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

• Sponsor: GlaxoSmithKline (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02879305
• Collaborator: (none)
• Enrollment: 2,964
• Locations: 462
• Arms: 2
• Actual Duration (Months): 49.4
• Patients Per Site: 6.4
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

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

Condition or Disease	Intervention/Treatment	Phase
Anaemia; Aspergillosis, Allergic Bronchopulmonary	Drug: Daprodustat; Drug: rhEPO; Drug: Placebo; Drug: Iron therapy	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 2964 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase 3 Randomized, Open-label (Sponsor-blind), Active-controlled, Parallel-group, Multi-center, Event Driven Study in Dialysis Subjects With Anemia Associated With Chronic Kidney Disease to Evaluate the Safety and Efficacy of Daprodustat Compared to Recombinant Human Erythropoietin, Following a Switch From Erythropoietin-stimulating Agents
• Actual Study Start Date: Sep 28, 2016
• Actual Primary Completion Date: Nov 9, 2020
• Actual Study Completion Date: Nov 9, 2020

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Daprodustat Participants will receive oral daprodustat once daily.	Drug: Daprodustat; Daprodustat dose is based on prior ESA dose, the dose is adjusted thereafter in order to achieve the target range.; Drug: Placebo; Oral placebo tablets will be taken from Week -4 up to randomization (Day 1).; Drug: Iron 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.
Active Comparator: rhEPO Participants on peritoneal dialysis (PD) will be administered darbepoetin alfa subcutaneously (SC) and participants on hemodialysis (HD) will be administered epoetin alfa intravenously (IV).	Drug: rhEPO; The initial ESA dose is based on converting the prior ESA dose to the nearest available study rhEPO dose and is administered IV. The dose is adjusted thereafter in order to achieve the target range.; Drug: Placebo; Oral placebo tablets will be taken from Week -4 up to randomization (Day 1).; Drug: Iron 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.

Outcome Measures

Primary Outcome Measures

1. Time to First Occurrence of Adjudicated Major Adverse Cardiovascular Event (MACE) During Cardiovascular (CV) Events Follow-up Time Period: Non-inferiority Analysis [Up to 3.9 person-years for CV follow-up time period]

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

2. Mean Change From Baseline in Hemoglobin (Hgb) Levels During 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 hemoglobin measurements. Hemoglobin during the evaluation period was defined as the mean of all available post-randomization hemoglobin values (on and off-treatment) during the evaluation period (Week 28 to Week 52). For the primary analysis, missing post-Baseline hemoglobin values were imputed using pre-specified multiple imputation methods. Change from Baseline was defined as post-Baseline value minus Baseline value. Baseline was defined as the latest non-missing pre-dose assessment on or before the randomization date.

Secondary Outcome Measures

1. Time to First Occurrence of Adjudicated MACE During CV Events Follow-up Time Period: Superiority Analysis [Up to 3.9 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, dialysis type and region as covariate. Time to the first occurrence was computed as (event date minus randomization date) + 1. The incidence rate per 100 person years calculated as (100*number of participants with at least 1 event)/first event person-years) is presented along with 95% CI. First event person years=(cumulative total time to first event for participants who have the event + cumulative total of censored time for participants without the event)/365.25, based on the CV follow-up time period. This endpoint was adjusted for multiplicity using the Holm-Bonferonni method.

2. Time to First Occurrence of Adjudicated MACE or Thromboembolic Event During CV Events Follow-up Time Period [Up to 3.9 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, dialysis type and region as covariates. Time to the first occurrence was computed as (event date minus randomization date) + 1. The incidence rate per 100 person years calculated as (100*number of participants with at least 1 event)/first event person-years) is presented along with 95% CI. First event person years=(cumulative total time to first event for participants who have the event + cumulative total of censored time for participants without the event)/365.25, based on the CV follow-up time period. This endpoint was adjusted for multiplicity using the Holm-Bonferonni method.

3. Time to First Occurrence of Adjudicated MACE or Hospitalization for Heart Failure During CV Events Follow-up Time Period [Up to 3.9 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, dialysis type and region as covariates. Time to the first occurrence was computed as (event date minus randomization date) + 1. The incidence rate per 100 person years calculated as (100*number of participants with at least 1 event)/first event person-years) is presented along with 95% CI. First event person years=(cumulative total time to first event for participants who have the event + cumulative total of censored time for participants without the event)/365.25, based on the CV follow-up time period. This endpoint was adjusted for multiplicity using the Holm-Bonferonni method.

4. Mean Average Monthly On-treatment IV Iron Dose Per Participant [Day 1 to Week 52]

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

5. Time to First Occurrence of Adjudicated All-Cause Mortality During Vital Status for Follow-up Time Period [Up to 3.9 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, dialysis type and region as covariates. Time to the first occurrence was computed as (event date minus randomization date) + 1. The incidence rate per 100 person years calculated as (100*number of participants with at least 1 event)/first event person-years) is presented along with 95% CI. First event person years=(cumulative total time to first event for participants who have the event + cumulative total of censored time for participants without the event)/365.25, based on the vital status for follow-up time period.

6. Time to First Occurrence of Adjudicated CV Mortality During CV Events Follow-up Time Period [Up to 3.9 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, dialysis type and region as covariates. Time to the first occurrence was computed as (event date minus randomization date) + 1. The incidence rate per 100 person years calculated as (100*number of participants with at least 1 event)/first event person-years) is presented along with 95% CI. First event person years=(cumulative total time to first event for participants who have the event + cumulative total of censored time for participants without the event)/365.25, based on the CV follow-up time period.

7. Time to First Occurrence of Adjudicated Myocardial Infarction (MI) (Fatal and Non-Fatal) During CV Events Follow-up Time Period [Up to 3.9 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, dialysis type and region as covariates. Time to the first occurrence was computed as (event date minus randomization date) + 1. The incidence rate per 100 person years calculated as (100*number of participants with at least 1 event)/first event person-years) is presented along with 95% CI. First event person years=(cumulative total time to first event for participants who have the event + cumulative total of censored time for participants without the event)/365.25, based on the CV follow-up time period.

8. Time to First Occurrence of Adjudicated Stroke (Fatal and Non-Fatal) During CV Events Follow-up Time Period [Up to 3.9 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, dialysis type and region as covariates. Time to the first occurrence was computed as (event date minus randomization date) + 1. The incidence rate per 100 person years calculated as (100*number of participants with at least 1 event)/first event person-years) is presented along with 95% CI. First event person years=(cumulative total time to first event for participants who have the event + cumulative total of censored time for participants without the event)/365.25, based on the CV follow-up time period.

9. Number of Participants With Adjudicated MACE or Hospitalization for Heart Failure (Recurrent Events Analysis) [Up to 3.9 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.

10. Time to First Occurrence of Adjudicated CV Mortality or Non-Fatal MI During CV Events Follow-up Time Period [Up to 3.9 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, dialysis type and region as covariates. Time to the first occurrence was computed as (event date minus randomization date) + 1. The incidence rate per 100 person years calculated as (100*number of participants with at least 1 event)/first event person-years) is presented along with 95% CI. First event person years=(cumulative total time to first event for participants who have the event + cumulative total of censored time for participants without the event)/365.25, based on the CV follow-up time period.

11. Time to First Occurrence of All-Cause Hospitalization During CV Events Follow-up Time Period [Up to 3.9 person-years for CV follow-up time period]

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

12. Time to First Occurrence of All-Cause Hospital Re-admission Within 30 Days During CV Events Follow-up Time Period [Up to 3.9 person-years for CV follow-up time period]

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

13. Time to First Occurrence of Adjudicated MACE or Hospitalization for Heart Failure or Thromboembolic Events During CV Events Follow-up Time Period [Up to 3.9 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, dialysis type and region as covariates. Time to the first occurrence was computed as (event date minus randomization date) + 1. The incidence rate per 100 person years calculated as (100*number of participants with at least 1 event)/first event person-years) is presented along with 95% CI. First event person years=(cumulative total time to first event for participants who have the event + cumulative total of censored time for participants without the event)/365.25, based on the CV follow-up time period.

14. Time to First Occurrence of Adjudicated Hospitalization for Heart Failure During CV Events Follow-up Time Period [Up to 3.9 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, dialysis type and region as covariates. Time to the first occurrence was computed as (event date minus randomization date) + 1. The incidence rate per 100 person years calculated as (100*number of participants with at least 1 event)/first event person-years) is presented along with 95% CI. First event person years=(cumulative total time to first event for participants who have the event + cumulative total of censored time for participants without the event)/365.25, based on the CV follow-up time period.

15. Time to First Occurrence of Adjudicated Thromboembolic Events During CV Events Follow-up Time Period [Up to 3.9 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, dialysis type and region as covariates. Time to the first occurrence was computed as (event date minus randomization date) + 1. The incidence rate per 100 person years calculated as (100*number of participants with at least 1 event)/first event person-years) is presented along with 95% CI. First event person years=(cumulative total time to first event for participants who have the event + cumulative total of censored time for participants without the event)/365.25, based on the CV follow-up time period.

16. Change From Baseline in Post-randomization Hemoglobin Levels at Week 52 [Baseline (Pre-dose on Day 1) and Week 52]

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

17. 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. Hemoglobin responders were defined as participants with a mean Hgb during the evaluation period that falls within the Hgb analysis range of 10-11.5 g/dL.

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

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

20. Percentage of Time With Hemoglobin in the Analysis Range (10 to 11.5 Grams/Deciliter) During Maintenance Period (Week 28 to End of Study): Non-inferiority Analysis [Week 28 to end of study (3.9 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)].

21. 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 (3.9 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)].

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

23. Change From Baseline in SBP, DBP, MAP at End of Treatment [Baseline (Week -4) and 45.1 months]

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

24. Blood Pressure (BP) Exacerbation Event Rate Per 100 Participant Years [Day 1 to end of study (3.9 person-years for follow-up time period)]

    BP exacerbation was defined (based on post-dialysis) as: SBP >= 25 millimeter of mercury (mmHg) increased from Baseline or SBP >=180 mmHg; DBP >=15 mmHg increased from Baseline or DBP >=110 mmHg. The BP exacerbation events per 100 participant years was estimated using the negative binomial model with treatment, dialysis type and region as covariates and the logarithm of time on-treatment as an offset variable. Data for post-dialysis BP measurements have been presented.

25. Number of Participants With at Least One BP Exacerbation Event During Study [Day 1 to end of study (3.9 person-years for follow-up time period)]

    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.

26. Percentage of Participants Permanently Stopping Randomized Treatment Due to Meeting Rescue Criteria [Day 1 to 45.1 months]

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

27. 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 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.

28. 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.

29. 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, general health, mental health, role-emotional (role limitations caused by emotional problems), role-physical (role limitations caused by physical problems), social functioning (Social fun), physical functioning (Phy. fun) and vitality. Each domain is scored from 0 (poorer health) to 100 (better health). Each domain score ranges from 0 to 100, higher score indicates a better health state and better functioning. Change from Baseline was calculated as on-treatment visit value minus Baseline value. Baseline was defined as the latest non-missing pre-dose assessment on or before the randomization date.

30. 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.

31. 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.

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

33. Change From Baseline in On-Treatment EuroQol 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 health one can imagine and 100 represents the best health one can imagine. Change from Baseline was calculated as on-treatment visit value minus Baseline value. Baseline was defined as the latest non-missing pre-dose assessment on or before the randomization date.

34. 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 worse outcome. Change from Baseline was calculated as on-treatment visit value minus Baseline value. Baseline was defined as the latest non-missing pre-dose assessment on or before the randomization date.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 99 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Age: 18 to 99 years of age (inclusive).

• Erythropoietin-stimulating agents (ESAs): Use of any approved ESA for at least the 6 weeks prior to screening and between screening and randomization.

• Hgb concentration: On Week -8: Hgb 8 to 12 grams per deciliter (g/dL). On randomization (Day 1): Hgb 8 to 11 g/dL and receiving at least the minimum ESA dose. Hgb >11 g/dL to 11.5 g/dL and receiving greater than the minimum ESA dose.

• Dialysis: On dialysis >90 days prior to screening and continuing on the same mode of dialysis from screening (Week -8) through to randomization (Day 1).

• Frequency of Dialysis: Hemodialysis (HD) >=2 times/week and peritoneal dialysis (PD)

=5 times/week. Home hemodialysis >=2 times/week.

• Compliance with placebo [randomization (Day 1) only]: >=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 listed in the consent form and in this protocol.

Exclusion Criteria:

• 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 that would contraindicate the use of recombinant human erythropoietin (rhEPO).

• 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 QT 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 epoetin alfa 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).

• 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 serum 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 listed in the List of Highly Effective Methods for Avoiding Pregnancy.

