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

• Sponsor: GlaxoSmithKline (Industry)
• Overall Status: Completed
• CT.gov ID: NCT03029208
• Collaborator: (none)
• Enrollment: 312
• Locations: 111
• Arms: 2
• Actual Duration (Months): 40.5
• Patients Per Site: 2.8
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

The purpose of this multi-center study is to evaluate the efficacy and safety of daprodustat in subjects with anemia associated with CKD.

Condition or Disease	Intervention/Treatment	Phase
Anaemia	Drug: Daprodustat; Drug: Darbepoetin alfa; Drug: Iron therapy	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 312 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A 52-week Open-label (Sponsor-blind), Randomized, Active-controlled, Parallel-group, Multi-center Study to Evaluate the Efficacy and Safety of Daprodustat Compared to Recombinant Human Erythropoietin in Subjects With Anemia Associated With Chronic Kidney Disease Who Are Initiating Dialysis
• Actual Study Start Date: May 11, 2017
• Actual Primary Completion Date: Sep 24, 2020
• Actual Study Completion Date: Sep 24, 2020

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Daprodustat treated anemic subjects Subjects will receive oral daprodustat once daily.	Drug: Daprodustat; Daprodustat will be supplied as film coated tablets for oral administration containing 1, 2, 4, 6, 8, or 10 mg of daprodustat. Doses of 12, 16, and 24 mg of daprodustat will be provided using multiples of these tablet strengths.; Drug: Iron therapy; Iron therapy will be administered if ferritin is <=100 ng/mL and/or TSAT is <=20%.
Active Comparator: Darbepoetin alfa treated anemic subjects Subjects will receive darbepoetin alfa subcutaneously or intravenously.	Drug: Darbepoetin alfa; Darbepoetin alfa will be supplied as prefilled syringes (PFS) for SC/IV injection available in strengths: 20, 30, 40, 60, 80, 100 and 150 mcg.; Drug: Iron therapy; Iron therapy will be administered if ferritin is <=100 ng/mL and/or TSAT is <=20%.

Outcome Measures

Primary Outcome Measures

1. Mean Change From Baseline in Hemoglobin (Hgb) 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 Hgb measurement. Hgb during the evaluation period was defined as the mean of all available post-randomization Hgb values (on and off-treatment) during the evaluation period (Week 28 to Week 52). For the primary analysis missing post-Baseline Hgb values were imputed using pre-specified multiple imputations. Change from Baseline was defined as the average of post-randomization values during the evaluation period minus Baseline value. Baseline was defined as the latest non-missing pre-dose assessment on or before the randomization date. An analysis of covariance (ANCOVA) model including randomization stratification factors Baseline Hgb and treatment was performed to obtain a point estimate and two-sided 95 percent (%) confidence interval (CI) for the treatment difference (daprodustat-darbepoetin alfa).

Secondary Outcome Measures

1. Average Monthly Intravenous Iron Dose (Milligrams) From Baseline to Week 52 [Baseline (Day 1) to Week 52]

   Total IV iron dose per participant was calculated from Day 1 to the earliest of (Week 52 visit date, first blood [red blood cells or whole blood] transfusion date and treatment stop date plus [+] 1 day) which corresponds to the time while the participant was on randomized treatment and before receiving a blood transfusion. Average monthly IV iron dose was calculated by Total IV iron dose divided by (/) (the number of days from Day 1 to the earliest of [Week 52 visit date, first blood transfusion date and treatment stop date +1] /30.4375 days). Data for participants until they underwent a red blood cells or whole blood transfusion was included in the analysis.

2. Change From Baseline in Systolic Blood Pressure (SBP), Diastolic Blood Pressure (DBP), Mean Arterial Blood Pressure (MAP) at Week 52 [Baseline (Day 1) 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 an average BP in an individual's arteries during a single cardiac cycle. Change from Baseline was calculated as post-dose 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 mixed model repeated measures (MMRM) model.

3. Change From Baseline in SBP, DBP, MAP at End of Treatment [Baseline (Day 1) and end of treatment (last on-treatment value until 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 an average BP in an individual's arteries during a single cardiac cycle. End of treatment value for the blood pressure parameters were defined as the latest value on or before the last non-zero dose date plus (+) 1 day. Change from Baseline was calculated as post-dose 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.

4. Blood Pressure (BP) Exacerbation Events Rate Per 100 Participant Years [Up to Week 52]

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

5. Number of Participants With at Least One Blood Pressure Exacerbation Event During Study [Up to Week 52]

   BP exacerbation was defined (based on post-dialysis BP) 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 blood pressure exacerbation event is presented.

6. Change From Baseline in Post-randomization Hgb at Week 52 [Baseline (Day 1) and Week 52]

   Blood samples were collected from participants for Hgb measurements. Change from Baseline was calculated as post-dose visit value minus Baseline value. Baseline was defined as the latest non-missing pre-dose assessment on or before the randomization date.

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

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

8. Percentage of Time for Which Hgb Was Within the Analysis Range (10 to 11.5 g/dL) During Evaluation Period (Week 28 to Week 52): Non-inferiority Analysis [Weeks 28 to 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 for which Hgb was within range for a participant was calculated by dividing 'the total number of days that Hgb was within range during Weeks 28 to 52' by 'the total number of days the participant remained on treatment during Weeks 28 to 52'.

9. Percentage of Time for Which Hgb Was Within the Analysis Range (10 to 11.5 g/dL) During Evaluation Period (Week 28 to Week 52): Superiority Analysis [Weeks 28 to 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 for which Hgb was within range for a participant was calculated by dividing 'the total number of days that Hgb was within range during Weeks 28 to 52' by 'the total number of days the participant remained on treatment during Weeks 28 to 52'.

10. Number of Participants Permanently Stopping Randomized Treatment Due to Meeting Rescue Criteria [Up to Week 52]

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

11. Change From Baseline in Physical Component Score (PCS) Using Short Form (SF)-36 Health-related Quality of Life (HRQoL) Questionnaire at Weeks 8, 12, 28, 52 [Baseline (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 post-dose visit value minus Baseline value. Baseline was defined as the latest non-missing pre-dose assessment on or before the randomization date.

12. Change From Baseline in Mental Component Score (MCS) Using SF-36 HRQoL Questionnaire at Weeks 8, 12, 28, 52 [Baseline (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 post-dose visit value minus Baseline value. Baseline was defined as the latest non-missing pre-dose assessment on or before the randomization date.

13. Change From Baseline in SF-36 HRQoL Scores for Bodily Pain, General Health, Mental Health, Role-Emotional, Role-Physical, Social Functioning at Weeks 8, 12, 28, 52 [Baseline (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, physical functioning and vitality. Each domain is scored from 0 (poorer health) to 100 (better health). Each domain score ranges from 0 to 100, higher score indicates a better health state and better functioning. Change from Baseline was calculated as post-dose visit value minus Baseline value. Baseline was defined as the latest non-missing pre-dose assessment on or before the randomization date.

14. Change From Baseline in Vitality Scores Using SF-36 HRQoL Questionnaire at Weeks 28, 52 [Baseline (Day 1), Weeks 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 ranges from 0 to 100; higher scores represent better health. Change from Baseline was calculated as post-dose visit value minus Baseline value. Baseline was defined as the latest non-missing pre-dose assessment on or before the randomization date.

15. Change From Baseline in Physical Functioning Domain Scores Using SF-36 HRQoL Questionnaire at Weeks 28, 52 [Baseline (Day 1), Weeks 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 ranges from 0 to 100; higher scores represent better health. Change from Baseline was calculated as post-dose visit value minus (-) Baseline value. Baseline was defined as the latest non-missing pre-dose assessment on or before the randomization date.

16. Change From Baseline in Health Utility EuroQol 5 Dimensions 5 Level (EQ-5D-5L) Questionnaire Score at Week 52 [Baseline (Day 1) and Week 52]

    EQ-5D-5L consists of 2 concepts-EQ-5D-5L descriptive system and EQ Visual Analogue Scale (EQ-VAS). EQ-5D-5L is self-assessment questionnaire, consisting of 5items covering 5 dimensions (mobility,self care, usual activities, pain/discomfort and anxiety/depression). Each dimension is measured by 5-point Likert scale(no problems, slight problems, moderate problems, severe problems and 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), higher the score better the health status. Change from Baseline was calculated as post-dose visit value-Baseline value. Baseline was latest non-missing pre-dose assessment on or before randomization date.

17. Change From Baseline in EQ Visual Analogue Scale (EQ-VAS) at Week 52 [Baseline (Day 1) and Week 52]

    The EQ-5D-5L consists of 2 concepts -EQ-5D-5L descriptive system and EQ-VAS. The EQ-5D-5L is a self-assessment questionnaire, consisting of five items covering five dimensions (mobility, self care, usual activities, pain/discomfort and anxiety/depression). Each dimension is measured by a five-point Likert scale (no problems, slight problems, moderate problems, severe problems, and extreme problems). The range for the EQ-5D-5L index score is 0 to 1 with '0' is worst health and '1' is full health. 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 post-dose visit value minus Baseline value. Baseline was defined as the latest non-missing pre-dose assessment on or before the randomization date.

18. Change From Baseline in Chronic Kidney Disease- Anemia Symptoms Questionnaire (CKD-AQ) at Week 52 [Baseline (Day 1) and Week 52]

    CKD-AQ is 21-item patient reported outcome measure assessing symptoms and symptom impact in participants with anemia associated with CKD. It had 3 domains: 1.Tired/Low Energy/Weak scale consisting of 10 items; 2.Chest Pain/Shortness of Breath scale consisting of 4 items; and 3.Cognitive scale consisting of 3 items. The 4 CKD-AQ single items are: (shortness of breath, no activity), (severity-short breath, resting), (difficulty standing for long time) and (difficulty sleeping). Single-item were recorded based on a 0-100 scoring with 0=worst possible and 100=best possible score. Three domains scores were calculated as average of items in each domain and ranged from 0-100 where 0=worst possible and 100=best possible score. Change from Baseline was calculated as post-dose visit value minus Baseline value. Baseline was defined as the latest non-missing pre-dose assessment on or before the randomization date.

19. Change From Baseline in Patient Global Impression of Severity (PGI-S) [Baseline (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 post-dose visit value minus Baseline value. Baseline was defined as the latest non-missing pre-dose assessment on or before the randomization date.

