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

A Phase 3 Randomized, Open-label (Sponsor-blind), Active-controlled, Parallel-group, Multi-center, Event Driven Study in Non-dialysis Subjects With Anemia Associated With Chronic Kidney Disease to Evaluate the Safety and Efficacy of Daprodustat Compared to Darbepoetin Alfa

Status

Completed

Phases

Phase 3

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT02876835

Enrollment

3872

Registered

2016-08-24

Start date

2016-09-27

Completion date

2021-04-19

Last updated

2024-04-02

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Anaemia

Keywords

GSK1278863, hemoglobin, anemia, non-dialysis, erythropoiesis stimulating agents, daprodustat, chronic kidney disease

Brief summary

The purpose of this multi-center event-driven study in non-dialysis (ND) participants with anemia associated with chronic kidney disease (CKD) is to evaluate the safety and efficacy of daprodustat compared to darbepoetin alfa.

Interventions

DRUGDaprodustat

The initial dose or oral daprodustat for ESA naïve subjects is based on Hgb and for ESA users is based on prior ESA dose. The dose is adjusted thereafter in order to achieve the target range.

DRUGDarbepoetin alfa

The initial dose of darbepoetin alfa to be administered for SC injection for ESA naïve subjects is based in Hgb and weight, and for ESA users is based on converting the prior ESA dose to the nearest available study darbepoetin alfa dose. The dose is adjusted thereafter in order to achieve the target range. IV darbepoetin alfa can be considered for participants transitioning to hemodialysis.

DRUGPlacebo

Oral placebo tablets will be taken from Week -4 up to randomization (Day 1).

DRUGIron Therapy

Participants will receive supplemental iron therapy if ferritin is \<=100 ng/mL or TSAT is \<=20%. The investigator will choose the route of administration and dose of iron.

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

18 Years to 99 Years

Healthy volunteers

Inclusion criteria

* Age: 18 to 99 years of age (inclusive) * CKD stage: Kidney Disease Outcomes Quality Initiative (KDOQI) CKD stages 3, 4, or 5 defined by electronic eGFR using the CKD Epidemiology Collaboration (CKD-EPI) formula. * Erythropoietin-stimulating agents (ESAs)/Hgb: Group 1 (not using ESAs): No ESA use within the 6 weeks prior to screening and no ESA use between screening and randomization (Day 1). Group 2 (ESA users): Use of any approved ESA for the 6 weeks prior to screening and continuing between screening and randomization. * For Group 1 (not using ESAs), Hgb concentration at Week -8 and Week 1 should be 8 to 10 gram per deciliter (g/dL). For Group 2 (ESA users), Hgb concentration at Week -8 should be 8 to 12 g/dL and at Week 1 should be 8 to 11 g/dL. * \>=80% and \<=120% compliance with placebo during run-in period. * Informed consent (screening only): capable of giving signed informed consent which includes compliance with the requirements and restrictions.

Exclusion criteria

* Dialysis: On dialysis or clinical evidence of impending need to initiate dialysis within 90 days after study start (Day 1). * Kidney transplant: Planned living-related or living-unrelated kidney transplant within 52 weeks after study start (Day 1). * Ferritin: \<=100 nanograms (ng)/milliliter (mL) (\<=100 micrograms/liter \[L\]) at screening. * Transferrin saturation (TSAT) (screening only): \<=20%. * Aplasias: History of bone marrow aplasia or pure red cell aplasia. * Other causes of anemia: untreated pernicious anemia, thalassemia major, sickle cell disease or myelodysplastic syndrome. * Gastrointestinal (GI) bleeding: Evidence of actively bleeding gastric, duodenal, or esophageal ulcer disease or clinically significant GI bleeding \<=4 weeks prior to screening through to randomization (Day 1). * MI or acute coronary syndrome: \<=4 weeks prior to screening through to randomization (Day 1). * Stroke or transient ischemic attack: \<=4 weeks prior to screening through to randomization (Day 1). * Heart failure (HF): Chronic Class IV HF, as defined by the New York Heart Association (NYHA) functional classification system. * Current uncontrolled hypertension: Current uncontrolled hypertension as determined by the investigator. * Bazett's corrected QT interval (QTcB) (Day 1): QTcB \>500 millisecond (msec), or QTcB \>530 msec in subjects with bundle branch block. There is no Q-T Interval Corrected for Heart Rate (QTc) exclusion for subjects with a predominantly ventricular paced rhythm. * Alanine transaminase (ALT): \>2x upper limit of normal (ULN) at screening. * Bilirubin: \>1.5xULN at screening. * Current unstable liver or biliary disease per investigator assessment, generally defined by the presence of ascites, encephalopathy, coagulopathy, hypoalbuminaemia, esophageal or gastric varices, persistent jaundice, or cirrhosis. * Malignancy: History of malignancy within the 2 years prior to screening through to randomization (Day 1) or currently receiving treatment for cancer, or complex kidney cyst (example \[e.g.\] Bosniak Category II F, III or IV) \> 3 centimeter (cm); with the exception of localized squamous cell or basal cell carcinoma of the skin that has been definitively treated \>=4 weeks prior to screening. * Severe allergic reactions: History of severe allergic or anaphylactic reactions or hypersensitivity to excipients in the investigational product, or darbepoetin alfa. * Drugs and supplements: Use of strong inhibitors of Cytochrome P4502C8 (CYP2C8) (e.g., gemfibrozil) or strong inducers of CYP2C8 (e.g., rifampin/rifampicin). * Other study participation: Use of other investigational agent or device prior to screening through to randomization (Day 1). At screening, this exclusion applies to use of the investigational agent within 30 days or within five half lives (whichever is longer). * Prior treatment with daprodustat: Any prior treatment with daprodustat for treatment duration of \>30 days. * Females only: Subject is pregnant \[as confirmed by a positive urine human chorionic gonadotrophin (hCG) test for females of reproductive potential (FRP) only\], subject is breastfeeding, or subject is of reproductive potential and does not agree to follow one of the contraceptive options. * Other Conditions: Any other condition, clinical or laboratory abnormality, or examination finding that the investigator considers would put the subject at unacceptable risk, which may affect study compliance (e.g., intolerance to darbepoetin alfa) or prevent understanding of the aims or investigational procedures or possible consequences of the study.

Design outcomes

Primary

Measure	Time frame	Description
Time to First Occurrence of Adjudicated Major Adverse Cardiovascular Event (MACE) During Cardiovascular (CV) Events Follow-up Time Period (Non-inferiority Analysis)	Up to 4.3 person-years for CV follow-up time period	Time to MACE defined as 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, current erythropoiesis-stimulating agents (ESA) use at randomization 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 \[\*\] 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.
Mean Change From Baseline in Hgb Levels Over the Evaluation Period (Week 28 to Week 52)	Baseline (Pre-dose on Day 1) and evaluation period (Week 28 to Week 52)	Blood samples were collected from participants for Hgb measurements. Hgb during the evaluation period was defined as the mean of all available post-randomization Hgb values (on and off-treatment) during the evaluation period (Week 28 to Week 52). For the primary analysis missing post-Baseline Hgb 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. Analysis was performed using the Analysis of covariance (ANCOVA) model with terms for treatment, Baseline Hgb, current ESA use and region.