• 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 rhEPO) or prevent understanding of the aims or investigational procedures or possible consequences of the study.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	GSK Investigational Site	Huntsville	Alabama	United States	35805
2	GSK Investigational Site	Pine Bluff	Arkansas	United States	71603
3	GSK Investigational Site	Anaheim	California	United States	92801
4	GSK Investigational Site	Bakersfield	California	United States	93308
5	GSK Investigational Site	Bakersfield	California	United States	93309
6	GSK Investigational Site	Beverly Hills	California	United States	90211
7	GSK Investigational Site	Cerritos	California	United States	90703
8	GSK Investigational Site	Chula Vista	California	United States	91910
9	GSK Investigational Site	El Centro	California	United States	92243
10	GSK Investigational Site	Escondido	California	United States	92025
11	GSK Investigational Site	Fairfield	California	United States	94534
12	GSK Investigational Site	Fountain Valley	California	United States	92708
13	GSK Investigational Site	Glendale	California	United States	91205
14	GSK Investigational Site	Granada Hills	California	United States	91344
15	GSK Investigational Site	Hacienda Heights	California	United States	91745
16	GSK Investigational Site	La Mesa	California	United States	91942
17	GSK Investigational Site	La Palma	California	United States	90623
18	GSK Investigational Site	Lakewood	California	United States	90712
19	GSK Investigational Site	Long Beach	California	United States	90806
20	GSK Investigational Site	Long Beach	California	United States	90807
21	GSK Investigational Site	Long Beach	California	United States	90813
22	GSK Investigational Site	Los Angeles	California	United States	90022
23	GSK Investigational Site	Los Angeles	California	United States	90095
24	GSK Investigational Site	Lynwood	California	United States	60262
25	GSK Investigational Site	Montebello	California	United States	90640
26	GSK Investigational Site	Monterey Park	California	United States	91754
27	GSK Investigational Site	Moreno Valley	California	United States	92553
28	GSK Investigational Site	Norco	California	United States	92860
29	GSK Investigational Site	Northridge	California	United States	91324
30	GSK Investigational Site	Ontario	California	United States	91762
31	GSK Investigational Site	Riverside	California	United States	92501
32	GSK Investigational Site	Sacramento	California	United States	95825
33	GSK Investigational Site	San Diego	California	United States	92103
34	GSK Investigational Site	San Diego	California	United States	92111
35	GSK Investigational Site	San Luis Obispo	California	United States	93405
36	GSK Investigational Site	Santa Clarita	California	United States	91387
37	GSK Investigational Site	Simi Valley	California	United States	93065-091
38	GSK Investigational Site	Tarzana	California	United States	91356
39	GSK Investigational Site	Whittier	California	United States	90602
40	GSK Investigational Site	Whittier	California	United States	90603
41	GSK Investigational Site	Yorba Linda	California	United States	92886
42	GSK Investigational Site	Middlebury	Connecticut	United States	06762
43	GSK Investigational Site	Washington	District of Columbia	United States	20037
44	GSK Investigational Site	Aventura	Florida	United States	33180
45	GSK Investigational Site	Coral Gables	Florida	United States	33134
46	GSK Investigational Site	Hollywood	Florida	United States	33024
47	GSK Investigational Site	Jacksonville	Florida	United States	32224
48	GSK Investigational Site	Lauderdale Lakes	Florida	United States	33313
49	GSK Investigational Site	Miami Gardens	Florida	United States	33169
50	GSK Investigational Site	Miami	Florida	United States	33126
51	GSK Investigational Site	Miami	Florida	United States	33143
52	GSK Investigational Site	Miami	Florida	United States	33150
53	GSK Investigational Site	Miami	Florida	United States	33156
54	GSK Investigational Site	Ocala	Florida	United States	34471
55	GSK Investigational Site	Port Charlotte	Florida	United States	33952
56	GSK Investigational Site	Spring Hill	Florida	United States	34608
57	GSK Investigational Site	Winter Park	Florida	United States	32789
58	GSK Investigational Site	Augusta	Georgia	United States	30904
59	GSK Investigational Site	Augusta	Georgia	United States	30912
60	GSK Investigational Site	Columbus	Georgia	United States	31904
61	GSK Investigational Site	Meridian	Idaho	United States	83642
62	GSK Investigational Site	Crystal Lake	Illinois	United States	60014
63	GSK Investigational Site	Fort Wayne	Indiana	United States	46804
64	GSK Investigational Site	Jeffersonville	Indiana	United States	47130
65	GSK Investigational Site	Merrillville	Indiana	United States	46410
66	GSK Investigational Site	Michigan City	Indiana	United States	46360
67	GSK Investigational Site	Iowa City	Iowa	United States	52242
68	GSK Investigational Site	Louisville	Kentucky	United States	40202
69	GSK Investigational Site	Baton Rouge	Louisiana	United States	70808
70	GSK Investigational Site	Baton Rouge	Louisiana	United States	70836
71	GSK Investigational Site	Greenbelt	Maryland	United States	20770
72	GSK Investigational Site	Takoma Park	Maryland	United States	20912-6385
73	GSK Investigational Site	Kalamazoo	Michigan	United States	49007
74	GSK Investigational Site	Pontiac	Michigan	United States	48341
75	GSK Investigational Site	Roseville	Michigan	United States	48066
76	GSK Investigational Site	Gulfport	Mississippi	United States	39501
77	GSK Investigational Site	Tupelo	Mississippi	United States	38801
78	GSK Investigational Site	Florissant	Missouri	United States	63033
79	GSK Investigational Site	Kansas City	Missouri	United States	64111
80	GSK Investigational Site	Saint Louis	Missouri	United States	63110
81	GSK Investigational Site	Las Vegas	Nevada	United States	89102
82	GSK Investigational Site	Las Vegas	Nevada	United States	89107
83	GSK Investigational Site	Portsmouth	New Hampshire	United States	3801
84	GSK Investigational Site	Gallup	New Mexico	United States	87301
85	GSK Investigational Site	Bronx	New York	United States	10461
86	GSK Investigational Site	Brooklyn	New York	United States	11203
87	GSK Investigational Site	Buffalo	New York	United States	14215
88	GSK Investigational Site	Flushing	New York	United States	11355
89	GSK Investigational Site	Mineola	New York	United States	11501
90	GSK Investigational Site	New York	New York	United States	10029
91	GSK Investigational Site	Ridgewood	New York	United States	11385
92	GSK Investigational Site	Yonkers	New York	United States	10710
93	GSK Investigational Site	Asheville	North Carolina	United States	28801
94	GSK Investigational Site	Clyde	North Carolina	United States	28721
95	GSK Investigational Site	Raleigh	North Carolina	United States	27609
96	GSK Investigational Site	Winston-Salem	North Carolina	United States	27103
97	GSK Investigational Site	Winston-Salem	North Carolina	United States	27517
98	GSK Investigational Site	Canton	Ohio	United States	44718
99	GSK Investigational Site	Cincinnati	Ohio	United States	45206
100	GSK Investigational Site	Cincinnati	Ohio	United States	45220
101	GSK Investigational Site	Roseburg	Oregon	United States	97471
102	GSK Investigational Site	Bethlehem	Pennsylvania	United States	18017
103	GSK Investigational Site	Philadelphia	Pennsylvania	United States	19140
104	GSK Investigational Site	Providence	Rhode Island	United States	02903
105	GSK Investigational Site	Anderson	South Carolina	United States	29621
106	GSK Investigational Site	Charleston	South Carolina	United States	29425
107	GSK Investigational Site	Sumter	South Carolina	United States	29150
108	GSK Investigational Site	Cordova	Tennessee	United States	38018
109	GSK Investigational Site	Knoxville	Tennessee	United States	37923
110	GSK Investigational Site	Knoxville	Tennessee	United States	37924
111	GSK Investigational Site	Nashville	Tennessee	United States	37205
112	GSK Investigational Site	Beaumont	Texas	United States	77701
113	GSK Investigational Site	Houston	Texas	United States	77004
114	GSK Investigational Site	Houston	Texas	United States	77030
115	GSK Investigational Site	Houston	Texas	United States	77099
116	GSK Investigational Site	Lufkin	Texas	United States	75904
117	GSK Investigational Site	San Antonio	Texas	United States	78207
118	GSK Investigational Site	San Antonio	Texas	United States	78221
119	GSK Investigational Site	San Antonio	Texas	United States	78251
120	GSK Investigational Site	San Antonio	Texas	United States	78258
121	GSK Investigational Site	Alexandria	Virginia	United States	22304
122	GSK Investigational Site	Fairfax	Virginia	United States	22033
123	GSK Investigational Site	Hampton	Virginia	United States	23666
124	GSK Investigational Site	Salem	Virginia	United States	24153
125	GSK Investigational Site	Bluefield	West Virginia	United States	24701
126	GSK Investigational Site	Shorewood	Wisconsin	United States	53211
127	GSK Investigational Site	Burzaco	Buenos Aires	Argentina	B1852FZD
128	GSK Investigational Site	Ciudad Evita	Buenos Aires	Argentina	B1778IFA
129	GSK Investigational Site	Pergamino	Buenos Aires	Argentina	B2700CPM
130	GSK Investigational Site	Pilar	Buenos Aires	Argentina	1629
131	GSK Investigational Site	Córdoba	Córdova	Argentina	X5016KEH
132	GSK Investigational Site	Buenos Aires		Argentina	1425
133	GSK Investigational Site	Buenos Aires		Argentina	C1181ACH
134	GSK Investigational Site	Buenos Aires		Argentina	CP1431FWO
135	GSK Investigational Site	Formosa		Argentina	P3600LLD
136	GSK Investigational Site	Mendoza		Argentina	M5500AFA
137	GSK Investigational Site	Moron		Argentina	B1708DPO
138	GSK Investigational Site	San Miguel de Tucumán		Argentina	T4000AHL
139	GSK Investigational Site	Concord	New South Wales	Australia	2139
140	GSK Investigational Site	Kingswood	New South Wales	Australia	2750
141	GSK Investigational Site	Kogarah	New South Wales	Australia	2217
142	GSK Investigational Site	Liverpool	New South Wales	Australia	2170
143	GSK Investigational Site	St Leonards	New South Wales	Australia	2065
144	GSK Investigational Site	Westmead	New South Wales	Australia	2145
145	GSK Investigational Site	Wollongong	New South Wales	Australia	2500
146	GSK Investigational Site	Birtinya	Queensland	Australia	4575
147	GSK Investigational Site	Herston	Queensland	Australia	4006
148	GSK Investigational Site	Woolloongabba	Queensland	Australia	4102
149	GSK Investigational Site	Adelaide	South Australia	Australia	5000
150	GSK Investigational Site	Clayton	Victoria	Australia	3168
151	GSK Investigational Site	Melbourne	Victoria	Australia	3004
152	GSK Investigational Site	St Albans	Victoria	Australia	3021
153	GSK Investigational Site	Nedlands	Western Australia	Australia	6009
154	GSK Investigational Site	Murdoch		Australia	6150
155	GSK Investigational Site	Graz		Austria	8036
156	GSK Investigational Site	St. Pölten		Austria	3100
157	GSK Investigational Site	Wien		Austria	1030
158	GSK Investigational Site	Wien		Austria	A-1130
159	GSK Investigational Site	Baudour		Belgium	7331
160	GSK Investigational Site	Brugge		Belgium	8310
161	GSK Investigational Site	Brussels		Belgium	1200
162	GSK Investigational Site	Bruxelles		Belgium	1020
163	GSK Investigational Site	Hasselt		Belgium	3500
164	GSK Investigational Site	Ieper		Belgium	8900
165	GSK Investigational Site	Leuven		Belgium	3000
166	GSK Investigational Site	Liège		Belgium	4000
167	GSK Investigational Site	Roeselare		Belgium	8800
168	GSK Investigational Site	Salvador	Bahia	Brazil	40415-065
169	GSK Investigational Site	Curitiba	Paraná	Brazil	80440-020
170	GSK Investigational Site	Curitiba	Paraná	Brazil	CEP 80230-130
171	GSK Investigational Site	Passo Fundo	Rio Grande Do Sul	Brazil	99010-080
172	GSK Investigational Site	Porto Alegre	Rio Grande Do Sul	Brazil	90610-000
173	GSK Investigational Site	Joinville	Santa Catarina	Brazil	89227-680
174	GSK Investigational Site	Sao Jose do Rio Preto	São Paulo	Brazil	15090-000
175	GSK Investigational Site	Belo Horizonte, Minas Gerais		Brazil	30150-221
176	GSK Investigational Site	Feira de Santana		Brazil	44001-584
177	GSK Investigational Site	Porto Alegre		Brazil	90035-070
178	GSK Investigational Site	Porto Alegre		Brazil	90035-903
179	GSK Investigational Site	Sao Paulo		Brazil	01323-001
180	GSK Investigational Site	São Paulo		Brazil	01323903
181	GSK Investigational Site	São Paulo		Brazil	04005-000
182	GSK Investigational Site	São Paulo		Brazil	04039-000
183	GSK Investigational Site	São Paulo		Brazil	08270-070
184	GSK Investigational Site	Blagoevgrad		Bulgaria	2700
185	GSK Investigational Site	Dobrich		Bulgaria	9300
186	GSK Investigational Site	Gabrovo		Bulgaria	5300
187	GSK Investigational Site	Lom		Bulgaria	3600
188	GSK Investigational Site	Lovech		Bulgaria	5500
189	GSK Investigational Site	Montana		Bulgaria	3400
190	GSK Investigational Site	Pazardzhik		Bulgaria	4400
191	GSK Investigational Site	Plovdiv		Bulgaria	4000
192	GSK Investigational Site	Plovdiv		Bulgaria	4003
193	GSK Investigational Site	Ruse		Bulgaria	7002
194	GSK Investigational Site	Smolyan		Bulgaria	4700
195	GSK Investigational Site	Sofia		Bulgaria	1233
196	GSK Investigational Site	Sofia		Bulgaria	1309
197	GSK Investigational Site	Sofia		Bulgaria	1709
198	GSK Investigational Site	Varna		Bulgaria	9000
199	GSK Investigational Site	Veliko Tarnovo		Bulgaria	5000
200	GSK Investigational Site	Edmonton	Alberta	Canada	T6G 2B7
201	GSK Investigational Site	London	Ontario	Canada	N6A 5A5
202	GSK Investigational Site	Toronto	Ontario	Canada	M3M 0B2
203	GSK Investigational Site	Beroun		Czechia	26601
204	GSK Investigational Site	Frýdek-mistek		Czechia	738 18
205	GSK Investigational Site	Ivancice		Czechia	664 95
206	GSK Investigational Site	Jilemnice		Czechia	514 01
207	GSK Investigational Site	Marianske Lazne		Czechia	353 01
208	GSK Investigational Site	Pardubice		Czechia	53203
209	GSK Investigational Site	Praha 2		Czechia	128 08
210	GSK Investigational Site	Praha 4		Czechia	14021
211	GSK Investigational Site	Praha 4		Czechia	142 00
212	GSK Investigational Site	Sokolov		Czechia	356 01
213	GSK Investigational Site	Aalborg		Denmark	DK-9000
214	GSK Investigational Site	Holstebro		Denmark	7500
215	GSK Investigational Site	Kolding		Denmark	6000
216	GSK Investigational Site	Odense C		Denmark	5000
217	GSK Investigational Site	Svendborg		Denmark	5700
218	GSK Investigational Site	Parnu		Estonia	80011
219	GSK Investigational Site	Tallinn		Estonia	EE-13419
220	GSK Investigational Site	Tartu		Estonia	50501
221	GSK Investigational Site	Annonay		France	07103
222	GSK Investigational Site	Bois-Guillaume		France	76230
223	GSK Investigational Site	Bordeaux		France	33076
224	GSK Investigational Site	Boulogne Billancourt		France	92100
225	GSK Investigational Site	Caen Cedex 9		France	14033
226	GSK Investigational Site	Mulhouse		France	68100
227	GSK Investigational Site	Poitiers		France	86021
228	GSK Investigational Site	Reims		France	51092
229	GSK Investigational Site	Tours cedex 9		France	37044
230	GSK Investigational Site	Mannheim	Baden-Wuerttemberg	Germany	68167
231	GSK Investigational Site	Bad Koenig	Hessen	Germany	64732
232	GSK Investigational Site	Wiesbaden	Hessen	Germany	65191
233	GSK Investigational Site	Rostock	Mecklenburg-Vorpommern	Germany	18059
234	GSK Investigational Site	Cloppenburg	Niedersachsen	Germany	49661
235	GSK Investigational Site	Duesseldorf	Nordrhein-Westfalen	Germany	40210
236	GSK Investigational Site	Kaiserslautern	Rheinland-Pfalz	Germany	67655
237	GSK Investigational Site	Kiel	Schleswig-Holstein	Germany	24105
238	GSK Investigational Site	Dieburg		Germany	64807
239	GSK Investigational Site	Freiburg		Germany	79110
240	GSK Investigational Site	Minden		Germany	32429
241	GSK Investigational Site	Alexandroupolis		Greece	68100
242	GSK Investigational Site	Arta		Greece	471 00
243	GSK Investigational Site	Athens		Greece	11527
244	GSK Investigational Site	Heraklion-Crete		Greece	71110
245	GSK Investigational Site	Ioannina		Greece	45001
246	GSK Investigational Site	Ioannina		Greece	45500
247	GSK Investigational Site	Komotini		Greece	69100
248	GSK Investigational Site	Larissa		Greece	41110
249	GSK Investigational Site	Patras		Greece	26500
250	GSK Investigational Site	Thessaloniki		Greece	546 42
251	GSK Investigational Site	Thessaloniki		Greece	54636
252	GSK Investigational Site	Thessaloniki		Greece	56403
253	GSK Investigational Site	Thessaloniki		Greece	57001
254	GSK Investigational Site	Budapest		Hungary	1077
255	GSK Investigational Site	Egri		Hungary	3300
256	GSK Investigational Site	Esztergom		Hungary	2500
257	GSK Investigational Site	Kecskemet		Hungary	6001
258	GSK Investigational Site	Miskolc		Hungary	3526
259	GSK Investigational Site	Pécs		Hungary	7624
260	GSK Investigational Site	Pécs		Hungary	7633
261	GSK Investigational Site	Szigetvar		Hungary	7900
262	GSK Investigational Site	Ahmedabad		India	380059
263	GSK Investigational Site	Bangalore		India	560054
264	GSK Investigational Site	Bangalore		India	560055
265	GSK Investigational Site	Calicut		India	673008
266	GSK Investigational Site	Chennai, Tamil Nadu		India	600 006
267	GSK Investigational Site	Chennai		India	600 034
268	GSK Investigational Site	Delhi		India	110076
269	GSK Investigational Site	Gurgaon		India	122001
270	GSK Investigational Site	Hyderabad		India	500034
271	GSK Investigational Site	Jaipur		India	302004
272	GSK Investigational Site	Mumbai		India	400016
273	GSK Investigational Site	Nadiad		India	387001
274	GSK Investigational Site	Nagpur		India	440010
275	GSK Investigational Site	New Delhi		India	110017
276	GSK Investigational Site	New Delhi		India	110025
277	GSK Investigational Site	New Delhi		India	110060
278	GSK Investigational Site	Pune		India	411004
279	GSK Investigational Site	Pune		India	411033
280	GSK Investigational Site	Secunderabad		India	560020
281	GSK Investigational Site	Trivandrum		India	695011
282	GSK Investigational Site	Catanzaro	Calabria	Italy	88100
283	GSK Investigational Site	Reggio Calabria	Calabria	Italy	89124
284	GSK Investigational Site	Napoli	Campania	Italy	80131
285	GSK Investigational Site	Piacenza	Emilia-Romagna	Italy	29100
286	GSK Investigational Site	Genova	Liguria	Italy	16132
287	GSK Investigational Site	Bergamo	Lombardia	Italy	24127
288	GSK Investigational Site	Lecco	Lombardia	Italy	23900
289	GSK Investigational Site	Milano	Lombardia	Italy	20153
290	GSK Investigational Site	Monza	Lombardia	Italy	20900
291	GSK Investigational Site	Pavia	Lombardia	Italy	27100
292	GSK Investigational Site	Seriate	Lombardia	Italy	24068
293	GSK Investigational Site	Torino	Piemonte	Italy	10154
294	GSK Investigational Site	Foggia	Puglia	Italy	71100
295	GSK Investigational Site	Cagliari	Sardegna	Italy	09100
296	GSK Investigational Site	Imola		Italy	40026
297	GSK Investigational Site	Mestre		Italy	30122
298	GSK Investigational Site	Anyang-Si, Gyeonggi-do		Korea, Republic of	14068
299	GSK Investigational Site	Bucheon-si,		Korea, Republic of	14647
300	GSK Investigational Site	Busan		Korea, Republic of	48108
301	GSK Investigational Site	Daegu-si		Korea, Republic of	42601
302	GSK Investigational Site	Daejeon		Korea, Republic of	35233
303	GSK Investigational Site	Goyang-si, Gyeonggi-do		Korea, Republic of	411706
304	GSK Investigational Site	Goyang-si		Korea, Republic of	10475
305	GSK Investigational Site	Goyang-si		Korea, Republic of	410-719
306	GSK Investigational Site	Gyeonggi-do		Korea, Republic of	463-707
307	GSK Investigational Site	Incheon		Korea, Republic of	405-760
308	GSK Investigational Site	Seoul		Korea, Republic of	05030
309	GSK Investigational Site	Seoul		Korea, Republic of	05355
310	GSK Investigational Site	Seoul		Korea, Republic of	07061
311	GSK Investigational Site	Seoul		Korea, Republic of	07441
312	GSK Investigational Site	Seoul		Korea, Republic of	134-727
313	GSK Investigational Site	Seoul		Korea, Republic of	135-720
314	GSK Investigational Site	Seoul		Korea, Republic of	150-713
315	GSK Investigational Site	Seoul		Korea, Republic of	158-710
316	GSK Investigational Site	Suwon		Korea, Republic of	442-723
317	GSK Investigational Site	Uijeongbu-si		Korea, Republic of	11765
318	GSK Investigational Site	Wonju-si		Korea, Republic of	26426
319	GSK Investigational Site	Batu Caves		Malaysia	68100
320	GSK Investigational Site	Ipoh		Malaysia	30990
321	GSK Investigational Site	Johor Bahru		Malaysia	80100
322	GSK Investigational Site	Kuala Lumpur		Malaysia	50603
323	GSK Investigational Site	Pahang		Malaysia	28000
324	GSK Investigational Site	Penang		Malaysia	10990
325	GSK Investigational Site	Saltillo	Coahuila	Mexico	CP 25230
326	GSK Investigational Site	Durango.	Durango	Mexico	34000
327	GSK Investigational Site	Ciudad De México	Estado De México	Mexico	14000
328	GSK Investigational Site	Cuautitlan Izcalli	Estado De México	Mexico	54769
329	GSK Investigational Site	Guadalajara	Jalisco	Mexico	44620
330	GSK Investigational Site	Guadalajara	Jalisco	Mexico	44650
331	GSK Investigational Site	Queretaro	Querétaro	Mexico	76000
332	GSK Investigational Site	Merida	Yucatán	Mexico	97070
333	GSK Investigational Site	Aguascalientes		Mexico	20230
334	GSK Investigational Site	Chihuahua		Mexico	31203
335	GSK Investigational Site	Chihuahua		Mexico	31217
336	GSK Investigational Site	México, D.F.		Mexico	14080
337	GSK Investigational Site	Zapopan, Jalisco		Mexico	45030
338	GSK Investigational Site	Amsterdam		Netherlands	1081 HV
339	GSK Investigational Site	Deventer		Netherlands	7416 SE
340	GSK Investigational Site	Rotterdam		Netherlands	3079 DZ
341	GSK Investigational Site	Hamilton		New Zealand	2001
342	GSK Investigational Site	Hastings		New Zealand	4156
343	GSK Investigational Site	Otahuhu		New Zealand	1640
344	GSK Investigational Site	Oslo		Norway	0405
345	GSK Investigational Site	Stavanger		Norway	4011
346	GSK Investigational Site	Biala Podlaska		Poland	21-500
347	GSK Investigational Site	Gdansk		Poland	80-462
348	GSK Investigational Site	Grojec		Poland	05-600
349	GSK Investigational Site	Kielce		Poland	25-736
350	GSK Investigational Site	Kolobrzeg		Poland	78-100
351	GSK Investigational Site	Kolo		Poland	62-600
352	GSK Investigational Site	Lodz		Poland	90-262
353	GSK Investigational Site	Lodz		Poland	92-213
354	GSK Investigational Site	Olkusz		Poland	32-300
355	GSK Investigational Site	Pruszkow		Poland	05-800
356	GSK Investigational Site	Tomaszow Mazowiecki		Poland	97-200
357	GSK Investigational Site	Warszawa		Poland	02-758
358	GSK Investigational Site	Zary		Poland	68-200
359	GSK Investigational Site	Amadora		Portugal	2700-391
360	GSK Investigational Site	Corroios.		Portugal	2855227
361	GSK Investigational Site	Covilhã		Portugal	6200-000
362	GSK Investigational Site	Forte Da Casa		Portugal	2625-437
363	GSK Investigational Site	Lisboa		Portugal	1069-166
364	GSK Investigational Site	Lisboa		Portugal	1250-203
365	GSK Investigational Site	Lisboa		Portugal	1400-195
366	GSK Investigational Site	Lisboa		Portugal	1750-130
367	GSK Investigational Site	Mirandela		Portugal	5370-530
368	GSK Investigational Site	Portimão		Portugal	8500-311
369	GSK Investigational Site	Vila Franca de Xira		Portugal	2600-076
370	GSK Investigational Site	Vila Real (Lordelo)		Portugal	5000-668
371	GSK Investigational Site	Arad		Romania	310141
372	GSK Investigational Site	Bucharest		Romania	022328
373	GSK Investigational Site	Resita		Romania	320166
374	GSK Investigational Site	Targu-Jiu		Romania	210146
375	GSK Investigational Site	Irkutsk		Russian Federation	664049
376	GSK Investigational Site	Krasnodar		Russian Federation	350029
377	GSK Investigational Site	Mytischi		Russian Federation	141009
378	GSK Investigational Site	Nizhniy Novgorod		Russian Federation	603126
379	GSK Investigational Site	Novosibirsk		Russian Federation	630087
380	GSK Investigational Site	Omsk		Russian Federation	644112
381	GSK Investigational Site	Orenburg		Russian Federation	460040
382	GSK Investigational Site	Penza		Russian Federation	440034
383	GSK Investigational Site	St-Petersburg		Russian Federation	197110
384	GSK Investigational Site	St. Petersburg		Russian Federation	191104
385	GSK Investigational Site	St. Petersburg		Russian Federation	194354
386	GSK Investigational Site	St. Petersburg		Russian Federation	196247
387	GSK Investigational Site	Volzhsky		Russian Federation	404120
388	GSK Investigational Site	Yaroslavl		Russian Federation	150062
389	GSK Investigational Site	Singapore		Singapore	119074
390	GSK Investigational Site	Singapore		Singapore	169608
391	GSK Investigational Site	Singapore		Singapore	308433
392	GSK Investigational Site	Cape Town.		South Africa	7925
393	GSK Investigational Site	Cape Town		South Africa	7500
394	GSK Investigational Site	Majadahonda	Madrid	Spain	28222
395	GSK Investigational Site	Alcala de Henares		Spain	28805
396	GSK Investigational Site	Aranda de Duero		Spain	09400
397	GSK Investigational Site	Badalona		Spain	08036
398	GSK Investigational Site	Badalona		Spain	08916
399	GSK Investigational Site	Barcelona		Spain	08003
400	GSK Investigational Site	Barcelona		Spain	08025
401	GSK Investigational Site	Ciudad Real		Spain	13005
402	GSK Investigational Site	Girona		Spain	17007
403	GSK Investigational Site	Guadalajara		Spain	19002
404	GSK Investigational Site	Madrid		Spain	28007
405	GSK Investigational Site	Madrid		Spain	28020
406	GSK Investigational Site	Madrid		Spain	28040
407	GSK Investigational Site	Manises (Valencia)		Spain	46940
408	GSK Investigational Site	Mollet del Valles		Spain	08100
409	GSK Investigational Site	Málaga		Spain	29530
410	GSK Investigational Site	Palma de Mallorca		Spain	07120
411	GSK Investigational Site	Sabadell		Spain	08208
412	GSK Investigational Site	Santiago de Compostela		Spain	15706
413	GSK Investigational Site	Sevilla		Spain	41071
414	GSK Investigational Site	Valladolid		Spain	47005
415	GSK Investigational Site	Stockholm		Sweden	SE-141 86
416	GSK Investigational Site	Stockholm		Sweden	SE-182 88
417	GSK Investigational Site	Uppsala		Sweden	756 55
418	GSK Investigational Site	Örebro		Sweden	SE-701 85
419	GSK Investigational Site	Kaohsiung		Taiwan	807
420	GSK Investigational Site	Kaohsiung		Taiwan	83301
421	GSK Investigational Site	Keelung		Taiwan	204
422	GSK Investigational Site	New Taipei City		Taiwan	23561
423	GSK Investigational Site	New Taipei City		Taiwan	237
424	GSK Investigational Site	New Taipei		Taiwan	220
425	GSK Investigational Site	Tainan		Taiwan	704
426	GSK Investigational Site	Taipei		Taiwan	112
427	GSK Investigational Site	Taipei		Taiwan	116
428	GSK Investigational Site	Taoyuan Hsien		Taiwan	333
429	GSK Investigational Site	Zhongzheng Dist., Taipei		Taiwan	10002
430	GSK Investigational Site	Adana		Turkey	01330
431	GSK Investigational Site	Ankara		Turkey	06100
432	GSK Investigational Site	Antalya		Turkey	07059
433	GSK Investigational Site	Edirne		Turkey	22030
434	GSK Investigational Site	Eskisehir		Turkey	26480
435	GSK Investigational Site	Kayseri		Turkey	38039
436	GSK Investigational Site	Chernihiv		Ukraine	14029
437	GSK Investigational Site	Chernivtsi		Ukraine	58005
438	GSK Investigational Site	Ivano-Frankivsk		Ukraine	76008
439	GSK Investigational Site	Kherson		Ukraine	73039
440	GSK Investigational Site	Kiev		Ukraine	04107
441	GSK Investigational Site	Kyiv		Ukraine	01023
442	GSK Investigational Site	Kyiv		Ukraine	04050
443	GSK Investigational Site	Kyiv		Ukraine	04112
444	GSK Investigational Site	Mykolaiv		Ukraine	54058
445	GSK Investigational Site	Ternopil		Ukraine	46002
446	GSK Investigational Site	Zaporizhzhia		Ukraine	69001
447	GSK Investigational Site	Zaporizhzhia		Ukraine	69600
448	GSK Investigational Site	Zhytomyr		Ukraine	10002
449	GSK Investigational Site	Stevenage	Hertfordshire	United Kingdom	SG1 4AB
450	GSK Investigational Site	Preston	Lancashire	United Kingdom	PR2 9HT
451	GSK Investigational Site	Wolverhampton	West Midlands	United Kingdom	WV10 0QP
452	GSK Investigational Site	Birmingham		United Kingdom	B9 5SS
453	GSK Investigational Site	Derby		United Kingdom	DE22 3NE
454	GSK Investigational Site	Doncaster		United Kingdom	DN2 5LT
455	GSK Investigational Site	Dundee		United Kingdom	DD1 9SY
456	GSK Investigational Site	Fife		United Kingdom	KY2 5AH
457	GSK Investigational Site	Glasgow		United Kingdom	G51 4TF
458	GSK Investigational Site	Hull		United Kingdom	HU3 2JZ
459	GSK Investigational Site	London		United Kingdom	E1 1BB
460	GSK Investigational Site	London		United Kingdom	SE5 9RS
461	GSK Investigational Site	Oxford		United Kingdom	OX3 7LE
462	GSK Investigational Site	Salford		United Kingdom	M6 8HD

Sponsors and Collaborators

• GlaxoSmithKline

Investigators

• Study Director: GSK Clinical Trials, GlaxoSmithKline

Study Documents (Full-Text)

• Study Protocol - Jul 30, 2020
• Statistical Analysis Plan - Mar 3, 2021

More Information

Publications

None provided.

• Responsible Party: GlaxoSmithKline
• ClinicalTrials.gov Identifier: NCT02879305
• Other Study ID Numbers: 200807; 2016-000541-31
• First Posted: Aug 25, 2016
• Last Update Posted: Dec 3, 2021
• Last Verified: Nov 1, 2021

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by GlaxoSmithKline: erythropoiesis stimulating agents; GSK1278863; daprodustat; anemia; chronic kidney disease; hemoglobin; recombinant human erythropoietin
• Additional relevant MeSH terms: Aspergillosis; Aspergillosis, Allergic Bronchopulmonary; Kidney Diseases; Renal Insufficiency, Chronic; Anemia

Study Results

Participant Flow

Recruitment Details	This was a randomized, open-label (sponsor blind), active-controlled, parallel-group, event-driven study conducted at 431 centers in 35 countries. Participants were randomized to receive daprodustat and recombinant human erythropoietin (rhEPO) (epoetin alfa or darbepoetin alfa).
Pre-assignment Detail	A total of 2964 participants were randomized in the study.

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

Baseline Characteristics

Arm/Group Title	Daprodustat	rhEPO	Total
Arm/Group Description	Participants received placebo tablets orally once daily in run-in period from Week -4 up to randomization (Day 1) and subsequently received daprodustat tablets at dose levels of 1, 2, 4, 6, 8, 10, 12, 16 and 24 milligrams (mg) orally once daily until the required number of major adverse cardiovascular event (MACE) occurred, at approximately 45.1 months of randomized treatment. Study treatment was dose-titrated to achieve and maintain hemoglobin in the target range (10 to 11 grams per deciliter [g/dL]).	Participants received placebo tablets orally once daily in run-in period from Week -4 up to randomization (Day 1) and subsequently received treatment with rhEPO. Participants on hemodialysis received epoetin alfa as intravenous (IV) injection once weekly or three-times weekly with total weekly dose levels ranging from 1500 to 60,000 Units. Participants on peritoneal dialysis received subcutaneous (SC) injection of darbepoetin alfa every 1, 2, or 4 weeks with 4-weekly total dose levels ranging from 20 to 400 microgram (mcg). Darbepoetin could be given by IV injection for peritoneal dialysis participants switching to hemodialysis. Study treatment was dose-titrated to achieve and maintain hemoglobin in the target range (10 to 11 g/dL) and administered until the required number of MACE events occurred, at approximately 45.1 months of randomized treatment.	Total of all reporting groups
Overall Participants	1487	1477	2964
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	57.2 (14.29)	57.3 (14.65)	57.2 (14.47)
Sex: Female, Male (Count of Participants)
Female	636 42.8%	630 42.7%	1266 42.7%
Male	851 57.2%	847 57.3%	1698 57.3%
Race/Ethnicity, Customized (Count of Participants)
American Indian or Alaskan Native	19 1.3%	32 2.2%	51 1.7%
Asian - Central/South Asian Heritage	36 2.4%	46 3.1%	82 2.8%
Asian - East Asian Heritage	97 6.5%	86 5.8%	183 6.2%
Asian - Japanese Heritage	3 0.2%	3 0.2%	6 0.2%
Asian - South East Asian Heritage	40 2.7%	45 3%	85 2.9%
Black or African American	228 15.3%	233 15.8%	461 15.6%
Native Hawaiian or Other Pacific Islander	26 1.7%	25 1.7%	51 1.7%
White - Arabic/North African Heritage	8 0.5%	14 0.9%	22 0.7%
White - White/Caucasian/European Heritage	987 66.4%	968 65.5%	1955 66%
Mixed Asian Race	0 0%	1 0.1%	1 0%
Mixed Race	43 2.9%	24 1.6%	67 2.3%

Outcome Measures

1. Primary Outcome

Title	Time to First Occurrence of Adjudicated Major Adverse Cardiovascular Event (MACE) During Cardiovascular (CV) Events Follow-up Time Period: Non-inferiority Analysis
Description	Time to MACE defined as the time to first occurrence of Clinical Events Committee (CEC) adjudicated MACE (composite of all-cause mortality, non-fatal myocardial infarction [MI] and non-fatal stroke) was analyzed using a Cox proportional hazards regression model with treatment group, dialysis type and region as covariates. Time to the first occurrence was computed as (event date minus randomization date) plus (+) 1. The incidence rate per 100 person years calculated as (100 multiplied by [*] number of participants with at least 1 event) divided by [/] first event person-years) is presented along with 95 percent (%) confidence interval (CI). First event person years=(cumulative total time to first event for participants who have the event + cumulative total of censored time for participants without the event)/365.25, based on the CV follow-up time period.
Time Frame	Up to 3.9 person-years for CV follow-up time period

Outcome Measure Data

Analysis Population Description

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/Group Title	Daprodustat	rhEPO
Arm/Group Description	Participants received placebo tablets orally once daily in run-in period from Week -4 up to randomization (Day 1) and subsequently received daprodustat tablets at dose levels of 1, 2, 4, 6, 8, 10, 12, 16 and 24 milligrams (mg) orally once daily until the required number of major adverse cardiovascular event (MACE) occurred, at approximately 45.1 months of randomized treatment. Study treatment was dose-titrated to achieve and maintain hemoglobin in the target range (10 to 11 grams per deciliter [g/dL]).	Participants received placebo tablets orally once daily in run-in period from Week -4 up to randomization (Day 1) and subsequently received treatment with rhEPO. Participants on hemodialysis received epoetin alfa as intravenous (IV) injection once weekly or three-times weekly with total weekly dose levels ranging from 1500 to 60,000 Units. Participants on peritoneal dialysis received subcutaneous (SC) injection of darbepoetin alfa every 1, 2, or 4 weeks with 4-weekly total dose levels ranging from 20 to 400 microgram (mcg). Darbepoetin could be given by IV injection for peritoneal dialysis participants switching to hemodialysis. Study treatment was dose-titrated to achieve and maintain hemoglobin in the target range (10 to 11 g/dL) and administered until the required number of MACE events occurred, at approximately 45.1 months of randomized treatment.
Measure Participants	1487	1477
Number (95% Confidence Interval) [Events per 100 person years]	11.07	11.86

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Daprodustat, rhEPO
	Comments
	Type of Statistical Test	Non-Inferiority
	Comments	Non-inferiority was achieved if the upper limit of the two-sided 95% CI for the hazard ratio was below the pre-specified non-inferiority margin of 1.25.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.93
	Confidence Interval	(2-Sided) 95%; 0.81 to 1.07
	Parameter Dispersion	Type: Value:
	Estimation Comments	Hazard ratio was estimated using a Cox proportional hazard regression model with treatment group, dialysis type and region as covariates.

2. Primary Outcome

Title	Mean Change From Baseline in Hemoglobin (Hgb) Levels During Evaluation Period (Week 28 to Week 52)
Description	Blood samples were collected from participants for hemoglobin measurements. Hemoglobin during the evaluation period was defined as the mean of all available post-randomization hemoglobin values (on and off-treatment) during the evaluation period (Week 28 to Week 52). For the primary analysis, missing post-Baseline hemoglobin values were imputed using pre-specified multiple imputation methods. Change from Baseline was defined as post-Baseline value minus Baseline value. Baseline was defined as the latest non-missing pre-dose assessment on or before the randomization date.
Time Frame	Baseline (Pre-dose on Day 1) and evaluation period (Week 28 to Week 52)

Outcome Measure Data

Analysis Population Description

All Randomized (ITT) Population.

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

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Daprodustat, rhEPO
	Comments
	Type of Statistical Test	Non-Inferiority
	Comments	Non-inferiority was to be established if the lower limit of the two-sided 95% CI for the treatment difference was greater than -0.75 g/dL.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least square (LS) mean difference
	Estimated Value	0.18
	Confidence Interval	(2-Sided) 95%; 0.12 to 0.24
	Parameter Dispersion	Type: Value:
	Estimation Comments	Analysis of covariance (ANCOVA) model adjusted for treatment, Baseline Hgb, dialysis type and region along with 95% CI for treatment difference (daprodustat-rhEPO).

3. Secondary Outcome

Title	Time to First Occurrence of Adjudicated MACE During CV Events Follow-up Time Period: Superiority Analysis
Description	Time to MACE defined as the time to first occurrence of CEC adjudicated MACE was analyzed using a Cox proportional hazards regression model with treatment group, dialysis type and region as covariate. Time to the first occurrence was computed as (event date minus randomization date) + 1. The incidence rate per 100 person years calculated as (100*number of participants with at least 1 event)/first event person-years) is presented along with 95% CI. First event person years=(cumulative total time to first event for participants who have the event + cumulative total of censored time for participants without the event)/365.25, based on the CV follow-up time period. This endpoint was adjusted for multiplicity using the Holm-Bonferonni method.
Time Frame	Up to 3.9 person-years for CV follow-up time period

Outcome Measure Data

Analysis Population Description

All Randomized (ITT) Population.