20. Plasma Concentration of Daprodustat (GSK1278863) and Its Metabolites GSK2391220 (M2), GSK2506104 (M3), and GSK2531401 (M13) [Pre-dose, 0.5, 1, 2 and 3 hours post-dose; each pharmacokinetic sample was taken at Week 4 or 8 or 12]

    Pharmacokinetic samples were collected at pre-dose, 0.5, 1, 2 and 3 hours post-dose on Week 4 or 8 or 12 for pharmacokinetic (PK) analysis of daprodustat (GSK1278863) and its metabolites GSK2391220 (M2), GSK2506104 (M3), and GSK2531401 (M13). GSK2391220, GSK2506104 and GSK2531401 are the metabolites of Daprodustat (GSK1278863). Protocol allowed participants to provide pharmacokinetic samples on Week 4 or 8 or 12. Pharmacokinetic Population comprised of participants for whom a pharmacokinetic sample was obtained and analyzed.

21. Observed Concentration at Dosing Interval (Ctau) of Daprodustat (GSK1278863) and Its Metabolites GSK2391220 (M2), GSK2506104 (M3), and GSK2531401 (M13) [Pre-Dose, 0.5, 1, 2 and 3 hours post-dose; each pharmacokinetic sample was taken at Week 4 or 8 or 12]

    Pharmacokinetic samples were collected at pre-dose, 0.5, 1, 2 and 3 hours post-dose on Week 4 or 8 or 12 for pharmacokinetic analysis of daprodustat (GSK1278863) and its metabolites GSK2391220 (M2), GSK2506104 (M3), and GSK2531401 (M13). GSK2391220, GSK2506104 and GSK2531401 are the metabolites of Daprodustat (GSK1278863). Protocol allowed participants to provide pharmacokinetic samples on Week 4 or 8 or 12.

22. Maximum Observed Concentration (Cmax) of Daprodustat (GSK1278863) and Its Metabolites GSK2391220 (M2), GSK2506104 (M3), and GSK2531401 (M13) [Pre-Dose, 0.5, 1, 2 and 3 hours post-dose; each pharmacokinetic sample was taken at Week 4 or 8 or 12]

    Pharmacokinetic samples were collected at pre-dose, 0.5, 1, 2 and 3 hours post-dose on Week 4 or 8 or 12 for pharmacokinetic analysis of daprodustat (GSK1278863) and its metabolites GSK2391220 (M2), GSK2506104 (M3), and GSK2531401 (M13). GSK2391220, GSK2506104 and GSK2531401 are the metabolites of Daprodustat (GSK1278863). Protocol allowed participants to provide pharmacokinetic samples on Week 4 or 8 or 12.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• 18 to 99 years of age inclusive.

• Planning to start chronic dialysis within the next 6 weeks (from the date of the screening visit) OR have started and received dialysis (as specified below) for end-stage renal disease for a maximum of <=90 days immediately prior to randomization and is not expected to stop dialysis during the duration of the trial: HD >=2 times per week or PD >=4 times per week including incremental schedule; subjects on continuous ambulatory peritoneal dialysis (CAPD) and automated peritoneal dialysis (APD) are eligible.

• Hemoglobin concentration as measured by HemoCue (range inclusive): 8 to 10.5 g/dL (5-6.5 millimoles per liter [mmol/L]) at screening and 8-11.0 g/dL (5 to 6.8 mmol/L) at randomization.

• 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:

• Planned living-related or living-unrelated kidney transplant during the study.

• Ferritin: <=100 nanograms per milliliter (ng/mL) (<=100 micrograms per liter [mcg/L]) at screening or after IV iron supplementation.

• Transferrin saturation (TSAT): <=20% at screening or after IV iron supplementation.

• Vitamin B12 (cobalamin): Below the lower limit of the reference range at screening or after vitamin B12 supplementation.

• Folate: <2.0 ng/mL (<4.5 nanomoles per liter [nmol/L]) at screening.

• Aplasias: History of bone marrow aplasia or pure red cell aplasia (PRCA).

• 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 <=10 weeks prior to screening through to randomization (Day 1).

• Use of any Erythropoiesis-stimulating agent (ESA) treatment within 8 weeks prior to screening except for limited use as part of dialysis initiation. Note : Limited use is defined as no more than 6 weeks of short acting ESA (rhEPO or biosimilars; maximum of 20000 unit total) or long acting ESA (darbepoetin alfa [maximum of 100 mcg total] or methoxy polyethylene glycol-epoetin beta [maximum of 125 mcg total]) received before or after starting dialysis.

• Myocardial infarction or acute coronary syndrome: <=10 weeks prior to screening through to randomization (Day 1).

• Stroke or transient ischemic attack: <=10 weeks prior to screening through to randomization (Day 1).

• Chronic Class IV heart failure, as defined by the New York Heart Association (NYHA) functional classification system.

• Current uncontrolled hypertension as determined by the Investigator that would contraindicate the use of rhEPO.

• QT correction using Bazett's (QTcB) (Day 1): QTcB >500 milliseconds (msec), or QTcB

530 msec in subjects with bundle branch block. There is no QTc exclusion for subjects with a predominantly ventricular paced rhythm.

• Liver disease (any one of the following): 1. Alanine transaminase (ALT) >2 times upper limit of normal (ULN) (screening only). 2. Bilirubin >1.5 times ULN (screening only) (NOTE: Isolated bilirubin >1.5 times ULN is acceptable if bilirubin is fractionated and direct bilirubin <35%). 3. Current unstable liver or biliary disease per investigator assessment, generally defined by the presence of ascites, encephalopathy, coagulopathy, hypoalbuminemia, esophageal or gastric varices, persistent jaundice, or cirrhosis. NOTE: Stable chronic liver disease (including asymptomatic gallstones, chronic hepatitis B or C, or Gilbert's syndrome) are acceptable if subject otherwise meets entry criteria.

• 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 (i.e. Bosniak Category II F, III or IV) >3 centimeter (cm). The only exception is localized squamous cell or basal cell carcinoma of the skin that has been definitively treated

=10 weeks prior to screening.

• History of severe allergic or anaphylactic reactions or hypersensitivity to excipients in the investigational product or to darbepoetin alfa.

• Use of strong Cytochrome P4502C8 (CYP2C8) inhibitors (example gemfibrozil) or strong CYP2C8 inducers (example rifampin/rifampicin).

• Use of other investigational agent or device prior to screening through to randomization (Day 1). At screening, this exclusion applies to use of the investigational agent within 30 days or within five half-lives (whichever is longer).

• Any prior treatment with daprodustat for treatment duration of >30 days.

• Females only: Subject is pregnant [as confirmed by a positive serum human chorionic gonadotropin (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 in the List of Highly Effective Methods for Avoiding Pregnancy.

• 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 (example 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	Anaheim	California	United States	92801
2	GSK Investigational Site	Cerritos	California	United States	90703
3	GSK Investigational Site	Escondido	California	United States	92025
4	GSK Investigational Site	Glendale	California	United States	91204
5	GSK Investigational Site	La Palma	California	United States	90623
6	GSK Investigational Site	Los Angeles	California	United States	90022
7	GSK Investigational Site	Los Angeles	California	United States	90095
8	GSK Investigational Site	Lynwood	California	United States	90262
9	GSK Investigational Site	Sacramento	California	United States	95825
10	GSK Investigational Site	Whittier	California	United States	90603
11	GSK Investigational Site	Middlebury	Connecticut	United States	06762
12	GSK Investigational Site	Coral Gables	Florida	United States	33134
13	GSK Investigational Site	Miami	Florida	United States	33126
14	GSK Investigational Site	Miami	Florida	United States	33169
15	GSK Investigational Site	Augusta	Georgia	United States	30912
16	GSK Investigational Site	Chicago	Illinois	United States	60637
17	GSK Investigational Site	Crystal Lake	Illinois	United States	60014
18	GSK Investigational Site	Fort Wayne	Indiana	United States	46804
19	GSK Investigational Site	Merrillville	Indiana	United States	46410
20	GSK Investigational Site	Michigan City	Indiana	United States	46360
21	GSK Investigational Site	Iowa City	Iowa	United States	52242
22	GSK Investigational Site	Baton Rouge	Louisiana	United States	70809
23	GSK Investigational Site	New Orleans	Louisiana	United States	70112
24	GSK Investigational Site	Baltimore	Maryland	United States	21287
25	GSK Investigational Site	Jackson	Mississippi	United States	39216
26	GSK Investigational Site	Kansas City	Missouri	United States	64111
27	GSK Investigational Site	Saint Louis	Missouri	United States	63110
28	GSK Investigational Site	Bronx	New York	United States	10461
29	GSK Investigational Site	Brooklyn	New York	United States	11203
30	GSK Investigational Site	Buffalo	New York	United States	14215
31	GSK Investigational Site	Mineola	New York	United States	11501
32	GSK Investigational Site	New York	New York	United States	10029
33	GSK Investigational Site	Houston	Texas	United States	77004
34	GSK Investigational Site	Lufkin	Texas	United States	75904
35	GSK Investigational Site	San Antonio	Texas	United States	78229
36	GSK Investigational Site	Hampton	Virginia	United States	23666
37	GSK Investigational Site	Ciudad Evita	Buenos Aires	Argentina	B1778IFA
38	GSK Investigational Site	La Plata	Buenos Aires	Argentina	B1902COS
39	GSK Investigational Site	Morón	Buenos Aires	Argentina	B1708DPO
40	GSK Investigational Site	Pergamino	Buenos Aires	Argentina	B2700CPM
41	GSK Investigational Site	Pilar	Buenos Aires	Argentina	1629
42	GSK Investigational Site	Buenos Aires		Argentina	1425
43	GSK Investigational Site	Formosa		Argentina	P3600LLD
44	GSK Investigational Site	Mendoza		Argentina	M5500AFA
45	GSK Investigational Site	San Miguel de Tucumán		Argentina	T4000AHL
46	GSK Investigational Site	Adelaide	South Australia	Australia	5000
47	GSK Investigational Site	Melbourne	Victoria	Australia	3004
48	GSK Investigational Site	St Albans	Victoria	Australia	3021
49	GSK Investigational Site	London	Ontario	Canada	N6A 5A5
50	GSK Investigational Site	Toronto	Ontario	Canada	M3M 0B2
51	GSK Investigational Site	Greenfield Park	Quebec	Canada	J4V 2H1
52	GSK Investigational Site	Duesseldorf	Nordrhein-Westfalen	Germany	40210
53	GSK Investigational Site	Kaiserslautern	Rheinland-Pfalz	Germany	67655
54	GSK Investigational Site	Wiesbaden		Germany	65191
55	GSK Investigational Site	Bangalore		India	560055
56	GSK Investigational Site	Chennai		India	600037
57	GSK Investigational Site	Delhi		India	110076
58	GSK Investigational Site	Gurgaon		India	122001
59	GSK Investigational Site	Kozhikode		India	673008
60	GSK Investigational Site	New Delhi		India	110060
61	GSK Investigational Site	Pune		India	411004
62	GSK Investigational Site	Secunderabad		India	560020
63	GSK Investigational Site	Thiruvananthapuram		India	695011
64	GSK Investigational Site	Genova	Liguria	Italy	16132
65	GSK Investigational Site	Milano	Lombardia	Italy	20153
66	GSK Investigational Site	Pavia	Lombardia	Italy	27100
67	GSK Investigational Site	Cagliari	Sardegna	Italy	09100
68	GSK Investigational Site	Anyang-Si, Gyeonggi-do		Korea, Republic of	14068
69	GSK Investigational Site	Bucheon-si,		Korea, Republic of	14647
70	GSK Investigational Site	Incheon		Korea, Republic of	6510
71	GSK Investigational Site	Seoul		Korea, Republic of	05030
72	GSK Investigational Site	Seoul		Korea, Republic of	08308
73	GSK Investigational Site	Suwon		Korea, Republic of	16499
74	GSK Investigational Site	Ipoh		Malaysia	30450
75	GSK Investigational Site	Kuala Lumpur		Malaysia	59100
76	GSK Investigational Site	Penang		Malaysia	10990
77	GSK Investigational Site	Torreon	Coahuila	Mexico	27000
78	GSK Investigational Site	Ciudad De México	Estado De México	Mexico	14000
79	GSK Investigational Site	Guadalajara.	Jalisco	Mexico	44600
80	GSK Investigational Site	Zapopan	Jalisco	Mexico	45030
81	GSK Investigational Site	Merida	Yucatán	Mexico	CP 97070
82	GSK Investigational Site	Mérida	Yucatán	Mexico	97130
83	GSK Investigational Site	Aguascalientes		Mexico	20259
84	GSK Investigational Site	Tlalnepantla		Mexico	54055
85	GSK Investigational Site	Gdansk		Poland	80-952
86	GSK Investigational Site	Kolo		Poland	62-600
87	GSK Investigational Site	Krakow		Poland	31-826
88	GSK Investigational Site	Lodz		Poland	92-213
89	GSK Investigational Site	Lodz		Poland	96-300
90	GSK Investigational Site	Ostroda		Poland	14-100
91	GSK Investigational Site	Ostroleka		Poland	7410
92	GSK Investigational Site	Szczecin		Poland	70-780
93	GSK Investigational Site	Irkutsk		Russian Federation	664049
94	GSK Investigational Site	Mytishchi		Russian Federation	141007
95	GSK Investigational Site	Omsk		Russian Federation	644112
96	GSK Investigational Site	Smolensk		Russian Federation	214006
97	GSK Investigational Site	St-Petersburg		Russian Federation	197110
98	GSK Investigational Site	St. Petersburg		Russian Federation	191104
99	GSK Investigational Site	St. Petersburg		Russian Federation	194354
100	GSK Investigational Site	St. Petersburg		Russian Federation	196247
101	GSK Investigational Site	Volzhskiy		Russian Federation	404120
102	GSK Investigational Site	Cape Town.		South Africa	7925
103	GSK Investigational Site	Badalona		Spain	08916
104	GSK Investigational Site	Barcelona		Spain	08035
105	GSK Investigational Site	Madrid		Spain	28040
106	GSK Investigational Site	Puerto Real		Spain	11510
107	GSK Investigational Site	Sevilla		Spain	41009
108	GSK Investigational Site	Birmingham		United Kingdom	B9 5SS
109	GSK Investigational Site	Doncaster		United Kingdom	DN2 5LT
110	GSK Investigational Site	London		United Kingdom	SE5 9RS
111	GSK Investigational Site	Middlesbrough		United Kingdom	TS4 3BW