Secondary

Measure	Time frame	Description
Time to First Occurrence of Adjudicated MACE or Hospitalization for Heart Failure During CV Events Follow-up Time Period	Up to 4.3 person-years for CV follow-up time period	Time to first occurrence of adjudicated MACE or hospitalization for heart failure was analyzed using a Cox proportional hazards regression model with treatment group, current ESA use at randomization, 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.
Time to First Occurrence of Chronic Kidney Disease (CKD) Progression During CV Events Follow-up Time Period	Up to 4.3 person-years for CV follow-up time period	Progression of CKD defined as: 40% decline in estimated glomerular filtration rate (eGFR) from Baseline or end stage renal disease (ESRD) as defined by either initiating chronic dialysis for \>=90 days or not initiating chronic dialysis when dialysis is indicated or kidney transplantation. Time to first occurrence of CKD progression was analyzed using Fine and Gray's proportional subdistribution hazard regression model with treatment group, Baseline ESA use 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.
Time to First Occurrence of Adjudicated All-Cause Mortality During Vital Status for Follow-up Time Period	Up to 4.3 person-years for vital status follow-up time period	Time to first occurrence of adjudicated all-cause mortality was analyzed using a Cox proportional hazards regression model with treatment group, current ESA use at randomization, 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 follow-up time period.
Time to First Occurrence of Adjudicated CV Mortality During CV Events Follow-up Time Period	Up to 4.3 person-years for CV follow-up time period	Time to first occurrence of adjudicated CV mortality was analyzed using a Cox proportional hazards regression model with treatment group, current ESA use at randomization, 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.
Time to First Occurrence of Adjudicated Myocardial Infarction (MI) (Fatal and Non-Fatal) During CV Events Follow-up Time Period	Up to 4.3 person-years for CV follow-up time period	Time to first occurrence of adjudicated MI (fatal and non-fatal) was analyzed using a Cox proportional hazards regression model with treatment group, current ESA use at randomization, 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.
Time to First Occurrence of Adjudicated Stroke (Fatal and Non-Fatal) During CV Events Follow-up Time Period	Up to 4.3 person-years for CV follow-up time period	Time to first occurrence of adjudicated stroke (fatal and non-fatal) was analyzed using a Cox proportional hazards regression model with treatment group, current ESA use at randomization, 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.
Number of Participants With Adjudicated MACE or Hospitalization for Heart Failure (Recurrent Events Analysis)	Up to 4.3 person-years for CV follow-up time period	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.
Time to First Occurrence of Adjudicated CV Mortality or Non-Fatal MI During CV Events Follow-up Time Period	Up to 4.3 person-years for CV follow-up time period	Time to first occurrence of adjudicated CV mortality or non-fatal MI was analyzed using a Cox proportional hazards regression model with treatment group, current ESA use at randomization, 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.
Time to First Occurrence of All-Cause Hospitalization During CV Events Follow-up Time Period	Up to 4.3 person-years for CV follow-up time period	All-cause hospitalization events were hospital admissions recorded on the hospitalization electronic case report form (eCRF) form 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, current ESA use at randomization, 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.
Time to First Occurrence of All-Cause Hospital Re-admission Within 30 Days During CV Events Follow-up Time Period	Up to 4.3 person-years for CV follow-up time period	All-cause hospital re-admissions within 30days are defined as hospital admissions recorded on hospitalization electronic case record form with hospitalization duration of \>=24 hours and admission date within 30days following previous discharge date of all-cause hospitalization event, where previous hospitalization was \>=24hours.Time to first occurrence of all-cause hospital re-admission within 30days was analyzed using Cox proportional hazards regression model with treatment group, current ESA use at randomization and region as covariates.Time to the first occurrence was computed as(event date - randomization date)+1. Incidence rate per 100 person years calculated as(100\*number of participants with at least 1event)/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.
Time to First Occurrence of Adjudicated MACE or Hospitalization for Heart Failure or Thromboembolic Events During CV Events Follow-up Time Period	Up to 4.3 person-years for CV follow-up time period	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, current ESA use at randomization, 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.
Time to First Occurrence of Adjudicated Hospitalization for Heart Failure During CV Events Follow-up Time Period	Up to 4.3 person-years for CV follow-up time period	Time to first occurrence of adjudicated hospitalization for heart failure was analyzed using a Cox proportional hazards regression model with treatment group, current ESA use at randomization, 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.
Time to First Occurrence of Adjudicated Thromboembolic Events During CV Events Follow-up Time Period	Up to 4.3 person-years for CV follow-up time period	Time to first occurrence of adjudicated thromboembolic events were analyzed using a Cox proportional hazards regression model with treatment group, current ESA use at randomization, 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.
Time to First Occurrence of Confirmed 40% Decline in eGFR During CV Events Follow-up Time Period	Up to 4.3 person-years for CV follow-up time period	Time to first occurrence of confirmed 40% decline in eGFR was analyzed using a Fine & Gray's proportional subdistribution hazard regression model with treatment group, Baseline ESA use 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.
Time to First Occurrence of Chronic Dialysis During CV Events Follow-up Time Period	Up to 4.3 person-years for CV follow-up time period	Time to first occurrence of chronic dialysis was analyzed using a Fine & Gray's proportional subdistribution hazard regression model with treatment group, Baseline ESA use and region as covariates. Chronic dialysis is defined by either initiating dialysis for \>=90 days or not initiating chronic dialysis when dialysis is indicated. 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.
Time to First Occurrence of Kidney Transplant During CV Events Follow-up Time Period	Up to 4.3 person-years for CV follow-up time period	Time to first occurrence of kidney transplant were analyzed using a Fine & Gray's proportional subdistribution hazard regression model with treatment group, Baseline ESA use 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.
Change From Baseline in Post-randomization Hgb Levels at Week 52	Baseline (Pre-dose on Day 1) and Week 52	Blood samples were collected from participants for Hgb measurements. Change from Baseline was defined as post-randomization 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, current ESA use, region, Baseline Hgb and Baseline Hgb by time and treatment by time interactions.
Number of Hgb Responders in the Hgb Analysis Range (10 to 11.5 Grams/Deciliter) During Evaluation Period (Week 28 to Week 52)	Week 28 to Week 52	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. Hgb 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.
Percentage of Time With Hgb in the Analysis Range (10 to 11.5 Grams/Deciliter) During Evaluation Period (Week 28 to Week 52): Non-inferiority Analysis	Week 28 to Week 52	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 / \[Earlier of (Date of the last evaluable Hgb value, Week 52 visit date) - Later of (Date of the first evaluable Hgb value that between Week 16 and Week 52 inclusive, Week 28 visit date)\].
Percentage of Time With Hgb in the Analysis Range (10 to 11.5 Grams/Deciliter) During Evaluation Period (Week 28 to Week 52): Superiority Analysis	Week 28 to Week 52	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 / \[Earlier of (Date of the last evaluable Hgb value, Week 52 visit date) - Later of (Date of the first evaluable Hgb value that between Week 16 and Week 52 inclusive, Week 28 visit date)\].
Percentage of Time With Hgb in the Analysis Range (10 to 11.5 Grams/Deciliter) During Maintenance Period (Week 28 to End of Study): Non-inferiority Analysis	Week 28 to end of study (4.3 person-years for follow-up time period)	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 / \[Earlier of (Date of the last evaluable Hgb value, End of study date)- Later of (Date of the first evaluable Hgb value that is on or after week 16, Week 28 visit date)\].
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	Week 28 to end of study (4.3 person-years for follow-up time period)	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 / \[Earlier of (Date of the last evaluable Hgb value, End of study date)- Later of (Date of the first evaluable Hgb value that is on or after week 16, Week 28 visit date)\].
Change From Baseline in Systolic Blood Pressure (SBP), Diastolic Blood Pressure (DBP) and Mean Arterial Blood Pressure (MAP) at Week 52	Baseline (Week -4) and Week 52	SBP, DBP and MAP were measured in a seated position 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 + current ESA use at randomization + region + Baseline value + Baseline value\time + treatment group\time, using an unstructured covariance matrix. Data for post-dialysis BP measurements have been presented.
Change From Baseline in SBP, DBP, MAP at End of Treatment	Baseline (Week -4) and 51.1 months	SBP, DBP and MAP were measured in a seated position 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. Analysis was performed using ANCOVA model with terms for treatment group, current ESA use at randomization, region and Baseline value. Data for post-dialysis BP measurements have been presented.
Blood Pressure (BP) Exacerbation Event Rate Per 100 Participant Years	Day 1 to end of treatment (51.1 months)	BP exacerbation event (based on post-dialysis) was defined 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, current ESA use at randomization and region as covariates and the logarithm of time on-treatment as an offset variable. Data for post-dialysis BP measurements have been presented.
Number of Participants With at Least One BP Exacerbation Event During Study	Day 1 to end of treatment (51.1 months)	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.
Percentage of Participants Permanently Stopping Randomized Treatment Due to Meeting Rescue Criteria	Day 1 to 51.1 months	Percentage of participants permanently stopping randomized treatment due to meeting rescue criteria has been presented.
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	Baseline (Pre-dose on Day 1), Weeks 8, 12, 28 and 52	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 score represents 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.
Change From Baseline in On-treatment Mental Component Score (MCS) Using SF-36 HRQoL Questionnaire at Weeks 8, 12, 28, 52	Baseline (Pre-dose on Day 1), Weeks 8, 12, 28 and 52	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.
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	Baseline (Pre-dose on Day 1), Weeks 8, 12, 28 and 52	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 (b pain), general health (GH), mental health (MH), role-emotional (RE) (role limitations caused by emotional problems), role-physical (RP) (role limitations caused by physical problems), social functioning (SF), physical functioning 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 (BL) 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.
Change From Baseline in On-treatment Vitality Scores Using SF-36 HRQoL Questionnaire at Weeks 8, 12, 28, 52	Baseline (Pre-dose on Day 1), Weeks 8, 12, 28 and 52	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.
Change From Baseline in On-treatment Physical Functioning Domain Scores Using SF-36 HRQoL Questionnaire at Weeks 8, 12, 28, 52	Baseline (Pre-dose on Day 1), Weeks 8, 12, 28 and 52	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.
Change From Baseline in On-treatment Health Utility EuroQol 5 Dimensions 5 Level (EQ-5D-5L) Questionnaire Score at Week 52	Baseline (Pre-dose on Day 1) and Week 52	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 minus Baseline value. Baseline was latest non-missing pre-dose assessment on or before randomization date.
Time to First Occurrence of Adjudicated MACE During CV Events Follow-up Time Period (Superiority Analysis)	Up to 4.3 person-years for CV follow-up time period	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, current ESA use at randomization, 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.
Change From Baseline in On-treatment Chronic Kidney Disease- Anemia Symptoms Questionnaire (CKD-AQ) at Weeks 8, 12, 28, 52	Baseline (Day 1) and Weeks 8, 12, 28, 52	CKD-AQ is 21-item patient reported outcome measure assessing symptoms and symptom impact in participants with anemia associated with CKD. It had 3 domains: 1.Tired/Low Energy (LE)/Weak scale consisting of 10 items; 2.Chest Pain (CP)/Shortness of Breath (SOB) scale consisting of 4 items; and 3.Cognitive (Cog) scale consisting of 3 items. The 4 CKD-AQ single items are: shortness of breath, no activity; severity-short breath (S-SB), resting; difficulty standing (diff. std.)for long time (LT) and difficulty sleeping (diff sleep). Single-item were recorded based on a 0-100 scoring with 0=worst possible and 100=best possible score. Three domains scores were calculated as average of items in each domain and ranged from 0-100 where 0=worst possible and 100=best possible score. 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.
Change From Baseline in On-treatment Patient Global Impression of Severity (PGI-S) at Weeks 8, 12, 28, 52	Baseline (Pre-dose on Day 1), Weeks 8, 12, 28 and 52	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 more disease severity. 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.
Change From Baseline in Post-randomization Estimated Glomerular Filtration Rate (eGFR) at Week 52	Baseline (Pre-dose on Day 1) and Week 52	Blood samples were collected to analyze estimated glomerular filtration rate. Change from Baseline was calculated as post-Baseline visit value minus Baseline value. Baseline was defined as the latest non-missing pre-dose assessment on or before the randomization date.
Change From Baseline in On-treatment EQ Visual Analogue Scale (EQ-VAS) at Week 52	Baseline (Pre-dose on Day 1) and Week 52	The EQ VAS records the respondent's self-rated health on a vertical VAS, ranging from 0 to 100, where 0 represents the worst imaginable health and 100 represents the best imaginable 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.
Time to First Occurrence of Adjudicated MACE or Thromboembolic Event During CV Events Follow-up Time Period	Up to 4.3 person-years for CV follow-up time period	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, current ESA use at randomization, 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.

Countries

Argentina, Australia, Belgium, Brazil, Bulgaria, Canada, Colombia, Czechia, Denmark, Estonia, France, Germany, Greece, Hong Kong, Hungary, India, Israel, Italy, Malaysia, Mexico, Netherlands, New Zealand, Philippines, Poland, Portugal, Romania, Russia, Singapore, South Africa, South Korea, Spain, Sweden, Taiwan, Thailand, Turkey (Türkiye), Ukraine, United Kingdom, United States, Vietnam

Participant flow

Recruitment details

This was a multicenter study conducted across 39 countries. Participants were randomized to receive either daprodustat or darbepoetin alfa.

Pre-assignment details

A total of 3872 participants were enrolled in the study.

Participants by arm

Arm	Count
Daprodustat Participants received placebo tablets orally once daily in run-in period from Week-4 up to randomization (Day 1) and subsequently received treatment with daprodustat film-coated tablets at dose levels ranging from 1, 2, 4, 6, 8, 10, 12, 16 and 24 milligrams (mg) orally once daily up to 51.1 month. Study treatment was dose-titrated to achieve and maintain hemoglobin (Hgb) in the target range (10 to 11 grams per deciliter \[g/dL\]).	1,937
Darbepoetin Alfa Participants received placebo tablets orally once daily in run-in period from Week-4 up to randomization (Day 1) and subsequently received treatment with darbepoetin alfa as prefilled syringes (PFS) for subcutaneous or intravenous (IV) injection at 4-weekly total dose levels ranging from 20, 30, 40, 60, 80, 100, 150, 200, 300 and 400 microgram (mcg) up to 51.1 month. Darbepoetin alfa IV injection was administered to participants undergoing hemodialysis. Study treatment was dose-titrated to achieve and maintain Hgb in the target range (10 to 11 g/dL).	1,935
Total	3,872

Withdrawals & dropouts

Period	Reason	FG000	FG001
Treatment Period (51.1 Month)	Investigator Site Closed	6	13
Treatment Period (51.1 Month)	Lost to Follow-up	25	29
Treatment Period (51.1 Month)	Other	1	0
Treatment Period (51.1 Month)	Withdrawal by Subject	32	23

Baseline characteristics

Characteristic	Daprodustat	Total	Darbepoetin Alfa
Age, Continuous	64.8 Years STANDARD_DEVIATION 14.03	64.8 Years STANDARD_DEVIATION 13.93	64.9 Years STANDARD_DEVIATION 13.83
Race/Ethnicity, Customized American Indian or Alaskan Native	88 Participants	188 Participants	100 Participants
Race/Ethnicity, Customized Asian - Central/South Asian Heritage	58 Participants	129 Participants	71 Participants
Race/Ethnicity, Customized Asian - East Asian Heritage	245 Participants	477 Participants	232 Participants
Race/Ethnicity, Customized Asian - Japanese Heritage	5 Participants	8 Participants	3 Participants
Race/Ethnicity, Customized Asian - South East Asian Heritage	216 Participants	445 Participants	229 Participants
Race/Ethnicity, Customized Black or African American	183 Participants	368 Participants	185 Participants
Race/Ethnicity, Customized Mixed Asian Race	1 Participants	3 Participants	2 Participants
Race/Ethnicity, Customized Mixed Race	36 Participants	87 Participants	51 Participants
Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander	7 Participants	14 Participants	7 Participants
Race/Ethnicity, Customized White - Arabic/North African Heritage	19 Participants	37 Participants	18 Participants
Race/Ethnicity, Customized White - White/Caucasian/European Heritage	1079 Participants	2116 Participants	1037 Participants
Sex: Female, Male Female	1102 Participants	2173 Participants	1071 Participants
Sex: Female, Male Male	835 Participants	1699 Participants	864 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk
deaths Total, all-cause mortality	0 / 3,872	301 / 1,937	298 / 1,935
other Total, other adverse events	0 / 3,872	851 / 1,937	825 / 1,933
serious Total, serious adverse events	63 / 3,872	850 / 1,937	703 / 1,933

Outcome results

Primary

Mean Change From Baseline in Hgb Levels Over the Evaluation Period (Week 28 to Week 52)

Blood samples were collected from participants for Hgb measurements. Hgb during the evaluation period was defined as the mean of all available post-randomization Hgb values (on and off-treatment) during the evaluation period (Week 28 to Week 52). For the primary analysis missing post-Baseline Hgb 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. Analysis was performed using the Analysis of covariance (ANCOVA) model with terms for treatment, Baseline Hgb, current ESA use and region.

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

Population: All Randomized (ITT) Population.

Arm	Measure	Value (LEAST_SQUARES_MEAN)	Dispersion
Daprodustat	Mean Change From Baseline in Hgb Levels Over the Evaluation Period (Week 28 to Week 52)	0.74 Grams per deciliter	Standard Error 0.019
Darbepoetin Alfa	Mean Change From Baseline in Hgb Levels Over the Evaluation Period (Week 28 to Week 52)	0.66 Grams per deciliter	Standard Error 0.019

95% CI: [0.03, 0.13]

Primary

Time to First Occurrence of Adjudicated Major Adverse Cardiovascular Event (MACE) During Cardiovascular (CV) Events Follow-up Time Period (Non-inferiority Analysis)

Time to MACE defined as 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, current erythropoiesis-stimulating agents (ESA) use at randomization 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 \[\*\] 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.