Arm/Group Title	Daprodustat	rhEPO
Arm/Group Description	Participants received placebo tablets orally once daily in run-in period from Week -4 up to randomization (Day 1) and subsequently received daprodustat tablets at dose levels of 1, 2, 4, 6, 8, 10, 12, 16 and 24 milligrams (mg) orally once daily until the required number of major adverse cardiovascular event (MACE) occurred, at approximately 45.1 months of randomized treatment. Study treatment was dose-titrated to achieve and maintain hemoglobin in the target range (10 to 11 grams per deciliter [g/dL]).	Participants received placebo tablets orally once daily in run-in period from Week -4 up to randomization (Day 1) and subsequently received treatment with rhEPO. Participants on hemodialysis received epoetin alfa as intravenous (IV) injection once weekly or three-times weekly with total weekly dose levels ranging from 1500 to 60,000 Units. Participants on peritoneal dialysis received subcutaneous (SC) injection of darbepoetin alfa every 1, 2, or 4 weeks with 4-weekly total dose levels ranging from 20 to 400 microgram (mcg). Darbepoetin could be given by IV injection for peritoneal dialysis participants switching to hemodialysis. Study treatment was dose-titrated to achieve and maintain hemoglobin in the target range (10 to 11 g/dL) and administered until the required number of MACE events occurred, at approximately 45.1 months of randomized treatment.
Measure Participants	1487	1477
Number (95% Confidence Interval) [Events per 100 person years]	11.07	11.86

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Daprodustat, rhEPO
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.156123
	Comments	The p-value was compared against 0.0125 based on the Holm-Bonferonni adjustment.
	Method	Wald test
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.93
	Confidence Interval	(2-Sided) 95%; 0.81 to 1.07
	Parameter Dispersion	Type: Value:
	Estimation Comments	Hazard ratio was estimated using a Cox proportional hazard regression model with treatment group, dialysis type and region as covariates.

4. Secondary Outcome

Title	Time to First Occurrence of Adjudicated MACE or Thromboembolic Event During CV Events Follow-up Time Period
Description	Time to first occurrence of adjudicated MACE or thromboembolic event (vascular access thrombosis, symptomatic deep vein thrombosis or symptomatic pulmonary embolism) was analyzed using a Cox proportional hazards regression model with with treatment group, dialysis type and region as covariates. Time to the first occurrence was computed as (event date minus randomization date) + 1. The incidence rate per 100 person years calculated as (100*number of participants with at least 1 event)/first event person-years) is presented along with 95% CI. First event person years=(cumulative total time to first event for participants who have the event + cumulative total of censored time for participants without the event)/365.25, based on the CV follow-up time period. This endpoint was adjusted for multiplicity using the Holm-Bonferonni method.
Time Frame	Up to 3.9 person-years for CV follow-up time period

Outcome Measure Data

Analysis Population Description

All Randomized (ITT) Population.

Arm/Group Title	Daprodustat	rhEPO
Arm/Group Description	Participants received placebo tablets orally once daily in run-in period from Week -4 up to randomization (Day 1) and subsequently received daprodustat tablets at dose levels of 1, 2, 4, 6, 8, 10, 12, 16 and 24 milligrams (mg) orally once daily until the required number of major adverse cardiovascular event (MACE) occurred, at approximately 45.1 months of randomized treatment. Study treatment was dose-titrated to achieve and maintain hemoglobin in the target range (10 to 11 grams per deciliter [g/dL]).	Participants received placebo tablets orally once daily in run-in period from Week -4 up to randomization (Day 1) and subsequently received treatment with rhEPO. Participants on hemodialysis received epoetin alfa as intravenous (IV) injection once weekly or three-times weekly with total weekly dose levels ranging from 1500 to 60,000 Units. Participants on peritoneal dialysis received subcutaneous (SC) injection of darbepoetin alfa every 1, 2, or 4 weeks with 4-weekly total dose levels ranging from 20 to 400 microgram (mcg). Darbepoetin could be given by IV injection for peritoneal dialysis participants switching to hemodialysis. Study treatment was dose-titrated to achieve and maintain hemoglobin in the target range (10 to 11 g/dL) and administered until the required number of MACE events occurred, at approximately 45.1 months of randomized treatment.
Measure Participants	1487	1477
Number (95% Confidence Interval) [Events per 100 person years]	15.84	17.85

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Daprodustat, rhEPO
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.023539
	Comments	The p-value was compared against 0.006250 based on the Holm-Bonferonni adjustment.
	Method	Wald test
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.88
	Confidence Interval	(2-Sided) 95%; 0.78 to 1.00
	Parameter Dispersion	Type: Value:
	Estimation Comments	Hazard ratio was estimated using a Cox proportional hazard regression model with treatment group, dialysis type and region as covariates.

5. Secondary Outcome

Title	Time to First Occurrence of Adjudicated MACE or Hospitalization for Heart Failure During CV Events Follow-up Time Period
Description	Time to first occurrence of adjudicated MACE or hospitalization for heart failure was analyzed using a Cox proportional hazards regression model with treatment group, dialysis type and region as covariates. Time to the first occurrence was computed as (event date minus randomization date) + 1. The incidence rate per 100 person years calculated as (100*number of participants with at least 1 event)/first event person-years) is presented along with 95% CI. First event person years=(cumulative total time to first event for participants who have the event + cumulative total of censored time for participants without the event)/365.25, based on the CV follow-up time period. This endpoint was adjusted for multiplicity using the Holm-Bonferonni method.
Time Frame	Up to 3.9 person-years for CV follow-up time period

Outcome Measure Data

Analysis Population Description

All Randomized (ITT) Population.

Arm/Group Title	Daprodustat	rhEPO
Arm/Group Description	Participants received placebo tablets orally once daily in run-in period from Week -4 up to randomization (Day 1) and subsequently received daprodustat tablets at dose levels of 1, 2, 4, 6, 8, 10, 12, 16 and 24 milligrams (mg) orally once daily until the required number of major adverse cardiovascular event (MACE) occurred, at approximately 45.1 months of randomized treatment. Study treatment was dose-titrated to achieve and maintain hemoglobin in the target range (10 to 11 grams per deciliter [g/dL]).	Participants received placebo tablets orally once daily in run-in period from Week -4 up to randomization (Day 1) and subsequently received treatment with rhEPO. Participants on hemodialysis received epoetin alfa as intravenous (IV) injection once weekly or three-times weekly with total weekly dose levels ranging from 1500 to 60,000 Units. Participants on peritoneal dialysis received subcutaneous (SC) injection of darbepoetin alfa every 1, 2, or 4 weeks with 4-weekly total dose levels ranging from 20 to 400 microgram (mcg). Darbepoetin could be given by IV injection for peritoneal dialysis participants switching to hemodialysis. Study treatment was dose-titrated to achieve and maintain hemoglobin in the target range (10 to 11 g/dL) and administered until the required number of MACE events occurred, at approximately 45.1 months of randomized treatment.
Measure Participants	1487	1477
Number (95% Confidence Interval) [Events per 100 person years]	12.98	13.38

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Daprodustat, rhEPO
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.325797
	Comments	The p-value was compared against 0.025000 based on the Holm-Bonferonni adjustment.
	Method	Wald test
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.97
	Confidence Interval	(2-Sided) 95%; 0.85 to 1.11
	Parameter Dispersion	Type: Value:
	Estimation Comments	Hazard ratio was estimated using a Cox proportional hazard regression model with treatment group, dialysis type and region as covariates.

6. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

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

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

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Daprodustat, rhEPO
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.026947
	Comments	The p-value was compared against 0.008333 based on the Holm-Bonferonni adjustment.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-9.1
	Confidence Interval	(2-Sided) 95%; -18.4 to 0.2
	Parameter Dispersion	Type: Value:
	Estimation Comments	Analysis was carried out by using ANCOVA model with terms for treatment, Baseline monthly IV iron dose, dialysis type and region.

7. Secondary Outcome

Title	Time to First Occurrence of Adjudicated All-Cause Mortality During Vital Status for Follow-up Time Period
Description	Time to first occurrence of adjudicated all-cause mortality was analyzed using a Cox proportional hazards regression model with treatment group, dialysis type and region as covariates. Time to the first occurrence was computed as (event date minus randomization date) + 1. The incidence rate per 100 person years calculated as (100*number of participants with at least 1 event)/first event person-years) is presented along with 95% CI. First event person years=(cumulative total time to first event for participants who have the event + cumulative total of censored time for participants without the event)/365.25, based on the vital status for follow-up time period.
Time Frame	Up to 3.9 person-years for vital status follow-up time period

Outcome Measure Data

Analysis Population Description

All Randomized (ITT) Population.

Arm/Group Title	Daprodustat	rhEPO
Arm/Group Description	Participants received placebo tablets orally once daily in run-in period from Week -4 up to randomization (Day 1) and subsequently received daprodustat tablets at dose levels of 1, 2, 4, 6, 8, 10, 12, 16 and 24 milligrams (mg) orally once daily until the required number of major adverse cardiovascular event (MACE) occurred, at approximately 45.1 months of randomized treatment. Study treatment was dose-titrated to achieve and maintain hemoglobin in the target range (10 to 11 grams per deciliter [g/dL]).	Participants received placebo tablets orally once daily in run-in period from Week -4 up to randomization (Day 1) and subsequently received treatment with rhEPO. Participants on hemodialysis received epoetin alfa as intravenous (IV) injection once weekly or three-times weekly with total weekly dose levels ranging from 1500 to 60,000 Units. Participants on peritoneal dialysis received subcutaneous (SC) injection of darbepoetin alfa every 1, 2, or 4 weeks with 4-weekly total dose levels ranging from 20 to 400 microgram (mcg). Darbepoetin could be given by IV injection for peritoneal dialysis participants switching to hemodialysis. Study treatment was dose-titrated to achieve and maintain hemoglobin in the target range (10 to 11 g/dL) and administered until the required number of MACE events occurred, at approximately 45.1 months of randomized treatment.
Measure Participants	1487	1477
Number (95% Confidence Interval) [Events per 100 person years]	8.32	8.59

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Daprodustat, rhEPO
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.3281
	Comments
	Method	Wald test
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.96
	Confidence Interval	(2-Sided) 95%; 0.82 to 1.13
	Parameter Dispersion	Type: Value:
	Estimation Comments	Hazard ratio was estimated using a Cox proportional hazard regression model with treatment group, dialysis type and region as covariates.

8. Secondary Outcome

Title	Time to First Occurrence of Adjudicated CV Mortality During CV Events Follow-up Time Period
Description	Time to first occurrence of adjudicated CV mortality was analyzed using a Cox proportional hazards regression model with treatment group, dialysis type and region as covariates. Time to the first occurrence was computed as (event date minus randomization date) + 1. The incidence rate per 100 person years calculated as (100*number of participants with at least 1 event)/first event person-years) is presented along with 95% CI. First event person years=(cumulative total time to first event for participants who have the event + cumulative total of censored time for participants without the event)/365.25, based on the CV follow-up time period.
Time Frame	Up to 3.9 person-years for CV follow-up time period

Outcome Measure Data

Analysis Population Description

All Randomized (ITT) Population.

Arm/Group Title	Daprodustat	rhEPO
Arm/Group Description	Participants received placebo tablets orally once daily in run-in period from Week -4 up to randomization (Day 1) and subsequently received daprodustat tablets at dose levels of 1, 2, 4, 6, 8, 10, 12, 16 and 24 milligrams (mg) orally once daily until the required number of major adverse cardiovascular event (MACE) occurred, at approximately 45.1 months of randomized treatment. Study treatment was dose-titrated to achieve and maintain hemoglobin in the target range (10 to 11 grams per deciliter [g/dL]).	Participants received placebo tablets orally once daily in run-in period from Week -4 up to randomization (Day 1) and subsequently received treatment with rhEPO. Participants on hemodialysis received epoetin alfa as intravenous (IV) injection once weekly or three-times weekly with total weekly dose levels ranging from 1500 to 60,000 Units. Participants on peritoneal dialysis received subcutaneous (SC) injection of darbepoetin alfa every 1, 2, or 4 weeks with 4-weekly total dose levels ranging from 20 to 400 microgram (mcg). Darbepoetin could be given by IV injection for peritoneal dialysis participants switching to hemodialysis. Study treatment was dose-titrated to achieve and maintain hemoglobin in the target range (10 to 11 g/dL) and administered until the required number of MACE events occurred, at approximately 45.1 months of randomized treatment.
Measure Participants	1487	1477
Number (95% Confidence Interval) [Events per 100 person years]	3.31	3.46

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Daprodustat, rhEPO
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.3553
	Comments
	Method	Wald test
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.95
	Confidence Interval	(2-Sided) 95%; 0.74 to 1.23
	Parameter Dispersion	Type: Value:
	Estimation Comments	Hazard ratio was estimated using a Cox proportional hazard regression model with treatment group, dialysis type and region as covariates.

9. Secondary Outcome

Title	Time to First Occurrence of Adjudicated Myocardial Infarction (MI) (Fatal and Non-Fatal) During CV Events Follow-up Time Period
Description	Time to first occurrence of adjudicated MI (fatal and non-fatal) was analyzed using a Cox proportional hazards regression model with treatment group, dialysis type and region as covariates. Time to the first occurrence was computed as (event date minus randomization date) + 1. The incidence rate per 100 person years calculated as (100*number of participants with at least 1 event)/first event person-years) is presented along with 95% CI. First event person years=(cumulative total time to first event for participants who have the event + cumulative total of censored time for participants without the event)/365.25, based on the CV follow-up time period.
Time Frame	Up to 3.9 person-years for CV follow-up time period

Outcome Measure Data

Analysis Population Description

All Randomized (ITT) Population.

Arm/Group Title	Daprodustat	rhEPO
Arm/Group Description	Participants received placebo tablets orally once daily in run-in period from Week -4 up to randomization (Day 1) and subsequently received daprodustat tablets at dose levels of 1, 2, 4, 6, 8, 10, 12, 16 and 24 milligrams (mg) orally once daily until the required number of major adverse cardiovascular event (MACE) occurred, at approximately 45.1 months of randomized treatment. Study treatment was dose-titrated to achieve and maintain hemoglobin in the target range (10 to 11 grams per deciliter [g/dL]).	Participants received placebo tablets orally once daily in run-in period from Week -4 up to randomization (Day 1) and subsequently received treatment with rhEPO. Participants on hemodialysis received epoetin alfa as intravenous (IV) injection once weekly or three-times weekly with total weekly dose levels ranging from 1500 to 60,000 Units. Participants on peritoneal dialysis received subcutaneous (SC) injection of darbepoetin alfa every 1, 2, or 4 weeks with 4-weekly total dose levels ranging from 20 to 400 microgram (mcg). Darbepoetin could be given by IV injection for peritoneal dialysis participants switching to hemodialysis. Study treatment was dose-titrated to achieve and maintain hemoglobin in the target range (10 to 11 g/dL) and administered until the required number of MACE events occurred, at approximately 45.1 months of randomized treatment.
Measure Participants	1487	1477
Number (95% Confidence Interval) [Events per 100 person years]	3.34	4.08

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Daprodustat, rhEPO
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0524
	Comments
	Method	Wald test
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.81
	Confidence Interval	(2-Sided) 95%; 0.63 to 1.04
	Parameter Dispersion	Type: Value:
	Estimation Comments	Hazard ratio was estimated using a Cox proportional hazard regression model with treatment group, dialysis type and region as covariates.

10. Secondary Outcome

Title	Time to First Occurrence of Adjudicated Stroke (Fatal and Non-Fatal) During CV Events Follow-up Time Period
Description	Time to first occurrence of adjudicated stroke (fatal and non-fatal) was analyzed using a Cox proportional hazards regression model with treatment group, dialysis type and region as covariates. Time to the first occurrence was computed as (event date minus randomization date) + 1. The incidence rate per 100 person years calculated as (100*number of participants with at least 1 event)/first event person-years) is presented along with 95% CI. First event person years=(cumulative total time to first event for participants who have the event + cumulative total of censored time for participants without the event)/365.25, based on the CV follow-up time period.
Time Frame	Up to 3.9 person-years for CV follow-up time period

Outcome Measure Data

Analysis Population Description

All Randomized (ITT) Population.

Arm/Group Title	Daprodustat	rhEPO
Arm/Group Description	Participants received placebo tablets orally once daily in run-in period from Week -4 up to randomization (Day 1) and subsequently received daprodustat tablets at dose levels of 1, 2, 4, 6, 8, 10, 12, 16 and 24 milligrams (mg) orally once daily until the required number of major adverse cardiovascular event (MACE) occurred, at approximately 45.1 months of randomized treatment. Study treatment was dose-titrated to achieve and maintain hemoglobin in the target range (10 to 11 grams per deciliter [g/dL]).	Participants received placebo tablets orally once daily in run-in period from Week -4 up to randomization (Day 1) and subsequently received treatment with rhEPO. Participants on hemodialysis received epoetin alfa as intravenous (IV) injection once weekly or three-times weekly with total weekly dose levels ranging from 1500 to 60,000 Units. Participants on peritoneal dialysis received subcutaneous (SC) injection of darbepoetin alfa every 1, 2, or 4 weeks with 4-weekly total dose levels ranging from 20 to 400 microgram (mcg). Darbepoetin could be given by IV injection for peritoneal dialysis participants switching to hemodialysis. Study treatment was dose-titrated to achieve and maintain hemoglobin in the target range (10 to 11 g/dL) and administered until the required number of MACE events occurred, at approximately 45.1 months of randomized treatment.
Measure Participants	1487	1477
Number (95% Confidence Interval) [Events per 100 person years]	1.23	1.48

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Daprodustat, rhEPO
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1927
	Comments
	Method	Wald test
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.84
	Confidence Interval	(2-Sided) 95%; 0.56 to 1.25
	Parameter Dispersion	Type: Value:
	Estimation Comments	Hazard ratio was estimated using a Cox proportional hazard regression model with treatment group, dialysis type and region as covariates.

11. Secondary Outcome

Title	Number of Participants With Adjudicated MACE or Hospitalization for Heart Failure (Recurrent Events Analysis)
Description	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 3.9 person-years for CV follow-up time period

Outcome Measure Data

Analysis Population Description

All Randomized (ITT) Population.

Arm/Group Title	Daprodustat	rhEPO
Arm/Group Description	Participants received placebo tablets orally once daily in run-in period from Week -4 up to randomization (Day 1) and subsequently received daprodustat tablets at dose levels of 1, 2, 4, 6, 8, 10, 12, 16 and 24 milligrams (mg) orally once daily until the required number of major adverse cardiovascular event (MACE) occurred, at approximately 45.1 months of randomized treatment. Study treatment was dose-titrated to achieve and maintain hemoglobin in the target range (10 to 11 grams per deciliter [g/dL]).	Participants received placebo tablets orally once daily in run-in period from Week -4 up to randomization (Day 1) and subsequently received treatment with rhEPO. Participants on hemodialysis received epoetin alfa as intravenous (IV) injection once weekly or three-times weekly with total weekly dose levels ranging from 1500 to 60,000 Units. Participants on peritoneal dialysis received subcutaneous (SC) injection of darbepoetin alfa every 1, 2, or 4 weeks with 4-weekly total dose levels ranging from 20 to 400 microgram (mcg). Darbepoetin could be given by IV injection for peritoneal dialysis participants switching to hemodialysis. Study treatment was dose-titrated to achieve and maintain hemoglobin in the target range (10 to 11 g/dL) and administered until the required number of MACE events occurred, at approximately 45.1 months of randomized treatment.
Measure Participants	1487	1477
Occurrences per participant: 0	1062 71.4%	1044 70.7%
Occurrences per participant: 1	315 21.2%	300 20.3%
Occurrences per participant: 2	72 4.8%	88 6%
Occurrences per participant: 3	25 1.7%	22 1.5%
Occurrences per participant: 4	3 0.2%	11 0.7%
Occurrences per participant: 5	4 0.3%	4 0.3%
Occurrences per participant: 6	4 0.3%	3 0.2%
Occurrences per participant: 7	0 0%	2 0.1%
Occurrences per participant: 8	0 0%	1 0.1%
Occurrences per participant: 9	1 0.1%	1 0.1%
Occurrences per participant: 10	1 0.1%	1 0.1%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Daprodustat, rhEPO
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0351
	Comments
	Method	Chi-squared
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.90
	Confidence Interval	(2-Sided) 95%; 0.80 to 1.01
	Parameter Dispersion	Type: Value:
	Estimation Comments	Overall HR is presented using Model 1. Model 1 assumed a common treatment effect, regardless of number of events experienced. HR was estimated using a Prentice, Williams and Peterson(PWP) model, with treatment, dialysis type and region as covariates.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Daprodustat, rhEPO
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.3258
	Comments
	Method	Chi-squared
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.97
	Confidence Interval	(2-Sided) 95%; 0.85 to 1.11
	Parameter Dispersion	Type: Value:
	Estimation Comments	First Event Hazard ratio is presented using Model 2. Model 2 assumed treatment effect differs by number of events experienced. Hazard Ratio (HR) was estimated using a PWP model, with treatment, dialysis type and region as covariates.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Daprodustat, rhEPO
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0158
	Comments
	Method	Chi-squared
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.75
	Confidence Interval	(2-Sided) 95%; 0.58 to 0.98
	Parameter Dispersion	Type: Value:
	Estimation Comments	Second Event Hazard ratio is presented using Model 2. Model 2 assumed treatment effect differs by number of events experienced. HR was estimated using a PWP model, with treatment, dialysis type and region as covariates.

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Daprodustat, rhEPO
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0981
	Comments
	Method	Chi-squared
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.74
	Confidence Interval	(2-Sided) 95%; 0.47 to 1.17
	Parameter Dispersion	Type: Value:
	Estimation Comments	Third Event Hazard ratio is presented using Model 2. Model 2 assumed treatment effect differs by number of events experienced. HR was estimated using a PWP model, with treatment, dialysis type and region as covariates.

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Daprodustat, rhEPO
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.3258
	Comments
	Method	Chi-squared
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.97
	Confidence Interval	(2-Sided) 95%; 0.85 to 1.11
	Parameter Dispersion	Type: Value:
	Estimation Comments	First Event Hazard ratio is presented using Model 3. Model 3 assumed treatment effect for first event differs from a common effect for subsequent events. HR was estimated using a PWP model, with treatment, dialysis type and region as covariates.

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Daprodustat, rhEPO
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0058
	Comments
	Method	Chi-squared
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.75
	Confidence Interval	(2-Sided) 95%; 0.60 to 0.94
	Parameter Dispersion	Type: Value:
	Estimation Comments	Subsequent Event Hazard ratio is presented using Model 3. Model 3 assumed treatment effect for first event differs from a common effect for subsequent events. HR was estimated using a PWP model, with treatment, dialysis type and region as covariates.

12. Secondary Outcome

Title	Time to First Occurrence of Adjudicated CV Mortality or Non-Fatal MI During CV Events Follow-up Time Period
Description	Time to first occurrence of adjudicated CV mortality or non-fatal MI was analyzed using a Cox proportional hazards regression model with treatment group, dialysis type and region as covariates. Time to the first occurrence was computed as (event date minus randomization date) + 1. The incidence rate per 100 person years calculated as (100*number of participants with at least 1 event)/first event person-years) is presented along with 95% CI. First event person years=(cumulative total time to first event for participants who have the event + cumulative total of censored time for participants without the event)/365.25, based on the CV follow-up time period.
Time Frame	Up to 3.9 person-years for CV follow-up time period

Outcome Measure Data

Analysis Population Description

All Randomized (ITT) Population.

Arm/Group Title	Daprodustat	rhEPO
Arm/Group Description	Participants received placebo tablets orally once daily in run-in period from Week -4 up to randomization (Day 1) and subsequently received daprodustat tablets at dose levels of 1, 2, 4, 6, 8, 10, 12, 16 and 24 milligrams (mg) orally once daily until the required number of major adverse cardiovascular event (MACE) occurred, at approximately 45.1 months of randomized treatment. Study treatment was dose-titrated to achieve and maintain hemoglobin in the target range (10 to 11 grams per deciliter [g/dL]).	Participants received placebo tablets orally once daily in run-in period from Week -4 up to randomization (Day 1) and subsequently received treatment with rhEPO. Participants on hemodialysis received epoetin alfa as intravenous (IV) injection once weekly or three-times weekly with total weekly dose levels ranging from 1500 to 60,000 Units. Participants on peritoneal dialysis received subcutaneous (SC) injection of darbepoetin alfa every 1, 2, or 4 weeks with 4-weekly total dose levels ranging from 20 to 400 microgram (mcg). Darbepoetin could be given by IV injection for peritoneal dialysis participants switching to hemodialysis. Study treatment was dose-titrated to achieve and maintain hemoglobin in the target range (10 to 11 g/dL) and administered until the required number of MACE events occurred, at approximately 45.1 months of randomized treatment.
Measure Participants	1487	1477
Number (95% Confidence Interval) [Events per 100 person years]	5.98	6.79

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Daprodustat, rhEPO
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0872
	Comments
	Method	Wald test
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.88
	Confidence Interval	(2-Sided) 95%; 0.73 to 1.06
	Parameter Dispersion	Type: Value:
	Estimation Comments	Hazard ratio was estimated using a Cox proportional hazard regression model with treatment group, dialysis type and region as covariates.

13. Secondary Outcome

Title	Time to First Occurrence of All-Cause Hospitalization During CV Events Follow-up Time Period
Description	All-cause hospitalization events were hospital admissions recorded on the Hospitalization electronic case report form (eCRF) with a hospitalization duration >=24 hours. Time to first occurrence of all-cause hospitalization was analyzed using a Cox proportional hazards regression model with treatment group, dialysis type and region as covariates. Time to the first occurrence was computed as (event date minus randomization date) + 1. The incidence rate per 100 person years calculated as (100*number of participants with at least 1 event)/first event person-years) is presented along with 95% CI. First event person years=(cumulative total time to first event for participants who have the event + cumulative total of censored time for participants without the event)/365.25, based on the CV follow-up time period.
Time Frame	Up to 3.9 person-years for CV follow-up time period

Outcome Measure Data

Analysis Population Description

All Randomized (ITT) Population.