Sponsors and Collaborators

• GlaxoSmithKline

Investigators

• Study Director: GSK Clinical Trials, GlaxoSmithKline

Study Documents (Full-Text)

• Study Protocol - Oct 6, 2017
• Statistical Analysis Plan - Nov 20, 2020

More Information

Publications

None provided.

• Responsible Party: GlaxoSmithKline
• ClinicalTrials.gov Identifier: NCT03029208
• Other Study ID Numbers: 201410; 2016-000507-86
• First Posted: Jan 24, 2017
• Last Update Posted: Oct 20, 2021
• Last Verified: Sep 1, 2021

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by GlaxoSmithKline: Daprodustat, recombinant human erythropoietin, darbepoetin, anemia, chronic kidney disease, dialysis, ESRD
• Additional relevant MeSH terms: Kidney Diseases; Renal Insufficiency, Chronic; Anemia; Darbepoetin alfa

Study Results

Participant Flow

Recruitment Details	This was a multicenter study conducted across 14 countries. Participants were randomized to receive either Daprodustat or Darbepoetin alfa.
Pre-assignment Detail	A total of 312 participants were randomized in the study.

Arm/Group Title	Daprodustat	Darbepoetin Alfa
Arm/Group Description	Participants received daprodustat film-coated tablets with titrated dose levels ranging from 1, 2, 4, 6, 8, 10, 12, 16, and 24 milligrams (mg) orally once daily for up to 52 weeks. Study treatment was dose-titrated to achieve and maintain hemoglobin (Hgb) in the target range (10 to 11 grams per deciliter [g/dL]).	Participants received darbepoetin alfa as prefilled syringes (PFS) for subcutaneous or intravenous (IV) injection with 4-weekly total dose levels ranging from 20, 30, 40, 60, 80, 120, 160, 200, 300 and 400 microgram (mcg) for 52 weeks. Study treatment was dose-titrated to achieve and maintain Hgb in the target range (10 to 11 g/dL).
Period Title: Overall Study
STARTED	157	155
COMPLETED	155	151
NOT COMPLETED	2	4

Baseline Characteristics

Arm/Group Title	Daprodustat	Darbepoetin Alfa	Total
Arm/Group Description	Participants received daprodustat film-coated tablets with titrated dose levels ranging from 1, 2, 4, 6, 8, 10, 12, 16, and 24 milligrams (mg) orally once daily for up to 52 weeks. Study treatment was dose-titrated to achieve and maintain hemoglobin (Hgb) in the target range (10 to 11 grams per deciliter [g/dL]).	Participants received darbepoetin alfa as prefilled syringes (PFS) for subcutaneous or intravenous (IV) injection with 4-weekly total dose levels ranging from 20, 30, 40, 60, 80, 120, 160, 200, 300 and 400 microgram (mcg) for 52 weeks. Study treatment was dose-titrated to achieve and maintain Hgb in the target range (10 to 11 g/dL).	Total of all reporting groups
Overall Participants	157	155	312
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	53.7 (14.31)	55.8 (15.70)	54.7 (15.03)
Sex: Female, Male (Count of Participants)
Female	61 38.9%	57 36.8%	118 37.8%
Male	96 61.1%	98 63.2%	194 62.2%
Race/Ethnicity, Customized (Count of Participants)
American Indian (AI) or Alaskan Native (AN)	5 3.2%	2 1.3%	7 2.2%
Asian: Central/South Asian Heritage	7 4.5%	6 3.9%	13 4.2%
Asian: East Asian Heritage	8 5.1%	16 10.3%	24 7.7%
Asian: South East Asian Heritage	11 7%	9 5.8%	20 6.4%
Black or African American	16 10.2%	13 8.4%	29 9.3%
White: Arabic/North African Heritage	1 0.6%	0 0%	1 0.3%
White: White/Caucasian/European Heritage	109 69.4%	107 69%	216 69.2%
Mixed race: AI or AN and White	0 0%	2 1.3%	2 0.6%

Outcome Measures

1. Primary Outcome

Title	Mean Change From Baseline in Hemoglobin (Hgb) During Evaluation Period (Week 28 to Week 52)
Description	Blood samples were collected from participants for Hgb measurement. Hgb during the evaluation period was defined as the mean of all available post-randomization Hgb values (on and off-treatment) during the evaluation period (Week 28 to Week 52). For the primary analysis missing post-Baseline Hgb values were imputed using pre-specified multiple imputations. Change from Baseline was defined as the average of post-randomization values during the evaluation period minus Baseline value. Baseline was defined as the latest non-missing pre-dose assessment on or before the randomization date. An analysis of covariance (ANCOVA) model including randomization stratification factors Baseline Hgb and treatment was performed to obtain a point estimate and two-sided 95 percent (%) confidence interval (CI) for the treatment difference (daprodustat-darbepoetin alfa).
Time Frame	Baseline (Pre-dose on Day 1) and evaluation period (Week 28 to Week 52)

Outcome Measure Data

Analysis Population Description

Intent-to-Treat (ITT) Population comprised all randomized participants (who received a treatment randomization number).

Arm/Group Title	Daprodustat	Darbepoetin Alfa
Arm/Group Description	Participants received daprodustat film-coated tablets with titrated dose levels ranging from 1, 2, 4, 6, 8, 10, 12, 16, and 24 milligrams (mg) orally once daily for up to 52 weeks. Study treatment was dose-titrated to achieve and maintain hemoglobin (Hgb) in the target range (10 to 11 grams per deciliter [g/dL]).	Participants received darbepoetin alfa as prefilled syringes (PFS) for subcutaneous or intravenous (IV) injection with 4-weekly total dose levels ranging from 20, 30, 40, 60, 80, 120, 160, 200, 300 and 400 microgram (mcg) for 52 weeks. Study treatment was dose-titrated to achieve and maintain Hgb in the target range (10 to 11 g/dL).
Measure Participants	157	155
Least Squares Mean (Standard Error) [Grams per deciliter]	1.02 (0.086)	1.12 (0.085)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Daprodustat, Darbepoetin Alfa
	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	Least square (LS) mean difference
	Estimated Value	-0.10
	Confidence Interval	(2-Sided) 95%; -0.34 to 0.14
	Parameter Dispersion	Type: Value:
	Estimation Comments	An ANCOVA model including randomization stratification factors Baseline Hgb and treatment was performed to obtain a point estimate and two-sided 95% CI for the treatment difference (daprodustat-darbepoetin alfa).