Time frame: Up to 4.3 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.

Arm	Measure	Value (NUMBER)
Daprodustat	Time to First Occurrence of Adjudicated Major Adverse Cardiovascular Event (MACE) During Cardiovascular (CV) Events Follow-up Time Period (Non-inferiority Analysis)	10.86 Events per 100 person years
Darbepoetin Alfa	Time to First Occurrence of Adjudicated Major Adverse Cardiovascular Event (MACE) During Cardiovascular (CV) Events Follow-up Time Period (Non-inferiority Analysis)	10.63 Events per 100 person years

95% CI: [0.89, 1.19]

Secondary

Blood Pressure (BP) Exacerbation Event Rate Per 100 Participant Years

BP exacerbation event (based on post-dialysis) was defined 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, current ESA use at randomization and region as covariates and the logarithm of time on-treatment as an offset variable. Data for post-dialysis BP measurements have been presented.

Time frame: Day 1 to end of treatment (51.1 months)

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

Arm	Measure	Value (NUMBER)
Daprodustat	Blood Pressure (BP) Exacerbation Event Rate Per 100 Participant Years	138.50 Events per 100 participant years
Darbepoetin Alfa	Blood Pressure (BP) Exacerbation Event Rate Per 100 Participant Years	157.35 Events per 100 participant years

p-value: 0.007495% CI: [0.79, 0.98]Negative binomial model

Secondary

Change From Baseline in On-treatment Chronic Kidney Disease- Anemia Symptoms Questionnaire (CKD-AQ) at Weeks 8, 12, 28, 52

CKD-AQ is 21-item patient reported outcome measure assessing symptoms and symptom impact in participants with anemia associated with CKD. It had 3 domains: 1.Tired/Low Energy (LE)/Weak scale consisting of 10 items; 2.Chest Pain (CP)/Shortness of Breath (SOB) scale consisting of 4 items; and 3.Cognitive (Cog) scale consisting of 3 items. The 4 CKD-AQ single items are: shortness of breath, no activity; severity-short breath (S-SB), resting; difficulty standing (diff. std.)for long time (LT) and difficulty sleeping (diff sleep). Single-item were recorded based on a 0-100 scoring with 0=worst possible and 100=best possible score. Three domains scores were calculated as average of items in each domain and ranged from 0-100 where 0=worst possible and 100=best possible score. 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.

Time frame: Baseline (Day 1) and Weeks 8, 12, 28, 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).

Arm	Measure	Group	Value (LEAST_SQUARES_MEAN)	Dispersion
Daprodustat	Change From Baseline in On-treatment Chronic Kidney Disease- Anemia Symptoms Questionnaire (CKD-AQ) at Weeks 8, 12, 28, 52	SOB, no activity: Week 28,n=1053,1047	-1.1 Scores on a scale	Standard Error 0.5
Daprodustat	Change From Baseline in On-treatment Chronic Kidney Disease- Anemia Symptoms Questionnaire (CKD-AQ) at Weeks 8, 12, 28, 52	Chest pain/SOB domain: Week 8,n=1340,1294	0.63 Scores on a scale	Standard Error 0.358
Daprodustat	Change From Baseline in On-treatment Chronic Kidney Disease- Anemia Symptoms Questionnaire (CKD-AQ) at Weeks 8, 12, 28, 52	SOB, no activity: Week 52,n=870,865	-1.7 Scores on a scale	Standard Error 0.57
Daprodustat	Change From Baseline in On-treatment Chronic Kidney Disease- Anemia Symptoms Questionnaire (CKD-AQ) at Weeks 8, 12, 28, 52	Cognitive domain: Week 8,n=1340,1294	0.13 Scores on a scale	Standard Error 0.413
Daprodustat	Change From Baseline in On-treatment Chronic Kidney Disease- Anemia Symptoms Questionnaire (CKD-AQ) at Weeks 8, 12, 28, 52	Severity-short breath, Resting: Week 8,n=1340,1294	-0.3 Scores on a scale	Standard Error 0.4
Daprodustat	Change From Baseline in On-treatment Chronic Kidney Disease- Anemia Symptoms Questionnaire (CKD-AQ) at Weeks 8, 12, 28, 52	Tired/Low energy/Weak domain: Week 12,n=1341,1360	2.11 Scores on a scale	Standard Error 0.437
Daprodustat	Change From Baseline in On-treatment Chronic Kidney Disease- Anemia Symptoms Questionnaire (CKD-AQ) at Weeks 8, 12, 28, 52	Severity-short breath, Resting:Week 12,n=1341,1360	-0.3 Scores on a scale	Standard Error 0.42
Daprodustat	Change From Baseline in On-treatment Chronic Kidney Disease- Anemia Symptoms Questionnaire (CKD-AQ) at Weeks 8, 12, 28, 52	Cognitive domain: Week 12,n=1341,1360	-0.17 Scores on a scale	Standard Error 0.414
Daprodustat	Change From Baseline in On-treatment Chronic Kidney Disease- Anemia Symptoms Questionnaire (CKD-AQ) at Weeks 8, 12, 28, 52	Severity-short breath, Resting:Week 28,n=1053,1047	-1.1 Scores on a scale	Standard Error 0.48
Daprodustat	Change From Baseline in On-treatment Chronic Kidney Disease- Anemia Symptoms Questionnaire (CKD-AQ) at Weeks 8, 12, 28, 52	Chest pain/ SOB domain: Week 12,n=1341,1360	0.88 Scores on a scale	Standard Error 0.37
Daprodustat	Change From Baseline in On-treatment Chronic Kidney Disease- Anemia Symptoms Questionnaire (CKD-AQ) at Weeks 8, 12, 28, 52	Severity-short breath, Resting:Week 52,n=870,865	-2.0 Scores on a scale	Standard Error 0.53
Daprodustat	Change From Baseline in On-treatment Chronic Kidney Disease- Anemia Symptoms Questionnaire (CKD-AQ) at Weeks 8, 12, 28, 52	Cognitive domain: Week 28,n=1053,1047	-0.40 Scores on a scale	Standard Error 0.468
Daprodustat	Change From Baseline in On-treatment Chronic Kidney Disease- Anemia Symptoms Questionnaire (CKD-AQ) at Weeks 8, 12, 28, 52	Diff std for long time: Week 8,n=1340,1294	1.0 Scores on a scale	Standard Error 0.62
Daprodustat	Change From Baseline in On-treatment Chronic Kidney Disease- Anemia Symptoms Questionnaire (CKD-AQ) at Weeks 8, 12, 28, 52	Tired/Low energy/Weak domain: Week 52,n=870,865	0.20 Scores on a scale	Standard Error 0.554
Daprodustat	Change From Baseline in On-treatment Chronic Kidney Disease- Anemia Symptoms Questionnaire (CKD-AQ) at Weeks 8, 12, 28, 52	Diff std for long time: Week 12,n=1341,1360	0.7 Scores on a scale	Standard Error 0.63
Daprodustat	Change From Baseline in On-treatment Chronic Kidney Disease- Anemia Symptoms Questionnaire (CKD-AQ) at Weeks 8, 12, 28, 52	Cognitive domain: Week 52,n=870,865	-2.00 Scores on a scale	Standard Error 0.526
Daprodustat	Change From Baseline in On-treatment Chronic Kidney Disease- Anemia Symptoms Questionnaire (CKD-AQ) at Weeks 8, 12, 28, 52	Diff std for long time: Week 28,n=1053,1047	0.4 Scores on a scale	Standard Error 0.71
Daprodustat	Change From Baseline in On-treatment Chronic Kidney Disease- Anemia Symptoms Questionnaire (CKD-AQ) at Weeks 8, 12, 28, 52	Chest pain/ SOB domain: Week 28,n=1053,1047	0.01 Scores on a scale	Standard Error 0.424
Daprodustat	Change From Baseline in On-treatment Chronic Kidney Disease- Anemia Symptoms Questionnaire (CKD-AQ) at Weeks 8, 12, 28, 52	Diff std for long time: Week 52,n=870,865	-2.1 Scores on a scale	Standard Error 0.76
Daprodustat	Change From Baseline in On-treatment Chronic Kidney Disease- Anemia Symptoms Questionnaire (CKD-AQ) at Weeks 8, 12, 28, 52	SOB, no activity: Week 8,n=1340,1294	-0.1 Scores on a scale	Standard Error 0.42
Daprodustat	Change From Baseline in On-treatment Chronic Kidney Disease- Anemia Symptoms Questionnaire (CKD-AQ) at Weeks 8, 12, 28, 52	Difficulty sleeping: Week 8,n=1340,1294	1.6 Scores on a scale	Standard Error 0.6
Daprodustat	Change From Baseline in On-treatment Chronic Kidney Disease- Anemia Symptoms Questionnaire (CKD-AQ) at Weeks 8, 12, 28, 52	Tired/Low energy/Weak domain: Week 28,n=1053,1047	1.27 Scores on a scale	Standard Error 0.495
Daprodustat	Change From Baseline in On-treatment Chronic Kidney Disease- Anemia Symptoms Questionnaire (CKD-AQ) at Weeks 8, 12, 28, 52	Difficulty sleeping: Week 12,n=1341,1360	0.5 Scores on a scale	Standard Error 0.6
Daprodustat	Change From Baseline in On-treatment Chronic Kidney Disease- Anemia Symptoms Questionnaire (CKD-AQ) at Weeks 8, 12, 28, 52	SOB, no activity: Week 12,n=1341,1360	0.1 Scores on a scale	Standard Error 0.43
Daprodustat	Change From Baseline in On-treatment Chronic Kidney Disease- Anemia Symptoms Questionnaire (CKD-AQ) at Weeks 8, 12, 28, 52	Difficulty sleeping: Week 28,n=1053,1047	-0.7 Scores on a scale	Standard Error 0.69
Daprodustat	Change From Baseline in On-treatment Chronic Kidney Disease- Anemia Symptoms Questionnaire (CKD-AQ) at Weeks 8, 12, 28, 52	Chest pain/ SOB domain: Week 52,n=870,865	-0.71 Scores on a scale	Standard Error 0.471
Daprodustat	Change From Baseline in On-treatment Chronic Kidney Disease- Anemia Symptoms Questionnaire (CKD-AQ) at Weeks 8, 12, 28, 52	Difficulty sleeping: Week 52,n=870,865	-2.6 Scores on a scale	Standard Error 0.78
Daprodustat	Change From Baseline in On-treatment Chronic Kidney Disease- Anemia Symptoms Questionnaire (CKD-AQ) at Weeks 8, 12, 28, 52	Tired/Low energy/Weak domain: Week 8,n=1340,1294	1.72 Scores on a scale	Standard Error 0.424
Darbepoetin Alfa	Change From Baseline in On-treatment Chronic Kidney Disease- Anemia Symptoms Questionnaire (CKD-AQ) at Weeks 8, 12, 28, 52	Difficulty sleeping: Week 52,n=870,865	-0.3 Scores on a scale	Standard Error 0.78
Darbepoetin Alfa	Change From Baseline in On-treatment Chronic Kidney Disease- Anemia Symptoms Questionnaire (CKD-AQ) at Weeks 8, 12, 28, 52	Tired/Low energy/Weak domain: Week 8,n=1340,1294	2.94 Scores on a scale	Standard Error 0.429
Darbepoetin Alfa	Change From Baseline in On-treatment Chronic Kidney Disease- Anemia Symptoms Questionnaire (CKD-AQ) at Weeks 8, 12, 28, 52	Tired/Low energy/Weak domain: Week 12,n=1341,1360	3.08 Scores on a scale	Standard Error 0.434
Darbepoetin Alfa	Change From Baseline in On-treatment Chronic Kidney Disease- Anemia Symptoms Questionnaire (CKD-AQ) at Weeks 8, 12, 28, 52	Tired/Low energy/Weak domain: Week 28,n=1053,1047	1.87 Scores on a scale	Standard Error 0.496
Darbepoetin Alfa	Change From Baseline in On-treatment Chronic Kidney Disease- Anemia Symptoms Questionnaire (CKD-AQ) at Weeks 8, 12, 28, 52	Tired/Low energy/Weak domain: Week 52,n=870,865	1.77 Scores on a scale	Standard Error 0.556
Darbepoetin Alfa	Change From Baseline in On-treatment Chronic Kidney Disease- Anemia Symptoms Questionnaire (CKD-AQ) at Weeks 8, 12, 28, 52	Chest pain/SOB domain: Week 8,n=1340,1294	1.83 Scores on a scale	Standard Error 0.363
Darbepoetin Alfa	Change From Baseline in On-treatment Chronic Kidney Disease- Anemia Symptoms Questionnaire (CKD-AQ) at Weeks 8, 12, 28, 52	Chest pain/ SOB domain: Week 12,n=1341,1360	1.53 Scores on a scale	Standard Error 0.368
Darbepoetin Alfa	Change From Baseline in On-treatment Chronic Kidney Disease- Anemia Symptoms Questionnaire (CKD-AQ) at Weeks 8, 12, 28, 52	Chest pain/ SOB domain: Week 28,n=1053,1047	0.53 Scores on a scale	Standard Error 0.425
Darbepoetin Alfa	Change From Baseline in On-treatment Chronic Kidney Disease- Anemia Symptoms Questionnaire (CKD-AQ) at Weeks 8, 12, 28, 52	Chest pain/ SOB domain: Week 52,n=870,865	0.47 Scores on a scale	Standard Error 0.473
Darbepoetin Alfa	Change From Baseline in On-treatment Chronic Kidney Disease- Anemia Symptoms Questionnaire (CKD-AQ) at Weeks 8, 12, 28, 52	Cognitive domain: Week 8,n=1340,1294	0.89 Scores on a scale	Standard Error 0.419
Darbepoetin Alfa	Change From Baseline in On-treatment Chronic Kidney Disease- Anemia Symptoms Questionnaire (CKD-AQ) at Weeks 8, 12, 28, 52	Cognitive domain: Week 12,n=1341,1360	1.01 Scores on a scale	Standard Error 0.412
Darbepoetin Alfa	Change From Baseline in On-treatment Chronic Kidney Disease- Anemia Symptoms Questionnaire (CKD-AQ) at Weeks 8, 12, 28, 52	Cognitive domain: Week 28,n=1053,1047	0.37 Scores on a scale	Standard Error 0.469
Darbepoetin Alfa	Change From Baseline in On-treatment Chronic Kidney Disease- Anemia Symptoms Questionnaire (CKD-AQ) at Weeks 8, 12, 28, 52	Cognitive domain: Week 52,n=870,865	-0.35 Scores on a scale	Standard Error 0.527
Darbepoetin Alfa	Change From Baseline in On-treatment Chronic Kidney Disease- Anemia Symptoms Questionnaire (CKD-AQ) at Weeks 8, 12, 28, 52	SOB, no activity: Week 8,n=1340,1294	1.0 Scores on a scale	Standard Error 0.42
Darbepoetin Alfa	Change From Baseline in On-treatment Chronic Kidney Disease- Anemia Symptoms Questionnaire (CKD-AQ) at Weeks 8, 12, 28, 52	SOB, no activity: Week 12,n=1341,1360	0.4 Scores on a scale	Standard Error 0.42
Darbepoetin Alfa	Change From Baseline in On-treatment Chronic Kidney Disease- Anemia Symptoms Questionnaire (CKD-AQ) at Weeks 8, 12, 28, 52	SOB, no activity: Week 28,n=1053,1047	-0.2 Scores on a scale	Standard Error 0.5
Darbepoetin Alfa	Change From Baseline in On-treatment Chronic Kidney Disease- Anemia Symptoms Questionnaire (CKD-AQ) at Weeks 8, 12, 28, 52	SOB, no activity: Week 52,n=870,865	-1.6 Scores on a scale	Standard Error 0.57
Darbepoetin Alfa	Change From Baseline in On-treatment Chronic Kidney Disease- Anemia Symptoms Questionnaire (CKD-AQ) at Weeks 8, 12, 28, 52	Severity-short breath, Resting: Week 8,n=1340,1294	0.8 Scores on a scale	Standard Error 0.4
Darbepoetin Alfa	Change From Baseline in On-treatment Chronic Kidney Disease- Anemia Symptoms Questionnaire (CKD-AQ) at Weeks 8, 12, 28, 52	Severity-short breath, Resting:Week 12,n=1341,1360	0.0 Scores on a scale	Standard Error 0.42
Darbepoetin Alfa	Change From Baseline in On-treatment Chronic Kidney Disease- Anemia Symptoms Questionnaire (CKD-AQ) at Weeks 8, 12, 28, 52	Severity-short breath, Resting:Week 28,n=1053,1047	-0.7 Scores on a scale	Standard Error 0.48
Darbepoetin Alfa	Change From Baseline in On-treatment Chronic Kidney Disease- Anemia Symptoms Questionnaire (CKD-AQ) at Weeks 8, 12, 28, 52	Severity-short breath, Resting:Week 52,n=870,865	-0.5 Scores on a scale	Standard Error 0.53
Darbepoetin Alfa	Change From Baseline in On-treatment Chronic Kidney Disease- Anemia Symptoms Questionnaire (CKD-AQ) at Weeks 8, 12, 28, 52	Diff std for long time: Week 8,n=1340,1294	2.5 Scores on a scale	Standard Error 0.63
Darbepoetin Alfa	Change From Baseline in On-treatment Chronic Kidney Disease- Anemia Symptoms Questionnaire (CKD-AQ) at Weeks 8, 12, 28, 52	Diff std for long time: Week 12,n=1341,1360	1.6 Scores on a scale	Standard Error 0.62
Darbepoetin Alfa	Change From Baseline in On-treatment Chronic Kidney Disease- Anemia Symptoms Questionnaire (CKD-AQ) at Weeks 8, 12, 28, 52	Diff std for long time: Week 28,n=1053,1047	1.7 Scores on a scale	Standard Error 0.71
Darbepoetin Alfa	Change From Baseline in On-treatment Chronic Kidney Disease- Anemia Symptoms Questionnaire (CKD-AQ) at Weeks 8, 12, 28, 52	Diff std for long time: Week 52,n=870,865	1.2 Scores on a scale	Standard Error 0.76
Darbepoetin Alfa	Change From Baseline in On-treatment Chronic Kidney Disease- Anemia Symptoms Questionnaire (CKD-AQ) at Weeks 8, 12, 28, 52	Difficulty sleeping: Week 8,n=1340,1294	1.1 Scores on a scale	Standard Error 0.61
Darbepoetin Alfa	Change From Baseline in On-treatment Chronic Kidney Disease- Anemia Symptoms Questionnaire (CKD-AQ) at Weeks 8, 12, 28, 52	Difficulty sleeping: Week 12,n=1341,1360	2.0 Scores on a scale	Standard Error 0.59
Darbepoetin Alfa	Change From Baseline in On-treatment Chronic Kidney Disease- Anemia Symptoms Questionnaire (CKD-AQ) at Weeks 8, 12, 28, 52	Difficulty sleeping: Week 28,n=1053,1047	-0.3 Scores on a scale	Standard Error 0.7