Arm/Group Title	Daprodustat	rhEPO
Arm/Group Description	Participants received placebo tablets orally once daily in run-in period from Week -4 up to randomization (Day 1) and subsequently received daprodustat tablets at dose levels of 1, 2, 4, 6, 8, 10, 12, 16 and 24 milligrams (mg) orally once daily until the required number of major adverse cardiovascular event (MACE) occurred, at approximately 45.1 months of randomized treatment. Study treatment was dose-titrated to achieve and maintain hemoglobin in the target range (10 to 11 grams per deciliter [g/dL]).	Participants received placebo tablets orally once daily in run-in period from Week -4 up to randomization (Day 1) and subsequently received treatment with rhEPO. Participants on hemodialysis received epoetin alfa as intravenous (IV) injection once weekly or three-times weekly with total weekly dose levels ranging from 1500 to 60,000 Units. Participants on peritoneal dialysis received subcutaneous (SC) injection of darbepoetin alfa every 1, 2, or 4 weeks with 4-weekly total dose levels ranging from 20 to 400 microgram (mcg). Darbepoetin could be given by IV injection for peritoneal dialysis participants switching to hemodialysis. Study treatment was dose-titrated to achieve and maintain hemoglobin in the target range (10 to 11 g/dL) and administered until the required number of MACE events occurred, at approximately 45.1 months of randomized treatment.
Measure Participants	1487	1477
Number (95% Confidence Interval) [Events per 100 person years]	43.92	46.03

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Daprodustat, rhEPO
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1540
	Comments
	Method	Wald test
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.95
	Confidence Interval	(2-Sided) 95%; 0.87 to 1.04
	Parameter Dispersion	Type: Value:
	Estimation Comments	Hazard ratio was estimated using a Cox proportional hazard regression model with treatment group, dialysis type and region as covariates.

14. Secondary Outcome

Title	Time to First Occurrence of All-Cause Hospital Re-admission Within 30 Days During CV Events Follow-up Time Period
Description	All-cause hospital re-admissions within 30days are defined as hospital admissions recorded on hospitalization eCRF with hospitalization duration of >=24 hours and admission date within 30days following previous discharge date of all-cause hospitalization event, where previous hospitalization was >=24 hours. Time to first occurrence of all-cause hospital re-admission within 30days was analyzed using Cox proportional hazards regression model with treatment group, dialysis type and region as covariates. Time to the first occurrence was computed as (event date minus randomization date)+1. Incidence rate per 100person years calculated as(100*number of participants with at least 1 event)/first event person-years) is presented along with 95% CI. First event person years=(cumulative total time to first event for participants who have the event+cumulative total of censored time for participants without the event)/365.25, based on the CV follow-up time period.
Time Frame	Up to 3.9 person-years for CV follow-up time period

Outcome Measure Data

Analysis Population Description

All Randomized (ITT) Population.

Arm/Group Title	Daprodustat	rhEPO
Arm/Group Description	Participants received placebo tablets orally once daily in run-in period from Week -4 up to randomization (Day 1) and subsequently received daprodustat tablets at dose levels of 1, 2, 4, 6, 8, 10, 12, 16 and 24 milligrams (mg) orally once daily until the required number of major adverse cardiovascular event (MACE) occurred, at approximately 45.1 months of randomized treatment. Study treatment was dose-titrated to achieve and maintain hemoglobin in the target range (10 to 11 grams per deciliter [g/dL]).	Participants received placebo tablets orally once daily in run-in period from Week -4 up to randomization (Day 1) and subsequently received treatment with rhEPO. Participants on hemodialysis received epoetin alfa as intravenous (IV) injection once weekly or three-times weekly with total weekly dose levels ranging from 1500 to 60,000 Units. Participants on peritoneal dialysis received subcutaneous (SC) injection of darbepoetin alfa every 1, 2, or 4 weeks with 4-weekly total dose levels ranging from 20 to 400 microgram (mcg). Darbepoetin could be given by IV injection for peritoneal dialysis participants switching to hemodialysis. Study treatment was dose-titrated to achieve and maintain hemoglobin in the target range (10 to 11 g/dL) and administered until the required number of MACE events occurred, at approximately 45.1 months of randomized treatment.
Measure Participants	1487	1477
Number (95% Confidence Interval) [Events per 100 person years]	8.86	9.67

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Daprodustat, rhEPO
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1244
	Comments
	Method	Wald test
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.91
	Confidence Interval	(2-Sided) 95%; 0.77 to 1.07
	Parameter Dispersion	Type: Value:
	Estimation Comments	Hazard ratio was estimated using a Cox proportional hazard regression model with treatment group, dialysis type and region as covariates.

15. Secondary Outcome

Title	Time to First Occurrence of Adjudicated MACE or Hospitalization for Heart Failure or Thromboembolic Events During CV Events Follow-up Time Period
Description	Time to first occurrence of adjudicated MACE or hospitalization for heart failure or thromboembolic events were analyzed using a Cox proportional hazards regression model with treatment group, dialysis type and region as covariates. Time to the first occurrence was computed as (event date minus randomization date) + 1. The incidence rate per 100 person years calculated as (100*number of participants with at least 1 event)/first event person-years) is presented along with 95% CI. First event person years=(cumulative total time to first event for participants who have the event + cumulative total of censored time for participants without the event)/365.25, based on the CV follow-up time period.
Time Frame	Up to 3.9 person-years for CV follow-up time period

Outcome Measure Data

Analysis Population Description

All Randomized (ITT) Population.

Arm/Group Title	Daprodustat	rhEPO
Arm/Group Description	Participants received placebo tablets orally once daily in run-in period from Week -4 up to randomization (Day 1) and subsequently received daprodustat tablets at dose levels of 1, 2, 4, 6, 8, 10, 12, 16 and 24 milligrams (mg) orally once daily until the required number of major adverse cardiovascular event (MACE) occurred, at approximately 45.1 months of randomized treatment. Study treatment was dose-titrated to achieve and maintain hemoglobin in the target range (10 to 11 grams per deciliter [g/dL]).	Participants received placebo tablets orally once daily in run-in period from Week -4 up to randomization (Day 1) and subsequently received treatment with rhEPO. Participants on hemodialysis received epoetin alfa as intravenous (IV) injection once weekly or three-times weekly with total weekly dose levels ranging from 1500 to 60,000 Units. Participants on peritoneal dialysis received subcutaneous (SC) injection of darbepoetin alfa every 1, 2, or 4 weeks with 4-weekly total dose levels ranging from 20 to 400 microgram (mcg). Darbepoetin could be given by IV injection for peritoneal dialysis participants switching to hemodialysis. Study treatment was dose-titrated to achieve and maintain hemoglobin in the target range (10 to 11 g/dL) and administered until the required number of MACE events occurred, at approximately 45.1 months of randomized treatment.
Measure Participants	1487	1477
Number (95% Confidence Interval) [Events per 100 person years]	17.74	19.50

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Daprodustat, rhEPO
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0540
	Comments
	Method	Wald test
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.91
	Confidence Interval	(2-Sided) 95%; 0.81 to 1.02
	Parameter Dispersion	Type: Value:
	Estimation Comments	Hazard ratio was estimated using a Cox proportional hazard regression model with treatment group, dialysis type and region as covariates.

16. Secondary Outcome

Title	Time to First Occurrence of Adjudicated Hospitalization for Heart Failure During CV Events Follow-up Time Period
Description	Time to first occurrence of adjudicated hospitalization for heart failure was analyzed using a Cox proportional hazards regression model with treatment group, dialysis type and region as covariates. Time to the first occurrence was computed as (event date minus randomization date) + 1. The incidence rate per 100 person years calculated as (100*number of participants with at least 1 event)/first event person-years) is presented along with 95% CI. First event person years=(cumulative total time to first event for participants who have the event + cumulative total of censored time for participants without the event)/365.25, based on the CV follow-up time period.
Time Frame	Up to 3.9 person-years for CV follow-up time period

Outcome Measure Data

Analysis Population Description

All Randomized (ITT) Population.

Arm/Group Title	Daprodustat	rhEPO
Arm/Group Description	Participants received placebo tablets orally once daily in run-in period from Week -4 up to randomization (Day 1) and subsequently received daprodustat tablets at dose levels of 1, 2, 4, 6, 8, 10, 12, 16 and 24 milligrams (mg) orally once daily until the required number of major adverse cardiovascular event (MACE) occurred, at approximately 45.1 months of randomized treatment. Study treatment was dose-titrated to achieve and maintain hemoglobin in the target range (10 to 11 grams per deciliter [g/dL]).	Participants received placebo tablets orally once daily in run-in period from Week -4 up to randomization (Day 1) and subsequently received treatment with rhEPO. Participants on hemodialysis received epoetin alfa as intravenous (IV) injection once weekly or three-times weekly with total weekly dose levels ranging from 1500 to 60,000 Units. Participants on peritoneal dialysis received subcutaneous (SC) injection of darbepoetin alfa every 1, 2, or 4 weeks with 4-weekly total dose levels ranging from 20 to 400 microgram (mcg). Darbepoetin could be given by IV injection for peritoneal dialysis participants switching to hemodialysis. Study treatment was dose-titrated to achieve and maintain hemoglobin in the target range (10 to 11 g/dL) and administered until the required number of MACE events occurred, at approximately 45.1 months of randomized treatment.
Measure Participants	1487	1477
Number (95% Confidence Interval) [Events per 100 person years]	3.30	3.01

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Daprodustat, rhEPO
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.7658
	Comments
	Method	Wald test
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.10
	Confidence Interval	(2-Sided) 95%; 0.84 to 1.45
	Parameter Dispersion	Type: Value:
	Estimation Comments	Hazard ratio was estimated using a Cox proportional hazard regression model with treatment group, dialysis type and region as covariates.

17. Secondary Outcome

Title	Time to First Occurrence of Adjudicated Thromboembolic Events During CV Events Follow-up Time Period
Description	Time to first occurrence of adjudicated thromboembolic events were analyzed using a Cox proportional hazards regression model with treatment group, dialysis type and region as covariates. Time to the first occurrence was computed as (event date minus randomization date) + 1. The incidence rate per 100 person years calculated as (100*number of participants with at least 1 event)/first event person-years) is presented along with 95% CI. First event person years=(cumulative total time to first event for participants who have the event + cumulative total of censored time for participants without the event)/365.25, based on the CV follow-up time period.
Time Frame	Up to 3.9 person-years for CV follow-up time period

Outcome Measure Data

Analysis Population Description

All Randomized (ITT) Population.

Arm/Group Title	Daprodustat	rhEPO
Arm/Group Description	Participants received placebo tablets orally once daily in run-in period from Week -4 up to randomization (Day 1) and subsequently received daprodustat tablets at dose levels of 1, 2, 4, 6, 8, 10, 12, 16 and 24 milligrams (mg) orally once daily until the required number of major adverse cardiovascular event (MACE) occurred, at approximately 45.1 months of randomized treatment. Study treatment was dose-titrated to achieve and maintain hemoglobin in the target range (10 to 11 grams per deciliter [g/dL]).	Participants received placebo tablets orally once daily in run-in period from Week -4 up to randomization (Day 1) and subsequently received treatment with rhEPO. Participants on hemodialysis received epoetin alfa as intravenous (IV) injection once weekly or three-times weekly with total weekly dose levels ranging from 1500 to 60,000 Units. Participants on peritoneal dialysis received subcutaneous (SC) injection of darbepoetin alfa every 1, 2, or 4 weeks with 4-weekly total dose levels ranging from 20 to 400 microgram (mcg). Darbepoetin could be given by IV injection for peritoneal dialysis participants switching to hemodialysis. Study treatment was dose-titrated to achieve and maintain hemoglobin in the target range (10 to 11 g/dL) and administered until the required number of MACE events occurred, at approximately 45.1 months of randomized treatment.
Measure Participants	1487	1477
Number (95% Confidence Interval) [Events per 100 person years]	5.66	6.75

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Daprodustat, rhEPO
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0425
	Comments
	Method	Wald test
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.84
	Confidence Interval	(2-Sided) 95%; 0.69 to 1.02
	Parameter Dispersion	Type: Value:
	Estimation Comments	Hazard ratio was estimated using a Cox proportional hazard regression model with treatment group, dialysis type and region as covariates.

18. Secondary Outcome

Title	Change From Baseline in Post-randomization Hemoglobin Levels at Week 52
Description	Blood samples were collected from participants for hemoglobin measurements. Change from Baseline was defined as post-Baseline value minus Baseline value. Baseline was defined as the latest non-missing pre-dose assessment on or before the randomization date. Analysis was performed using mixed model repeated measures (MMRM) model fitted from Baseline up to Week 52, excluding values collected during the stabilization period, with factors for treatment, time, dialysis type, region, Baseline hemoglobin and Baseline hemoglobin by time and treatment by time interactions.
Time Frame	Baseline (Pre-dose on Day 1) and Week 52

Outcome Measure Data

Analysis Population Description

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

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

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Daprodustat, rhEPO
	Comments
	Type of Statistical Test	Non-Inferiority
	Comments	Non-inferiority was to be established if the lower limit of the two-sided 95% CI for the treatment difference was greater than the pre-specified non-inferiority margin of -0.75 g/dL.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	0.12
	Confidence Interval	(2-Sided) 95%; 0.03 to 0.21
	Parameter Dispersion	Type: Value:
	Estimation Comments

19. Secondary Outcome

Title	Number of Hgb Responders in the Hgb Analysis Range (10 to 11.5 Grams/Deciliter) During Evaluation Period (Week 28 to Week 52)
Description	Mean Hgb during the evaluation period was defined as the mean of all evaluable Hgb values during the evaluation period (Week 28 to Week 52) including any evaluable unscheduled Hgb values that were taken during this time period. Hemoglobin responders were defined as participants with a mean Hgb during the evaluation period that falls within the Hgb analysis range of 10-11.5 g/dL.
Time Frame	Week 28 to Week 52

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Daprodustat	rhEPO
Arm/Group Description	Participants received placebo tablets orally once daily in run-in period from Week -4 up to randomization (Day 1) and subsequently received daprodustat tablets at dose levels of 1, 2, 4, 6, 8, 10, 12, 16 and 24 milligrams (mg) orally once daily until the required number of major adverse cardiovascular event (MACE) occurred, at approximately 45.1 months of randomized treatment. Study treatment was dose-titrated to achieve and maintain hemoglobin in the target range (10 to 11 grams per deciliter [g/dL]).	Participants received placebo tablets orally once daily in run-in period from Week -4 up to randomization (Day 1) and subsequently received treatment with rhEPO. Participants on hemodialysis received epoetin alfa as intravenous (IV) injection once weekly or three-times weekly with total weekly dose levels ranging from 1500 to 60,000 Units. Participants on peritoneal dialysis received subcutaneous (SC) injection of darbepoetin alfa every 1, 2, or 4 weeks with 4-weekly total dose levels ranging from 20 to 400 microgram (mcg). Darbepoetin could be given by IV injection for peritoneal dialysis participants switching to hemodialysis. Study treatment was dose-titrated to achieve and maintain hemoglobin in the target range (10 to 11 g/dL) and administered until the required number of MACE events occurred, at approximately 45.1 months of randomized treatment.
Measure Participants	1238	1247
Count of Participants [Participants]	903 60.7%	866 58.6%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Daprodustat, rhEPO
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0367
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments
Method of Estimation	Estimation Parameter	Difference in response rate
	Estimated Value	3.5
	Confidence Interval	(2-Sided) 95%; -0.1 to 7.1
	Parameter Dispersion	Type: Value:
	Estimation Comments	Cochran-Mantel-Haenszel (CMH) test adjusted for dialysis type, and region was used to compare the number of responders between the treatment groups.

20. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

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

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

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Daprodustat, rhEPO
	Comments
	Type of Statistical Test	Non-Inferiority
	Comments	Non-inferiority was to be established if the lower limit of the two-sided 95% confidence interval for the treatment difference was greater than non-inferiority margin of -15%.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Median Difference (Final Values)
	Estimated Value	1.06
	Confidence Interval	(2-Sided) 95%; 0.00 to 3.86
	Parameter Dispersion	Type: Value:
	Estimation Comments	Hodges-Lehmann estimate of the treatment difference (daprodustat-rhEPO) and associated two-sided asymptotic 95% CI is presented.

21. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

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

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

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Daprodustat, rhEPO
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0805
	Comments
	Method	van Elteren test
	Comments
Method of Estimation	Estimation Parameter	Probability
	Estimated Value	0.52
	Confidence Interval	(2-Sided) 95%; 0.49 to 0.54
	Parameter Dispersion	Type: Value:
	Estimation Comments	Mann-Whitney estimate (Probability) of the treatment effect has been presented.

22. Secondary Outcome

Title	Percentage of Time With Hemoglobin in the Analysis Range (10 to 11.5 Grams/Deciliter) During Maintenance Period (Week 28 to End of Study): Non-inferiority Analysis
Description	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 (3.9 person-years for follow-up time period)

Outcome Measure Data

Analysis Population Description

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

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

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Daprodustat, rhEPO
	Comments
	Type of Statistical Test	Non-Inferiority
	Comments	Non-inferiority was to be established if the lower limit of the two-sided 95% confidence interval for the treatment difference was greater than non-inferiority margin of -15%.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Median Difference (Final Values)
	Estimated Value	2.18
	Confidence Interval	(2-Sided) 95%; 0.28 to 4.05
	Parameter Dispersion	Type: Value:
	Estimation Comments	Hodges-Lehmann estimate of the treatment difference (daprodustat-rhEPO) and associated two-sided asymptotic 95% CI is presented.

23. Secondary Outcome

Title	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
Description	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 (3.9 person-years for follow-up time period)

Outcome Measure Data

Analysis Population Description

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

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

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Daprodustat, rhEPO
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0139
	Comments
	Method	van Elteren test
	Comments
Method of Estimation	Estimation Parameter	Probability
	Estimated Value	0.53
	Confidence Interval	(2-Sided) 95%; 0.50 to 0.55
	Parameter Dispersion	Type: Value:
	Estimation Comments	Mann-Whitney estimate (Probability) of the treatment effect has been presented.

24. Secondary Outcome

Title	Change From Baseline in Systolic Blood Pressure (SBP), Diastolic Blood Pressure (DBP) and Mean Arterial Blood Pressure (MAP) at Week 52
Description	SBP, DBP and MAP were measured in a semi-supine or seated position in the dialysis chair after at least a 5-minutes of rest. MAP is the average BP in an individual's arteries during a single cardiac cycle. Change from Baseline was calculated as on-treatment visit value minus Baseline value. Baseline was defined as the latest non-missing pre-dose assessment on or before the randomization date. Analysis was performed using MMRM model with treatment group + time + dialysis type + region + Baseline value + Baseline value*time + treatment group*time, using an unstructured covariance matrix. Data for post-dialysis BP measurements have been presented.
Time Frame	Baseline (Week -4) and Week 52

Outcome Measure Data

Analysis Population Description

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

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

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Daprodustat, rhEPO
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.6551
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	0.33
	Confidence Interval	(2-Sided) 95%; -1.28 to 1.94
	Parameter Dispersion	Type: Value:
	Estimation Comments	The difference in change from Baseline in SBP at Week 52 was analyzed with a MMRM approach with an unstructured covariance matrix to compare the difference in means between arms.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Daprodustat, rhEPO
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1586
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-0.46
	Confidence Interval	(2-Sided) 95%; -1.36 to 0.44
	Parameter Dispersion	Type: Value:
	Estimation Comments	The difference in change from Baseline in DBP at Week 52 was analyzed with a MMRM approach with an unstructured covariance matrix to compare the difference in means between arms.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Daprodustat, rhEPO
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.3646
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-0.18
	Confidence Interval	(2-Sided) 95%; -1.20 to 0.84
	Parameter Dispersion	Type: Value:
	Estimation Comments	The difference in change from Baseline in MAP at Week 52 was analyzed with a MMRM approach with an unstructured covariance matrix to compare the difference in means between arms.

25. Secondary Outcome

Title	Change From Baseline in SBP, DBP, MAP at End of Treatment
Description	SBP, DBP and MAP were measured in a semi-supine or seated position in the dialysis chair after at least a 5-minutes of rest. MAP is an average BP in an individual's arteries during a single cardiac cycle. Change from Baseline was calculated as on-treatment visit value minus Baseline value. Baseline was defined as the latest non-missing pre-dose assessment on or before the randomization date. This analysis was carried out by using ANCOVA model with terms for treatment group, dialysis type, region and Baseline value. Data for post-dialysis BP measurements have been presented.
Time Frame	Baseline (Week -4) and 45.1 months

Outcome Measure Data

Analysis Population Description

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

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

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Daprodustat, rhEPO
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.5012
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	0.00
	Confidence Interval	(2-Sided) 95%; -1.54 to 1.54
	Parameter Dispersion	Type: Value:
	Estimation Comments	For SBP: Treatment group comparisons were based on an ANCOVA model with terms for treatment group, dialysis type, region and Baseline value.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Daprodustat, rhEPO
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.8451
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	0.45
	Confidence Interval	(2-Sided) 95%; -0.42 to 1.31
	Parameter Dispersion	Type: Value:
	Estimation Comments	For DBP: Treatment group comparisons were based on an ANCOVA model with terms for treatment group, dialysis type, region and Baseline value.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Daprodustat, rhEPO
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.7312
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	0.31
	Confidence Interval	(2-Sided) 95%; -0.67 to 1.28
	Parameter Dispersion	Type: Value:
	Estimation Comments	For MAP: Treatment group comparisons were based on an ANCOVA model with terms for treatment group, dialysis type, region and Baseline value.

26. Secondary Outcome

Title	Blood Pressure (BP) Exacerbation Event Rate Per 100 Participant Years
Description	BP exacerbation was defined (based on post-dialysis) as: SBP >= 25 millimeter of mercury (mmHg) increased from Baseline or SBP >=180 mmHg; DBP >=15 mmHg increased from Baseline or DBP >=110 mmHg. The BP exacerbation events per 100 participant years was estimated using the negative binomial model with treatment, dialysis type and region as covariates and the logarithm of time on-treatment as an offset variable. Data for post-dialysis BP measurements have been presented.
Time Frame	Day 1 to end of study (3.9 person-years for follow-up time period)

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Daprodustat	rhEPO
Arm/Group Description	Participants received placebo tablets orally once daily in run-in period from Week -4 up to randomization (Day 1) and subsequently received daprodustat tablets at dose levels of 1, 2, 4, 6, 8, 10, 12, 16 and 24 milligrams (mg) orally once daily until the required number of major adverse cardiovascular event (MACE) occurred, at approximately 45.1 months of randomized treatment. Study treatment was dose-titrated to achieve and maintain hemoglobin in the target range (10 to 11 grams per deciliter [g/dL]).	Participants received placebo tablets orally once daily in run-in period from Week -4 up to randomization (Day 1) and subsequently received treatment with rhEPO. Participants on hemodialysis received epoetin alfa as intravenous (IV) injection once weekly or three-times weekly with total weekly dose levels ranging from 1500 to 60,000 Units. Participants on peritoneal dialysis received subcutaneous (SC) injection of darbepoetin alfa every 1, 2, or 4 weeks with 4-weekly total dose levels ranging from 20 to 400 microgram (mcg). Darbepoetin could be given by IV injection for peritoneal dialysis participants switching to hemodialysis. Study treatment was dose-titrated to achieve and maintain hemoglobin in the target range (10 to 11 g/dL) and administered until the required number of MACE events occurred, at approximately 45.1 months of randomized treatment.
Measure Participants	1470	1458
Number (95% Confidence Interval) [Events per 100 participant years]	207.13	206.38

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Daprodustat, rhEPO
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.5290
	Comments
	Method	Negative binomial model
	Comments
Method of Estimation	Estimation Parameter	Ratio of exacerbation rate
	Estimated Value	1.00
	Confidence Interval	(2-Sided) 95%; 0.91 to 1.11
	Parameter Dispersion	Type: Value:
	Estimation Comments	Ratio of model estimated exacerbation rates and CIs were estimated using a negative binomial model for the treatment group comparison.

27. Secondary Outcome

Title	Number of Participants With at Least One BP Exacerbation Event During Study
Description	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 study (3.9 person-years for follow-up time period)

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Daprodustat	rhEPO
Arm/Group Description	Participants received placebo tablets orally once daily in run-in period from Week -4 up to randomization (Day 1) and subsequently received daprodustat tablets at dose levels of 1, 2, 4, 6, 8, 10, 12, 16 and 24 milligrams (mg) orally once daily until the required number of major adverse cardiovascular event (MACE) occurred, at approximately 45.1 months of randomized treatment. Study treatment was dose-titrated to achieve and maintain hemoglobin in the target range (10 to 11 grams per deciliter [g/dL]).	Participants received placebo tablets orally once daily in run-in period from Week -4 up to randomization (Day 1) and subsequently received treatment with rhEPO. Participants on hemodialysis received epoetin alfa as intravenous (IV) injection once weekly or three-times weekly with total weekly dose levels ranging from 1500 to 60,000 Units. Participants on peritoneal dialysis received subcutaneous (SC) injection of darbepoetin alfa every 1, 2, or 4 weeks with 4-weekly total dose levels ranging from 20 to 400 microgram (mcg). Darbepoetin could be given by IV injection for peritoneal dialysis participants switching to hemodialysis. Study treatment was dose-titrated to achieve and maintain hemoglobin in the target range (10 to 11 g/dL) and administered until the required number of MACE events occurred, at approximately 45.1 months of randomized treatment.
Measure Participants	1480	1470
Count of Participants [Participants]	1191 80.1%	1186 80.3%

28. Secondary Outcome

Title	Percentage of Participants Permanently Stopping Randomized Treatment Due to Meeting Rescue Criteria
Description	Percentage of participants permanently stopping randomized treatment due to meeting rescue criteria has been presented.
Time Frame	Day 1 to 45.1 months

Outcome Measure Data

Analysis Population Description

All Randomized (ITT) Population.

Arm/Group Title	Daprodustat	rhEPO
Arm/Group Description	Participants received placebo tablets orally once daily in run-in period from Week -4 up to randomization (Day 1) and subsequently received daprodustat tablets at dose levels of 1, 2, 4, 6, 8, 10, 12, 16 and 24 milligrams (mg) orally once daily until the required number of major adverse cardiovascular event (MACE) occurred, at approximately 45.1 months of randomized treatment. Study treatment was dose-titrated to achieve and maintain hemoglobin in the target range (10 to 11 grams per deciliter [g/dL]).	Participants received placebo tablets orally once daily in run-in period from Week -4 up to randomization (Day 1) and subsequently received treatment with rhEPO. Participants on hemodialysis received epoetin alfa as intravenous (IV) injection once weekly or three-times weekly with total weekly dose levels ranging from 1500 to 60,000 Units. Participants on peritoneal dialysis received subcutaneous (SC) injection of darbepoetin alfa every 1, 2, or 4 weeks with 4-weekly total dose levels ranging from 20 to 400 microgram (mcg). Darbepoetin could be given by IV injection for peritoneal dialysis participants switching to hemodialysis. Study treatment was dose-titrated to achieve and maintain hemoglobin in the target range (10 to 11 g/dL) and administered until the required number of MACE events occurred, at approximately 45.1 months of randomized treatment.
Measure Participants	1487	1477
Number [Percentage of participants]	3.6 0.2%	3.6 0.2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Daprodustat, rhEPO
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.5772
	Comments
	Method	Wald test
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.04
	Confidence Interval	(2-Sided) 95%; 0.71 to 1.52
	Parameter Dispersion	Type: Value:
	Estimation Comments	Hazard ratio was estimated using a Cox proportional hazard regression model adjusted for treatment group, dialysis type and region.