2. Secondary Outcome

Title	Average Monthly Intravenous Iron Dose (Milligrams) From Baseline to Week 52
Description	Total IV iron dose per participant was calculated from Day 1 to the earliest of (Week 52 visit date, first blood [red blood cells or whole blood] transfusion date and treatment stop date plus [+] 1 day) which corresponds to the time while the participant was on randomized treatment and before receiving a blood transfusion. Average monthly IV iron dose was calculated by Total IV iron dose divided by (/) (the number of days from Day 1 to the earliest of [Week 52 visit date, first blood transfusion date and treatment stop date +1] /30.4375 days). Data for participants until they underwent a red blood cells or whole blood transfusion was included in the analysis.
Time Frame	Baseline (Day 1) to Week 52

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Daprodustat	Darbepoetin Alfa
Arm/Group Description	Participants received daprodustat film-coated tablets with titrated dose levels ranging from 1, 2, 4, 6, 8, 10, 12, 16, and 24 milligrams (mg) orally once daily for up to 52 weeks. Study treatment was dose-titrated to achieve and maintain hemoglobin (Hgb) in the target range (10 to 11 grams per deciliter [g/dL]).	Participants received darbepoetin alfa as prefilled syringes (PFS) for subcutaneous or intravenous (IV) injection with 4-weekly total dose levels ranging from 20, 30, 40, 60, 80, 120, 160, 200, 300 and 400 microgram (mcg) for 52 weeks. Study treatment was dose-titrated to achieve and maintain Hgb in the target range (10 to 11 g/dL).
Measure Participants	156	154
Least Squares Mean (Standard Error) [Milligram]	144.7 (10.90)	125.3 (10.97)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Daprodustat, Darbepoetin Alfa
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.8949
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	19.4
	Confidence Interval	(2-Sided) 95%; -11.0 to 49.9
	Parameter Dispersion	Type: Value:
	Estimation Comments	An ANCOVA model was used to compare the difference in this average monthly IV iron dose between arms, including factors for Baseline dose, treatment and the randomization stratification factors.

3. Secondary Outcome

Title	Change From Baseline in Systolic Blood Pressure (SBP), Diastolic Blood Pressure (DBP), 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 an average BP in an individual's arteries during a single cardiac cycle. Change from Baseline was calculated as post-dose 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 mixed model repeated measures (MMRM) model.
Time Frame	Baseline (Day 1) and Week 52

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Daprodustat	Darbepoetin Alfa
Arm/Group Description	Participants received daprodustat film-coated tablets with titrated dose levels ranging from 1, 2, 4, 6, 8, 10, 12, 16, and 24 milligrams (mg) orally once daily for up to 52 weeks. Study treatment was dose-titrated to achieve and maintain hemoglobin (Hgb) in the target range (10 to 11 grams per deciliter [g/dL]).	Participants received darbepoetin alfa as prefilled syringes (PFS) for subcutaneous or intravenous (IV) injection with 4-weekly total dose levels ranging from 20, 30, 40, 60, 80, 120, 160, 200, 300 and 400 microgram (mcg) for 52 weeks. Study treatment was dose-titrated to achieve and maintain Hgb in the target range (10 to 11 g/dL).
Measure Participants	153	149
SBP	-3.57 (2.063)	-6.80 (2.931)
DBP	0.21 (1.216)	-4.01 (1.650)
MAP	-0.95 (1.364)	-5.05 (1.894)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Daprodustat, Darbepoetin Alfa
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.8168
	Comments
	Method	Mixed model repeated measures (MMRM)
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	3.23
	Confidence Interval	(2-Sided) 95%; -3.82 to 10.27
	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 LS means between arms.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Daprodustat, Darbepoetin Alfa
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.9793
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	4.21
	Confidence Interval	(2-Sided) 95%; 0.17 to 8.26
	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 LS means between arms.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Daprodustat, Darbepoetin Alfa
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.9597
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	4.10
	Confidence Interval	(2-Sided) 95%; -0.51 to 8.70
	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 LS means between arms.

4. 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. End of treatment value for the blood pressure parameters were defined as the latest value on or before the last non-zero dose date plus (+) 1 day. Change from Baseline was calculated as post-dose 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.
Time Frame	Baseline (Day 1) and end of treatment (last on-treatment value until Week 52)

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Daprodustat	Darbepoetin Alfa
Arm/Group Description	Participants received daprodustat film-coated tablets with titrated dose levels ranging from 1, 2, 4, 6, 8, 10, 12, 16, and 24 milligrams (mg) orally once daily for up to 52 weeks. Study treatment was dose-titrated to achieve and maintain hemoglobin (Hgb) in the target range (10 to 11 grams per deciliter [g/dL]).	Participants received darbepoetin alfa as prefilled syringes (PFS) for subcutaneous or intravenous (IV) injection with 4-weekly total dose levels ranging from 20, 30, 40, 60, 80, 120, 160, 200, 300 and 400 microgram (mcg) for 52 weeks. Study treatment was dose-titrated to achieve and maintain Hgb in the target range (10 to 11 g/dL).
Measure Participants	154	153
SBP	-3.23 (1.659)	-3.14 (1.664)
DBP	0.60 (1.016)	-1.39 (1.020)
MAP	-0.68 (1.092)	-1.97 (1.096)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Daprodustat, Darbepoetin Alfa
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.4840
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-0.09
	Confidence Interval	(2-Sided) 95%; -4.72 to 4.53
	Parameter Dispersion	Type: Value:
	Estimation Comments	The difference in change from Baseline in SBP at the derived end of treatment was analyzed with an ANCOVA model including terms for treatment, prognostic randomization stratification factors.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Daprodustat, Darbepoetin Alfa
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.9156
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	1.99
	Confidence Interval	(2-Sided) 95%; -0.85 to 4.82
	Parameter Dispersion	Type: Value:
	Estimation Comments	The difference in change from Baseline in DBP at the derived end of treatment was analyzed with an ANCOVA model including terms for treatment, prognostic randomization stratification factors.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Daprodustat, Darbepoetin Alfa
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.7966
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	1.29
	Confidence Interval	(2-Sided) 95%; -1.76 to 4.33
	Parameter Dispersion	Type: Value:
	Estimation Comments	The difference in change from Baseline in MAP at the derived end of treatment was analyzed with an ANCOVA model including terms for treatment, prognostic randomization stratification factors.

5. Secondary Outcome

Title	Blood Pressure (BP) Exacerbation Events Rate Per 100 Participant Years
Description	BP exacerbation event is defined (based on post-dialysis BP) as SBP >=25 millimeter of mercury (mmHg) increased from Baseline or SBP >=180 mmHg; or DBP >=15 mmHg increased from Baseline or DBP >=110 mmHg. The BP exacerbation events per 100 participant years was estimated using the Negative Binomial Model.
Time Frame	Up to Week 52

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Daprodustat	Darbepoetin Alfa
Arm/Group Description	Participants received daprodustat film-coated tablets with titrated dose levels ranging from 1, 2, 4, 6, 8, 10, 12, 16, and 24 milligrams (mg) orally once daily for up to 52 weeks. Study treatment was dose-titrated to achieve and maintain hemoglobin (Hgb) in the target range (10 to 11 grams per deciliter [g/dL]).	Participants received darbepoetin alfa as prefilled syringes (PFS) for subcutaneous or intravenous (IV) injection with 4-weekly total dose levels ranging from 20, 30, 40, 60, 80, 120, 160, 200, 300 and 400 microgram (mcg) for 52 weeks. Study treatment was dose-titrated to achieve and maintain Hgb in the target range (10 to 11 g/dL).
Measure Participants	155	154
Number (95% Confidence Interval) [Events per 100 participant year]	352.50	350.00

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Daprodustat, Darbepoetin Alfa
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.5174
	Comments
	Method	Negative binomial model
	Comments
Method of Estimation	Estimation Parameter	Ratio of exacerbation rate
	Estimated Value	1.01
	Confidence Interval	(2-Sided) 95%; 0.73 to 1.39
	Parameter Dispersion	Type: Value:
	Estimation Comments	Model estimated exacerbation rates, ratio of model estimated exacerbation rates and CIs were estimated using a negative binomial model for the treatment group comparison.

6. Secondary Outcome

Title	Number of Participants With at Least One Blood Pressure Exacerbation Event During Study
Description	BP exacerbation was defined (based on post-dialysis BP) 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 blood pressure exacerbation event is presented.
Time Frame	Up to Week 52

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Daprodustat	Darbepoetin Alfa
Arm/Group Description	Participants received daprodustat film-coated tablets with titrated dose levels ranging from 1, 2, 4, 6, 8, 10, 12, 16, and 24 milligrams (mg) orally once daily for up to 52 weeks. Study treatment was dose-titrated to achieve and maintain hemoglobin (Hgb) in the target range (10 to 11 grams per deciliter [g/dL]).	Participants received darbepoetin alfa as prefilled syringes (PFS) for subcutaneous or intravenous (IV) injection with 4-weekly total dose levels ranging from 20, 30, 40, 60, 80, 120, 160, 200, 300 and 400 microgram (mcg) for 52 weeks. Study treatment was dose-titrated to achieve and maintain Hgb in the target range (10 to 11 g/dL).
Measure Participants	155	154
Count of Participants [Participants]	91 58%	100 64.5%

7. Secondary Outcome

Title	Change From Baseline in Post-randomization Hgb at Week 52
Description	Blood samples were collected from participants for Hgb measurements. Change from Baseline was calculated as post-dose visit value minus Baseline value. Baseline was defined as the latest non-missing pre-dose assessment on or before the randomization date.
Time Frame	Baseline (Day 1) and Week 52

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Daprodustat	Darbepoetin Alfa
Arm/Group Description	Participants received daprodustat film-coated tablets with titrated dose levels ranging from 1, 2, 4, 6, 8, 10, 12, 16, and 24 milligrams (mg) orally once daily for up to 52 weeks. Study treatment was dose-titrated to achieve and maintain hemoglobin (Hgb) in the target range (10 to 11 grams per deciliter [g/dL]).	Participants received darbepoetin alfa as prefilled syringes (PFS) for subcutaneous or intravenous (IV) injection with 4-weekly total dose levels ranging from 20, 30, 40, 60, 80, 120, 160, 200, 300 and 400 microgram (mcg) for 52 weeks. Study treatment was dose-titrated to achieve and maintain Hgb in the target range (10 to 11 g/dL).
Measure Participants	139	141
Least Squares Mean (Standard Error) [Grams per deciliter]	1.17 (0.117)	1.13 (0.115)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Daprodustat, Darbepoetin Alfa
	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	0.04
	Confidence Interval	(2-Sided) 95%; -0.29 to 0.36
	Parameter Dispersion	Type: Value:
	Estimation Comments	The difference in change from Baseline in post-randomization Hgb at Week 52 was analyzed with a MMRM approach with an unstructured covariance matrix to compare the difference in LS means between arms.