p-value: 0.97895% CI: [-2.4, -0.03]MMRM

p-value: 0.94395% CI: [-2.18, 0.23]MMRM

p-value: 0.804295% CI: [-1.98, 0.77]MMRM

p-value: 0.97795% CI: [-3.11, -0.03]MMRM

p-value: 0.990595% CI: [-2.2, -0.2]MMRM

p-value: 0.893995% CI: [-1.67, 0.37]LS mean difference

p-value: 0.80795% CI: [-1.7, 0.66]MMRM

p-value: 0.961595% CI: [-2.49, 0.13]MMRM

p-value: 0.901595% CI: [-1.91, 0.39]MMRM

p-value: 0.978195% CI: [-2.32, -0.03]MMRM

p-value: 0.877895% CI: [-2.07, 0.53]MMRM

p-value: 0.986495% CI: [-3.11, -0.19]MMRM

p-value: 0.972595% CI: [-2.3, 0]MMRM

p-value: 0.718895% CI: [-1.5, 0.8]MMRM

p-value: 0.890395% CI: [-2.3, 0.5]MMRM

p-value: 0.501195% CI: [-1.6, 1.6]MMRM

p-value: 0.971695% CI: [-2.2, 0]MMRM

p-value: 0.690895% CI: [-1.4, 0.9]MMRM

p-value: 0.746295% CI: [-1.8, 0.9]MMRM

p-value: 0.97795% CI: [-2.9, 0]MMRM

p-value: 0.947195% CI: [-3.2, 0.3]MMRM

p-value: 0.83395% CI: [-2.6, 0.9]MMRM

p-value: 0.891895% CI: [-3.2, 0.7]MMRM

p-value: 0.998695% CI: [-5.4, -1.1]MMRM

p-value: 0.303595% CI: [-1.2, 2.1]MMRM

p-value: 0.956395% CI: [-3.1, 0.2]MMRM

p-value: 0.654895% CI: [-2.3, 1.5]MMRM

p-value: 0.983295% CI: [-4.5, -0.2]MMRM

Secondary

Change From Baseline in On-treatment EQ Visual Analogue Scale (EQ-VAS) at Week 52

The EQ VAS records the respondent's self-rated health on a vertical VAS, ranging from 0 to 100, where 0 represents the worst imaginable health and 100 represents the best imaginable 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.

Time frame: 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.

Arm	Measure	Value (LEAST_SQUARES_MEAN)	Dispersion
Daprodustat	Change From Baseline in On-treatment EQ Visual Analogue Scale (EQ-VAS) at Week 52	-0.7 Scores on a scale	Standard Error 0.78
Darbepoetin Alfa	Change From Baseline in On-treatment EQ Visual Analogue Scale (EQ-VAS) at Week 52	-1.4 Scores on a scale	Standard Error 0.82

p-value: 0.268795% CI: [-1.5, 2.9]MMRM

Secondary

Change From Baseline in On-treatment Health Utility EuroQol 5 Dimensions 5 Level (EQ-5D-5L) Questionnaire Score at Week 52

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 minus Baseline value. Baseline was latest non-missing pre-dose assessment on or before randomization date.

Time frame: 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.

Arm	Measure	Value (LEAST_SQUARES_MEAN)	Dispersion
Daprodustat	Change From Baseline in On-treatment Health Utility EuroQol 5 Dimensions 5 Level (EQ-5D-5L) Questionnaire Score at Week 52	-0.0253 Scores on a scale	Standard Error 0.00842
Darbepoetin Alfa	Change From Baseline in On-treatment Health Utility EuroQol 5 Dimensions 5 Level (EQ-5D-5L) Questionnaire Score at Week 52	-0.0018 Scores on a scale	Standard Error 0.00883

p-value: 0.972495% CI: [-0.0474, 0.0005]MMRM

Secondary

Change From Baseline in On-treatment Mental Component Score (MCS) Using SF-36 HRQoL Questionnaire at Weeks 8, 12, 28, 52

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.

Time frame: 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).

Arm	Measure	Group	Value (LEAST_SQUARES_MEAN)	Dispersion
Daprodustat	Change From Baseline in On-treatment Mental Component Score (MCS) Using SF-36 HRQoL Questionnaire at Weeks 8, 12, 28, 52	Week 8, n=1238,1187	0.08 Scores on a scale	Standard Error 0.217
Daprodustat	Change From Baseline in On-treatment Mental Component Score (MCS) Using SF-36 HRQoL Questionnaire at Weeks 8, 12, 28, 52	Week 12, n=1237,1227	0.02 Scores on a scale	Standard Error 0.223
Daprodustat	Change From Baseline in On-treatment Mental Component Score (MCS) Using SF-36 HRQoL Questionnaire at Weeks 8, 12, 28, 52	Week 28, n=968,956	-0.35 Scores on a scale	Standard Error 0.244
Daprodustat	Change From Baseline in On-treatment Mental Component Score (MCS) Using SF-36 HRQoL Questionnaire at Weeks 8, 12, 28, 52	Week 52, n=804,780	-0.71 Scores on a scale	Standard Error 0.29
Darbepoetin Alfa	Change From Baseline in On-treatment Mental Component Score (MCS) Using SF-36 HRQoL Questionnaire at Weeks 8, 12, 28, 52	Week 52, n=804,780	-0.35 Scores on a scale	Standard Error 0.294
Darbepoetin Alfa	Change From Baseline in On-treatment Mental Component Score (MCS) Using SF-36 HRQoL Questionnaire at Weeks 8, 12, 28, 52	Week 8, n=1238,1187	0.37 Scores on a scale	Standard Error 0.221
Darbepoetin Alfa	Change From Baseline in On-treatment Mental Component Score (MCS) Using SF-36 HRQoL Questionnaire at Weeks 8, 12, 28, 52	Week 28, n=968,956	-0.02 Scores on a scale	Standard Error 0.245
Darbepoetin Alfa	Change From Baseline in On-treatment Mental Component Score (MCS) Using SF-36 HRQoL Questionnaire at Weeks 8, 12, 28, 52	Week 12, n=1237,1227	0.18 Scores on a scale	Standard Error 0.224

p-value: 0.826895% CI: [-0.9, 0.32]MMRM

p-value: 0.685195% CI: [-0.77, 0.47]MMRM

p-value: 0.831695% CI: [-1.01, 0.35]MMRM

p-value: 0.803295% CI: [-1.16, 0.46]MMRM

Secondary

Change From Baseline in On-treatment Patient Global Impression of Severity (PGI-S) at Weeks 8, 12, 28, 52

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 more disease severity. 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.