29. Secondary Outcome

Title	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
Description	The SF-36 acute version 2 is a 36-item generic quality of life instrument designed to measure a participant's level of performance in the following 8 health domains: physical functioning, role-physical (role limitations caused by physical problems), social functioning, bodily pain, mental health, role-emotional (role limitations caused by emotional problems), vitality and general health. Each domain is scored from 0 (poorer health) to 100 (better health). The PCS is an average score derived from 4 domains (physical functioning, role-physical, bodily pain and general health) representing overall physical health. PCS ranges from 0 to 100; higher scores represent better health. Change from Baseline was calculated as on-treatment visit value minus Baseline value. Baseline was defined as the latest non-missing pre-dose assessment on or before the randomization date.
Time Frame	Baseline (Pre-dose on Day 1), Weeks 8, 12, 28 and 52

Outcome Measure Data

Analysis Population Description

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

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Daprodustat, rhEPO
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1620
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	0.29
	Confidence Interval	(2-Sided) 95%; -0.29 to 0.86
	Parameter Dispersion	Type: Value:
	Estimation Comments	Week 8: Model was fitted from Baseline up to Week 52 and the model adjusted Week 8 data has been presented, with factors for treatment, time, dialysis type, region, Baseline value and Baseline value by time and treatment by time interactions.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Daprodustat, rhEPO
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0180
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	0.61
	Confidence Interval	(2-Sided) 95%; 0.04 to 1.18
	Parameter Dispersion	Type: Value:
	Estimation Comments	Week 12: Model was fitted from Baseline up to Week 52 and the model adjusted Week 12 data has been presented, with factors for treatment, time, dialysis type, region, Baseline value and Baseline value by time and treatment by time interactions.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Daprodustat, rhEPO
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1530
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	0.33
	Confidence Interval	(2-Sided) 95%; -0.31 to 0.97
	Parameter Dispersion	Type: Value:
	Estimation Comments	Week 28: Model was fitted from Baseline up to Week 52 and the model adjusted Week 28 data has been presented, with factors for treatment, time, dialysis type, region, Baseline value and Baseline value by time and treatment by time interactions.

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Daprodustat, rhEPO
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0686
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	0.53
	Confidence Interval	(2-Sided) 95%; -0.17 to 1.22
	Parameter Dispersion	Type: Value:
	Estimation Comments	Week 52: Model was fitted from Baseline up to Week 52 and the model adjusted Week 52 data has been presented, with factors for treatment, time, dialysis type, region, Baseline value and Baseline value by time and treatment by time interactions.

30. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

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

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Daprodustat, rhEPO
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.6807
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-0.17
	Confidence Interval	(2-Sided) 95%; -0.88 to 0.54
	Parameter Dispersion	Type: Value:
	Estimation Comments	Week 8: Model was fitted from Baseline up to Week 52 and the model adjusted Week 8 data has been presented, with factors for treatment, time, dialysis type, region, Baseline value and Baseline value by time and treatment by time interactions.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Daprodustat, rhEPO
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.3256
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	0.17
	Confidence Interval	(2-Sided) 95%; -0.57 to 0.91
	Parameter Dispersion	Type: Value:
	Estimation Comments	Week 12: Model was fitted from Baseline up to Week 52 and the model adjusted Week 12 data has been presented, with factors for treatment, time, dialysis type, region, Baseline value and Baseline value by time and treatment by time interactions.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Daprodustat, rhEPO
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.5144
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-0.01
	Confidence Interval	(2-Sided) 95%; -0.81 to 0.78
	Parameter Dispersion	Type: Value:
	Estimation Comments	Week 28: Model was fitted from Baseline up to Week 52 and the model adjusted Week 28 data has been presented, with factors for treatment, time, dialysis type, region, Baseline value and Baseline value by time and treatment by time interactions.

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Daprodustat, rhEPO
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.9120
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-0.60
	Confidence Interval	(2-Sided) 95%; -1.47 to 0.27
	Parameter Dispersion	Type: Value:
	Estimation Comments	Week 52: Model was fitted from Baseline up to Week 52 and the model adjusted Week 52 data has been presented, with factors for treatment, time, dialysis type, region, Baseline value and Baseline value by time and treatment by time interactions.

31. Secondary Outcome

Title	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
Description	The SF-36 acute version 2 is a 36-item generic quality of life instrument designed to measure a participant's level of performance in the following 8 health domains: bodily pain, general health, mental health, role-emotional (role limitations caused by emotional problems), role-physical (role limitations caused by physical problems), social functioning (Social fun), physical functioning (Phy. fun) and vitality. Each domain is scored from 0 (poorer health) to 100 (better health). Each domain score ranges from 0 to 100, higher score indicates a better health state and better functioning. Change from Baseline was calculated as on-treatment visit value minus Baseline value. Baseline was defined as the latest non-missing pre-dose assessment on or before the randomization date.
Time Frame	Baseline (Pre-dose on Day 1), Weeks 8, 12, 28 and 52

Outcome Measure Data

Analysis Population Description

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

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Daprodustat, rhEPO
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.7432
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-0.25
	Confidence Interval	(2-Sided) 95%; -0.99 to 0.50
	Parameter Dispersion	Type: Value:
	Estimation Comments	Bodily pain,Week8: Model was fitted from Baseline up to Week52 and model adjusted Week8 data has been presented, with factors for treatment, time, dialysis type, region, Baseline value and Baseline value by time and treatment by time interactions.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Daprodustat, rhEPO
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0631
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	0.58
	Confidence Interval	(2-Sided) 95%; -0.16 to 1.33
	Parameter Dispersion	Type: Value:
	Estimation Comments	Bodily pain,Week12: Model was fitted from Baseline up to Week52 and model adjusted Week12 data has been presented, with factors for treatment, time, dialysis type, region, Baseline value and Baseline value by time and treatment by time interactions.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Daprodustat, rhEPO
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.4604
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	0.04
	Confidence Interval	(2-Sided) 95%; -0.79 to 0.87
	Parameter Dispersion	Type: Value:
	Estimation Comments	Bodily pain,Week28: Model was fitted from Baseline up to Week52 and model adjusted Week28 data has been presented, with factors for treatment, time, dialysis type, region, Baseline value and Baseline value by time and treatment by time interactions.

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Daprodustat, rhEPO
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.2688
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	0.28
	Confidence Interval	(2-Sided) 95%; -0.60 to 1.15
	Parameter Dispersion	Type: Value:
	Estimation Comments	Bodily pain,Week52: Model was fitted from Baseline up to Week52 and model adjusted Week52 data has been presented, with factors for treatment, time, dialysis type, region, Baseline value and Baseline value by time and treatment by time interactions.

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Daprodustat, rhEPO
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1918
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	0.26
	Confidence Interval	(2-Sided) 95%; -0.32 to 0.84
	Parameter Dispersion	Type: Value:
	Estimation Comments	General health,Week8:Model was fitted from Baseline up to Week52 and model adjusted Week8 data has been presented, with factors for treatment, time, dialysis type, region, Baseline value and Baseline value by time and treatment by time interactions.

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Daprodustat, rhEPO
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0677
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	0.45
	Confidence Interval	(2-Sided) 95%; -0.14 to 1.04
	Parameter Dispersion	Type: Value:
	Estimation Comments	General health,Week12:Model was fitted from Baseline up to Week52 and model adjusted Week12 data has been presented, with factors for treatment, time, dialysis type, region,Baseline value and Baseline value by time and treatment by time interactions.

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Daprodustat, rhEPO
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.8386
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-0.33
	Confidence Interval	(2-Sided) 95%; -0.98 to 0.32
	Parameter Dispersion	Type: Value:
	Estimation Comments	General health,Week28:Model was fitted from Baseline up to Week52 and model adjusted Week28 data has been presented, with factors for treatment, time, dialysis type, region,Baseline value and Baseline value by time and treatment by time interactions.

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Daprodustat, rhEPO
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.7928
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-0.29
	Confidence Interval	(2-Sided) 95%; -0.99 to 0.41
	Parameter Dispersion	Type: Value:
	Estimation Comments	General health,Week52:Model was fitted from Baseline up to Week52 and model adjusted Week52 data has been presented, with factors for treatment, time, dialysis type, region,Baseline value and Baseline value by time and treatment by time interactions.

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	Daprodustat, rhEPO
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.4537
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	0.04
	Confidence Interval	(2-Sided) 95%; -0.63 to 0.71
	Parameter Dispersion	Type: Value:
	Estimation Comments	Mental health,Week8:Model was fitted from Baseline up to Week52 and model adjusted Week8 data has been presented, with factors for treatment, time, dialysis type, region, Baseline value and Baseline value by time and treatment by time interactions.

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	Daprodustat, rhEPO
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.5548
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-0.05
	Confidence Interval	(2-Sided) 95%; -0.74 to 0.65
	Parameter Dispersion	Type: Value:
	Estimation Comments	Mental health,Week12:Model was fitted from Baseline up to Week52 and model adjusted Week12 data has been presented, with factors for treatment, time, dialysis type, region,Baseline value and Baseline value by time and treatment by time interactions.

Statistical Analysis 11

Statistical Analysis Overview	Comparison Group Selection	Daprodustat, rhEPO
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.3626
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	0.13
	Confidence Interval	(2-Sided) 95%; -0.61 to 0.88
	Parameter Dispersion	Type: Value:
	Estimation Comments	Mental health,Week28:Model was fitted from Baseline up to Week52 and model adjusted Week28 data has been presented, with factors for treatment, time, dialysis type, region,Baseline value and Baseline value by time and treatment by time interactions.

Statistical Analysis 12

Statistical Analysis Overview	Comparison Group Selection	Daprodustat, rhEPO
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.9721
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-0.81
	Confidence Interval	(2-Sided) 95%; -1.64 to 0.02
	Parameter Dispersion	Type: Value:
	Estimation Comments	Mental health,Week52:Model was fitted from Baseline up to Week52 and model adjusted Week52 data has been presented, with factors for treatment, time, dialysis type, region,Baseline value and Baseline value by time and treatment by time interactions.

Statistical Analysis 13

Statistical Analysis Overview	Comparison Group Selection	Daprodustat, rhEPO
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.5789
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-0.09
	Confidence Interval	(2-Sided) 95%; -0.96 to 0.78
	Parameter Dispersion	Type: Value:
	Estimation Comments	Role-emotional,Week8:Model was fitted from Baseline up to Week52 and model adjusted Week8 data has been presented, with factors for treatment, time, dialysis type, region, Baseline value and Baseline value by time and treatment by time interactions.

Statistical Analysis 14

Statistical Analysis Overview	Comparison Group Selection	Daprodustat, rhEPO
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.2054
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	0.37
	Confidence Interval	(2-Sided) 95%; -0.51 to 1.24
	Parameter Dispersion	Type: Value:
	Estimation Comments	Role-emotional,Week12:Model was fitted from Baseline up to Week52 and model adjusted Week12 data has been presented, with factors for treatment, time, dialysis type, region,Baseline value and Baseline value by time and treatment by time interactions.

Statistical Analysis 15

Statistical Analysis Overview	Comparison Group Selection	Daprodustat, rhEPO
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.5389
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-0.05
	Confidence Interval	(2-Sided) 95%; -0.98 to 0.89
	Parameter Dispersion	Type: Value:
	Estimation Comments	Role-emotional,Week28:Model was fitted from Baseline up to Week52 and model adjusted Week28 data has been presented, with factors for treatment, time, dialysis type, region,Baseline value and Baseline value by time and treatment by time interactions.

Statistical Analysis 16

Statistical Analysis Overview	Comparison Group Selection	Daprodustat, rhEPO
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.4289
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	0.09
	Confidence Interval	(2-Sided) 95%; -0.91 to 1.09
	Parameter Dispersion	Type: Value:
	Estimation Comments	Role-emotional,Week52:Model was fitted from Baseline up to Week52 and model adjusted Week52 data has been presented, with factors for treatment, time, dialysis type, region,Baseline value and Baseline value by time and treatment by time interactions.

Statistical Analysis 17

Statistical Analysis Overview	Comparison Group Selection	Daprodustat, rhEPO
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.4096
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	0.08
	Confidence Interval	(2-Sided) 95%; -0.60 to 0.75
	Parameter Dispersion	Type: Value:
	Estimation Comments	Role-physical,Week8:Model was fitted from Baseline up to Week52 and model adjusted Week8 data has been presented, with factors for treatment, time, dialysis type, region, Baseline value and Baseline value by time and treatment by time interactions.

Statistical Analysis 18

Statistical Analysis Overview	Comparison Group Selection	Daprodustat, rhEPO
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1196
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	0.40
	Confidence Interval	(2-Sided) 95%; -0.27 to 1.07
	Parameter Dispersion	Type: Value:
	Estimation Comments	Role-physical,Week12:Model was fitted from Baseline up to Week52 and model adjusted Week12 data has been presented, with factors for treatment, time, dialysis type, region,Baseline value and Baseline value by time and treatment by time interactions

Statistical Analysis 19

Statistical Analysis Overview	Comparison Group Selection	Daprodustat, rhEPO
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.2093
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	0.30
	Confidence Interval	(2-Sided) 95%; -0.42 to 1.01
	Parameter Dispersion	Type: Value:
	Estimation Comments	Role-physical,Week28:Model was fitted from Baseline up to Week52 and model adjusted Week28 data has been presented, with factors for treatment, time, dialysis type, region,Baseline value and Baseline value by time and treatment by time interactions

Statistical Analysis 20

Statistical Analysis Overview	Comparison Group Selection	Daprodustat, rhEPO
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1674
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	0.39
	Confidence Interval	(2-Sided) 95%; -0.40 to 1.19
	Parameter Dispersion	Type: Value:
	Estimation Comments	Role-physical,Week52:Model was fitted from Baseline up to Week52 and model adjusted Week52 data has been presented, with factors for treatment, time, dialysis type, region,Baseline value and Baseline value by time and treatment by time interactions

Statistical Analysis 21

Statistical Analysis Overview	Comparison Group Selection	Daprodustat, rhEPO
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.6585
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-0.14
	Confidence Interval	(2-Sided) 95%; -0.82 to 0.54
	Parameter Dispersion	Type: Value:
	Estimation Comments	Social fun, Week 8: Model was fitted from Baseline up to Week52 and model adjusted Week8 data has been presented, with factors for treatment, time, dialysis type, region, Baseline value and Baseline value by time and treatment by time interactions.

Statistical Analysis 22

Statistical Analysis Overview	Comparison Group Selection	Daprodustat, rhEPO
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0293
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	0.69
	Confidence Interval	(2-Sided) 95%; -0.03 to 1.40
	Parameter Dispersion	Type: Value:
	Estimation Comments	Social fun, Week 12: Model was fitted from Baseline up to Week52 and model adjusted Week12 data has been presented, with factors for treatment, time, dialysis type, region, Baseline value and Baseline value by time and treatment by time interactions.

Statistical Analysis 23

Statistical Analysis Overview	Comparison Group Selection	Daprodustat, rhEPO
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.2057
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	0.33
	Confidence Interval	(2-Sided) 95%; -0.45 to 1.11
	Parameter Dispersion	Type: Value:
	Estimation Comments	Social fun, Week 28: Model was fitted from Baseline up to Week52 and model adjusted Week28 data has been presented, with factors for treatment, time, dialysis type, region, Baseline value and Baseline value by time and treatment by time interactions.

Statistical Analysis 24

Statistical Analysis Overview	Comparison Group Selection	Daprodustat, rhEPO
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.4849
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	0.02
	Confidence Interval	(2-Sided) 95%; -0.86 to 0.90
	Parameter Dispersion	Type: Value:
	Estimation Comments	Social fun, Week 52: Model was fitted from Baseline up to Week52 and model adjusted Week52 data has been presented, with factors for treatment, time, dialysis type, region, Baseline value and Baseline value by time and treatment by time interactions.

32. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

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

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Daprodustat, rhEPO
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.4621
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	0.03
	Confidence Interval	(2-Sided) 95%; -0.58 to 0.64
	Parameter Dispersion	Type: Value:
	Estimation Comments	Week 8: Model was fitted from Baseline up to Week 52 and model adjusted Week 8 data has been presented, with factors for treatment, time, dialysis type, region, Baseline value and Baseline value by time and treatment by time interactions.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Daprodustat, rhEPO
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1439
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	0.35
	Confidence Interval	(2-Sided) 95%; -0.29 to 0.98
	Parameter Dispersion	Type: Value:
	Estimation Comments	Week 12: Model was fitted from Baseline up to Week 52 and model adjusted Week 12 data has been presented, with factors for treatment, time, dialysis type, region, Baseline value and Baseline value by time and treatment by time interactions.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Daprodustat, rhEPO
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.2392
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	0.24
	Confidence Interval	(2-Sided) 95%; -0.43 to 0.92
	Parameter Dispersion	Type: Value:
	Estimation Comments	Week 28: Model was fitted from Baseline up to Week 52 and model adjusted Week 28 data has been presented, with factors for treatment, time, dialysis type, region, Baseline value and Baseline value by time and treatment by time interactions.

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Daprodustat, rhEPO
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.6545
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-0.15
	Confidence Interval	(2-Sided) 95%; -0.90 to 0.60
	Parameter Dispersion	Type: Value:
	Estimation Comments	Week 52: Model was fitted from Baseline up to Week 52 and model adjusted Week 52 data has been presented, with factors for treatment, time, dialysis type, region, Baseline value and Baseline value by time and treatment by time interactions.

33. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

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

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Daprodustat, rhEPO
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0290
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	0.64
	Confidence Interval	(2-Sided) 95%; -0.02 to 1.31
	Parameter Dispersion	Type: Value:
	Estimation Comments	Week 8: Model was fitted from Baseline up to Week 52 and model adjusted Week 8 data has been presented, with factors for treatment, time, dialysis type, region, Baseline value and Baseline value by time and treatment by time interactions.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Daprodustat, rhEPO
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0509
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	0.56
	Confidence Interval	(2-Sided) 95%; -0.11 to 1.24
	Parameter Dispersion	Type: Value:
	Estimation Comments	Week 12: Model was fitted from Baseline up to Week 52 and model adjusted Week 12 data has been presented, with factors for treatment, time, dialysis type, region, Baseline value and Baseline value by time and treatment by time interactions.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Daprodustat, rhEPO
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0237
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	0.77
	Confidence Interval	(2-Sided) 95%; 0.01 to 1.53
	Parameter Dispersion	Type: Value:
	Estimation Comments	Week 28: Model was fitted from Baseline up to Week 52 and model adjusted Week 28 data has been presented, with factors for treatment, time, dialysis type, region, Baseline value and Baseline value by time and treatment by time interactions.

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Daprodustat, rhEPO
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0828
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	0.58
	Confidence Interval	(2-Sided) 95%; -0.24 to 1.39
	Parameter Dispersion	Type: Value:
	Estimation Comments	Week 52: Model was fitted from Baseline up to Week 52 and model adjusted Week 52 data has been presented, with factors for treatment, time, dialysis type, region, Baseline value and Baseline value by time and treatment by time interactions.

34. Secondary Outcome

Title	Change From Baseline in On-Treatment Health Utility EuroQol 5 Dimensions 5 Level (EQ-5D-5L) Questionnaire Score at Week 52
Description	EQ-5D-5L is self-assessment questionnaire,consisting of 5 items covering 5 dimensions (mobility,self care,usual activities,pain/discomfort and anxiety/depression). Each dimension is measured by 5-point Likert scale (1=no problems, 2=slight problems, 3=moderate problems, 4=severe problems and 5=extreme problems). Responses for 5 dimensions together formed a 5-figure description of health state (e.g.11111 indicates no problems in all 5 dimensions). Each of these 5 figure health states were converted to a single index score by applying country-specific value set formula that attaches weights to dimensions and levels. Range for EQ-5D-5L index score is -0.594 (worst health) to 1 (full health state). Change from Baseline was calculated as on-treatment visit value-Baseline value. Baseline was latest non-missing pre-dose assessment on or before randomization date.
Time Frame	Baseline (Pre-dose on Day 1) and Week 52

Outcome Measure Data

Analysis Population Description

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

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

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Daprodustat, rhEPO
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.4939
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	0.0003
	Confidence Interval	(2-Sided) 95%; -0.0326 to 0.0331
	Parameter Dispersion	Type: Value:
	Estimation Comments	MMRM model was fitted from Baseline up to Week 52 with factors for treatment, time, dialysis type, region, Baseline value and Baseline value by time and treatment by time interactions.

35. Secondary Outcome

Title	Change From Baseline in On-Treatment EuroQol Visual Analogue Scale (EQ-VAS) at Week 52
Description	The EQ VAS records the respondent's self-rated health on a vertical VAS, ranging from 0 to 100, where 0 represents the worst health one can imagine and 100 represents the best health one can imagine. Change from Baseline was calculated as on-treatment visit value minus Baseline value. Baseline was defined as the latest non-missing pre-dose assessment on or before the randomization date.
Time Frame	Baseline (Pre-dose on Day 1) and Week 52

Outcome Measure Data

Analysis Population Description

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

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

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Daprodustat, rhEPO
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.9292
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-1.8
	Confidence Interval	(2-Sided) 95%; -4.2 to 0.6
	Parameter Dispersion	Type: Value:
	Estimation Comments	MMRM model was fitted from Baseline up to Week 52 with factors for treatment, time, dialysis type, region, Baseline value and Baseline value by time and treatment by time interactions.

36. Secondary Outcome

Title	Change From Baseline in On-Treatment Patient Global Impression of Severity (PGI-S) at Weeks 8, 12, 28, 52
Description	The PGI-S is a 1-item questionnaire designed to assess participant's impression of disease severity on a 5-point disease severity scale (0=absent, 1=mild, 2=moderate, 3=severe, or 4=very severe). A higher score indicated worse outcome. Change from Baseline was calculated as on-treatment visit value minus Baseline value. Baseline was defined as the latest non-missing pre-dose assessment on or before the randomization date.
Time Frame	Baseline (Pre-dose on Day 1), Weeks 8, 12, 28 and 52

Outcome Measure Data

Analysis Population Description

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

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Daprodustat, rhEPO
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0428
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-0.06
	Confidence Interval	(2-Sided) 95%; -0.13 to 0.01
	Parameter Dispersion	Type: Value:
	Estimation Comments	Week 8: Model was fitted from Baseline up to Week 52 and model adjusted Week 8 data has been presented, with factors for treatment, time, dialysis type, region, Baseline value and Baseline value by time and treatment by time interactions.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Daprodustat, rhEPO
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1155
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-0.04
	Confidence Interval	(2-Sided) 95%; -0.11 to 0.03
	Parameter Dispersion	Type: Value:
	Estimation Comments	Week 12: Model was fitted from Baseline up to Week 52 and model adjusted Week 12 data has been presented, with factors for treatment, time, dialysis type, region, Baseline value and Baseline value by time and treatment by time interactions.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Daprodustat, rhEPO
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1426
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-0.04
	Confidence Interval	(2-Sided) 95%; -0.12 to 0.03
	Parameter Dispersion	Type: Value:
	Estimation Comments	Week 28: Model was fitted from Baseline up to Week 52 and model adjusted Week 28 data has been presented, with factors for treatment, time, dialysis type, region, Baseline value and Baseline value by time and treatment by time interactions.

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Daprodustat, rhEPO
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1152
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-0.05
	Confidence Interval	(2-Sided) 95%; -0.13 to 0.03
	Parameter Dispersion	Type: Value:
	Estimation Comments	Week 52: Model was fitted from Baseline up to Week 52 and model adjusted Week 52 data has been presented, with factors for treatment, time, dialysis type, region, Baseline value and Baseline value by time and treatment by time interactions.