8. Secondary Outcome

Title	Number of Hgb Responders (Hgb in the Analysis Range of 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. Hgb responders were defined as number of participants with a mean Hgb during the evaluation period that falls within the Hgb analysis range of 10-11.5 g/dL.
Time Frame	Weeks 28 to 52

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Daprodustat	Darbepoetin Alfa
Arm/Group Description	Participants received daprodustat film-coated tablets with titrated dose levels ranging from 1, 2, 4, 6, 8, 10, 12, 16, and 24 milligrams (mg) orally once daily for up to 52 weeks. Study treatment was dose-titrated to achieve and maintain hemoglobin (Hgb) in the target range (10 to 11 grams per deciliter [g/dL]).	Participants received darbepoetin alfa as prefilled syringes (PFS) for subcutaneous or intravenous (IV) injection with 4-weekly total dose levels ranging from 20, 30, 40, 60, 80, 120, 160, 200, 300 and 400 microgram (mcg) for 52 weeks. Study treatment was dose-titrated to achieve and maintain Hgb in the target range (10 to 11 g/dL).
Measure Participants	133	133
Count of Participants [Participants]	86 54.8%	87 56.1%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Daprodustat, Darbepoetin Alfa
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.5411
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments
Method of Estimation	Estimation Parameter	Difference in response rate
	Estimated Value	-0.8
	Confidence Interval	(2-Sided) 95%; -12.2 to 10.7
	Parameter Dispersion	Type: Value:
	Estimation Comments	A Cochran-Mantel-Haenszel (CMH) test adjusted for treatment and randomization stratification factors were used to compare the number of responders between the treatment groups.

9. Secondary Outcome

Title	Percentage of Time for Which Hgb Was Within the Analysis Range (10 to 11.5 g/dL) 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 for which Hgb was within range for a participant was calculated by dividing 'the total number of days that Hgb was within range during Weeks 28 to 52' by 'the total number of days the participant remained on treatment during Weeks 28 to 52'.
Time Frame	Weeks 28 to 52

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Daprodustat	Darbepoetin Alfa
Arm/Group Description	Participants received daprodustat film-coated tablets with titrated dose levels ranging from 1, 2, 4, 6, 8, 10, 12, 16, and 24 milligrams (mg) orally once daily for up to 52 weeks. Study treatment was dose-titrated to achieve and maintain hemoglobin (Hgb) in the target range (10 to 11 grams per deciliter [g/dL]).	Participants received darbepoetin alfa as prefilled syringes (PFS) for subcutaneous or intravenous (IV) injection with 4-weekly total dose levels ranging from 20, 30, 40, 60, 80, 120, 160, 200, 300 and 400 microgram (mcg) for 52 weeks. Study treatment was dose-titrated to achieve and maintain Hgb in the target range (10 to 11 g/dL).
Measure Participants	128	129
Median (Full Range) [Percentage of days]	57.0	54.7

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Daprodustat, Darbepoetin Alfa
	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	2.05
	Confidence Interval	(2-Sided) 95%; -4.45 to 11.27
	Parameter Dispersion	Type: Value:
	Estimation Comments	Hodges-Lehmann Estimate of Treatment Difference has been reported.

10. Secondary Outcome

Title	Percentage of Time for Which Hgb Was Within the Analysis Range (10 to 11.5 g/dL) 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 for which Hgb was within range for a participant was calculated by dividing 'the total number of days that Hgb was within range during Weeks 28 to 52' by 'the total number of days the participant remained on treatment during Weeks 28 to 52'.
Time Frame	Weeks 28 to 52

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Daprodustat	Darbepoetin Alfa
Arm/Group Description	Participants received daprodustat film-coated tablets with titrated dose levels ranging from 1, 2, 4, 6, 8, 10, 12, 16, and 24 milligrams (mg) orally once daily for up to 52 weeks. Study treatment was dose-titrated to achieve and maintain hemoglobin (Hgb) in the target range (10 to 11 grams per deciliter [g/dL]).	Participants received darbepoetin alfa as prefilled syringes (PFS) for subcutaneous or intravenous (IV) injection with 4-weekly total dose levels ranging from 20, 30, 40, 60, 80, 120, 160, 200, 300 and 400 microgram (mcg) for 52 weeks. Study treatment was dose-titrated to achieve and maintain Hgb in the target range (10 to 11 g/dL).
Measure Participants	128	129
Median (Full Range) [Percentage of days]	57.0	54.7

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Daprodustat, Darbepoetin Alfa
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1538
	Comments
	Method	van Elteren test
	Comments
Method of Estimation	Estimation Parameter	Probability
	Estimated Value	0.54
	Confidence Interval	(2-Sided) 95%; 0.46 to 0.61
	Parameter Dispersion	Type: Value:
	Estimation Comments	Mann-Whitney estimate (Probability) of the treatment effect has been presented.

11. Secondary Outcome

Title	Number of Participants Permanently Stopping Randomized Treatment Due to Meeting Rescue Criteria
Description	Number of participants permanently stopping randomized treatment due to meeting rescue criteria has been presented.
Time Frame	Up to Week 52

Outcome Measure Data

Analysis Population Description

ITT Population.

Arm/Group Title	Daprodustat	Darbepoetin Alfa
Arm/Group Description	Participants received daprodustat film-coated tablets with titrated dose levels ranging from 1, 2, 4, 6, 8, 10, 12, 16, and 24 milligrams (mg) orally once daily for up to 52 weeks. Study treatment was dose-titrated to achieve and maintain hemoglobin (Hgb) in the target range (10 to 11 grams per deciliter [g/dL]).	Participants received darbepoetin alfa as prefilled syringes (PFS) for subcutaneous or intravenous (IV) injection with 4-weekly total dose levels ranging from 20, 30, 40, 60, 80, 120, 160, 200, 300 and 400 microgram (mcg) for 52 weeks. Study treatment was dose-titrated to achieve and maintain Hgb in the target range (10 to 11 g/dL).
Measure Participants	157	155
Count of Participants [Participants]	5 3.2%	5 3.2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Daprodustat, Darbepoetin Alfa
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.5348
	Comments
	Method	Wald test
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.06
	Confidence Interval	(2-Sided) 95%; 0.31 to 3.66
	Parameter Dispersion	Type: Value:
	Estimation Comments	Hazard ratio was estimated using a Cox proportional hazard regression model adjusted for treatment group, dialysis type and dialysis start manner.

12. Secondary Outcome

Title	Change From Baseline in 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 post-dose visit value minus Baseline value. Baseline was defined as the latest non-missing pre-dose assessment on or before the randomization date.
Time Frame	Baseline (Day 1), Weeks 8, 12, 28 and 52

Outcome Measure Data

Analysis Population Description

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	Darbepoetin Alfa
Arm/Group Description	Participants received daprodustat film-coated tablets with titrated dose levels ranging from 1, 2, 4, 6, 8, 10, 12, 16, and 24 milligrams (mg) orally once daily for up to 52 weeks. Study treatment was dose-titrated to achieve and maintain hemoglobin (Hgb) in the target range (10 to 11 grams per deciliter [g/dL]).	Participants received darbepoetin alfa as prefilled syringes (PFS) for subcutaneous or intravenous (IV) injection with 4-weekly total dose levels ranging from 20, 30, 40, 60, 80, 120, 160, 200, 300 and 400 microgram (mcg) for 52 weeks. Study treatment was dose-titrated to achieve and maintain Hgb in the target range (10 to 11 g/dL).
Measure Participants	88	88
Week 8, n=88,86	0.79 (0.648)	1.18 (0.658)
Week 12, n=88,88	1.67 (0.627)	0.54 (0.631)
Week 28, n=80,74	0.94 (0.697)	0.45 (0.725)
Week 52, n=67,65	0.61 (0.755)	1.93 (0.774)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Daprodustat, Darbepoetin Alfa
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.6641
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-0.39
	Confidence Interval	(2-Sided) 95%; -2.22 to 1.44
	Parameter Dispersion	Type: Value:
	Estimation Comments	SF-36 HRQoL PCS domain score was analyzed using an MMRM approach with an unstructured covariance matrix to compare the difference in LS means between arms at Week 8.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Daprodustat, Darbepoetin Alfa
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1030
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	1.13
	Confidence Interval	(2-Sided) 95%; -0.63 to 2.89
	Parameter Dispersion	Type: Value:
	Estimation Comments	SF-36 HRQoL PCS domain score was analyzed using an MMRM approach with an unstructured covariance matrix to compare the difference in LS means between arms at Week 12.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Daprodustat, Darbepoetin Alfa
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.3157
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	0.49
	Confidence Interval	(2-Sided) 95%; -1.51 to 2.48
	Parameter Dispersion	Type: Value:
	Estimation Comments	SF-36 HRQoL PCS domain score was analyzed using an MMRM approach with an unstructured covariance matrix to compare the difference in LS means between arms at Week 28.

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Daprodustat, Darbepoetin Alfa
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.8855
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-1.31
	Confidence Interval	(2-Sided) 95%; -3.46 to 0.84
	Parameter Dispersion	Type: Value:
	Estimation Comments	SF-36 HRQoL PCS domain score was analyzed using an MMRM approach with an unstructured covariance matrix to compare the difference in LS means between arms at Week 52.

13. Secondary Outcome

Title	Change From Baseline in 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 post-dose visit value minus Baseline value. Baseline was defined as the latest non-missing pre-dose assessment on or before the randomization date.
Time Frame	Baseline (Day 1), Weeks 8, 12, 28 and 52

Outcome Measure Data

Analysis Population Description

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	Darbepoetin Alfa
Arm/Group Description	Participants received daprodustat film-coated tablets with titrated dose levels ranging from 1, 2, 4, 6, 8, 10, 12, 16, and 24 milligrams (mg) orally once daily for up to 52 weeks. Study treatment was dose-titrated to achieve and maintain hemoglobin (Hgb) in the target range (10 to 11 grams per deciliter [g/dL]).	Participants received darbepoetin alfa as prefilled syringes (PFS) for subcutaneous or intravenous (IV) injection with 4-weekly total dose levels ranging from 20, 30, 40, 60, 80, 120, 160, 200, 300 and 400 microgram (mcg) for 52 weeks. Study treatment was dose-titrated to achieve and maintain Hgb in the target range (10 to 11 g/dL).
Measure Participants	88	88
Week 8, n=88,86	0.10 (0.822)	0.76 (0.839)
Week 12, n=88,88	0.08 (0.813)	1.60 (0.824)
Week 28, n=80,74	-0.02 (0.905)	0.30 (0.942)
Week 52, n=67,65	-0.95 (1.029)	-0.72 (1.051)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Daprodustat, Darbepoetin Alfa
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.7146
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-0.67
	Confidence Interval	(2-Sided) 95%; -2.99 to 1.66
	Parameter Dispersion	Type: Value:
	Estimation Comments	SF-36 HRQoL MCS domain score was analyzed using an MMRM approach with an unstructured covariance matrix to compare the difference in LS means between arms at Week 8.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Daprodustat, Darbepoetin Alfa
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.9050
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-1.53
	Confidence Interval	(2-Sided) 95%; -3.82 to 0.76
	Parameter Dispersion	Type: Value:
	Estimation Comments	SF-36 HRQoL MCS domain score was analyzed using an MMRM approach with an unstructured covariance matrix to compare the difference in LS means between arms at Week 12.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Daprodustat, Darbepoetin Alfa
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.5950
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-0.32
	Confidence Interval	(2-Sided) 95%; -2.91 to 2.28
	Parameter Dispersion	Type: Value:
	Estimation Comments	SF-36 HRQoL MCS domain score was analyzed using an MMRM approach with an unstructured covariance matrix to compare the difference in LS means between arms at Week 28.