Time frame: 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).

Arm	Measure	Group	Value (LEAST_SQUARES_MEAN)	Dispersion
Daprodustat	Change From Baseline in On-treatment Patient Global Impression of Severity (PGI-S) at Weeks 8, 12, 28, 52	Week 8, n=1341,1295	0.00 Scores on a scale	Standard Error 0.022
Daprodustat	Change From Baseline in On-treatment Patient Global Impression of Severity (PGI-S) at Weeks 8, 12, 28, 52	Week 12, n=1341,1362	0.03 Scores on a scale	Standard Error 0.022
Daprodustat	Change From Baseline in On-treatment Patient Global Impression of Severity (PGI-S) at Weeks 8, 12, 28, 52	Week 28, n=1054,1051	0.05 Scores on a scale	Standard Error 0.025
Daprodustat	Change From Baseline in On-treatment Patient Global Impression of Severity (PGI-S) at Weeks 8, 12, 28, 52	Week 52, n=871,865	0.11 Scores on a scale	Standard Error 0.028
Darbepoetin Alfa	Change From Baseline in On-treatment Patient Global Impression of Severity (PGI-S) at Weeks 8, 12, 28, 52	Week 52, n=871,865	0.06 Scores on a scale	Standard Error 0.029
Darbepoetin Alfa	Change From Baseline in On-treatment Patient Global Impression of Severity (PGI-S) at Weeks 8, 12, 28, 52	Week 8, n=1341,1295	-0.02 Scores on a scale	Standard Error 0.022
Darbepoetin Alfa	Change From Baseline in On-treatment Patient Global Impression of Severity (PGI-S) at Weeks 8, 12, 28, 52	Week 28, n=1054,1051	0.09 Scores on a scale	Standard Error 0.025
Darbepoetin Alfa	Change From Baseline in On-treatment Patient Global Impression of Severity (PGI-S) at Weeks 8, 12, 28, 52	Week 12, n=1341,1362	-0.02 Scores on a scale	Standard Error 0.022

p-value: 0.691795% CI: [-0.05, 0.08]MMRM

p-value: 0.95195% CI: [-0.01, 0.11]MMRM

p-value: 0.113695% CI: [-0.11, 0.03]MMRM

p-value: 0.885995% CI: [-0.03, 0.13]MMRM

Secondary

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

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 score represents 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.

Time frame: 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).

Arm	Measure	Group	Value (LEAST_SQUARES_MEAN)	Dispersion
Daprodustat	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=1238,1187	0.42 Scores on a scale	Standard Error 0.169
Daprodustat	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=1237,1227	0.60 Scores on a scale	Standard Error 0.171
Daprodustat	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=968,956	0.16 Scores on a scale	Standard Error 0.197
Daprodustat	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=804,780	-0.32 Scores on a scale	Standard Error 0.218
Darbepoetin Alfa	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=804,780	-0.12 Scores on a scale	Standard Error 0.221
Darbepoetin Alfa	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=1238,1187	0.78 Scores on a scale	Standard Error 0.172
Darbepoetin Alfa	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=968,956	0.04 Scores on a scale	Standard Error 0.198
Darbepoetin Alfa	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=1237,1227	0.71 Scores on a scale	Standard Error 0.172

p-value: 0.93295% CI: [-0.83, 0.11]MMRM

p-value: 0.676195% CI: [-0.59, 0.36]MMRM

p-value: 0.333595% CI: [-0.43, 0.67]MMRM

p-value: 0.742395% CI: [-0.81, 0.41]MMRM

Secondary

Change From Baseline in On-treatment Physical Functioning Domain Scores Using SF-36 HRQoL Questionnaire at Weeks 8, 12, 28, 52

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.

Time frame: 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).

Arm	Measure	Group	Value (LEAST_SQUARES_MEAN)	Dispersion
Daprodustat	Change From Baseline in On-treatment Physical Functioning Domain Scores Using SF-36 HRQoL Questionnaire at Weeks 8, 12, 28, 52	Week 8, n=1238,1187	0.51 Scores on a scale	Standard Error 0.2
Daprodustat	Change From Baseline in On-treatment Physical Functioning Domain Scores Using SF-36 HRQoL Questionnaire at Weeks 8, 12, 28, 52	Week 12, n=1237,1227	0.65 Scores on a scale	Standard Error 0.195
Daprodustat	Change From Baseline in On-treatment Physical Functioning Domain Scores Using SF-36 HRQoL Questionnaire at Weeks 8, 12, 28, 52	Week 28, n=968,956	0.05 Scores on a scale	Standard Error 0.224
Daprodustat	Change From Baseline in On-treatment Physical Functioning Domain Scores Using SF-36 HRQoL Questionnaire at Weeks 8, 12, 28, 52	Week 52, n=804,780	-0.69 Scores on a scale	Standard Error 0.262
Darbepoetin Alfa	Change From Baseline in On-treatment Physical Functioning Domain Scores Using SF-36 HRQoL Questionnaire at Weeks 8, 12, 28, 52	Week 52, n=804,780	-0.37 Scores on a scale	Standard Error 0.266
Darbepoetin Alfa	Change From Baseline in On-treatment Physical Functioning Domain Scores Using SF-36 HRQoL Questionnaire at Weeks 8, 12, 28, 52	Week 8, n=1238,1187	0.83 Scores on a scale	Standard Error 0.203
Darbepoetin Alfa	Change From Baseline in On-treatment Physical Functioning Domain Scores Using SF-36 HRQoL Questionnaire at Weeks 8, 12, 28, 52	Week 28, n=968,956	-0.10 Scores on a scale	Standard Error 0.225
Darbepoetin Alfa	Change From Baseline in On-treatment Physical Functioning Domain Scores Using SF-36 HRQoL Questionnaire at Weeks 8, 12, 28, 52	Week 12, n=1237,1227	0.52 Scores on a scale	Standard Error 0.196

p-value: 0.870395% CI: [-0.88, 0.24]MMRM

p-value: 0.316795% CI: [-0.41, 0.67]MMRM

p-value: 0.315595% CI: [-0.47, 0.78]MMRM

p-value: 0.806995% CI: [-1.06, 0.41]MMRM

Secondary

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

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 (b pain), general health (GH), mental health (MH), role-emotional (RE) (role limitations caused by emotional problems), role-physical (RP) (role limitations caused by physical problems), social functioning (SF), physical functioning 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 (BL) 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.

Time frame: 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).

Arm	Measure	Group	Value (LEAST_SQUARES_MEAN)	Dispersion
Daprodustat	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=968,956	-0.48 Scores on a scale	Standard Error 0.261
Daprodustat	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=1238,1187	0.36 Scores on a scale	Standard Error 0.171
Daprodustat	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=1238,1187	-0.19 Scores on a scale	Standard Error 0.204
Daprodustat	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=804,780	-0.90 Scores on a scale	Standard Error 0.339
Daprodustat	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=1237,1227	0.21 Scores on a scale	Standard Error 0.224
Daprodustat	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=804,780	-0.58 Scores on a scale	Standard Error 0.282
Daprodustat	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=1238,1187	0.11 Scores on a scale	Standard Error 0.221
Daprodustat	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=1237,1227	0.35 Scores on a scale	Standard Error 0.223
Daprodustat	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=804,780	-0.34 Scores on a scale	Standard Error 0.283
Daprodustat	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=1237,1227	0.28 Scores on a scale	Standard Error 0.174
Daprodustat	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=968,956	0.14 Scores on a scale	Standard Error 0.2
Daprodustat	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=804,780	-0.27 Scores on a scale	Standard Error 0.22
Daprodustat	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=1237,1227	-0.07 Scores on a scale	Standard Error 0.21
Daprodustat	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=968,956	-0.67 Scores on a scale	Standard Error 0.231
Daprodustat	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=804,780	-0.85 Scores on a scale	Standard Error 0.271
Daprodustat	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=1238,1187	0.45 Scores on a scale	Standard Error 0.253
Daprodustat	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=1237,1227	0.17 Scores on a scale	Standard Error 0.258
Daprodustat	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=968,956	-0.30 Scores on a scale	Standard Error 0.29
Daprodustat	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=1238,1187	0.33 Scores on a scale	Standard Error 0.202
Daprodustat	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=1237,1227	0.40 Scores on a scale	Standard Error 0.203
Daprodustat	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=968,956	0.06 Scores on a scale	Standard Error 0.23
Daprodustat	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=804,780	-0.63 Scores on a scale	Standard Error 0.259
Daprodustat	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=1238,1187	0.19 Scores on a scale	Standard Error 0.224
Daprodustat	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=968,956	0.04 Scores on a scale	Standard Error 0.247
Darbepoetin Alfa	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=1237,1227	0.73 Scores on a scale	Standard Error 0.204
Darbepoetin Alfa	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=968,956	-0.37 Scores on a scale	Standard Error 0.232
Darbepoetin Alfa	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=804,780	-0.19 Scores on a scale	Standard Error 0.224
Darbepoetin Alfa	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=1237,1227	0.53 Scores on a scale	Standard Error 0.225
Darbepoetin Alfa	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=1237,1227	0.43 Scores on a scale	Standard Error 0.259
Darbepoetin Alfa	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=804,780	-0.61 Scores on a scale	Standard Error 0.275
Darbepoetin Alfa	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=968,956	0.00 Scores on a scale	Standard Error 0.232
Darbepoetin Alfa	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=1238,1187	0.54 Scores on a scale	Standard Error 0.258
Darbepoetin Alfa	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=804,780	-0.20 Scores on a scale	Standard Error 0.286
Darbepoetin Alfa	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=1238,1187	0.45 Scores on a scale	Standard Error 0.225
Darbepoetin Alfa	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=804,780	-0.44 Scores on a scale	Standard Error 0.263
Darbepoetin Alfa	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=1237,1227	0.50 Scores on a scale	Standard Error 0.224
Darbepoetin Alfa	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=968,956	0.07 Scores on a scale	Standard Error 0.292
Darbepoetin Alfa	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=968,956	0.02 Scores on a scale	Standard Error 0.263
Darbepoetin Alfa	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=804,780	0.13 Scores on a scale	Standard Error 0.288
Darbepoetin Alfa	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=1238,1187	0.43 Scores on a scale	Standard Error 0.174
Darbepoetin Alfa	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=804,780	-0.38 Scores on a scale	Standard Error 0.344
Darbepoetin Alfa	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=1237,1227	0.48 Scores on a scale	Standard Error 0.175
Darbepoetin Alfa	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=968,956	0.17 Scores on a scale	Standard Error 0.249
Darbepoetin Alfa	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=968,956	0.04 Scores on a scale	Standard Error 0.201
Darbepoetin Alfa	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=1238,1187	0.83 Scores on a scale	Standard Error 0.205
Darbepoetin Alfa	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=1238,1187	0.12 Scores on a scale	Standard Error 0.208
Darbepoetin Alfa	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=1238,1187	0.82 Scores on a scale	Standard Error 0.228
Darbepoetin Alfa	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=1237,1227	-0.09 Scores on a scale	Standard Error 0.211

p-value: 0.785295% CI: [-0.68, 0.29]MMRM

p-value: 0.467395% CI: [-0.56, 0.61]MMRM

p-value: 0.826295% CI: [-0.95, 0.33]MMRM

p-value: 0.856295% CI: [-0.95, 0.28]MMRM

p-value: 0.684995% CI: [-0.77, 0.47]MMRM

p-value: 0.907495% CI: [-1.22, 0.24]MMRM

p-value: 0.876595% CI: [-1.26, 0.32]MMRM

p-value: 0.625295% CI: [-0.56, 0.4]MMRM

p-value: 0.361495% CI: [-0.46, 0.66]MMRM

p-value: 0.599195% CI: [-0.7, 0.54]MMRM

p-value: 0.852695% CI: [-0.88, 0.27]MMRM

p-value: 0.73895% CI: [-1, 0.51]MMRM

p-value: 0.599795% CI: [-0.8, 0.62]MMRM

p-value: 0.764995% CI: [-0.98, 0.45]MMRM

p-value: 0.817595% CI: [-1.18, 0.43]MMRM

p-value: 0.859195% CI: [-1.47, 0.43]MMRM

p-value: 0.958895% CI: [-1.06, 0.06]MMRM

p-value: 0.876195% CI: [-0.9, 0.23]MMRM

p-value: 0.429395% CI: [-0.58, 0.7]MMRM

p-value: 0.698395% CI: [-0.92, 0.53]MMRM

p-value: 0.974395% CI: [-1.25, 0]MMRM

p-value: 0.840595% CI: [-0.94, 0.31]MMRM

p-value: 0.645995% CI: [-0.82, 0.56]MMRM

p-value: 0.827295% CI: [-1.17, 0.41]MMRM

Secondary

Change From Baseline in On-treatment Vitality Scores Using SF-36 HRQoL Questionnaire at Weeks 8, 12, 28, 52

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.