Adverse Events

Time Frame	All-cause mortality, treatment emergent serious adverse events (TESAEs) and non-serious treatment emergent adverse events (TEAEs) were collected up to 3.9 person-years for CV follow-up time period
Adverse Event Reporting Description	All-cause mortality used All Randomized (ITT) Population consisting of all randomized participants and analyzed based on treatment to which they were randomized. TESAEs and non-serious TEAEs used Safety Population, which included all randomized participants who received at least 1 dose of treatment and analyzed based on treatment received. Eight participants in All Randomized (ITT) Population did not receive treatment and were excluded from Safety Population.
Arm/Group Title	Daprodustat		rhEPO
Arm/Group Description	Participants received placebo tablets orally once daily in run-in period from Week -4 up to randomization (Day 1) and subsequently received daprodustat tablets at dose levels of 1, 2, 4, 6, 8, 10, 12, 16 and 24 milligrams (mg) orally once daily until the required number of major adverse cardiovascular event (MACE) occurred, at approximately 45.1 months of randomized treatment. Study treatment was dose-titrated to achieve and maintain hemoglobin in the target range (10 to 11 grams per deciliter [g/dL]).		Participants received placebo tablets orally once daily in run-in period from Week -4 up to randomization (Day 1) and subsequently received treatment with rhEPO. Participants on hemodialysis received epoetin alfa as intravenous (IV) injection once weekly or three-times weekly with total weekly dose levels ranging from 1500 to 60,000 Units. Participants on peritoneal dialysis received subcutaneous (SC) injection of darbepoetin alfa every 1, 2, or 4 weeks with 4-weekly total dose levels ranging from 20 to 400 microgram (mcg). Darbepoetin could be given by IV injection for peritoneal dialysis participants switching to hemodialysis. Study treatment was dose-titrated to achieve and maintain hemoglobin in the target range (10 to 11 g/dL) and administered until the required number of MACE events occurred, at approximately 45.1 months of randomized treatment.
All Cause Mortality
	Daprodustat		rhEPO
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	294/1487 (19.8%)		300/1477 (20.3%)
Serious Adverse Events
	Daprodustat		rhEPO
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	773/1482 (52.2%)		748/1474 (50.7%)
Blood and lymphatic system disorders
Anaemia	26/1482 (1.8%)	29	41/1474 (2.8%)	52
Blood loss anaemia	4/1482 (0.3%)	5	3/1474 (0.2%)	3
Lymphadenitis	1/1482 (0.1%)	1	1/1474 (0.1%)	1
Pancytopenia	2/1482 (0.1%)	2	0/1474 (0%)	0
Aplastic anaemia	1/1482 (0.1%)	1	0/1474 (0%)	0
Coagulopathy	0/1482 (0%)	0	1/1474 (0.1%)	2
Cytopenia	1/1482 (0.1%)	1	0/1474 (0%)	0
Leukocytosis	1/1482 (0.1%)	1	0/1474 (0%)	0
Leukopenia	1/1482 (0.1%)	1	0/1474 (0%)	0
Lymphadenopathy	1/1482 (0.1%)	1	0/1474 (0%)	0
Non-immune heparin associated thrombocytopenia	0/1482 (0%)	0	1/1474 (0.1%)	1
Normocytic anaemia	0/1482 (0%)	0	1/1474 (0.1%)	1
Cardiac disorders
Acute myocardial infarction	30/1482 (2%)	33	31/1474 (2.1%)	40
Atrial fibrillation	23/1482 (1.6%)	26	35/1474 (2.4%)	44
Cardiac arrest	20/1482 (1.3%)	20	15/1474 (1%)	15
Angina pectoris	18/1482 (1.2%)	19	16/1474 (1.1%)	18
Cardiac failure	18/1482 (1.2%)	23	15/1474 (1%)	15
Cardiac failure congestive	18/1482 (1.2%)	19	15/1474 (1%)	19
Myocardial infarction	11/1482 (0.7%)	11	17/1474 (1.2%)	17
Angina unstable	14/1482 (0.9%)	14	13/1474 (0.9%)	15
Coronary artery disease	10/1482 (0.7%)	11	16/1474 (1.1%)	16
Acute coronary syndrome	3/1482 (0.2%)	3	10/1474 (0.7%)	10
Cardio-respiratory arrest	8/1482 (0.5%)	8	5/1474 (0.3%)	5
Bradycardia	2/1482 (0.1%)	2	8/1474 (0.5%)	8
Acute left ventricular failure	4/1482 (0.3%)	4	5/1474 (0.3%)	6
Atrial flutter	4/1482 (0.3%)	4	5/1474 (0.3%)	5
Cardiac failure acute	8/1482 (0.5%)	8	1/1474 (0.1%)	1
Aortic valve stenosis	2/1482 (0.1%)	2	5/1474 (0.3%)	5
Pericardial effusion	3/1482 (0.2%)	3	4/1474 (0.3%)	6
Atrioventricular block complete	2/1482 (0.1%)	2	4/1474 (0.3%)	4
Mitral valve incompetence	4/1482 (0.3%)	4	2/1474 (0.1%)	2
Myocardial ischaemia	4/1482 (0.3%)	4	2/1474 (0.1%)	2
Pericarditis	2/1482 (0.1%)	2	3/1474 (0.2%)	3
Cardiac tamponade	1/1482 (0.1%)	1	3/1474 (0.2%)	3
Congestive cardiomyopathy	3/1482 (0.2%)	3	1/1474 (0.1%)	1
Right ventricular failure	2/1482 (0.1%)	2	2/1474 (0.1%)	2
Sinus bradycardia	1/1482 (0.1%)	1	3/1474 (0.2%)	3
Supraventricular tachycardia	2/1482 (0.1%)	2	2/1474 (0.1%)	2
Ventricular tachycardia	3/1482 (0.2%)	3	1/1474 (0.1%)	1
Atrioventricular block	1/1482 (0.1%)	1	2/1474 (0.1%)	2
Cardiogenic shock	2/1482 (0.1%)	2	1/1474 (0.1%)	1
Cardiomyopathy	1/1482 (0.1%)	1	2/1474 (0.1%)	2
Coronary artery stenosis	1/1482 (0.1%)	1	2/1474 (0.1%)	2
Sinus node dysfunction	0/1482 (0%)	0	3/1474 (0.2%)	3
Coronary artery occlusion	1/1482 (0.1%)	1	1/1474 (0.1%)	1
Ischaemic cardiomyopathy	1/1482 (0.1%)	1	1/1474 (0.1%)	1
Nodal arrhythmia	1/1482 (0.1%)	1	1/1474 (0.1%)	1
Pericarditis uraemic	2/1482 (0.1%)	3	0/1474 (0%)	0
Pulseless electrical activity	1/1482 (0.1%)	1	1/1474 (0.1%)	1
Stress cardiomyopathy	1/1482 (0.1%)	1	1/1474 (0.1%)	1
Tachycardia	0/1482 (0%)	0	2/1474 (0.1%)	2
Ventricular fibrillation	1/1482 (0.1%)	1	1/1474 (0.1%)	1
Aortic valve incompetence	1/1482 (0.1%)	1	0/1474 (0%)	0
Arrhythmia	0/1482 (0%)	0	1/1474 (0.1%)	1
Atrial tachycardia	0/1482 (0%)	0	1/1474 (0.1%)	2
Atrial thrombosis	0/1482 (0%)	0	1/1474 (0.1%)	1
Atrioventricular block second degree	0/1482 (0%)	0	1/1474 (0.1%)	1
Bradyarrhythmia	1/1482 (0.1%)	1	0/1474 (0%)	0
Cardiac discomfort	1/1482 (0.1%)	1	0/1474 (0%)	0
Cardiomegaly	0/1482 (0%)	0	1/1474 (0.1%)	1
Chronic left ventricular failure	0/1482 (0%)	0	1/1474 (0.1%)	1
Endocarditis noninfective	1/1482 (0.1%)	1	0/1474 (0%)	0
Left ventricular dysfunction	0/1482 (0%)	0	1/1474 (0.1%)	1
Left ventricular failure	0/1482 (0%)	0	1/1474 (0.1%)	1
Mitral valve calcification	1/1482 (0.1%)	1	0/1474 (0%)	0
Myocarditis	1/1482 (0.1%)	1	0/1474 (0%)	0
Nodal rhythm	0/1482 (0%)	0	1/1474 (0.1%)	1
Palpitations	0/1482 (0%)	0	1/1474 (0.1%)	1
Pericardial haemorrhage	1/1482 (0.1%)	1	0/1474 (0%)	0
Sinus tachycardia	1/1482 (0.1%)	1	0/1474 (0%)	0
Subendocardial ischaemia	0/1482 (0%)	0	1/1474 (0.1%)	1
Ventricular arrhythmia	0/1482 (0%)	0	1/1474 (0.1%)	1
Congenital, familial and genetic disorders
Atrial septal defect	1/1482 (0.1%)	1	0/1474 (0%)	0
Congenital cystic kidney disease	0/1482 (0%)	0	1/1474 (0.1%)	1
Protein C deficiency	0/1482 (0%)	0	1/1474 (0.1%)	1
Ear and labyrinth disorders
Vertigo	2/1482 (0.1%)	2	1/1474 (0.1%)	1
Deafness bilateral	0/1482 (0%)	0	1/1474 (0.1%)	1
Deafness unilateral	0/1482 (0%)	0	1/1474 (0.1%)	1
Hypoacusis	0/1482 (0%)	0	1/1474 (0.1%)	1
Inner ear disorder	0/1482 (0%)	0	1/1474 (0.1%)	1
Endocrine disorders
Hyperparathyroidism	2/1482 (0.1%)	2	2/1474 (0.1%)	2
Hyperparathyroidism secondary	2/1482 (0.1%)	2	1/1474 (0.1%)	1
Adrenal insufficiency	0/1482 (0%)	0	2/1474 (0.1%)	2
Hyperparathyroidism tertiary	2/1482 (0.1%)	4	0/1474 (0%)	0
Goitre	0/1482 (0%)	0	1/1474 (0.1%)	1
Secondary adrenocortical insufficiency	0/1482 (0%)	0	1/1474 (0.1%)	1
Eye disorders
Cataract	2/1482 (0.1%)	3	5/1474 (0.3%)	6
Retinal artery occlusion	2/1482 (0.1%)	2	0/1474 (0%)	0
Vitreous haemorrhage	2/1482 (0.1%)	2	0/1474 (0%)	0
Cataract nuclear	1/1482 (0.1%)	1	0/1474 (0%)	0
Diabetic retinopathy	1/1482 (0.1%)	1	0/1474 (0%)	0
Diplopia	1/1482 (0.1%)	1	0/1474 (0%)	0
Eye haemorrhage	0/1482 (0%)	0	1/1474 (0.1%)	1
Eye pain	1/1482 (0.1%)	1	0/1474 (0%)	0
Eyelid ptosis	1/1482 (0.1%)	1	0/1474 (0%)	0
Glaucoma	1/1482 (0.1%)	1	0/1474 (0%)	0
Macular fibrosis	1/1482 (0.1%)	1	0/1474 (0%)	0
Ophthalmoplegia	1/1482 (0.1%)	1	0/1474 (0%)	0
Retinal artery embolism	0/1482 (0%)	0	1/1474 (0.1%)	1
Retinal detachment	1/1482 (0.1%)	1	0/1474 (0%)	0
Retinopathy	1/1482 (0.1%)	1	0/1474 (0%)	0
Sympathetic ophthalmia	0/1482 (0%)	0	1/1474 (0.1%)	1
Tolosa-Hunt syndrome	0/1482 (0%)	0	1/1474 (0.1%)	1
Ulcerative keratitis	1/1482 (0.1%)	1	0/1474 (0%)	0
Gastrointestinal disorders
Gastrointestinal haemorrhage	12/1482 (0.8%)	13	11/1474 (0.7%)	12
Diarrhoea	6/1482 (0.4%)	6	7/1474 (0.5%)	7
Ascites	4/1482 (0.3%)	4	4/1474 (0.3%)	4
Gastric ulcer	3/1482 (0.2%)	3	5/1474 (0.3%)	5
Gastritis erosive	7/1482 (0.5%)	7	1/1474 (0.1%)	1
Pancreatitis acute	2/1482 (0.1%)	2	6/1474 (0.4%)	6
Upper gastrointestinal haemorrhage	4/1482 (0.3%)	4	4/1474 (0.3%)	4
Abdominal pain	5/1482 (0.3%)	5	2/1474 (0.1%)	2
Duodenal ulcer	3/1482 (0.2%)	3	4/1474 (0.3%)	4
Inguinal hernia	4/1482 (0.3%)	5	3/1474 (0.2%)	3
Colitis	3/1482 (0.2%)	3	3/1474 (0.2%)	3
Colitis ischaemic	2/1482 (0.1%)	2	4/1474 (0.3%)	4
Gastritis	3/1482 (0.2%)	5	3/1474 (0.2%)	3
Gastrooesophageal reflux disease	1/1482 (0.1%)	1	5/1474 (0.3%)	5
Chronic gastritis	3/1482 (0.2%)	3	2/1474 (0.1%)	2
Constipation	1/1482 (0.1%)	1	4/1474 (0.3%)	4
Haemorrhoids	3/1482 (0.2%)	3	2/1474 (0.1%)	2
Intestinal ischaemia	2/1482 (0.1%)	2	3/1474 (0.2%)	3
Small intestinal obstruction	3/1482 (0.2%)	5	2/1474 (0.1%)	2
Umbilical hernia	3/1482 (0.2%)	3	2/1474 (0.1%)	2
Diabetic gastroparesis	3/1482 (0.2%)	4	1/1474 (0.1%)	1
Duodenal ulcer haemorrhage	4/1482 (0.3%)	4	0/1474 (0%)	0
Gastric ulcer haemorrhage	2/1482 (0.1%)	2	2/1474 (0.1%)	2
Lower gastrointestinal haemorrhage	2/1482 (0.1%)	2	2/1474 (0.1%)	2
Pancreatitis chronic	2/1482 (0.1%)	2	2/1474 (0.1%)	2
Diverticulum	2/1482 (0.1%)	2	1/1474 (0.1%)	1
Haemorrhoidal haemorrhage	2/1482 (0.1%)	2	1/1474 (0.1%)	1
Impaired gastric emptying	3/1482 (0.2%)	3	0/1474 (0%)	0
Intestinal haemorrhage	1/1482 (0.1%)	1	2/1474 (0.1%)	2
Intestinal obstruction	2/1482 (0.1%)	2	1/1474 (0.1%)	1
Pancreatitis	1/1482 (0.1%)	1	2/1474 (0.1%)	2
Rectal haemorrhage	0/1482 (0%)	0	3/1474 (0.2%)	3
Vomiting	1/1482 (0.1%)	1	2/1474 (0.1%)	2
Abdominal adhesions	2/1482 (0.1%)	2	0/1474 (0%)	0
Abdominal hernia	1/1482 (0.1%)	1	1/1474 (0.1%)	1
Abdominal pain upper	1/1482 (0.1%)	1	1/1474 (0.1%)	1
Dieulafoy's vascular malformation	1/1482 (0.1%)	1	1/1474 (0.1%)	1
Diverticulum intestinal	0/1482 (0%)	0	2/1474 (0.1%)	2
Faecaloma	1/1482 (0.1%)	1	1/1474 (0.1%)	2
Gastric polyps	2/1482 (0.1%)	2	0/1474 (0%)	0
Gastroduodenal ulcer	1/1482 (0.1%)	1	1/1474 (0.1%)	1
Gastrointestinal angiectasia	0/1482 (0%)	0	2/1474 (0.1%)	2
Gastrointestinal polyp haemorrhage	2/1482 (0.1%)	3	0/1474 (0%)	0
Gastrointestinal vascular malformation haemorrhagic	1/1482 (0.1%)	1	1/1474 (0.1%)	1
Haematochezia	1/1482 (0.1%)	1	1/1474 (0.1%)	1
Ileus	1/1482 (0.1%)	1	1/1474 (0.1%)	1
Obstructive pancreatitis	2/1482 (0.1%)	4	0/1474 (0%)	0
Oesophageal ulcer haemorrhage	0/1482 (0%)	0	2/1474 (0.1%)	2
Oesophagitis	1/1482 (0.1%)	1	1/1474 (0.1%)	1
Pneumoperitoneum	0/1482 (0%)	0	2/1474 (0.1%)	2
Retroperitoneal haemorrhage	0/1482 (0%)	0	2/1474 (0.1%)	3
Abdominal wall haemorrhage	1/1482 (0.1%)	1	0/1474 (0%)	0
Alcoholic pancreatitis	1/1482 (0.1%)	1	0/1474 (0%)	0
Anal fissure	0/1482 (0%)	0	1/1474 (0.1%)	1
Anal fistula	0/1482 (0%)	0	1/1474 (0.1%)	1
Anal inflammation	0/1482 (0%)	0	1/1474 (0.1%)	1
Crohn's disease	0/1482 (0%)	0	1/1474 (0.1%)	1
Discoloured vomit	1/1482 (0.1%)	1	0/1474 (0%)	0
Diverticulum intestinal haemorrhagic	0/1482 (0%)	0	1/1474 (0.1%)	1
Duodenal ulcer perforation	0/1482 (0%)	0	1/1474 (0.1%)	1
Duodenitis	0/1482 (0%)	0	1/1474 (0.1%)	1
Dysphagia	0/1482 (0%)	0	1/1474 (0.1%)	1
Enteritis	1/1482 (0.1%)	1	0/1474 (0%)	0
Enterocolitis haemorrhagic	0/1482 (0%)	0	1/1474 (0.1%)	1
Epiploic appendagitis	1/1482 (0.1%)	1	0/1474 (0%)	0
Erosive oesophagitis	0/1482 (0%)	0	1/1474 (0.1%)	1
Gastric disorder	1/1482 (0.1%)	1	0/1474 (0%)	0
Gastric dysplasia	0/1482 (0%)	0	1/1474 (0.1%)	1
Gastric haemorrhage	1/1482 (0.1%)	1	0/1474 (0%)	0
Gastric mucosa erythema	0/1482 (0%)	0	1/1474 (0.1%)	1
Gastric perforation	1/1482 (0.1%)	1	0/1474 (0%)	0
Gastrointestinal erosion	0/1482 (0%)	0	1/1474 (0.1%)	1
Gastrointestinal obstruction	0/1482 (0%)	0	1/1474 (0.1%)	1
Gingival bleeding	0/1482 (0%)	0	1/1474 (0.1%)	1
Haemoperitoneum	1/1482 (0.1%)	1	0/1474 (0%)	0
Haemorrhagic erosive gastritis	1/1482 (0.1%)	1	0/1474 (0%)	0
Haemorrhagic necrotic pancreatitis	1/1482 (0.1%)	1	0/1474 (0%)	0
Hiatus hernia	1/1482 (0.1%)	1	0/1474 (0%)	0
Ileus paralytic	0/1482 (0%)	0	1/1474 (0.1%)	1
Incarcerated umbilical hernia	0/1482 (0%)	0	1/1474 (0.1%)	1
Intestinal perforation	0/1482 (0%)	0	1/1474 (0.1%)	1
Intussusception	1/1482 (0.1%)	1	0/1474 (0%)	0
Irritable bowel syndrome	1/1482 (0.1%)	1	0/1474 (0%)	0
Large intestinal haemorrhage	1/1482 (0.1%)	1	0/1474 (0%)	0
Large intestine polyp	0/1482 (0%)	0	1/1474 (0.1%)	1
Lumbar hernia	0/1482 (0%)	0	1/1474 (0.1%)	1
Mallory-Weiss syndrome	0/1482 (0%)	0	1/1474 (0.1%)	1
Mechanical ileus	1/1482 (0.1%)	1	0/1474 (0%)	0
Nausea	0/1482 (0%)	0	1/1474 (0.1%)	1
Oesophageal motility disorder	0/1482 (0%)	0	1/1474 (0.1%)	1
Oesophageal perforation	1/1482 (0.1%)	1	0/1474 (0%)	0
Oesophageal ulcer	0/1482 (0%)	0	1/1474 (0.1%)	1
Oesophagitis ulcerative	0/1482 (0%)	0	1/1474 (0.1%)	1
Rectal ulcer	0/1482 (0%)	0	1/1474 (0.1%)	1
Retroperitoneal haematoma	1/1482 (0.1%)	1	0/1474 (0%)	0
Small intestinal perforation	0/1482 (0%)	0	1/1474 (0.1%)	1
Ulcerative gastritis	0/1482 (0%)	0	1/1474 (0.1%)	1
General disorders
Non-cardiac chest pain	10/1482 (0.7%)	11	16/1474 (1.1%)	23
Pyrexia	7/1482 (0.5%)	7	8/1474 (0.5%)	8
Asthenia	5/1482 (0.3%)	5	6/1474 (0.4%)	6
Death	9/1482 (0.6%)	9	2/1474 (0.1%)	2
Chest pain	2/1482 (0.1%)	2	5/1474 (0.3%)	5
Oedema peripheral	1/1482 (0.1%)	2	4/1474 (0.3%)	4
Sudden cardiac death	3/1482 (0.2%)	3	1/1474 (0.1%)	1
Sudden death	3/1482 (0.2%)	3	1/1474 (0.1%)	1
Fatigue	0/1482 (0%)	0	3/1474 (0.2%)	3
Impaired healing	1/1482 (0.1%)	1	2/1474 (0.1%)	2
Catheter site haemorrhage	0/1482 (0%)	0	2/1474 (0.1%)	3
Complication associated with device	0/1482 (0%)	0	2/1474 (0.1%)	2
Device related thrombosis	1/1482 (0.1%)	1	1/1474 (0.1%)	1
General physical health deterioration	1/1482 (0.1%)	1	1/1474 (0.1%)	1
Generalised oedema	0/1482 (0%)	0	2/1474 (0.1%)	4
Multiple organ dysfunction syndrome	1/1482 (0.1%)	1	1/1474 (0.1%)	1
Peripheral swelling	2/1482 (0.1%)	2	0/1474 (0%)	0
Systemic inflammatory response syndrome	2/1482 (0.1%)	2	0/1474 (0%)	0
Vascular stent stenosis	2/1482 (0.1%)	3	0/1474 (0%)	0
Catheter site oedema	1/1482 (0.1%)	1	0/1474 (0%)	0
Catheter site thrombosis	0/1482 (0%)	0	1/1474 (0.1%)	1
Chest discomfort	1/1482 (0.1%)	1	0/1474 (0%)	0
Cyst	0/1482 (0%)	0	1/1474 (0.1%)	1
Drug withdrawal syndrome	1/1482 (0.1%)	1	0/1474 (0%)	0
Gait disturbance	1/1482 (0.1%)	1	0/1474 (0%)	0
Mucosal inflammation	0/1482 (0%)	0	1/1474 (0.1%)	1
Oedema	0/1482 (0%)	0	1/1474 (0.1%)	1
Serositis	1/1482 (0.1%)	1	0/1474 (0%)	0
Swelling face	1/1482 (0.1%)	1	0/1474 (0%)	0
Ulcer	0/1482 (0%)	0	1/1474 (0.1%)	1
Ulcer haemorrhage	1/1482 (0.1%)	1	0/1474 (0%)	0
Vascular stent thrombosis	0/1482 (0%)	0	1/1474 (0.1%)	1
Hepatobiliary disorders
Cholelithiasis	3/1482 (0.2%)	3	7/1474 (0.5%)	7
Cholecystitis acute	5/1482 (0.3%)	5	3/1474 (0.2%)	3
Cholecystitis chronic	3/1482 (0.2%)	3	2/1474 (0.1%)	2
Hepatic cirrhosis	4/1482 (0.3%)	4	1/1474 (0.1%)	1
Bile duct stone	2/1482 (0.1%)	4	2/1474 (0.1%)	2
Cholangitis	1/1482 (0.1%)	2	2/1474 (0.1%)	2
Cholecystitis	1/1482 (0.1%)	1	2/1474 (0.1%)	2
Biliary colic	0/1482 (0%)	0	2/1474 (0.1%)	4
Hepatic ischaemia	0/1482 (0%)	0	2/1474 (0.1%)	2
Bile duct stenosis	1/1482 (0.1%)	1	0/1474 (0%)	0
Biliary dyskinesia	1/1482 (0.1%)	1	0/1474 (0%)	0
Gallbladder polyp	0/1482 (0%)	0	1/1474 (0.1%)	1
Gallbladder rupture	1/1482 (0.1%)	1	0/1474 (0%)	0
Hepatic failure	0/1482 (0%)	0	1/1474 (0.1%)	1
Hepatic mass	0/1482 (0%)	0	1/1474 (0.1%)	1
Hydrocholecystis	0/1482 (0%)	0	1/1474 (0.1%)	1
Ischaemic hepatitis	1/1482 (0.1%)	1	0/1474 (0%)	0
Immune system disorders
Anaphylactic reaction	1/1482 (0.1%)	1	2/1474 (0.1%)	2
Amyloidosis	1/1482 (0.1%)	1	0/1474 (0%)	0
Hypersensitivity	0/1482 (0%)	0	1/1474 (0.1%)	1
Kidney transplant rejection	0/1482 (0%)	0	1/1474 (0.1%)	1
Renal transplant failure	1/1482 (0.1%)	1	0/1474 (0%)	0
Infections and infestations
Pneumonia	86/1482 (5.8%)	97	81/1474 (5.5%)	96
Sepsis	29/1482 (2%)	31	37/1474 (2.5%)	37
Peritonitis	31/1482 (2.1%)	42	24/1474 (1.6%)	34
COVID-19	22/1482 (1.5%)	22	22/1474 (1.5%)	22
Cellulitis	16/1482 (1.1%)	18	21/1474 (1.4%)	26
Gangrene	15/1482 (1%)	19	19/1474 (1.3%)	28
Osteomyelitis	15/1482 (1%)	18	13/1474 (0.9%)	16
Septic shock	8/1482 (0.5%)	9	16/1474 (1.1%)	17
Urinary tract infection	13/1482 (0.9%)	14	11/1474 (0.7%)	16
Device related infection	13/1482 (0.9%)	14	9/1474 (0.6%)	10
Gastroenteritis	9/1482 (0.6%)	9	13/1474 (0.9%)	15
Lower respiratory tract infection	9/1482 (0.6%)	10	11/1474 (0.7%)	11
Staphylococcal sepsis	10/1482 (0.7%)	10	10/1474 (0.7%)	10
Influenza	8/1482 (0.5%)	8	11/1474 (0.7%)	11
Arteriovenous fistula site infection	12/1482 (0.8%)	13	6/1474 (0.4%)	6
Bronchitis	8/1482 (0.5%)	8	7/1474 (0.5%)	8
Staphylococcal bacteraemia	8/1482 (0.5%)	9	7/1474 (0.5%)	9
Peritonitis bacterial	6/1482 (0.4%)	6	8/1474 (0.5%)	14
Device related sepsis	7/1482 (0.5%)	11	6/1474 (0.4%)	7
Diabetic foot infection	7/1482 (0.5%)	7	6/1474 (0.4%)	6