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Daprodustat, Darbepoetin Alfa
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.5619
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-0.23
	Confidence Interval	(2-Sided) 95%; -3.17 to 2.70
	Parameter Dispersion	Type: Value:
	Estimation Comments	SF-36 HRQoL MCS domain score was analyzed using an MMRM approach with an unstructured covariance matrix to compare the difference in LS means between arms at Week 52.

14. Secondary Outcome

Title	Change From Baseline in 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, physical functioning and vitality. Each domain is scored from 0 (poorer health) to 100 (better health). Each domain score ranges from 0 to 100, higher score indicates a better health state and better functioning. Change from Baseline was calculated as post-dose visit value minus Baseline value. Baseline was defined as the latest non-missing pre-dose assessment on or before the randomization date.
Time Frame	Baseline (Day 1), Weeks 8, 12, 28 and 52

Outcome Measure Data

Analysis Population Description

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	Darbepoetin Alfa
Arm/Group Description	Participants received daprodustat film-coated tablets with titrated dose levels ranging from 1, 2, 4, 6, 8, 10, 12, 16, and 24 milligrams (mg) orally once daily for up to 52 weeks. Study treatment was dose-titrated to achieve and maintain hemoglobin (Hgb) in the target range (10 to 11 grams per deciliter [g/dL]).	Participants received darbepoetin alfa as prefilled syringes (PFS) for subcutaneous or intravenous (IV) injection with 4-weekly total dose levels ranging from 20, 30, 40, 60, 80, 120, 160, 200, 300 and 400 microgram (mcg) for 52 weeks. Study treatment was dose-titrated to achieve and maintain Hgb in the target range (10 to 11 g/dL).
Measure Participants	88	88
Bodily pain: Week 8, n=88,86	-0.41 (0.833)	-0.55 (0.843)
Bodily pain: Week 12, n=88,88	-0.13 (0.892)	-0.06 (0.895)
Bodily pain: Week 28, n=80,74	1.08 (0.941)	-1.26 (0.976)
Bodily pain: Week 52, n=67,65	-2.00 (1.084)	0.61 (1.109)
General health: Week 8, n=88,86	0.80 (0.662)	0.75 (0.674)
General health: Week 12, n=88,88	0.87 (0.651)	0.59 (0.658)
General health: Week 28, n=80,74	0.63 (0.693)	0.37 (0.720)
General health: Week 52, n=67,65	0.40 (0.823)	0.58 (0.841)
Mental health: Week 8, n=88,86	-0.90 (0.825)	0.25 (0.841)
Mental health: Week 12, n=88,88	0.01 (0.707)	1.42 (0.712)
Mental health: Week 28, n=80,74	-0.69 (0.866)	-0.21 (0.902)
Mental health: Week 52, n=67,65	-0.53 (0.994)	-0.27 (1.013)
Role-emotional: Week 8, n=88,86	0.83 (0.880)	0.50 (0.896)
Role-emotional: Week 12, n=88,88	0.55 (0.934)	-0.07 (0.946)
Role-emotional: Week 28, n=80,74	0.91 (0.929)	0.39 (0.964)
Role-emotional: Week 52, n=67,65	-1.60 (1.193)	-0.11 (1.216)
Role-physical: Week 8, n=88,86	1.34 (0.806)	2.64 (0.818)
Role-physical: Week 12, n=88,88	2.39 (0.712)	1.69 (0.716)
Role-physical: Week 28, n=80,74	0.62 (0.799)	1.49 (0.829)
Role-physical: Week 52, n=67,65	1.49 (0.895)	2.22 (0.913)
Social functioning: Week 8, n=88,86	0.52 (0.929)	1.55 (0.947)
Social functioning: Week 12, n=88,88	0.98 (0.774)	2.15 (0.783)
Social functioning: Week 28, n=80,74	1.03 (0.943)	0.95 (0.980)
Social functioning: Week 52, n=67,65	0.39 (1.085)	-0.33 (1.105)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Daprodustat, Darbepoetin Alfa
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.4523
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	0.14
	Confidence Interval	(2-Sided) 95%; -2.21 to 2.49
	Parameter Dispersion	Type: Value:
	Estimation Comments	SF-36 HRQoL bodily pain domain score was analyzed using an MMRM approach with an unstructured covariance matrix to compare the difference in LS means between arms at Week 8.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Daprodustat, Darbepoetin Alfa
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.5222
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-0.07
	Confidence Interval	(2-Sided) 95%; -2.57 to 2.43
	Parameter Dispersion	Type: Value:
	Estimation Comments	SF-36 HRQoL bodily pain domain score was analyzed using an MMRM approach with an unstructured covariance matrix to compare the difference in LS means between arms at Week 12.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Daprodustat, Darbepoetin Alfa
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0440
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	2.33
	Confidence Interval	(2-Sided) 95%; -0.35 to 5.02
	Parameter Dispersion	Type: Value:
	Estimation Comments	SF-36 HRQoL bodily pain domain score was analyzed using an MMRM approach with an unstructured covariance matrix to compare the difference in LS means between arms at Week 28.

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Daprodustat, Darbepoetin Alfa
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.9523
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-2.61
	Confidence Interval	(2-Sided) 95%; -5.68 to 0.46
	Parameter Dispersion	Type: Value:
	Estimation Comments	SF-36 HRQoL bodily pain domain score was analyzed using an MMRM approach with an unstructured covariance matrix to compare the difference in LS means between arms at Week 52.

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Daprodustat, Darbepoetin Alfa
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.4811
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	0.05
	Confidence Interval	(2-Sided) 95%; -1.82 to 1.91
	Parameter Dispersion	Type: Value:
	Estimation Comments	SF-36 HRQoL general health domain score was analyzed using an MMRM approach with an unstructured covariance matrix to compare the difference in LS means between arms at Week 8.

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Daprodustat, Darbepoetin Alfa
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.3834
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	0.28
	Confidence Interval	(2-Sided) 95%; -1.56 to 2.11
	Parameter Dispersion	Type: Value:
	Estimation Comments	SF-36 HRQoL general health domain score was analyzed using an MMRM approach with an unstructured covariance matrix to compare the difference in LS means between arms at Week 12.

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Daprodustat, Darbepoetin Alfa
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.3983
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	0.26
	Confidence Interval	(2-Sided) 95%; -1.72 to 2.24
	Parameter Dispersion	Type: Value:
	Estimation Comments	SF-36 HRQoL general health domain score was analyzed using an MMRM approach with an unstructured covariance matrix to compare the difference in LS means between arms at Week 28.

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Daprodustat, Darbepoetin Alfa
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.5617
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-0.18
	Confidence Interval	(2-Sided) 95%; -2.51 to 2.15
	Parameter Dispersion	Type: Value:
	Estimation Comments	SF-36 HRQoL general health domain score was analyzed using an MMRM approach with an unstructured covariance matrix to compare the difference in LS means between arms at Week 52.

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	Daprodustat, Darbepoetin Alfa
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.8336
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-1.15
	Confidence Interval	(2-Sided) 95%; -3.48 to 1.18
	Parameter Dispersion	Type: Value:
	Estimation Comments	SF-36 HRQoL mental health domain score was analyzed using an MMRM approach with an unstructured covariance matrix to compare the difference in LS means between arms at Week 8.

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	Daprodustat, Darbepoetin Alfa
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.9188
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-1.41
	Confidence Interval	(2-Sided) 95%; -3.40 to 0.57
	Parameter Dispersion	Type: Value:
	Estimation Comments	SF-36 HRQoL mental health domain score was analyzed using an MMRM approach with an unstructured covariance matrix to compare the difference in LS means between arms at Week 12.

Statistical Analysis 11

Statistical Analysis Overview	Comparison Group Selection	Daprodustat, Darbepoetin Alfa
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.6495
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-0.48
	Confidence Interval	(2-Sided) 95%; -2.96 to 1.99
	Parameter Dispersion	Type: Value:
	Estimation Comments	SF-36 HRQoL mental health domain score was analyzed using an MMRM approach with an unstructured covariance matrix to compare the difference in LS means between arms at Week 28.

Statistical Analysis 12

Statistical Analysis Overview	Comparison Group Selection	Daprodustat, Darbepoetin Alfa
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.5737
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-0.27
	Confidence Interval	(2-Sided) 95%; -3.09 to 2.56
	Parameter Dispersion	Type: Value:
	Estimation Comments	SF-36 HRQoL mental health domain score was analyzed using an MMRM approach with an unstructured covariance matrix to compare the difference in LS means between arms at Week 52.

Statistical Analysis 13

Statistical Analysis Overview	Comparison Group Selection	Daprodustat, Darbepoetin Alfa
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.3963
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	0.33
	Confidence Interval	(2-Sided) 95%; -2.15 to 2.82
	Parameter Dispersion	Type: Value:
	Estimation Comments	SF-36 HRQoL role-emotional domain score was analyzed using an MMRM approach with an unstructured covariance matrix to compare the difference in LS means between arms at Week 8.

Statistical Analysis 14

Statistical Analysis Overview	Comparison Group Selection	Daprodustat, Darbepoetin Alfa
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.3220
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	0.62
	Confidence Interval	(2-Sided) 95%; -2.01 to 3.25
	Parameter Dispersion	Type: Value:
	Estimation Comments	SF-36 HRQoL role-emotional domain score was analyzed using an MMRM approach with an unstructured covariance matrix to compare the difference in LS means between arms at Week 12.

