatment.
Change From Baseline in On-Treatment Health Utility EuroQol 5 Dimensions 5 Level (EQ-5D-5L) Questionnaire Score at Week 52	-0.0198 Scores on a scale Standard Error 0.01179	-0.0201 Scores on a scale Standard Error 0.01187

SECONDARY outcome

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

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

The EQ VAS records the respondent's self-rated health on a vertical VAS, ranging from 0 to 100, where 0 represents the worst health one can imagine and 100 represents the best health one can imagine. Change from Baseline was calculated as on-treatment visit value minus Baseline value. Baseline was defined as the latest non-missing pre-dose assessment on or before the randomization date.

Outcome measures

Outcome measures
Measure	Daprodustat n=333 Participants Participants received placebo tablets orally once daily in run-in period from Week -4 up to randomization (Day 1) and subsequently received daprodustat tablets at dose levels of 1, 2, 4, 6, 8, 10, 12, 16 and 24 milligrams (mg) orally once daily until the required number of major adverse cardiovascular event (MACE) occurred, at approximately 45.1 months of randomized treatment. Study treatment was dose-titrated to achieve and maintain hemoglobin in the target range (10 to 11 grams per deciliter \[g/dL\]).	rhEPO n=329 Participants Participants received placebo tablets orally once daily in run-in period from Week -4 up to randomization (Day 1) and subsequently received treatment with rhEPO. Participants on hemodialysis received epoetin alfa as intravenous (IV) injection once weekly or three-times weekly with total weekly dose levels ranging from 1500 to 60,000 Units. Participants on peritoneal dialysis received subcutaneous (SC) injection of darbepoetin alfa every 1, 2, or 4 weeks with 4-weekly total dose levels ranging from 20 to 400 microgram (mcg). Darbepoetin could be given by IV injection for peritoneal dialysis participants switching to hemodialysis. Study treatment was dose-titrated to achieve and maintain hemoglobin in the target range (10 to 11 g/dL) and administered until the required number of MACE events occurred, at approximately 45.1 months of randomized treatment.
Change From Baseline in On-Treatment EuroQol Visual Analogue Scale (EQ-VAS) at Week 52	-1.0 Scores on a scale Standard Error 0.86	0.8 Scores on a scale Standard Error 0.87

SECONDARY outcome

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

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

The PGI-S is a 1-item questionnaire designed to assess participant's impression of disease severity on a 5-point disease severity scale (0=absent, 1=mild, 2=moderate, 3=severe, or 4=very severe). A higher score indicated worse outcome. Change from Baseline was calculated as on-treatment visit value minus Baseline value. Baseline was defined as the latest non-missing pre-dose assessment on or before the randomization date.

Outcome measures

Outcome measures
Measure	Daprodustat n=1102 Participants Participants received placebo tablets orally once daily in run-in period from Week -4 up to randomization (Day 1) and subsequently received daprodustat tablets at dose levels of 1, 2, 4, 6, 8, 10, 12, 16 and 24 milligrams (mg) orally once daily until the required number of major adverse cardiovascular event (MACE) occurred, at approximately 45.1 months of randomized treatment. Study treatment was dose-titrated to achieve and maintain hemoglobin in the target range (10 to 11 grams per deciliter \[g/dL\]).	rhEPO n=1073 Participants Participants received placebo tablets orally once daily in run-in period from Week -4 up to randomization (Day 1) and subsequently received treatment with rhEPO. Participants on hemodialysis received epoetin alfa as intravenous (IV) injection once weekly or three-times weekly with total weekly dose levels ranging from 1500 to 60,000 Units. Participants on peritoneal dialysis received subcutaneous (SC) injection of darbepoetin alfa every 1, 2, or 4 weeks with 4-weekly total dose levels ranging from 20 to 400 microgram (mcg). Darbepoetin could be given by IV injection for peritoneal dialysis participants switching to hemodialysis. Study treatment was dose-titrated to achieve and maintain hemoglobin in the target range (10 to 11 g/dL) and administered until the required number of MACE events occurred, at approximately 45.1 months of randomized treatment.
Change From Baseline in On-Treatment Patient Global Impression of Severity (PGI-S) at Weeks 8, 12, 28, 52 Week 8, n=1102,1064	-0.03 Scores on a scale Standard Error 0.024	0.02 Scores on a scale Standard Error 0.025
Change From Baseline in On-Treatment Patient Global Impression of Severity (PGI-S) at Weeks 8, 12, 28, 52 Week 12, n=1102,1073	0.02 Scores on a scale Standard Error 0.025	0.06 Scores on a scale Standard Error 0.025
Change From Baseline in On-Treatment Patient Global Impression of Severity (PGI-S) at Weeks 8, 12, 28, 52 Week 28, n=934,933	0.04 Scores on a scale Standard Error 0.027	0.08 Scores on a scale Standard Error 0.027
Change From Baseline in On-Treatment Patient Global Impression of Severity (PGI-S) at Weeks 8, 12, 28, 52 Week 52, n=826,814	0.06 Scores on a scale Standard Error 0.029	0.11 Scores on a scale Standard Error 0.030

Adverse Events

Daprodustat

Serious events: 773 serious events

Other events: 830 other events

Deaths: 294 deaths

rhEPO

Serious events: 748 serious events

Other events: 827 other events

Deaths: 300 deaths

Serious adverse events

Other adverse events

Additional Information

GSK Response Center

GlaxoSmithKline

Phone: 866-435-7343

Email: [email protected]

Results disclosure agreements

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

Restriction type: OTHER