Upper respiratory tract infection	4/1482 (0.3%)	4	8/1474 (0.5%)	9
Urosepsis	7/1482 (0.5%)	7	5/1474 (0.3%)	5
Bacteraemia	4/1482 (0.3%)	4	7/1474 (0.5%)	7
Staphylococcal infection	8/1482 (0.5%)	9	3/1474 (0.2%)	3
Postoperative wound infection	6/1482 (0.4%)	8	4/1474 (0.3%)	4
Arteriovenous graft site infection	4/1482 (0.3%)	4	5/1474 (0.3%)	5
Clostridium difficile colitis	5/1482 (0.3%)	5	4/1474 (0.3%)	4
Endocarditis	6/1482 (0.4%)	6	3/1474 (0.2%)	3
Gastroenteritis viral	3/1482 (0.2%)	3	6/1474 (0.4%)	6
Abscess limb	4/1482 (0.3%)	4	3/1474 (0.2%)	3
Catheter site infection	5/1482 (0.3%)	8	2/1474 (0.1%)	2
Localised infection	2/1482 (0.1%)	3	5/1474 (0.3%)	5
Arthritis bacterial	3/1482 (0.2%)	3	3/1474 (0.2%)	4
Post procedural infection	1/1482 (0.1%)	1	5/1474 (0.3%)	5
Vascular device infection	2/1482 (0.1%)	2	4/1474 (0.3%)	5
Diverticulitis	1/1482 (0.1%)	1	4/1474 (0.3%)	4
Herpes zoster	3/1482 (0.2%)	4	2/1474 (0.1%)	2
Infected skin ulcer	2/1482 (0.1%)	2	3/1474 (0.2%)	3
Intervertebral discitis	3/1482 (0.2%)	3	2/1474 (0.1%)	2
Pneumonia viral	2/1482 (0.1%)	2	3/1474 (0.2%)	3
Vascular access site infection	4/1482 (0.3%)	4	1/1474 (0.1%)	1
Wound infection	2/1482 (0.1%)	2	3/1474 (0.2%)	4
Anal abscess	2/1482 (0.1%)	2	2/1474 (0.1%)	2
Diabetic gangrene	2/1482 (0.1%)	3	2/1474 (0.1%)	2
Escherichia sepsis	2/1482 (0.1%)	2	2/1474 (0.1%)	2
Fungal peritonitis	4/1482 (0.3%)	4	0/1474 (0%)	0
Infection	3/1482 (0.2%)	3	1/1474 (0.1%)	1
Pneumonia influenzal	0/1482 (0%)	0	4/1474 (0.3%)	4
Suspected COVID-19	3/1482 (0.2%)	4	1/1474 (0.1%)	1
Cystitis	1/1482 (0.1%)	1	2/1474 (0.1%)	2
Device related bacteraemia	2/1482 (0.1%)	3	1/1474 (0.1%)	1
Endocarditis bacterial	2/1482 (0.1%)	2	1/1474 (0.1%)	1
Enterobacter sepsis	1/1482 (0.1%)	1	2/1474 (0.1%)	2
Erysipelas	2/1482 (0.1%)	2	1/1474 (0.1%)	1
Escherichia infection	2/1482 (0.1%)	2	1/1474 (0.1%)	1
Hepatitis C	0/1482 (0%)	0	3/1474 (0.2%)	3
Klebsiella infection	2/1482 (0.1%)	2	1/1474 (0.1%)	1
Pneumonia streptococcal	1/1482 (0.1%)	1	2/1474 (0.1%)	2
Pulmonary tuberculosis	1/1482 (0.1%)	1	2/1474 (0.1%)	2
Pyelonephritis	2/1482 (0.1%)	2	1/1474 (0.1%)	1
Pyelonephritis chronic	2/1482 (0.1%)	2	1/1474 (0.1%)	2
Respiratory tract infection	1/1482 (0.1%)	1	2/1474 (0.1%)	2
Streptococcal sepsis	0/1482 (0%)	0	3/1474 (0.2%)	3
Subcutaneous abscess	1/1482 (0.1%)	1	2/1474 (0.1%)	2
Viral upper respiratory tract infection	2/1482 (0.1%)	2	1/1474 (0.1%)	1
Abdominal sepsis	1/1482 (0.1%)	1	1/1474 (0.1%)	1
Abdominal wall abscess	1/1482 (0.1%)	1	1/1474 (0.1%)	1
Acute hepatitis B	2/1482 (0.1%)	2	0/1474 (0%)	0
Appendicitis	0/1482 (0%)	0	2/1474 (0.1%)	2
Appendicitis perforated	2/1482 (0.1%)	2	0/1474 (0%)	0
Arthritis infective	0/1482 (0%)	0	2/1474 (0.1%)	2
Atypical pneumonia	2/1482 (0.1%)	2	0/1474 (0%)	0
Bacterial infection	1/1482 (0.1%)	1	1/1474 (0.1%)	1
Carbuncle	2/1482 (0.1%)	2	0/1474 (0%)	0
Cholecystitis infective	2/1482 (0.1%)	2	0/1474 (0%)	0
Clostridium difficile infection	1/1482 (0.1%)	1	1/1474 (0.1%)	1
Colonic abscess	1/1482 (0.1%)	1	1/1474 (0.1%)	1
Endocarditis staphylococcal	0/1482 (0%)	0	2/1474 (0.1%)	3
Gas gangrene	1/1482 (0.1%)	1	1/1474 (0.1%)	1
Hepatic cyst infection	1/1482 (0.1%)	1	1/1474 (0.1%)	1
Infectious pleural effusion	1/1482 (0.1%)	1	1/1474 (0.1%)	1
Klebsiella bacteraemia	0/1482 (0%)	0	2/1474 (0.1%)	2
Klebsiella sepsis	1/1482 (0.1%)	1	1/1474 (0.1%)	1
Large intestine infection	1/1482 (0.1%)	1	1/1474 (0.1%)	1
Lung abscess	0/1482 (0%)	0	2/1474 (0.1%)	2
Lymph node tuberculosis	1/1482 (0.1%)	1	1/1474 (0.1%)	1
Nasopharyngitis	1/1482 (0.1%)	1	1/1474 (0.1%)	1
Otitis externa	1/1482 (0.1%)	1	1/1474 (0.1%)	1
Parainfluenzae virus infection	2/1482 (0.1%)	2	0/1474 (0%)	0
Pharyngitis	1/1482 (0.1%)	1	1/1474 (0.1%)	1
Proteus infection	2/1482 (0.1%)	2	0/1474 (0%)	0
Pseudomonal sepsis	2/1482 (0.1%)	2	0/1474 (0%)	0
Pulmonary sepsis	2/1482 (0.1%)	2	0/1474 (0%)	0
Pyelonephritis acute	0/1482 (0%)	0	2/1474 (0.1%)	2
Renal cyst infection	0/1482 (0%)	0	2/1474 (0.1%)	2
Rhinovirus infection	2/1482 (0.1%)	2	0/1474 (0%)	0
Scrotal abscess	0/1482 (0%)	0	2/1474 (0.1%)	2
Tuberculosis	2/1482 (0.1%)	2	0/1474 (0%)	0
Varicella	2/1482 (0.1%)	2	0/1474 (0%)	0
Viral infection	2/1482 (0.1%)	2	0/1474 (0%)	0
Abdominal abscess	0/1482 (0%)	0	1/1474 (0.1%)	1
Abscess neck	0/1482 (0%)	0	1/1474 (0.1%)	1
Acinetobacter bacteraemia	1/1482 (0.1%)	1	0/1474 (0%)	0
Arteriovenous graft site abscess	1/1482 (0.1%)	1	0/1474 (0%)	0
Bacterial sepsis	1/1482 (0.1%)	2	0/1474 (0%)	0
Biliary sepsis	0/1482 (0%)	0	1/1474 (0.1%)	1
Bone abscess	1/1482 (0.1%)	1	0/1474 (0%)	0
Bone tuberculosis	1/1482 (0.1%)	1	0/1474 (0%)	0
Boutonneuse fever	0/1482 (0%)	0	1/1474 (0.1%)	1
Burn infection	0/1482 (0%)	0	1/1474 (0.1%)	1
Bursitis infective	1/1482 (0.1%)	1	0/1474 (0%)	0
Campylobacter gastroenteritis	0/1482 (0%)	0	1/1474 (0.1%)	1
Candida pneumonia	1/1482 (0.1%)	1	0/1474 (0%)	0
Catheter site abscess	1/1482 (0.1%)	1	0/1474 (0%)	0
Complicated appendicitis	1/1482 (0.1%)	1	0/1474 (0%)	0
Dengue fever	1/1482 (0.1%)	1	0/1474 (0%)	0
Diarrhoea infectious	1/1482 (0.1%)	1	0/1474 (0%)	0
Douglas' abscess	0/1482 (0%)	0	1/1474 (0.1%)	1
Endophthalmitis	1/1482 (0.1%)	1	0/1474 (0%)	0
Enteritis infectious	1/1482 (0.1%)	1	0/1474 (0%)	0
Enterobacter bacteraemia	0/1482 (0%)	0	1/1474 (0.1%)	1
Enterobacter infection	1/1482 (0.1%)	1	0/1474 (0%)	0
Enterobacter pneumonia	1/1482 (0.1%)	1	0/1474 (0%)	0
Enterococcal bacteraemia	0/1482 (0%)	0	1/1474 (0.1%)	1
Enterococcal sepsis	0/1482 (0%)	0	1/1474 (0.1%)	1
Escherichia bacteraemia	1/1482 (0.1%)	1	0/1474 (0%)	0
Escherichia peritonitis	1/1482 (0.1%)	1	0/1474 (0%)	0
Febrile infection	1/1482 (0.1%)	1	0/1474 (0%)	0
Fungaemia	1/1482 (0.1%)	1	0/1474 (0%)	0
Fungal oesophagitis	0/1482 (0%)	0	1/1474 (0.1%)	1
Furuncle	0/1482 (0%)	0	1/1474 (0.1%)	1
Gastroenteritis bacterial	1/1482 (0.1%)	1	0/1474 (0%)	0
Gastroenteritis staphylococcal	0/1482 (0%)	0	1/1474 (0.1%)	1
Graft infection	0/1482 (0%)	0	1/1474 (0.1%)	1
Groin abscess	1/1482 (0.1%)	1	0/1474 (0%)	0
Groin infection	0/1482 (0%)	0	1/1474 (0.1%)	1
Helicobacter gastritis	1/1482 (0.1%)	1	0/1474 (0%)	0
Hepatic echinococciasis	0/1482 (0%)	0	1/1474 (0.1%)	1
Hepatitis B	0/1482 (0%)	0	1/1474 (0.1%)	1
Herpes ophthalmic	0/1482 (0%)	0	1/1474 (0.1%)	1
Herpes zoster meningitis	0/1482 (0%)	0	1/1474 (0.1%)	1
Infected cyst	1/1482 (0.1%)	1	0/1474 (0%)	0
Infected fistula	0/1482 (0%)	0	1/1474 (0.1%)	1
Infective aneurysm	1/1482 (0.1%)	1	0/1474 (0%)	0
Infective exacerbation of chronic obstructive airways disease	1/1482 (0.1%)	1	0/1474 (0%)	0
Kidney infection	0/1482 (0%)	0	1/1474 (0.1%)	1
Listeraemia	0/1482 (0%)	0	1/1474 (0.1%)	1
Listeria sepsis	0/1482 (0%)	0	1/1474 (0.1%)	1
Liver abscess	1/1482 (0.1%)	1	0/1474 (0%)	0
Mastoiditis	0/1482 (0%)	0	1/1474 (0.1%)	1
Measles	0/1482 (0%)	0	1/1474 (0.1%)	1
Meningitis	1/1482 (0.1%)	1	0/1474 (0%)	0
Meningitis aseptic	1/1482 (0.1%)	1	0/1474 (0%)	0
Mesenteric abscess	0/1482 (0%)	0	1/1474 (0.1%)	1
Metapneumovirus infection	1/1482 (0.1%)	1	0/1474 (0%)	0
Oesophageal candidiasis	1/1482 (0.1%)	1	0/1474 (0%)	0
Orchitis	0/1482 (0%)	0	1/1474 (0.1%)	1
Osteomyelitis acute	0/1482 (0%)	0	1/1474 (0.1%)	1
Osteomyelitis chronic	0/1482 (0%)	0	1/1474 (0.1%)	1
Otitis media	0/1482 (0%)	0	1/1474 (0.1%)	2
Paronychia	1/1482 (0.1%)	1	0/1474 (0%)	0
Parotitis	1/1482 (0.1%)	1	0/1474 (0%)	0
Pelvic infection	1/1482 (0.1%)	1	0/1474 (0%)	0
Pericarditis infective	0/1482 (0%)	0	1/1474 (0.1%)	1
Pneumocystis jirovecii pneumonia	0/1482 (0%)	0	1/1474 (0.1%)	1
Pneumonia bacterial	0/1482 (0%)	0	1/1474 (0.1%)	1
Pneumonia haemophilus	0/1482 (0%)	0	1/1474 (0.1%)	1
Post procedural sepsis	1/1482 (0.1%)	1	0/1474 (0%)	0
Postoperative abscess	1/1482 (0.1%)	1	0/1474 (0%)	0
Pyuria	1/1482 (0.1%)	1	0/1474 (0%)	0
Respiratory syncytial virus infection	0/1482 (0%)	0	1/1474 (0.1%)	1
Respiratory tract infection viral	0/1482 (0%)	0	1/1474 (0.1%)	1
Retroperitoneal infection	1/1482 (0.1%)	1	0/1474 (0%)	0
Salmonella sepsis	0/1482 (0%)	0	1/1474 (0.1%)	1
Septic embolus	1/1482 (0.1%)	1	0/1474 (0%)	0
Septic encephalopathy	0/1482 (0%)	0	1/1474 (0.1%)	1
Shigella infection	1/1482 (0.1%)	1	0/1474 (0%)	0
Shunt infection	0/1482 (0%)	0	1/1474 (0.1%)	1
Sinusitis	0/1482 (0%)	0	1/1474 (0.1%)	1
Skin infection	0/1482 (0%)	0	1/1474 (0.1%)	2
Soft tissue infection	1/1482 (0.1%)	1	0/1474 (0%)	0
Staphylococcal osteomyelitis	1/1482 (0.1%)	1	0/1474 (0%)	0
Streptococcal endocarditis	1/1482 (0.1%)	1	0/1474 (0%)	0
Tonsillitis	0/1482 (0%)	0	1/1474 (0.1%)	1
Tooth abscess	1/1482 (0.1%)	1	0/1474 (0%)	0
Tooth infection	1/1482 (0.1%)	1	0/1474 (0%)	0
Tracheitis	0/1482 (0%)	0	1/1474 (0.1%)	1
Tracheobronchitis	1/1482 (0.1%)	1	0/1474 (0%)	0
Vestibulitis	0/1482 (0%)	0	1/1474 (0.1%)	1
Injury, poisoning and procedural complications
Arteriovenous fistula thrombosis	36/1482 (2.4%)	43	57/1474 (3.9%)	74
Arteriovenous fistula site haemorrhage	12/1482 (0.8%)	12	12/1474 (0.8%)	12
Arteriovenous graft thrombosis	7/1482 (0.5%)	9	15/1474 (1%)	25
Fall	14/1482 (0.9%)	15	7/1474 (0.5%)	7
Arteriovenous fistula site complication	9/1482 (0.6%)	10	8/1474 (0.5%)	10
Femur fracture	8/1482 (0.5%)	9	5/1474 (0.3%)	5
Vascular access site thrombosis	7/1482 (0.5%)	9	5/1474 (0.3%)	7
Arteriovenous fistula aneurysm	6/1482 (0.4%)	6	5/1474 (0.3%)	7
Vascular access malfunction	6/1482 (0.4%)	6	5/1474 (0.3%)	5
Arteriovenous fistula occlusion	5/1482 (0.3%)	6	5/1474 (0.3%)	5
Femoral neck fracture	4/1482 (0.3%)	4	5/1474 (0.3%)	5
Hip fracture	5/1482 (0.3%)	5	4/1474 (0.3%)	4
Pelvic fracture	3/1482 (0.2%)	3	5/1474 (0.3%)	5
Ankle fracture	5/1482 (0.3%)	5	2/1474 (0.1%)	2
Arteriovenous fistula site pseudoaneurysm	2/1482 (0.1%)	2	5/1474 (0.3%)	5
Fibula fracture	6/1482 (0.4%)	6	1/1474 (0.1%)	1
Subdural haematoma	3/1482 (0.2%)	3	4/1474 (0.3%)	4
Arteriovenous graft site stenosis	4/1482 (0.3%)	8	2/1474 (0.1%)	4
Head injury	0/1482 (0%)	0	6/1474 (0.4%)	6
Post procedural haemorrhage	4/1482 (0.3%)	4	1/1474 (0.1%)	1
Rib fracture	1/1482 (0.1%)	1	4/1474 (0.3%)	4
Tibia fracture	4/1482 (0.3%)	4	1/1474 (0.1%)	1
Vascular access complication	3/1482 (0.2%)	3	2/1474 (0.1%)	2
Arteriovenous graft site haemorrhage	3/1482 (0.2%)	3	1/1474 (0.1%)	1
Foot fracture	2/1482 (0.1%)	2	2/1474 (0.1%)	2
Peritoneal dialysis complication	1/1482 (0.1%)	1	3/1474 (0.2%)	3
Shunt thrombosis	1/1482 (0.1%)	2	3/1474 (0.2%)	3
Thermal burn	1/1482 (0.1%)	1	3/1474 (0.2%)	3
Acetabulum fracture	2/1482 (0.1%)	2	1/1474 (0.1%)	1
Clavicle fracture	1/1482 (0.1%)	1	2/1474 (0.1%)	2
Contusion	2/1482 (0.1%)	2	1/1474 (0.1%)	1
Dialysis related complication	2/1482 (0.1%)	2	1/1474 (0.1%)	1
Hand fracture	2/1482 (0.1%)	2	1/1474 (0.1%)	1
Limb injury	2/1482 (0.1%)	2	1/1474 (0.1%)	1
Patella fracture	2/1482 (0.1%)	2	1/1474 (0.1%)	1
Post procedural haematoma	1/1482 (0.1%)	1	2/1474 (0.1%)	2
Procedural haemorrhage	2/1482 (0.1%)	2	1/1474 (0.1%)	1
Shunt blood flow excessive	1/1482 (0.1%)	1	2/1474 (0.1%)	2
Spinal compression fracture	2/1482 (0.1%)	3	1/1474 (0.1%)	1
Toxicity to various agents	1/1482 (0.1%)	1	2/1474 (0.1%)	2
Vascular access steal syndrome	2/1482 (0.1%)	2	1/1474 (0.1%)	1
Arteriovenous fistula site haematoma	1/1482 (0.1%)	1	1/1474 (0.1%)	1
Facial bones fracture	0/1482 (0%)	0	2/1474 (0.1%)	2
Graft thrombosis	0/1482 (0%)	0	2/1474 (0.1%)	2
Humerus fracture	0/1482 (0%)	0	2/1474 (0.1%)	2
Joint dislocation	1/1482 (0.1%)	1	1/1474 (0.1%)	1
Joint injury	2/1482 (0.1%)	2	0/1474 (0%)	0
Lower limb fracture	0/1482 (0%)	0	2/1474 (0.1%)	2
Poisoning	0/1482 (0%)	0	2/1474 (0.1%)	2
Postoperative wound complication	1/1482 (0.1%)	1	1/1474 (0.1%)	1
Radius fracture	2/1482 (0.1%)	2	0/1474 (0%)	0
Vascular access site haemorrhage	0/1482 (0%)	0	2/1474 (0.1%)	2
Vascular graft occlusion	2/1482 (0.1%)	3	0/1474 (0%)	0
Vascular pseudoaneurysm	0/1482 (0%)	0	2/1474 (0.1%)	2
Vascular pseudoaneurysm ruptured	2/1482 (0.1%)	2	0/1474 (0%)	0
Anaemia postoperative	0/1482 (0%)	0	1/1474 (0.1%)	1
Aortic pseudoaneurysm	1/1482 (0.1%)	1	0/1474 (0%)	0
Arteriovenous graft aneurysm	0/1482 (0%)	0	1/1474 (0.1%)	1
Bronchial injury	1/1482 (0.1%)	1	0/1474 (0%)	0
Burns second degree	1/1482 (0.1%)	1	0/1474 (0%)	0
Cervical vertebral fracture	1/1482 (0.1%)	1	0/1474 (0%)	0
Delayed graft function	1/1482 (0.1%)	1	0/1474 (0%)	0
Delayed recovery from anaesthesia	0/1482 (0%)	0	1/1474 (0.1%)	1
Forearm fracture	1/1482 (0.1%)	1	0/1474 (0%)	0
Foreign body in gastrointestinal tract	0/1482 (0%)	0	1/1474 (0.1%)	1
Fractured sacrum	1/1482 (0.1%)	1	0/1474 (0%)	0
Graft loss	1/1482 (0.1%)	1	0/1474 (0%)	0
Implantation complication	1/1482 (0.1%)	1	0/1474 (0%)	0
Keratorhexis	1/1482 (0.1%)	1	0/1474 (0%)	0
Lumbar vertebral fracture	1/1482 (0.1%)	1	0/1474 (0%)	0
Meniscus injury	1/1482 (0.1%)	1	0/1474 (0%)	0
Multiple fractures	0/1482 (0%)	0	1/1474 (0.1%)	1
Multiple injuries	1/1482 (0.1%)	1	0/1474 (0%)	0
Muscle rupture	0/1482 (0%)	0	1/1474 (0.1%)	2
Periorbital haematoma	0/1482 (0%)	0	1/1474 (0.1%)	1
Post procedural hypotension	0/1482 (0%)	0	1/1474 (0.1%)	1
Post procedural inflammation	1/1482 (0.1%)	1	0/1474 (0%)	0
Post procedural swelling	1/1482 (0.1%)	1	0/1474 (0%)	0
Post procedural urine leak	0/1482 (0%)	0	1/1474 (0.1%)	1
Postoperative hypertension	1/1482 (0.1%)	1	0/1474 (0%)	0
Procedural pain	0/1482 (0%)	0	1/1474 (0.1%)	1
Restenosis	0/1482 (0%)	0	1/1474 (0.1%)	1
Road traffic accident	1/1482 (0.1%)	1	0/1474 (0%)	0
Shunt aneurysm	0/1482 (0%)	0	1/1474 (0.1%)	1
Skeletal injury	1/1482 (0.1%)	1	0/1474 (0%)	0
Skin laceration	0/1482 (0%)	0	1/1474 (0.1%)	1
Skull fracture	1/1482 (0.1%)	1	0/1474 (0%)	0
Spinal cord injury	0/1482 (0%)	0	1/1474 (0.1%)	1
Spinal fracture	1/1482 (0.1%)	1	0/1474 (0%)	0
Sternal fracture	0/1482 (0%)	0	1/1474 (0.1%)	1
Subdural haemorrhage	0/1482 (0%)	0	1/1474 (0.1%)	1
Tendon injury	1/1482 (0.1%)	1	0/1474 (0%)	0
Thoracic vertebral fracture	0/1482 (0%)	0	1/1474 (0.1%)	1
Traumatic fracture	0/1482 (0%)	0	1/1474 (0.1%)	1
Upper limb fracture	0/1482 (0%)	0	1/1474 (0.1%)	1
Vascular access site swelling	1/1482 (0.1%)	1	0/1474 (0%)	0
Vascular graft complication	1/1482 (0.1%)	1	0/1474 (0%)	0
Vascular graft thrombosis	1/1482 (0.1%)	1	0/1474 (0%)	0
Vascular pseudoaneurysm thrombosis	0/1482 (0%)	0	1/1474 (0.1%)	1
Vena cava injury	1/1482 (0.1%)	1	0/1474 (0%)	0
Wound necrosis	0/1482 (0%)	0	1/1474 (0.1%)	1
Investigations
Transaminases increased	0/1482 (0%)	0	4/1474 (0.3%)	4
Blood pressure increased	2/1482 (0.1%)	3	1/1474 (0.1%)	1
Ejection fraction decreased	2/1482 (0.1%)	2	1/1474 (0.1%)	1
Troponin increased	1/1482 (0.1%)	1	2/1474 (0.1%)	2
Alanine aminotransferase increased	1/1482 (0.1%)	1	1/1474 (0.1%)	1
Haemoglobin decreased	0/1482 (0%)	0	2/1474 (0.1%)	2
International normalised ratio increased	0/1482 (0%)	0	2/1474 (0.1%)	2
Anticoagulation drug level below therapeutic	0/1482 (0%)	0	1/1474 (0.1%)	2
Aspartate aminotransferase increased	1/1482 (0.1%)	1	0/1474 (0%)	0
Blood pressure decreased	0/1482 (0%)	0	1/1474 (0.1%)	1
Blood urine present	0/1482 (0%)	0	1/1474 (0.1%)	1
C-reactive protein increased	0/1482 (0%)	0	1/1474 (0.1%)	1
Electrocardiogram T wave inversion	0/1482 (0%)	0	1/1474 (0.1%)	1
Hepatic enzyme increased	1/1482 (0.1%)	1	0/1474 (0%)	0
Oxygen saturation decreased	1/1482 (0.1%)	1	0/1474 (0%)	0
Respiratory syncytial virus test positive	1/1482 (0.1%)	1	0/1474 (0%)	0
Staphylococcus test positive	0/1482 (0%)	0	1/1474 (0.1%)	1
Troponin I increased	1/1482 (0.1%)	1	0/1474 (0%)	0
Troponin T increased	0/1482 (0%)	0	1/1474 (0.1%)	1
Metabolism and nutrition disorders
Fluid overload	42/1482 (2.8%)	53	45/1474 (3.1%)	57
Hyperkalaemia	19/1482 (1.3%)	23	36/1474 (2.4%)	41
Hypoglycaemia	11/1482 (0.7%)	12	9/1474 (0.6%)	10
Hypervolaemia	5/1482 (0.3%)	8	3/1474 (0.2%)	3
Hyperglycaemia	5/1482 (0.3%)	5	2/1474 (0.1%)	2
Hyponatraemia	2/1482 (0.1%)	2	4/1474 (0.3%)	4
Dehydration	1/1482 (0.1%)	1	4/1474 (0.3%)	4
Hypocalcaemia	2/1482 (0.1%)	2	3/1474 (0.2%)	4
Diabetic ketoacidosis	2/1482 (0.1%)	2	2/1474 (0.1%)	2
Malnutrition	2/1482 (0.1%)	2	2/1474 (0.1%)	3
Diabetes mellitus inadequate control	1/1482 (0.1%)	1	2/1474 (0.1%)	2
Hypokalaemia	0/1482 (0%)	0	3/1474 (0.2%)	3
Calciphylaxis	2/1482 (0.1%)	2	0/1474 (0%)	0
Diabetes mellitus	2/1482 (0.1%)	2	0/1474 (0%)	0
Diabetic metabolic decompensation	1/1482 (0.1%)	1	1/1474 (0.1%)	1
Fluid retention	0/1482 (0%)	0	2/1474 (0.1%)	3
Metabolic acidosis	1/1482 (0.1%)	1	1/1474 (0.1%)	1
Type 1 diabetes mellitus	2/1482 (0.1%)	2	0/1474 (0%)	0
Diabetic complication	1/1482 (0.1%)	1	0/1474 (0%)	0
Electrolyte imbalance	0/1482 (0%)	0	1/1474 (0.1%)	1
Hypercalcaemia	0/1482 (0%)	0	1/1474 (0.1%)	1
Hypoalbuminaemia	1/1482 (0.1%)	1	0/1474 (0%)	0
Hypophagia	0/1482 (0%)	0	1/1474 (0.1%)	2
Hypovolaemia	0/1482 (0%)	0	1/1474 (0.1%)	1
Insulin-requiring type 2 diabetes mellitus	1/1482 (0.1%)	1	0/1474 (0%)	0
Obesity	0/1482 (0%)	0	1/1474 (0.1%)	1
Vitamin B12 deficiency	1/1482 (0.1%)	1	0/1474 (0%)	0
Musculoskeletal and connective tissue disorders
Musculoskeletal chest pain	5/1482 (0.3%)	5	6/1474 (0.4%)	6
Osteoarthritis	5/1482 (0.3%)	5	6/1474 (0.4%)	6
Bursitis	1/1482 (0.1%)	1	4/1474 (0.3%)	4
Back pain	2/1482 (0.1%)	2	2/1474 (0.1%)	2
Arthralgia	2/1482 (0.1%)	3	1/1474 (0.1%)	1