Statistical Analysis 15

Statistical Analysis Overview	Comparison Group Selection	Daprodustat, Darbepoetin Alfa
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.3485
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	0.53
	Confidence Interval	(2-Sided) 95%; -2.13 to 3.18
	Parameter Dispersion	Type: Value:
	Estimation Comments	SF-36 HRQoL role-emotional domain score was analyzed using an MMRM approach with an unstructured covariance matrix to compare the difference in LS means between arms at Week 28.

Statistical Analysis 16

Statistical Analysis Overview	Comparison Group Selection	Daprodustat, Darbepoetin Alfa
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.8064
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-1.49
	Confidence Interval	(2-Sided) 95%; -4.87 to 1.90
	Parameter Dispersion	Type: Value:
	Estimation Comments	SF-36 HRQoL role-emotional domain score was analyzed using an MMRM approach with an unstructured covariance matrix to compare the difference in LS means between arms at Week 52.

Statistical Analysis 17

Statistical Analysis Overview	Comparison Group Selection	Daprodustat, Darbepoetin Alfa
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.8687
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-1.29
	Confidence Interval	(2-Sided) 95%; -3.57 to 0.98
	Parameter Dispersion	Type: Value:
	Estimation Comments	SF-36 HRQoL role-physical domain score was analyzed using an MMRM approach with an unstructured covariance matrix to compare the difference in LS means between arms at Week 8.

Statistical Analysis 18

Statistical Analysis Overview	Comparison Group Selection	Daprodustat, Darbepoetin Alfa
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.2435
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	0.71
	Confidence Interval	(2-Sided) 95%; -1.29 to 2.70
	Parameter Dispersion	Type: Value:
	Estimation Comments	SF-36 HRQoL role-physical domain score was analyzed using an MMRM approach with an unstructured covariance matrix to compare the difference in LS means between arms at Week 12.

Statistical Analysis 19

Statistical Analysis Overview	Comparison Group Selection	Daprodustat, Darbepoetin Alfa
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.7747
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-0.87
	Confidence Interval	(2-Sided) 95%; -3.15 to 1.41
	Parameter Dispersion	Type: Value:
	Estimation Comments	SF-36 HRQoL role-physical domain score was analyzed using an MMRM approach with an unstructured covariance matrix to compare the difference in LS means between arms at Week 28.

Statistical Analysis 20

Statistical Analysis Overview	Comparison Group Selection	Daprodustat, Darbepoetin Alfa
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.7141
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-0.73
	Confidence Interval	(2-Sided) 95%; -3.26 to 1.81
	Parameter Dispersion	Type: Value:
	Estimation Comments	SF-36 HRQoL role-physical domain score was analyzed using an MMRM approach with an unstructured covariance matrix to compare the difference in LS means between arms at Week 52.

Statistical Analysis 21

Statistical Analysis Overview	Comparison Group Selection	Daprodustat, Darbepoetin Alfa
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.7803
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-1.03
	Confidence Interval	(2-Sided) 95%; -3.65 to 1.59
	Parameter Dispersion	Type: Value:
	Estimation Comments	SF-36 HRQoL social functioning domain score was analyzed using an MMRM approach with an unstructured covariance matrix to compare the difference in LS means between arms at Week 8.

Statistical Analysis 22

Statistical Analysis Overview	Comparison Group Selection	Daprodustat, Darbepoetin Alfa
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.8556
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-1.18
	Confidence Interval	(2-Sided) 95%; -3.35 to 1.00
	Parameter Dispersion	Type: Value:
	Estimation Comments	SF-36 HRQoL social functioning domain score was analyzed using an MMRM approach with an unstructured covariance matrix to compare the difference in LS means between arms at Week 12.

Statistical Analysis 23

Statistical Analysis Overview	Comparison Group Selection	Daprodustat, Darbepoetin Alfa
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.4763
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	0.08
	Confidence Interval	(2-Sided) 95%; -2.61 to 2.77
	Parameter Dispersion	Type: Value:
	Estimation Comments	SF-36 HRQoL social functioning domain score was analyzed using an MMRM approach with an unstructured covariance matrix to compare the difference in LS means between arms at Week 28.

Statistical Analysis 24

Statistical Analysis Overview	Comparison Group Selection	Daprodustat, Darbepoetin Alfa
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.3208
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	0.73
	Confidence Interval	(2-Sided) 95%; -2.35 to 3.80
	Parameter Dispersion	Type: Value:
	Estimation Comments	SF-36 HRQoL social functioning domain score was analyzed using an MMRM approach with an unstructured covariance matrix to compare the difference in LS means between arms at Week 52.

15. Secondary Outcome

Title	Change From Baseline in Vitality Scores Using SF-36 HRQoL Questionnaire at Weeks 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 ranges from 0 to 100; higher scores represent better health. Change from Baseline was calculated as post-dose visit value minus Baseline value. Baseline was defined as the latest non-missing pre-dose assessment on or before the randomization date.
Time Frame	Baseline (Day 1), Weeks 28 and 52

Outcome Measure Data

Analysis Population Description

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	Darbepoetin Alfa
Arm/Group Description	Participants received daprodustat film-coated tablets with titrated dose levels ranging from 1, 2, 4, 6, 8, 10, 12, 16, and 24 milligrams (mg) orally once daily for up to 52 weeks. Study treatment was dose-titrated to achieve and maintain hemoglobin (Hgb) in the target range (10 to 11 grams per deciliter [g/dL]).	Participants received darbepoetin alfa as prefilled syringes (PFS) for subcutaneous or intravenous (IV) injection with 4-weekly total dose levels ranging from 20, 30, 40, 60, 80, 120, 160, 200, 300 and 400 microgram (mcg) for 52 weeks. Study treatment was dose-titrated to achieve and maintain Hgb in the target range (10 to 11 g/dL).
Measure Participants	80	74
Week 28, n=80,74	-0.08 (0.866)	0.95 (0.902)
Week 52, n=67,65	0.16 (0.907)	1.61 (0.925)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Daprodustat, Darbepoetin Alfa
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.7910
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-1.02
	Confidence Interval	(2-Sided) 95%; -3.50 to 1.46
	Parameter Dispersion	Type: Value:
	Estimation Comments	SF-36 HRQoL vitality domain score was analyzed using an MMRM approach with an unstructured covariance matrix to compare the difference in LS means between arms at Week 28.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Daprodustat, Darbepoetin Alfa
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.8648
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-1.45
	Confidence Interval	(2-Sided) 95%; -4.03 to 1.14
	Parameter Dispersion	Type: Value:
	Estimation Comments	SF-36 HRQoL vitality domain score was analyzed using an MMRM approach with an unstructured covariance matrix to compare the difference in LS means between arms at Week 52.

16. Secondary Outcome

Title	Change From Baseline in Physical Functioning Domain Scores Using SF-36 HRQoL Questionnaire at Weeks 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 ranges from 0 to 100; higher scores represent better health. Change from Baseline was calculated as post-dose visit value minus (-) Baseline value. Baseline was defined as the latest non-missing pre-dose assessment on or before the randomization date.
Time Frame	Baseline (Day 1), Weeks 28 and 52

Outcome Measure Data

Analysis Population Description

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	Darbepoetin Alfa
Arm/Group Description	Participants received daprodustat film-coated tablets with titrated dose levels ranging from 1, 2, 4, 6, 8, 10, 12, 16, and 24 milligrams (mg) orally once daily for up to 52 weeks. Study treatment was dose-titrated to achieve and maintain hemoglobin (Hgb) in the target range (10 to 11 grams per deciliter [g/dL]).	Participants received darbepoetin alfa as prefilled syringes (PFS) for subcutaneous or intravenous (IV) injection with 4-weekly total dose levels ranging from 20, 30, 40, 60, 80, 120, 160, 200, 300 and 400 microgram (mcg) for 52 weeks. Study treatment was dose-titrated to achieve and maintain Hgb in the target range (10 to 11 g/dL).
Measure Participants	80	74
Week 28, n=80,74	0.55 (0.863)	0.83 (0.898)
Week 52, n=67,65	0.14 (0.947)	1.58 (0.973)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Daprodustat, Darbepoetin Alfa
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.5879
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-0.28
	Confidence Interval	(2-Sided) 95%; -2.75 to 2.19
	Parameter Dispersion	Type: Value:
	Estimation Comments	SF-36 HRQoL physical functioning domain score was analyzed using an MMRM approach with an unstructured covariance matrix to compare the difference in LS means between arms at Week 28.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Daprodustat, Darbepoetin Alfa
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.8525
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-1.43
	Confidence Interval	(2-Sided) 95%; -4.12 to 1.26
	Parameter Dispersion	Type: Value:
	Estimation Comments	SF-36 HRQoL physical functioning domain scor was analyzed using an MMRM approach with an unstructured covariance matrix to compare the difference in LS means between arms at Week 52.

17. Secondary Outcome

Title	Change From Baseline in Health Utility EuroQol 5 Dimensions 5 Level (EQ-5D-5L) Questionnaire Score at Week 52
Description	EQ-5D-5L consists of 2 concepts-EQ-5D-5L descriptive system and EQ Visual Analogue Scale (EQ-VAS). EQ-5D-5L is self-assessment questionnaire, consisting of 5items covering 5 dimensions (mobility,self care, usual activities, pain/discomfort and anxiety/depression). Each dimension is measured by 5-point Likert scale(no problems, slight problems, moderate problems, severe problems and 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), higher the score better the health status. Change from Baseline was calculated as post-dose visit value-Baseline value. Baseline was latest non-missing pre-dose assessment on or before randomization date.
Time Frame	Baseline (Day 1) and Week 52

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Daprodustat	Darbepoetin Alfa
Arm/Group Description	Participants received daprodustat film-coated tablets with titrated dose levels ranging from 1, 2, 4, 6, 8, 10, 12, 16, and 24 milligrams (mg) orally once daily for up to 52 weeks. Study treatment was dose-titrated to achieve and maintain hemoglobin (Hgb) in the target range (10 to 11 grams per deciliter [g/dL]).	Participants received darbepoetin alfa as prefilled syringes (PFS) for subcutaneous or intravenous (IV) injection with 4-weekly total dose levels ranging from 20, 30, 40, 60, 80, 120, 160, 200, 300 and 400 microgram (mcg) for 52 weeks. Study treatment was dose-titrated to achieve and maintain Hgb in the target range (10 to 11 g/dL).
Measure Participants	24	25
Least Squares Mean (Standard Error) [Scores on a scale]	0.00 (0.041)	-0.03 (0.040)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Daprodustat, Darbepoetin Alfa
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.3154
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	0.03
	Confidence Interval	(2-Sided) 95%; -0.09 to 0.14
	Parameter Dispersion	Type: Value:
	Estimation Comments	MMRM model was fitted from Baseline up to Week 52 with factors for treatment, time, dialysis type, dialysis start manner, Baseline value and Baseline value by time and treatment by time interactions.