Time frame: 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).

Arm	Measure	Group	Value (LEAST_SQUARES_MEAN)	Dispersion
Daprodustat	Change From Baseline in On-treatment Vitality Scores Using SF-36 HRQoL Questionnaire at Weeks 8, 12, 28, 52	Week 8, n=1238,1187	0.35 Scores on a scale	Standard Error 0.192
Daprodustat	Change From Baseline in On-treatment Vitality Scores Using SF-36 HRQoL Questionnaire at Weeks 8, 12, 28, 52	Week 12, n=1237,1227	0.62 Scores on a scale	Standard Error 0.2
Daprodustat	Change From Baseline in On-treatment Vitality Scores Using SF-36 HRQoL Questionnaire at Weeks 8, 12, 28, 52	Week 28, n=968,956	0.22 Scores on a scale	Standard Error 0.222
Daprodustat	Change From Baseline in On-treatment Vitality Scores Using SF-36 HRQoL Questionnaire at Weeks 8, 12, 28, 52	Week 52, n=804,780	-0.14 Scores on a scale	Standard Error 0.25
Darbepoetin Alfa	Change From Baseline in On-treatment Vitality Scores Using SF-36 HRQoL Questionnaire at Weeks 8, 12, 28, 52	Week 52, n=804,780	0.35 Scores on a scale	Standard Error 0.253
Darbepoetin Alfa	Change From Baseline in On-treatment Vitality Scores Using SF-36 HRQoL Questionnaire at Weeks 8, 12, 28, 52	Week 8, n=1238,1187	0.90 Scores on a scale	Standard Error 0.195
Darbepoetin Alfa	Change From Baseline in On-treatment Vitality Scores Using SF-36 HRQoL Questionnaire at Weeks 8, 12, 28, 52	Week 28, n=968,956	0.32 Scores on a scale	Standard Error 0.223
Darbepoetin Alfa	Change From Baseline in On-treatment Vitality Scores Using SF-36 HRQoL Questionnaire at Weeks 8, 12, 28, 52	Week 12, n=1237,1227	0.74 Scores on a scale	Standard Error 0.201

p-value: 0.978695% CI: [-1.09, -0.02]MMRM

p-value: 0.664295% CI: [-0.68, 0.44]MMRM

p-value: 0.626195% CI: [-0.72, 0.52]MMRM

p-value: 0.916195% CI: [-1.19, 0.21]MMRM

Secondary

Change From Baseline in Post-randomization Estimated Glomerular Filtration Rate (eGFR) at Week 52

Blood samples were collected to analyze estimated glomerular filtration rate. Change from Baseline was calculated as post-Baseline visit value minus Baseline value. Baseline was defined as the latest non-missing pre-dose assessment on or before the randomization date.

Time frame: 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.

Arm	Measure	Value (LEAST_SQUARES_MEAN)	Dispersion
Daprodustat	Change From Baseline in Post-randomization Estimated Glomerular Filtration Rate (eGFR) at Week 52	-2.88 mL per minute per 1.73 square meter	Standard Error 0.193
Darbepoetin Alfa	Change From Baseline in Post-randomization Estimated Glomerular Filtration Rate (eGFR) at Week 52	-2.67 mL per minute per 1.73 square meter	Standard Error 0.193

p-value: 0.771695% CI: [-0.74, 0.33]MMRM

Secondary

Change From Baseline in Post-randomization Hgb Levels at Week 52

Blood samples were collected from participants for Hgb measurements. Change from Baseline was defined as post-randomization 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, current ESA use, region, Baseline Hgb and Baseline Hgb by time and treatment by time interactions.

Time frame: 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.

Arm	Measure	Value (LEAST_SQUARES_MEAN)	Dispersion
Daprodustat	Change From Baseline in Post-randomization Hgb Levels at Week 52	0.76 Grams per deciliter	Standard Error 0.029
Darbepoetin Alfa	Change From Baseline in Post-randomization Hgb Levels at Week 52	0.73 Grams per deciliter	Standard Error 0.029

95% CI: [-0.05, 0.11]

Secondary

Change From Baseline in SBP, DBP, MAP at End of Treatment

SBP, DBP and MAP were measured in a seated position 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. Analysis was performed using ANCOVA model with terms for treatment group, current ESA use at randomization, region and Baseline value. Data for post-dialysis BP measurements have been presented.

Time frame: Baseline (Week -4) and 51.1 months

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).

Arm	Measure	Group	Value (LEAST_SQUARES_MEAN)	Dispersion
Daprodustat	Change From Baseline in SBP, DBP, MAP at End of Treatment	SBP, n=1919, 1884	-1.19 Millimeter of mercury	Standard Error 0.395
Daprodustat	Change From Baseline in SBP, DBP, MAP at End of Treatment	DBP, n=1918, 1884	-0.26 Millimeter of mercury	Standard Error 0.229
Daprodustat	Change From Baseline in SBP, DBP, MAP at End of Treatment	MAP, n=1918, 1884	-0.57 Millimeter of mercury	Standard Error 0.248
Darbepoetin Alfa	Change From Baseline in SBP, DBP, MAP at End of Treatment	SBP, n=1919, 1884	-1.10 Millimeter of mercury	Standard Error 0.398
Darbepoetin Alfa	Change From Baseline in SBP, DBP, MAP at End of Treatment	DBP, n=1918, 1884	-0.38 Millimeter of mercury	Standard Error 0.231
Darbepoetin Alfa	Change From Baseline in SBP, DBP, MAP at End of Treatment	MAP, n=1918, 1884	-0.62 Millimeter of mercury	Standard Error 0.251

p-value: 0.44295% CI: [-1.18, 1.02]ANCOVA

p-value: 0.636995% CI: [-0.52, 0.75]ANCOVA

p-value: 0.54995% CI: [-0.65, 0.74]ANCOVA

Secondary

Change From Baseline in Systolic Blood Pressure (SBP), Diastolic Blood Pressure (DBP) and Mean Arterial Blood Pressure (MAP) at Week 52

SBP, DBP and MAP were measured in a seated position 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 + current ESA use at randomization + region + Baseline value + Baseline value\*time + treatment group\*time, using an unstructured covariance matrix. Data for post-dialysis BP measurements have been presented.

Time frame: Baseline (Week -4) and Week 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).

Arm	Measure	Group	Value (LEAST_SQUARES_MEAN)	Dispersion
Daprodustat	Change From Baseline in Systolic Blood Pressure (SBP), Diastolic Blood Pressure (DBP) and Mean Arterial Blood Pressure (MAP) at Week 52	SBP, n=1913, 1884	-0.62 Millimeter of mercury	Standard Error 0.488
Daprodustat	Change From Baseline in Systolic Blood Pressure (SBP), Diastolic Blood Pressure (DBP) and Mean Arterial Blood Pressure (MAP) at Week 52	DBP, n=1912, 1884	0.06 Millimeter of mercury	Standard Error 0.267
Daprodustat	Change From Baseline in Systolic Blood Pressure (SBP), Diastolic Blood Pressure (DBP) and Mean Arterial Blood Pressure (MAP) at Week 52	MAP, n=1912, 1884	-0.17 Millimeter of mercury	Standard Error 0.3
Darbepoetin Alfa	Change From Baseline in Systolic Blood Pressure (SBP), Diastolic Blood Pressure (DBP) and Mean Arterial Blood Pressure (MAP) at Week 52	SBP, n=1913, 1884	-1.17 Millimeter of mercury	Standard Error 0.479
Darbepoetin Alfa	Change From Baseline in Systolic Blood Pressure (SBP), Diastolic Blood Pressure (DBP) and Mean Arterial Blood Pressure (MAP) at Week 52	DBP, n=1912, 1884	-0.59 Millimeter of mercury	Standard Error 0.262
Darbepoetin Alfa	Change From Baseline in Systolic Blood Pressure (SBP), Diastolic Blood Pressure (DBP) and Mean Arterial Blood Pressure (MAP) at Week 52	MAP, n=1912, 1884	-0.77 Millimeter of mercury	Standard Error 0.294

p-value: 0.791695% CI: [-0.79, 1.9]MMRM

p-value: 0.958195% CI: [-0.09, 1.38]MMRM

p-value: 0.924195% CI: [-0.22, 1.43]MMRM

Secondary

Number of Hgb Responders in the Hgb Analysis Range (10 to 11.5 Grams/Deciliter) During Evaluation Period (Week 28 to Week 52)

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. Hgb 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.

Time frame: Week 28 to Week 52

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

Arm	Measure	Value (COUNT_OF_PARTICIPANTS)
Daprodustat	Number of Hgb Responders in the Hgb Analysis Range (10 to 11.5 Grams/Deciliter) During Evaluation Period (Week 28 to Week 52)	1167 Participants
Darbepoetin Alfa	Number of Hgb Responders in the Hgb Analysis Range (10 to 11.5 Grams/Deciliter) During Evaluation Period (Week 28 to Week 52)	1063 Participants

p-value: <0.000195% CI: [5.2, 11.4]Cochran-Mantel-Haenszel

Secondary

Number of Participants With Adjudicated MACE or Hospitalization for Heart Failure (Recurrent Events Analysis)

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.

Time frame: Up to 4.3 person-years for CV follow-up time period

Population: All Randomized (ITT) Population.

Arm	Measure	Group	Value (COUNT_OF_PARTICIPANTS)
Daprodustat	Number of Participants With Adjudicated MACE or Hospitalization for Heart Failure (Recurrent Events Analysis)	Occurrences per participant: 8	0 Participants
Daprodustat	Number of Participants With Adjudicated MACE or Hospitalization for Heart Failure (Recurrent Events Analysis)	Occurrences per participant: 0	1493 Participants
Daprodustat	Number of Participants With Adjudicated MACE or Hospitalization for Heart Failure (Recurrent Events Analysis)	Occurrences per participant: 1	318 Participants
Daprodustat	Number of Participants With Adjudicated MACE or Hospitalization for Heart Failure (Recurrent Events Analysis)	Occurrences per participant: 2	76 Participants
Daprodustat	Number of Participants With Adjudicated MACE or Hospitalization for Heart Failure (Recurrent Events Analysis)	Occurrences per participant: 3	26 Participants
Daprodustat	Number of Participants With Adjudicated MACE or Hospitalization for Heart Failure (Recurrent Events Analysis)	Occurrences per participant: 4	14 Participants
Daprodustat	Number of Participants With Adjudicated MACE or Hospitalization for Heart Failure (Recurrent Events Analysis)	Occurrences per participant: 5	5 Participants
Daprodustat	Number of Participants With Adjudicated MACE or Hospitalization for Heart Failure (Recurrent Events Analysis)	Occurrences per participant: 6	1 Participants
Daprodustat	Number of Participants With Adjudicated MACE or Hospitalization for Heart Failure (Recurrent Events Analysis)	Occurrences per participant: 7	4 Participants
Darbepoetin Alfa	Number of Participants With Adjudicated MACE or Hospitalization for Heart Failure (Recurrent Events Analysis)	Occurrences per participant: 6	0 Participants
Darbepoetin Alfa	Number of Participants With Adjudicated MACE or Hospitalization for Heart Failure (Recurrent Events Analysis)	Occurrences per participant: 4	9 Participants
Darbepoetin Alfa	Number of Participants With Adjudicated MACE or Hospitalization for Heart Failure (Recurrent Events Analysis)	Occurrences per participant: 0	1518 Participants
Darbepoetin Alfa	Number of Participants With Adjudicated MACE or Hospitalization for Heart Failure (Recurrent Events Analysis)	Occurrences per participant: 8	1 Participants
Darbepoetin Alfa	Number of Participants With Adjudicated MACE or Hospitalization for Heart Failure (Recurrent Events Analysis)	Occurrences per participant: 1	317 Participants
Darbepoetin Alfa	Number of Participants With Adjudicated MACE or Hospitalization for Heart Failure (Recurrent Events Analysis)	Occurrences per participant: 5	3 Participants
Darbepoetin Alfa	Number of Participants With Adjudicated MACE or Hospitalization for Heart Failure (Recurrent Events Analysis)	Occurrences per participant: 2	64 Participants
Darbepoetin Alfa	Number of Participants With Adjudicated MACE or Hospitalization for Heart Failure (Recurrent Events Analysis)	Occurrences per participant: 7	1 Participants
Darbepoetin Alfa	Number of Participants With Adjudicated MACE or Hospitalization for Heart Failure (Recurrent Events Analysis)	Occurrences per participant: 3	22 Participants

p-value: 0.942295% CI: [0.98, 1.23]Chi-squared

p-value: 0.886295% CI: [0.95, 1.24]Chi-squared

p-value: 0.678995% CI: [0.82, 1.39]Chi-squared

p-value: 0.901695% CI: [0.85, 2.19]Chi-squared

p-value: 0.886295% CI: [0.95, 1.24]Chi-squared

p-value: 0.898995% CI: [0.92, 1.46]Chi-squared

Secondary

Number of Participants With at Least One BP Exacerbation Event During Study

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.