Costochondritis	1/1482 (0.1%)	1	2/1474 (0.1%)	2
Haematoma muscle	0/1482 (0%)	0	3/1474 (0.2%)	3
Hungry bone syndrome	2/1482 (0.1%)	2	1/1474 (0.1%)	1
Osteonecrosis	0/1482 (0%)	0	3/1474 (0.2%)	3
Pathological fracture	2/1482 (0.1%)	2	1/1474 (0.1%)	1
Spinal stenosis	1/1482 (0.1%)	1	2/1474 (0.1%)	2
Cervical spinal stenosis	1/1482 (0.1%)	1	1/1474 (0.1%)	1
Flank pain	1/1482 (0.1%)	1	1/1474 (0.1%)	1
Intervertebral disc protrusion	1/1482 (0.1%)	1	1/1474 (0.1%)	1
Arthritis reactive	1/1482 (0.1%)	1	0/1474 (0%)	0
Chest wall haematoma	0/1482 (0%)	0	1/1474 (0.1%)	1
Chondropathy	1/1482 (0.1%)	1	0/1474 (0%)	0
Compartment syndrome	0/1482 (0%)	0	1/1474 (0.1%)	1
High turnover osteopathy	1/1482 (0.1%)	1	0/1474 (0%)	0
Lumbar spinal stenosis	0/1482 (0%)	0	1/1474 (0.1%)	1
Muscular weakness	0/1482 (0%)	0	1/1474 (0.1%)	1
Musculoskeletal pain	1/1482 (0.1%)	1	0/1474 (0%)	0
Myalgia	1/1482 (0.1%)	1	0/1474 (0%)	0
Myositis	1/1482 (0.1%)	2	0/1474 (0%)	0
Neuropathic arthropathy	1/1482 (0.1%)	1	0/1474 (0%)	0
Osteitis	0/1482 (0%)	0	1/1474 (0.1%)	1
Osteoporosis	0/1482 (0%)	0	1/1474 (0.1%)	1
Rhabdomyolysis	1/1482 (0.1%)	1	0/1474 (0%)	0
Rheumatoid arthritis	1/1482 (0.1%)	1	0/1474 (0%)	0
Sacroiliitis	0/1482 (0%)	0	1/1474 (0.1%)	1
Spinal osteoarthritis	0/1482 (0%)	0	1/1474 (0.1%)	1
Spondylitis	0/1482 (0%)	0	1/1474 (0.1%)	1
Synovial cyst	1/1482 (0.1%)	1	0/1474 (0%)	0
Synovitis	0/1482 (0%)	0	1/1474 (0.1%)	1
Tendon disorder	0/1482 (0%)	0	1/1474 (0.1%)	1
Tenosynovitis	0/1482 (0%)	0	1/1474 (0.1%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Renal cancer	2/1482 (0.1%)	2	2/1474 (0.1%)	2
Basal cell carcinoma	1/1482 (0.1%)	1	2/1474 (0.1%)	2
Bladder cancer	1/1482 (0.1%)	1	2/1474 (0.1%)	2
Hepatic cancer	0/1482 (0%)	0	3/1474 (0.2%)	3
Parathyroid tumour benign	3/1482 (0.2%)	3	0/1474 (0%)	0
Renal neoplasm	2/1482 (0.1%)	2	1/1474 (0.1%)	1
Breast cancer	0/1482 (0%)	0	2/1474 (0.1%)	2
Colon adenoma	2/1482 (0.1%)	2	0/1474 (0%)	0
Colon cancer	1/1482 (0.1%)	1	1/1474 (0.1%)	1
Papillary renal cell carcinoma	2/1482 (0.1%)	2	0/1474 (0%)	0
Papillary thyroid cancer	2/1482 (0.1%)	2	0/1474 (0%)	0
Plasma cell myeloma	1/1482 (0.1%)	1	1/1474 (0.1%)	1
Renal cell carcinoma	1/1482 (0.1%)	1	1/1474 (0.1%)	1
Squamous cell carcinoma of skin	1/1482 (0.1%)	1	1/1474 (0.1%)	1
Thyroid adenoma	1/1482 (0.1%)	1	1/1474 (0.1%)	1
Transitional cell carcinoma	2/1482 (0.1%)	2	0/1474 (0%)	0
Uterine leiomyoma	2/1482 (0.1%)	2	0/1474 (0%)	0
Acute myeloid leukaemia	0/1482 (0%)	0	1/1474 (0.1%)	1
Adenocarcinoma gastric	1/1482 (0.1%)	1	0/1474 (0%)	0
Adenocarcinoma of colon	1/1482 (0.1%)	1	0/1474 (0%)	0
Adrenal adenoma	1/1482 (0.1%)	1	0/1474 (0%)	0
B-cell type acute leukaemia	0/1482 (0%)	0	1/1474 (0.1%)	1
Benign neoplasm of ampulla of Vater	0/1482 (0%)	0	1/1474 (0.1%)	1
Benign renal neoplasm	1/1482 (0.1%)	1	0/1474 (0%)	0
Bile duct cancer	1/1482 (0.1%)	1	0/1474 (0%)	0
Bladder cancer stage 0, with cancer in situ	1/1482 (0.1%)	1	0/1474 (0%)	0
Bladder papilloma	0/1482 (0%)	0	1/1474 (0.1%)	1
Bladder transitional cell carcinoma	0/1482 (0%)	0	1/1474 (0.1%)	1
Bone neoplasm	1/1482 (0.1%)	1	0/1474 (0%)	0
Breast cancer stage II	1/1482 (0.1%)	1	0/1474 (0%)	0
Carcinoid tumour pulmonary	1/1482 (0.1%)	1	0/1474 (0%)	0
Carcinoma in situ of eye	0/1482 (0%)	0	1/1474 (0.1%)	1
Cardiac valve fibroelastoma	1/1482 (0.1%)	1	0/1474 (0%)	0
Colon cancer metastatic	0/1482 (0%)	0	1/1474 (0.1%)	1
Endometrial adenocarcinoma	0/1482 (0%)	0	1/1474 (0.1%)	1
External ear neoplasm malignant	0/1482 (0%)	0	1/1474 (0.1%)	1
Inflammatory pseudotumour	1/1482 (0.1%)	1	0/1474 (0%)	0
Lung adenocarcinoma	1/1482 (0.1%)	1	0/1474 (0%)	0
Lung cancer metastatic	0/1482 (0%)	0	1/1474 (0.1%)	1
Malignant melanoma	1/1482 (0.1%)	1	0/1474 (0%)	0
Meningioma	0/1482 (0%)	0	1/1474 (0.1%)	1
Metastases to bone	1/1482 (0.1%)	1	0/1474 (0%)	0
Metastases to lung	1/1482 (0.1%)	1	0/1474 (0%)	0
Metastatic neoplasm	0/1482 (0%)	0	1/1474 (0.1%)	1
Ovarian cancer	1/1482 (0.1%)	1	0/1474 (0%)	0
Ovarian cancer metastatic	1/1482 (0.1%)	1	0/1474 (0%)	0
Pancreatic carcinoma	0/1482 (0%)	0	1/1474 (0.1%)	1
Papilloma	0/1482 (0%)	0	1/1474 (0.1%)	1
Prostate cancer	0/1482 (0%)	0	1/1474 (0.1%)	1
Prostate cancer metastatic	1/1482 (0.1%)	1	0/1474 (0%)	0
Rectal adenocarcinoma	0/1482 (0%)	0	1/1474 (0.1%)	1
Refractory cytopenia with unilineage dysplasia	1/1482 (0.1%)	1	0/1474 (0%)	0
Renal cell carcinoma stage I	1/1482 (0.1%)	1	0/1474 (0%)	0
Salivary gland cancer	1/1482 (0.1%)	1	0/1474 (0%)	0
Squamous cell carcinoma	1/1482 (0.1%)	1	0/1474 (0%)	0
Squamous cell carcinoma of lung	1/1482 (0.1%)	1	0/1474 (0%)	0
Ureteric cancer regional	1/1482 (0.1%)	1	0/1474 (0%)	0
Urinary tract neoplasm	0/1482 (0%)	0	1/1474 (0.1%)	1
Nervous system disorders
Ischaemic stroke	11/1482 (0.7%)	11	11/1474 (0.7%)	11
Cerebrovascular accident	9/1482 (0.6%)	11	11/1474 (0.7%)	13
Syncope	5/1482 (0.3%)	6	13/1474 (0.9%)	13
Transient ischaemic attack	7/1482 (0.5%)	7	10/1474 (0.7%)	12
Metabolic encephalopathy	3/1482 (0.2%)	3	9/1474 (0.6%)	10
Seizure	4/1482 (0.3%)	4	5/1474 (0.3%)	5
Encephalopathy	2/1482 (0.1%)	2	4/1474 (0.3%)	5
Cerebral infarction	2/1482 (0.1%)	2	3/1474 (0.2%)	3
Hypertensive encephalopathy	3/1482 (0.2%)	3	2/1474 (0.1%)	2
Carotid artery stenosis	2/1482 (0.1%)	2	2/1474 (0.1%)	2
Cerebral haemorrhage	2/1482 (0.1%)	2	2/1474 (0.1%)	2
Carpal tunnel syndrome	1/1482 (0.1%)	1	2/1474 (0.1%)	2
Dizziness	0/1482 (0%)	0	3/1474 (0.2%)	4
Facial paralysis	2/1482 (0.1%)	2	1/1474 (0.1%)	1
Sciatica	2/1482 (0.1%)	2	1/1474 (0.1%)	1
Toxic encephalopathy	1/1482 (0.1%)	1	2/1474 (0.1%)	2
Epilepsy	0/1482 (0%)	0	2/1474 (0.1%)	2
Generalised tonic-clonic seizure	1/1482 (0.1%)	1	1/1474 (0.1%)	1
Haemorrhagic stroke	2/1482 (0.1%)	2	0/1474 (0%)	0
Headache	1/1482 (0.1%)	1	1/1474 (0.1%)	1
Hepatic encephalopathy	2/1482 (0.1%)	3	0/1474 (0%)	0
Hypocalcaemic seizure	1/1482 (0.1%)	1	1/1474 (0.1%)	1
Nervous system disorder	2/1482 (0.1%)	2	0/1474 (0%)	0
Thalamus haemorrhage	1/1482 (0.1%)	1	1/1474 (0.1%)	1
Tremor	2/1482 (0.1%)	2	0/1474 (0%)	0
Uraemic encephalopathy	1/1482 (0.1%)	1	1/1474 (0.1%)	1
Altered state of consciousness	1/1482 (0.1%)	1	0/1474 (0%)	0
Aphasia	1/1482 (0.1%)	1	0/1474 (0%)	0
Brain injury	0/1482 (0%)	0	1/1474 (0.1%)	1
Brain stem infarction	0/1482 (0%)	0	1/1474 (0.1%)	1
Brain stem ischaemia	1/1482 (0.1%)	1	0/1474 (0%)	0
Cerebellar stroke	0/1482 (0%)	0	1/1474 (0.1%)	1
Cerebral artery stenosis	0/1482 (0%)	0	1/1474 (0.1%)	1
Cerebral circulatory failure	0/1482 (0%)	0	1/1474 (0.1%)	1
Cognitive disorder	1/1482 (0.1%)	1	0/1474 (0%)	0
Coma	0/1482 (0%)	0	1/1474 (0.1%)	1
Dysarthria	1/1482 (0.1%)	1	0/1474 (0%)	0
Dyskinesia	0/1482 (0%)	0	1/1474 (0.1%)	1
Embolic stroke	1/1482 (0.1%)	1	0/1474 (0%)	0
Focal dyscognitive seizures	0/1482 (0%)	0	1/1474 (0.1%)	1
Haemorrhage intracranial	0/1482 (0%)	0	1/1474 (0.1%)	1
IIIrd nerve paralysis	1/1482 (0.1%)	1	0/1474 (0%)	0
Intracranial aneurysm	1/1482 (0.1%)	1	0/1474 (0%)	0
Intraventricular haemorrhage	1/1482 (0.1%)	1	0/1474 (0%)	0
Loss of consciousness	0/1482 (0%)	0	1/1474 (0.1%)	1
Lumbar radiculopathy	0/1482 (0%)	0	1/1474 (0.1%)	1
Myelopathy	0/1482 (0%)	0	1/1474 (0.1%)	1
Neuropathy peripheral	0/1482 (0%)	0	1/1474 (0.1%)	1
Neurotoxicity	0/1482 (0%)	0	1/1474 (0.1%)	1
Pachymeningitis	0/1482 (0%)	0	1/1474 (0.1%)	1
Paraesthesia	0/1482 (0%)	0	1/1474 (0.1%)	1
Parkinson's disease	0/1482 (0%)	0	1/1474 (0.1%)	1
Partial seizures	1/1482 (0.1%)	1	0/1474 (0%)	0
Polyneuropathy	1/1482 (0.1%)	1	0/1474 (0%)	0
Post herpetic neuralgia	0/1482 (0%)	0	1/1474 (0.1%)	1
Postictal state	1/1482 (0.1%)	1	0/1474 (0%)	0
Presyncope	1/1482 (0.1%)	1	0/1474 (0%)	0
Seizure cluster	1/1482 (0.1%)	1	0/1474 (0%)	0
Somnolence	1/1482 (0.1%)	1	0/1474 (0%)	0
Subarachnoid haemorrhage	1/1482 (0.1%)	1	0/1474 (0%)	0
VIth nerve paralysis	0/1482 (0%)	0	1/1474 (0.1%)	1
Pregnancy, puerperium and perinatal conditions
Abortion spontaneous	0/1482 (0%)	0	1/1474 (0.1%)	1
Product Issues
Device malfunction	7/1482 (0.5%)	8	11/1474 (0.7%)	11
Thrombosis in device	2/1482 (0.1%)	2	4/1474 (0.3%)	4
Device dislocation	1/1482 (0.1%)	1	3/1474 (0.2%)	3
Device expulsion	0/1482 (0%)	0	1/1474 (0.1%)	1
Device kink	0/1482 (0%)	0	1/1474 (0.1%)	1
Device leakage	1/1482 (0.1%)	1	0/1474 (0%)	0
Device occlusion	0/1482 (0%)	0	1/1474 (0.1%)	1
Psychiatric disorders
Confusional state	4/1482 (0.3%)	4	1/1474 (0.1%)	1
Mental status changes	1/1482 (0.1%)	1	3/1474 (0.2%)	3
Depression	1/1482 (0.1%)	1	1/1474 (0.1%)	1
Panic attack	1/1482 (0.1%)	1	1/1474 (0.1%)	1
Adjustment disorder with depressed mood	1/1482 (0.1%)	1	0/1474 (0%)	0
Adjustment disorder with mixed disturbance of emotion and conduct	1/1482 (0.1%)	1	0/1474 (0%)	0
Anorexia nervosa	0/1482 (0%)	0	1/1474 (0.1%)	1
Bipolar disorder	0/1482 (0%)	0	1/1474 (0.1%)	2
Delirium	0/1482 (0%)	0	1/1474 (0.1%)	1
Disorientation	1/1482 (0.1%)	1	0/1474 (0%)	0
Hallucination, visual	0/1482 (0%)	0	1/1474 (0.1%)	1
Major depression	0/1482 (0%)	0	1/1474 (0.1%)	1
Psychotic disorder	0/1482 (0%)	0	1/1474 (0.1%)	1
Suicidal ideation	1/1482 (0.1%)	2	0/1474 (0%)	0
Suicide attempt	0/1482 (0%)	0	1/1474 (0.1%)	1
Renal and urinary disorders
Chronic kidney disease	2/1482 (0.1%)	2	5/1474 (0.3%)	5
Azotaemia	2/1482 (0.1%)	2	4/1474 (0.3%)	4
End stage renal disease	5/1482 (0.3%)	5	1/1474 (0.1%)	1
Haematuria	1/1482 (0.1%)	1	4/1474 (0.3%)	4
Nephrolithiasis	1/1482 (0.1%)	1	2/1474 (0.1%)	2
Cystitis haemorrhagic	1/1482 (0.1%)	1	0/1474 (0%)	0
Hydronephrosis	1/1482 (0.1%)	1	0/1474 (0%)	0
Lupus nephritis	0/1482 (0%)	0	1/1474 (0.1%)	1
Renal artery thrombosis	0/1482 (0%)	0	1/1474 (0.1%)	1
Renal cyst haemorrhage	0/1482 (0%)	0	1/1474 (0.1%)	1
Renal cyst ruptured	0/1482 (0%)	0	1/1474 (0.1%)	1
Renal disorder	1/1482 (0.1%)	1	0/1474 (0%)	0
Renal failure	1/1482 (0.1%)	1	0/1474 (0%)	0
Stag horn calculus	1/1482 (0.1%)	1	0/1474 (0%)	0
Subcapsular renal haematoma	1/1482 (0.1%)	1	0/1474 (0%)	0
Urinary tract disorder	0/1482 (0%)	0	1/1474 (0.1%)	1
Urinary tract obstruction	1/1482 (0.1%)	1	0/1474 (0%)	0
Reproductive system and breast disorders
Prostatitis	4/1482 (0.3%)	4	2/1474 (0.1%)	2
Endometriosis	2/1482 (0.1%)	2	0/1474 (0%)	0
Menorrhagia	1/1482 (0.1%)	1	1/1474 (0.1%)	1
Ovarian cyst	2/1482 (0.1%)	2	0/1474 (0%)	0
Acquired hydrocele	1/1482 (0.1%)	1	0/1474 (0%)	0
Adenomyosis	1/1482 (0.1%)	1	0/1474 (0%)	0
Benign prostatic hyperplasia	1/1482 (0.1%)	1	0/1474 (0%)	0
Ovarian disorder	0/1482 (0%)	0	1/1474 (0.1%)	1
Postmenopausal haemorrhage	1/1482 (0.1%)	1	0/1474 (0%)	0
Scrotal oedema	1/1482 (0.1%)	1	0/1474 (0%)	0
Testicular infarction	0/1482 (0%)	0	1/1474 (0.1%)	1
Uterine haemorrhage	0/1482 (0%)	0	1/1474 (0.1%)	1
Respiratory, thoracic and mediastinal disorders
Acute respiratory failure	14/1482 (0.9%)	16	13/1474 (0.9%)	14
Pulmonary oedema	11/1482 (0.7%)	14	15/1474 (1%)	17
Acute pulmonary oedema	10/1482 (0.7%)	10	15/1474 (1%)	16
Dyspnoea	13/1482 (0.9%)	14	12/1474 (0.8%)	12
Pleural effusion	13/1482 (0.9%)	13	11/1474 (0.7%)	11
Chronic obstructive pulmonary disease	11/1482 (0.7%)	11	9/1474 (0.6%)	10
Respiratory failure	10/1482 (0.7%)	10	10/1474 (0.7%)	10
Pulmonary embolism	4/1482 (0.3%)	4	9/1474 (0.6%)	9
Epistaxis	3/1482 (0.2%)	3	4/1474 (0.3%)	5
Pneumonia aspiration	4/1482 (0.3%)	4	2/1474 (0.1%)	3
Interstitial lung disease	2/1482 (0.1%)	2	3/1474 (0.2%)	3
Asthma	2/1482 (0.1%)	3	2/1474 (0.1%)	2
Pulmonary hypertension	0/1482 (0%)	0	4/1474 (0.3%)	4
Pleuritic pain	1/1482 (0.1%)	1	2/1474 (0.1%)	2
Pulmonary congestion	2/1482 (0.1%)	2	1/1474 (0.1%)	1
Dyspnoea exertional	1/1482 (0.1%)	1	1/1474 (0.1%)	1
Haemoptysis	1/1482 (0.1%)	1	1/1474 (0.1%)	1
Hypoxia	0/1482 (0%)	0	2/1474 (0.1%)	2
Obstructive airways disorder	2/1482 (0.1%)	2	0/1474 (0%)	0
Respiratory distress	1/1482 (0.1%)	1	1/1474 (0.1%)	1
Apnoea	0/1482 (0%)	0	1/1474 (0.1%)	1
Aspiration	1/1482 (0.1%)	1	0/1474 (0%)	0
Dysphonia	0/1482 (0%)	0	1/1474 (0.1%)	1
Haemothorax	0/1482 (0%)	0	1/1474 (0.1%)	1
Hydrothorax	1/1482 (0.1%)	1	0/1474 (0%)	0
Pleurisy	0/1482 (0%)	0	1/1474 (0.1%)	1
Pneumonitis	1/1482 (0.1%)	1	0/1474 (0%)	0
Pneumothorax	0/1482 (0%)	0	1/1474 (0.1%)	1
Pulmonary arterial hypertension	0/1482 (0%)	0	1/1474 (0.1%)	1
Pulmonary thrombosis	0/1482 (0%)	0	1/1474 (0.1%)	1
Respiratory acidosis	1/1482 (0.1%)	1	0/1474 (0%)	0
Respiratory arrest	0/1482 (0%)	0	1/1474 (0.1%)	1
Sleep apnoea syndrome	0/1482 (0%)	0	1/1474 (0.1%)	1
Skin and subcutaneous tissue disorders
Diabetic foot	8/1482 (0.5%)	9	3/1474 (0.2%)	3
Skin ulcer	7/1482 (0.5%)	7	1/1474 (0.1%)	1
Decubitus ulcer	3/1482 (0.2%)	3	3/1474 (0.2%)	3
Angioedema	2/1482 (0.1%)	2	0/1474 (0%)	0
Blister	0/1482 (0%)	0	1/1474 (0.1%)	1
Diabetic wound	0/1482 (0%)	0	1/1474 (0.1%)	1
Hyperkeratosis	1/1482 (0.1%)	1	0/1474 (0%)	0
Ischaemic skin ulcer	0/1482 (0%)	0	1/1474 (0.1%)	1
Skin weeping	1/1482 (0.1%)	1	0/1474 (0%)	0
Urticaria	1/1482 (0.1%)	1	0/1474 (0%)	0
Social circumstances
Loss of personal independence in daily activities	1/1482 (0.1%)	1	0/1474 (0%)	0
Vascular disorders
Hypertension	16/1482 (1.1%)	18	11/1474 (0.7%)	14
Hypotension	5/1482 (0.3%)	5	19/1474 (1.3%)	19
Peripheral ischaemia	12/1482 (0.8%)	14	7/1474 (0.5%)	7
Hypertensive urgency	6/1482 (0.4%)	7	8/1474 (0.5%)	10
Peripheral arterial occlusive disease	6/1482 (0.4%)	6	6/1474 (0.4%)	6
Dialysis hypotension	6/1482 (0.4%)	6	5/1474 (0.3%)	5
Hypertensive emergency	3/1482 (0.2%)	3	8/1474 (0.5%)	8
Extremity necrosis	3/1482 (0.2%)	4	7/1474 (0.5%)	9
Haematoma	5/1482 (0.3%)	5	5/1474 (0.3%)	6
Aortic stenosis	2/1482 (0.1%)	2	7/1474 (0.5%)	9
Hypertensive crisis	5/1482 (0.3%)	5	4/1474 (0.3%)	5
Orthostatic hypotension	5/1482 (0.3%)	5	3/1474 (0.2%)	3
Accelerated hypertension	1/1482 (0.1%)	1	5/1474 (0.3%)	6
Brachiocephalic vein stenosis	3/1482 (0.2%)	4	2/1474 (0.1%)	2
Peripheral vascular disorder	4/1482 (0.3%)	4	1/1474 (0.1%)	1
Subclavian vein stenosis	3/1482 (0.2%)	7	2/1474 (0.1%)	2
Deep vein thrombosis	3/1482 (0.2%)	3	1/1474 (0.1%)	1
Dry gangrene	3/1482 (0.2%)	3	1/1474 (0.1%)	1
Hypovolaemic shock	3/1482 (0.2%)	3	1/1474 (0.1%)	1
Haemorrhage	2/1482 (0.1%)	2	1/1474 (0.1%)	1
Peripheral artery occlusion	0/1482 (0%)	0	3/1474 (0.2%)	3
Shock haemorrhagic	3/1482 (0.2%)	3	0/1474 (0%)	0
Steal syndrome	1/1482 (0.1%)	1	2/1474 (0.1%)	2
Arterial haemorrhage	0/1482 (0%)	0	2/1474 (0.1%)	2
Jugular vein thrombosis	1/1482 (0.1%)	1	1/1474 (0.1%)	1
Vena cava thrombosis	0/1482 (0%)	0	2/1474 (0.1%)	2
Venous stenosis	1/1482 (0.1%)	3	1/1474 (0.1%)	5
Venous thrombosis limb	1/1482 (0.1%)	1	1/1474 (0.1%)	1
Aortic dissection	0/1482 (0%)	0	1/1474 (0.1%)	1
Arterial disorder	1/1482 (0.1%)	1	0/1474 (0%)	0
Arterial occlusive disease	0/1482 (0%)	0	1/1474 (0.1%)	1
Circulatory collapse	0/1482 (0%)	0	1/1474 (0.1%)	1
Diabetic microangiopathy	0/1482 (0%)	0	1/1474 (0.1%)	1
Diabetic vascular disorder	0/1482 (0%)	0	1/1474 (0.1%)	1
Granulomatosis with polyangiitis	0/1482 (0%)	0	1/1474 (0.1%)	1
Ischaemic limb pain	1/1482 (0.1%)	1	0/1474 (0%)	0
Peripheral artery stenosis	1/1482 (0.1%)	1	0/1474 (0%)	0
Peripheral artery thrombosis	1/1482 (0.1%)	1	0/1474 (0%)	0
Peripheral vein occlusion	0/1482 (0%)	0	1/1474 (0.1%)	1
Shock	1/1482 (0.1%)	1	0/1474 (0%)	0
Subclavian vein thrombosis	0/1482 (0%)	0	1/1474 (0.1%)	1
Superior vena cava occlusion	0/1482 (0%)	0	1/1474 (0.1%)	1
Superior vena cava syndrome	1/1482 (0.1%)	1	0/1474 (0%)	0
Thrombophlebitis	0/1482 (0%)	0	1/1474 (0.1%)	1
Thrombosis	1/1482 (0.1%)	1	0/1474 (0%)	0
Venous thrombosis	0/1482 (0%)	0	1/1474 (0.1%)	1
Other (Not Including Serious) Adverse Events
	Daprodustat		rhEPO
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	830/1482 (56%)		827/1474 (56.1%)
Gastrointestinal disorders
Diarrhoea	161/1482 (10.9%)	225	176/1474 (11.9%)	228
Nausea	83/1482 (5.6%)	95	84/1474 (5.7%)	106
Vomiting	83/1482 (5.6%)	103	76/1474 (5.2%)	98
Infections and infestations
Nasopharyngitis	113/1482 (7.6%)	188	104/1474 (7.1%)	188
Upper respiratory tract infection	99/1482 (6.7%)	144	92/1474 (6.2%)	125
Bronchitis	87/1482 (5.9%)	116	97/1474 (6.6%)	124
Urinary tract infection	73/1482 (4.9%)	99	79/1474 (5.4%)	97
Injury, poisoning and procedural complications
Fall	73/1482 (4.9%)	96	84/1474 (5.7%)	119
Arteriovenous fistula site complication	61/1482 (4.1%)	90	89/1474 (6%)	121
Metabolism and nutrition disorders
Hyperkalaemia	76/1482 (5.1%)	92	62/1474 (4.2%)	72
Musculoskeletal and connective tissue disorders
Arthralgia	101/1482 (6.8%)	120	111/1474 (7.5%)	138
Pain in extremity	85/1482 (5.7%)	105	76/1474 (5.2%)	99
Back pain	64/1482 (4.3%)	87	88/1474 (6%)	103
Nervous system disorders
Headache	115/1482 (7.8%)	176	139/1474 (9.4%)	216
Respiratory, thoracic and mediastinal disorders
Cough	101/1482 (6.8%)	128	101/1474 (6.9%)	133
Dyspnoea	58/1482 (3.9%)	67	74/1474 (5%)	88
Vascular disorders
Hypertension	235/1482 (15.9%)	366	232/1474 (15.7%)	356
Dialysis hypotension	135/1482 (9.1%)	254	105/1474 (7.1%)	206
Hypotension	115/1482 (7.8%)	140	92/1474 (6.2%)	130

Limitations/Caveats

[Not Specified]

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Certain Agreements

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

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