Time frame: Day 1 to end of treatment (51.1 months)

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

Arm	Measure	Value (COUNT_OF_PARTICIPANTS)
Daprodustat	Number of Participants With at Least One BP Exacerbation Event During Study	939 Participants
Darbepoetin Alfa	Number of Participants With at Least One BP Exacerbation Event During Study	1012 Participants

Secondary

Percentage of Participants Permanently Stopping Randomized Treatment Due to Meeting Rescue Criteria

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

Time frame: Day 1 to 51.1 months

Population: All Randomized (ITT) Population.

Arm	Measure	Value (NUMBER)
Daprodustat	Percentage of Participants Permanently Stopping Randomized Treatment Due to Meeting Rescue Criteria	2.0 Percentage of participants
Darbepoetin Alfa	Percentage of Participants Permanently Stopping Randomized Treatment Due to Meeting Rescue Criteria	3.3 Percentage of participants

p-value: 0.011395% CI: [0.42, 0.94]Wald test

Secondary

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

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 / \[Earlier of (Date of the last evaluable Hgb value, End of study date)- Later of (Date of the first evaluable Hgb value that is on or after week 16, Week 28 visit date)\].

Time frame: Week 28 to end of study (4.3 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.

Arm	Measure	Value (MEDIAN)
Daprodustat	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	66.1 Percentage of days
Darbepoetin Alfa	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	62.1 Percentage of days

p-value: <0.000195% CI: [0.52, 0.56]van Elteren test

Secondary

Percentage of Time With Hgb in the Analysis Range (10 to 11.5 Grams/Deciliter) During Evaluation Period (Week 28 to Week 52): Non-inferiority Analysis

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 / \[Earlier of (Date of the last evaluable Hgb value, Week 52 visit date) - Later of (Date of the first evaluable Hgb value that between Week 16 and Week 52 inclusive, Week 28 visit date)\].

Time frame: Week 28 to Week 52

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

Arm	Measure	Value (MEDIAN)
Daprodustat	Percentage of Time With Hgb in the Analysis Range (10 to 11.5 Grams/Deciliter) During Evaluation Period (Week 28 to Week 52): Non-inferiority Analysis	70.5 Percentage of days
Darbepoetin Alfa	Percentage of Time With Hgb in the Analysis Range (10 to 11.5 Grams/Deciliter) During Evaluation Period (Week 28 to Week 52): Non-inferiority Analysis	63.2 Percentage of days

95% CI: [2.04, 7.11]

Secondary

Percentage of Time With Hgb in the Analysis Range (10 to 11.5 Grams/Deciliter) During Evaluation Period (Week 28 to Week 52): Superiority Analysis

Time frame: Week 28 to Week 52

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

Arm	Measure	Value (MEDIAN)
Daprodustat	Percentage of Time With Hgb in the Analysis Range (10 to 11.5 Grams/Deciliter) During Evaluation Period (Week 28 to Week 52): Superiority Analysis	70.5 Percentage of days
Darbepoetin Alfa	Percentage of Time With Hgb in the Analysis Range (10 to 11.5 Grams/Deciliter) During Evaluation Period (Week 28 to Week 52): Superiority Analysis	63.2 Percentage of days

p-value: <0.000195% CI: [0.53, 0.57]van Elteren test

Secondary

Percentage of Time With Hgb in the Analysis Range (10 to 11.5 Grams/Deciliter) During Maintenance Period (Week 28 to End of Study): Non-inferiority Analysis

Time frame: Week 28 to end of study (4.3 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.

Arm	Measure	Value (MEDIAN)
Daprodustat	Percentage of Time With Hgb in the Analysis Range (10 to 11.5 Grams/Deciliter) During Maintenance Period (Week 28 to End of Study): Non-inferiority Analysis	66.1 Percentage of days
Darbepoetin Alfa	Percentage of Time With Hgb in the Analysis Range (10 to 11.5 Grams/Deciliter) During Maintenance Period (Week 28 to End of Study): Non-inferiority Analysis	62.1 Percentage of days

95% CI: [1.9, 5.91]

Secondary

Time to First Occurrence of Adjudicated All-Cause Mortality During Vital Status for Follow-up Time Period

Time to first occurrence of adjudicated all-cause mortality was analyzed using a Cox proportional hazards regression model with treatment group, current ESA use at randomization, 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 follow-up time period.

Time frame: Up to 4.3 person-years for vital status follow-up time period

Population: All Randomized (ITT) Population.

Arm	Measure	Value (NUMBER)
Daprodustat	Time to First Occurrence of Adjudicated All-Cause Mortality During Vital Status for Follow-up Time Period	8.35 Events per 100 person years
Darbepoetin Alfa	Time to First Occurrence of Adjudicated All-Cause Mortality During Vital Status for Follow-up Time Period	8.27 Events per 100 person years

p-value: 0.619795% CI: [0.87, 1.2]Wald test

Secondary

Time to First Occurrence of Adjudicated CV Mortality During CV Events Follow-up Time Period

Time to first occurrence of adjudicated CV mortality was analyzed using a Cox proportional hazards regression model with treatment group, current ESA use at randomization, 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.

Time frame: Up to 4.3 person-years for CV follow-up time period

Population: All Randomized (ITT) Population.

Arm	Measure	Value (NUMBER)
Daprodustat	Time to First Occurrence of Adjudicated CV Mortality During CV Events Follow-up Time Period	3.02 Events per 100 person years
Darbepoetin Alfa	Time to First Occurrence of Adjudicated CV Mortality During CV Events Follow-up Time Period	2.55 Events per 100 person years

p-value: 0.897695% CI: [0.91, 1.58]Wald test

Secondary

Time to First Occurrence of Adjudicated CV Mortality or Non-Fatal MI During CV Events Follow-up Time Period

Time to first occurrence of adjudicated CV mortality or non-fatal MI was analyzed using a Cox proportional hazards regression model with treatment group, current ESA use at randomization, 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.

Time frame: Up to 4.3 person-years for CV follow-up time period

Population: All Randomized (ITT) Population.

Arm	Measure	Value (NUMBER)
Daprodustat	Time to First Occurrence of Adjudicated CV Mortality or Non-Fatal MI During CV Events Follow-up Time Period	5.36 Events per 100 person years
Darbepoetin Alfa	Time to First Occurrence of Adjudicated CV Mortality or Non-Fatal MI During CV Events Follow-up Time Period	4.98 Events per 100 person years

p-value: 0.767395% CI: [0.88, 1.33]Wald test

Secondary

Time to First Occurrence of Adjudicated Hospitalization for Heart Failure During CV Events Follow-up Time Period

Time to first occurrence of adjudicated hospitalization for heart failure was analyzed using a Cox proportional hazards regression model with treatment group, current ESA use at randomization, 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.

Time frame: Up to 4.3 person-years for CV follow-up time period

Population: All Randomized (ITT) Population.

Arm	Measure	Value (NUMBER)
Daprodustat	Time to First Occurrence of Adjudicated Hospitalization for Heart Failure During CV Events Follow-up Time Period	4.05 Events per 100 person years
Darbepoetin Alfa	Time to First Occurrence of Adjudicated Hospitalization for Heart Failure During CV Events Follow-up Time Period	3.30 Events per 100 person years

p-value: 0.941295% CI: [0.95, 1.56]Wald test

Secondary

Time to First Occurrence of Adjudicated MACE During CV Events Follow-up Time Period (Superiority Analysis)

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, current ESA use at randomization, 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.

Time frame: Up to 4.3 person-years for CV follow-up time period

Population: All Randomized (ITT) Population.

Arm	Measure	Value (NUMBER)
Daprodustat	Time to First Occurrence of Adjudicated MACE During CV Events Follow-up Time Period (Superiority Analysis)	10.86 Events per 100 person years
Darbepoetin Alfa	Time to First Occurrence of Adjudicated MACE During CV Events Follow-up Time Period (Superiority Analysis)	10.63 Events per 100 person years

p-value: 0.67088495% CI: [0.89, 1.19]Wald test

Secondary

Time to First Occurrence of Adjudicated MACE or Hospitalization for Heart Failure During CV Events Follow-up Time Period

Time to first occurrence of adjudicated MACE or hospitalization for heart failure was analyzed using a Cox proportional hazards regression model with treatment group, current ESA use at randomization, 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.

Time frame: Up to 4.3 person-years for CV follow-up time period

Population: All Randomized (ITT) Population.

Arm	Measure	Value (NUMBER)
Daprodustat	Time to First Occurrence of Adjudicated MACE or Hospitalization for Heart Failure During CV Events Follow-up Time Period	13.16 Events per 100 person years
Darbepoetin Alfa	Time to First Occurrence of Adjudicated MACE or Hospitalization for Heart Failure During CV Events Follow-up Time Period	12.22 Events per 100 person years

p-value: 0.88619595% CI: [0.95, 1.24]Wald test

Secondary

Time to First Occurrence of Adjudicated MACE or Hospitalization for Heart Failure or Thromboembolic Events During CV Events Follow-up Time Period

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, current ESA use at randomization, 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.

Time frame: Up to 4.3 person-years for CV follow-up time period

Population: All Randomized (ITT) Population.

Arm	Measure	Value (NUMBER)
Daprodustat	Time to First Occurrence of Adjudicated MACE or Hospitalization for Heart Failure or Thromboembolic Events During CV Events Follow-up Time Period	14.60 Events per 100 person years
Darbepoetin Alfa	Time to First Occurrence of Adjudicated MACE or Hospitalization for Heart Failure or Thromboembolic Events During CV Events Follow-up Time Period	13.32 Events per 100 person years

p-value: 0.939395% CI: [0.97, 1.26]Wald test

Secondary

Time to First Occurrence of Adjudicated MACE or Thromboembolic Event During CV Events Follow-up Time Period

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, current ESA use at randomization, 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.

Time frame: Up to 4.3 person-years for CV follow-up time period

Population: All Randomized (ITT) Population.

Arm	Measure	Value (NUMBER)
Daprodustat	Time to First Occurrence of Adjudicated MACE or Thromboembolic Event During CV Events Follow-up Time Period	12.34 Events per 100 person years
Darbepoetin Alfa	Time to First Occurrence of Adjudicated MACE or Thromboembolic Event During CV Events Follow-up Time Period	11.77 Events per 100 person years

p-value: 0.80081395% CI: [0.93, 1.22]Wald test

Secondary

Time to First Occurrence of Adjudicated Myocardial Infarction (MI) (Fatal and Non-Fatal) During CV Events Follow-up Time Period

Time to first occurrence of adjudicated MI (fatal and non-fatal) was analyzed using a Cox proportional hazards regression model with treatment group, current ESA use at randomization, 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.

Time frame: Up to 4.3 person-years for CV follow-up time period

Population: All Randomized (ITT) Population.

Arm	Measure	Value (NUMBER)
Daprodustat	Time to First Occurrence of Adjudicated Myocardial Infarction (MI) (Fatal and Non-Fatal) During CV Events Follow-up Time Period	2.94 Events per 100 person years
Darbepoetin Alfa	Time to First Occurrence of Adjudicated Myocardial Infarction (MI) (Fatal and Non-Fatal) During CV Events Follow-up Time Period	2.76 Events per 100 person years

p-value: 0.658195% CI: [0.8, 1.4]Wald test

Secondary

Time to First Occurrence of Adjudicated Stroke (Fatal and Non-Fatal) During CV Events Follow-up Time Period

Time to first occurrence of adjudicated stroke (fatal and non-fatal) was analyzed using a Cox proportional hazards regression model with treatment group, current ESA use at randomization, 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.

Time frame: Up to 4.3 person-years for CV follow-up time period

Population: All Randomized (ITT) Population.

Arm	Measure	Value (NUMBER)
Daprodustat	Time to First Occurrence of Adjudicated Stroke (Fatal and Non-Fatal) During CV Events Follow-up Time Period	1.26 Events per 100 person years
Darbepoetin Alfa	Time to First Occurrence of Adjudicated Stroke (Fatal and Non-Fatal) During CV Events Follow-up Time Period	0.95 Events per 100 person years

p-value: 0.89495% CI: [0.85, 2.07]Wald test

Secondary

Time to First Occurrence of Adjudicated Thromboembolic Events During CV Events Follow-up Time Period

Time to first occurrence of adjudicated thromboembolic events were analyzed using a Cox proportional hazards regression model with treatment group, current ESA use at randomization, 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.

Time frame: Up to 4.3 person-years for CV follow-up time period

Population: All Randomized (ITT) Population.

Arm	Measure	Value (NUMBER)
Daprodustat	Time to First Occurrence of Adjudicated Thromboembolic Events During CV Events Follow-up Time Period	1.81 Events per 100 person years
Darbepoetin Alfa	Time to First Occurrence of Adjudicated Thromboembolic Events During CV Events Follow-up Time Period	1.43 Events per 100 person years

p-value: 0.899495% CI: [0.88, 1.84]Wald test

Secondary

Time to First Occurrence of All-Cause Hospitalization During CV Events Follow-up Time Period

All-cause hospitalization events were hospital admissions recorded on the hospitalization electronic case report form (eCRF) form 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, current ESA use at randomization, 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.

Time frame: Up to 4.3 person-years for CV follow-up time period

Population: All Randomized (ITT) Population.

Arm	Measure	Value (NUMBER)
Daprodustat	Time to First Occurrence of All-Cause Hospitalization During CV Events Follow-up Time Period	41.13 Events per 100 person years
Darbepoetin Alfa	Time to First Occurrence of All-Cause Hospitalization During CV Events Follow-up Time Period	38.99 Events per 100 person years

p-value: 0.860195% CI: [0.96, 1.15]Wald test

Secondary

Time to First Occurrence of All-Cause Hospital Re-admission Within 30 Days During CV Events Follow-up Time Period

All-cause hospital re-admissions within 30days are defined as hospital admissions recorded on hospitalization electronic case record form with hospitalization duration of \>=24 hours and admission date within 30days following previous discharge date of all-cause hospitalization event, where previous hospitalization was \>=24hours.Time to first occurrence of all-cause hospital re-admission within 30days was analyzed using Cox proportional hazards regression model with treatment group, current ESA use at randomization and region as covariates.Time to the first occurrence was computed as(event date - randomization date)+1. Incidence rate per 100 person years calculated as(100\*number of participants with at least 1event)/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.

Time frame: Up to 4.3 person-years for CV follow-up time period

Population: All Randomized (ITT) Population.

Arm	Measure	Value (NUMBER)
Daprodustat	Time to First Occurrence of All-Cause Hospital Re-admission Within 30 Days During CV Events Follow-up Time Period	7.78 Events per 100 person years
Darbepoetin Alfa	Time to First Occurrence of All-Cause Hospital Re-admission Within 30 Days During CV Events Follow-up Time Period	7.55 Events per 100 person years

p-value: 0.620795% CI: [0.86, 1.22]Wald test

Secondary

Time to First Occurrence of Chronic Dialysis During CV Events Follow-up Time Period

Time to first occurrence of chronic dialysis was analyzed using a Fine & Gray's proportional subdistribution hazard regression model with treatment group, Baseline ESA use and region as covariates. Chronic dialysis is defined by either initiating dialysis for \>=90 days or not initiating chronic dialysis when dialysis is indicated. 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.

Time frame: Up to 4.3 person-years for CV follow-up time period

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

Arm	Measure	Value (NUMBER)
Daprodustat	Time to First Occurrence of Chronic Dialysis During CV Events Follow-up Time Period	12.20 Events per 100 person years
Darbepoetin Alfa	Time to First Occurrence of Chronic Dialysis During CV Events Follow-up Time Period	12.06 Events per 100 person years

p-value: 0.506895% CI: [0.84, 1.19]Wald test

Secondary

Time to First Occurrence of Chronic Kidney Disease (CKD) Progression During CV Events Follow-up Time Period

Progression of CKD defined as: 40% decline in estimated glomerular filtration rate (eGFR) from Baseline or end stage renal disease (ESRD) as defined by either initiating chronic dialysis for \>=90 days or not initiating chronic dialysis when dialysis is indicated or kidney transplantation. Time to first occurrence of CKD progression was analyzed using Fine and Gray's proportional subdistribution hazard regression model with treatment group, Baseline ESA use 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.

Time frame: Up to 4.3 person-years for CV follow-up time period

Population: All Randomized (ITT) Population. Only those participants with data available at the indicated time points were analyzed. Additionally, this analysis population was restricted to those with a Baseline eGFR \>=15milliliter per minute (mL/min).

Arm	Measure	Value (NUMBER)
Daprodustat	Time to First Occurrence of Chronic Kidney Disease (CKD) Progression During CV Events Follow-up Time Period	17.55 Events per 100 person years
Darbepoetin Alfa	Time to First Occurrence of Chronic Kidney Disease (CKD) Progression During CV Events Follow-up Time Period	17.76 Events per 100 person years

p-value: 0.3694795% CI: [0.84, 1.13]Wald test

Secondary

Time to First Occurrence of Confirmed 40% Decline in eGFR During CV Events Follow-up Time Period

Time to first occurrence of confirmed 40% decline in eGFR was analyzed using a Fine & Gray's proportional subdistribution hazard regression model with treatment group, Baseline ESA use 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.

Time frame: Up to 4.3 person-years for CV follow-up time period

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

Arm	Measure	Value (NUMBER)
Daprodustat	Time to First Occurrence of Confirmed 40% Decline in eGFR During CV Events Follow-up Time Period	8.21 Events per 100 person years
Darbepoetin Alfa	Time to First Occurrence of Confirmed 40% Decline in eGFR During CV Events Follow-up Time Period	8.90 Events per 100 person years

p-value: 0.207395% CI: [0.75, 1.13]Wald test

Secondary

Time to First Occurrence of Kidney Transplant During CV Events Follow-up Time Period

Time to first occurrence of kidney transplant were analyzed using a Fine & Gray's proportional subdistribution hazard regression model with treatment group, Baseline ESA use 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.

Time frame: Up to 4.3 person-years for CV follow-up time period

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

Arm	Measure	Value (NUMBER)
Daprodustat	Time to First Occurrence of Kidney Transplant During CV Events Follow-up Time Period	1.00 Events per 100 person years
Darbepoetin Alfa	Time to First Occurrence of Kidney Transplant During CV Events Follow-up Time Period	1.14 Events per 100 person years

p-value: 0.328595% CI: [0.51, 1.54]Wald test

Source: ClinicalTrials.gov · Data processed: Feb 15, 2026

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

Conditions

Keywords

Brief summary

Related papers

Interventions

Sponsors

Study design

Eligibility

Inclusion criteria

Exclusion criteria

Design outcomes

Primary

Secondary

Countries

Participant flow

Recruitment details

Pre-assignment details

Participants by arm

Withdrawals & dropouts

Baseline characteristics

Adverse events

Outcome results

Mean Change From Baseline in Hgb Levels Over the Evaluation Period (Week 28 to Week 52)

Time to First Occurrence of Adjudicated Major Adverse Cardiovascular Event (MACE) During Cardiovascular (CV) Events Follow-up Time Period (Non-inferiority Analysis)

Blood Pressure (BP) Exacerbation Event Rate Per 100 Participant Years

Change From Baseline in On-treatment Chronic Kidney Disease- Anemia Symptoms Questionnaire (CKD-AQ) at Weeks 8, 12, 28, 52

Change From Baseline in On-treatment EQ Visual Analogue Scale (EQ-VAS) at Week 52

Change From Baseline in On-treatment Health Utility EuroQol 5 Dimensions 5 Level (EQ-5D-5L) Questionnaire Score at Week 52

Change From Baseline in On-treatment Mental Component Score (MCS) Using SF-36 HRQoL Questionnaire at Weeks 8, 12, 28, 52

Change From Baseline in On-treatment Patient Global Impression of Severity (PGI-S) at Weeks 8, 12, 28, 52

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

Change From Baseline in On-treatment Physical Functioning Domain Scores Using SF-36 HRQoL Questionnaire at Weeks 8, 12, 28, 52

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

Change From Baseline in On-treatment Vitality Scores Using SF-36 HRQoL Questionnaire at Weeks 8, 12, 28, 52

Change From Baseline in Post-randomization Estimated Glomerular Filtration Rate (eGFR) at Week 52

Change From Baseline in Post-randomization Hgb Levels at Week 52

Change From Baseline in SBP, DBP, MAP at End of Treatment

Change From Baseline in Systolic Blood Pressure (SBP), Diastolic Blood Pressure (DBP) and Mean Arterial Blood Pressure (MAP) at Week 52

Number of Hgb Responders in the Hgb Analysis Range (10 to 11.5 Grams/Deciliter) During Evaluation Period (Week 28 to Week 52)

Number of Participants With Adjudicated MACE or Hospitalization for Heart Failure (Recurrent Events Analysis)

Number of Participants With at Least One BP Exacerbation Event During Study

Percentage of Participants Permanently Stopping Randomized Treatment Due to Meeting Rescue Criteria

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

Percentage of Time With Hgb in the Analysis Range (10 to 11.5 Grams/Deciliter) During Evaluation Period (Week 28 to Week 52): Non-inferiority Analysis

Percentage of Time With Hgb in the Analysis Range (10 to 11.5 Grams/Deciliter) During Evaluation Period (Week 28 to Week 52): Superiority Analysis

Percentage of Time With Hgb in the Analysis Range (10 to 11.5 Grams/Deciliter) During Maintenance Period (Week 28 to End of Study): Non-inferiority Analysis

Time to First Occurrence of Adjudicated All-Cause Mortality During Vital Status for Follow-up Time Period

Time to First Occurrence of Adjudicated CV Mortality During CV Events Follow-up Time Period

Time to First Occurrence of Adjudicated CV Mortality or Non-Fatal MI During CV Events Follow-up Time Period

Time to First Occurrence of Adjudicated Hospitalization for Heart Failure During CV Events Follow-up Time Period

Time to First Occurrence of Adjudicated MACE During CV Events Follow-up Time Period (Superiority Analysis)

Time to First Occurrence of Adjudicated MACE or Hospitalization for Heart Failure During CV Events Follow-up Time Period

Time to First Occurrence of Adjudicated MACE or Hospitalization for Heart Failure or Thromboembolic Events During CV Events Follow-up Time Period

Time to First Occurrence of Adjudicated MACE or Thromboembolic Event During CV Events Follow-up Time Period

Time to First Occurrence of Adjudicated Myocardial Infarction (MI) (Fatal and Non-Fatal) During CV Events Follow-up Time Period

Time to First Occurrence of Adjudicated Stroke (Fatal and Non-Fatal) During CV Events Follow-up Time Period

Time to First Occurrence of Adjudicated Thromboembolic Events During CV Events Follow-up Time Period

Time to First Occurrence of All-Cause Hospitalization During CV Events Follow-up Time Period

Time to First Occurrence of All-Cause Hospital Re-admission Within 30 Days During CV Events Follow-up Time Period

Time to First Occurrence of Chronic Dialysis During CV Events Follow-up Time Period

Time to First Occurrence of Chronic Kidney Disease (CKD) Progression During CV Events Follow-up Time Period

Time to First Occurrence of Confirmed 40% Decline in eGFR During CV Events Follow-up Time Period

Time to First Occurrence of Kidney Transplant During CV Events Follow-up Time Period