18. Secondary Outcome

Title	Change From Baseline in EQ Visual Analogue Scale (EQ-VAS) at Week 52
Description	The EQ-5D-5L consists of 2 concepts -EQ-5D-5L descriptive system and EQ-VAS. The EQ-5D-5L is a self-assessment questionnaire, consisting of five items covering five dimensions (mobility, self care, usual activities, pain/discomfort and anxiety/depression). Each dimension is measured by a five-point Likert scale (no problems, slight problems, moderate problems, severe problems, and extreme problems). The range for the EQ-5D-5L index score is 0 to 1 with '0' is worst health and '1' is full health. 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 post-dose visit value minus Baseline value. Baseline was defined as the latest non-missing pre-dose assessment on or before the randomization date.
Time Frame	Baseline (Day 1) and Week 52

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Daprodustat	Darbepoetin Alfa
Arm/Group Description	Participants received daprodustat film-coated tablets with titrated dose levels ranging from 1, 2, 4, 6, 8, 10, 12, 16, and 24 milligrams (mg) orally once daily for up to 52 weeks. Study treatment was dose-titrated to achieve and maintain hemoglobin (Hgb) in the target range (10 to 11 grams per deciliter [g/dL]).	Participants received darbepoetin alfa as prefilled syringes (PFS) for subcutaneous or intravenous (IV) injection with 4-weekly total dose levels ranging from 20, 30, 40, 60, 80, 120, 160, 200, 300 and 400 microgram (mcg) for 52 weeks. Study treatment was dose-titrated to achieve and maintain Hgb in the target range (10 to 11 g/dL).
Measure Participants	24	25
Least Squares Mean (Standard Error) [Scores on a scale]	3.4 (3.27)	6.8 (3.28)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Daprodustat, Darbepoetin Alfa
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.7651
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-3.4
	Confidence Interval	(2-Sided) 95%; -12.7 to 5.9
	Parameter Dispersion	Type: Value:
	Estimation Comments	MMRM model was fitted from Baseline up to Week 52 with factors for treatment, time, dialysis type, dialysis start manner, Baseline value and Baseline value by time and treatment by time interactions.

19. Secondary Outcome

Title	Change From Baseline in Chronic Kidney Disease- Anemia Symptoms Questionnaire (CKD-AQ) at Week 52
Description	CKD-AQ is 21-item patient reported outcome measure assessing symptoms and symptom impact in participants with anemia associated with CKD. It had 3 domains: 1.Tired/Low Energy/Weak scale consisting of 10 items; 2.Chest Pain/Shortness of Breath scale consisting of 4 items; and 3.Cognitive scale consisting of 3 items. The 4 CKD-AQ single items are: (shortness of breath, no activity), (severity-short breath, resting), (difficulty standing for long time) and (difficulty sleeping). Single-item were recorded based on a 0-100 scoring with 0=worst possible and 100=best possible score. Three domains scores were calculated as average of items in each domain and ranged from 0-100 where 0=worst possible and 100=best possible score. Change from Baseline was calculated as post-dose visit value minus Baseline value. Baseline was defined as the latest non-missing pre-dose assessment on or before the randomization date.
Time Frame	Baseline (Day 1) and Week 52

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Daprodustat	Darbepoetin Alfa
Arm/Group Description	Participants received daprodustat film-coated tablets with titrated dose levels ranging from 1, 2, 4, 6, 8, 10, 12, 16, and 24 milligrams (mg) orally once daily for up to 52 weeks. Study treatment was dose-titrated to achieve and maintain hemoglobin (Hgb) in the target range (10 to 11 grams per deciliter [g/dL]).	Participants received darbepoetin alfa as prefilled syringes (PFS) for subcutaneous or intravenous (IV) injection with 4-weekly total dose levels ranging from 20, 30, 40, 60, 80, 120, 160, 200, 300 and 400 microgram (mcg) for 52 weeks. Study treatment was dose-titrated to achieve and maintain Hgb in the target range (10 to 11 g/dL).
Measure Participants	76	80
Tired/Low energy/Weak domain	-2.36 (2.007)	4.07 (1.990)
Chest pain/Shortness of breath domain	-1.83 (1.593)	2.28 (1.557)
Cognitive domain	-4.17 (1.893)	2.43 (1.852)
Shortness of breath, no activity	-1.90 (1.861)	1.14 (1.826)
Severity-short breath, Resting	-4.16 (1.869)	0.12 (1.836)
Difficulty standing for long time	-2.00 (2.812)	3.30 (2.754)
Difficulty sleeping	-5.27 (2.667)	1.26 (2.611)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Daprodustat, Darbepoetin Alfa
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.9875
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-6.43
	Confidence Interval	(2-Sided) 95%; -12.05 to -0.82
	Parameter Dispersion	Type: Value:
	Estimation Comments	Tired/Low energy/Weak domain: MMRM model was fitted from Baseline up to Week 52 with factors for treatment, time, dialysis type, dialysis start manner, Baseline value and Baseline value by time and treatment by time interactions.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Daprodustat, Darbepoetin Alfa
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.9663
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-4.11
	Confidence Interval	(2-Sided) 95%; -8.52 to 0.30
	Parameter Dispersion	Type: Value:
	Estimation Comments	Chest pain/Shortness of breath domain: MMRM model was fitted from Baseline up to Week 52 with factors for treatment, time, dialysis type, dialysis start manner, Baseline value and Baseline value by time and treatment by time interactions.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Daprodustat, Darbepoetin Alfa
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.9930
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-6.60
	Confidence Interval	(2-Sided) 95%; -11.84 to -1.35
	Parameter Dispersion	Type: Value:
	Estimation Comments	Cognitive domain: MMRM model was fitted from Baseline up to Week 52 with factors for treatment, time, dialysis type, dialysis start manner, Baseline value and Baseline value by time and treatment by time interactions.

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Daprodustat, Darbepoetin Alfa
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.8765
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-3.03
	Confidence Interval	(2-Sided) 95%; -8.19 to 2.12
	Parameter Dispersion	Type: Value:
	Estimation Comments	Shortness of breath, no activity: MMRM model was fitted from Baseline up to Week 52 with factors for treatment, time, dialysis type, dialysis start manner, Baseline value and Baseline value by time and treatment by time interactions.

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Daprodustat, Darbepoetin Alfa
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.9464
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-4.27
	Confidence Interval	(2-Sided) 95%; -9.48 to 0.94
	Parameter Dispersion	Type: Value:
	Estimation Comments	Severity-short breath, Resting: MMRM model was fitted from Baseline up to Week 52 with factors for treatment, time, dialysis type, dialysis start manner, Baseline value and Baseline value by time and treatment by time interactions.

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Daprodustat, Darbepoetin Alfa
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.9101
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-5.31
	Confidence Interval	(2-Sided) 95%; -13.09 to 2.47
	Parameter Dispersion	Type: Value:
	Estimation Comments	Difficulty standing for long time: MMRM model was fitted from Baseline up to Week 52 with factors for treatment, time, dialysis type, dialysis start manner, Baseline value and Baseline value by time and treatment by time interactions.

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Daprodustat, Darbepoetin Alfa
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.9586
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-6.52
	Confidence Interval	(2-Sided) 95%; -13.90 to 0.86
	Parameter Dispersion	Type: Value:
	Estimation Comments	Difficulty sleeping: MMRM model was fitted from Baseline up to Week 52 with factors for treatment, time, dialysis type, dialysis start manner, Baseline value and Baseline value by time and treatment by time interactions.

20. Secondary Outcome

Title	Change From Baseline in Patient Global Impression of Severity (PGI-S)
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 post-dose visit value minus Baseline value. Baseline was defined as the latest non-missing pre-dose assessment on or before the randomization date.
Time Frame	Baseline (Day 1), Weeks 8, 12, 28 and 52

Outcome Measure Data

Analysis Population Description

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	Darbepoetin Alfa
Arm/Group Description	Participants received daprodustat film-coated tablets with titrated dose levels ranging from 1, 2, 4, 6, 8, 10, 12, 16, and 24 milligrams (mg) orally once daily for up to 52 weeks. Study treatment was dose-titrated to achieve and maintain hemoglobin (Hgb) in the target range (10 to 11 grams per deciliter [g/dL]).	Participants received darbepoetin alfa as prefilled syringes (PFS) for subcutaneous or intravenous (IV) injection with 4-weekly total dose levels ranging from 20, 30, 40, 60, 80, 120, 160, 200, 300 and 400 microgram (mcg) for 52 weeks. Study treatment was dose-titrated to achieve and maintain Hgb in the target range (10 to 11 g/dL).
Measure Participants	100	103
Week 8, n=100,100	0.16 (0.091)	-0.11 (0.092)
Week 12, n=100,103	0.02 (0.077)	-0.03 (0.077)
Week 28, n=92,85	0.09 (0.086)	-0.07 (0.089)
Week 52, n=75,77	0.22 (0.106)	0.04 (0.105)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Daprodustat, Darbepoetin Alfa
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.9810
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	0.27
	Confidence Interval	(2-Sided) 95%; 0.02 to 0.53
	Parameter Dispersion	Type: Value:
	Estimation Comments	MMRM model was fitted from Baseline up to Week 8 with factors for treatment, time, dialysis type, dialysis start manner, Baseline value and Baseline value by time and treatment by time interactions.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Daprodustat, Darbepoetin Alfa
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.6743
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	0.05
	Confidence Interval	(2-Sided) 95%; -0.17 to 0.26
	Parameter Dispersion	Type: Value:
	Estimation Comments	MMRM model was fitted from Baseline up to Week 12 with factors for treatment, time, dialysis type, dialysis start manner, Baseline value and Baseline value by time and treatment by time interactions.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Daprodustat, Darbepoetin Alfa
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.8997
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	0.16
	Confidence Interval	(2-Sided) 95%; -0.09 to 0.40
	Parameter Dispersion	Type: Value:
	Estimation Comments	MMRM model was fitted from Baseline up to Week 28 with factors for treatment, time, dialysis type, dialysis start manner, Baseline value and Baseline value by time and treatment by time interactions.

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Daprodustat, Darbepoetin Alfa
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.8835
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	0.18
	Confidence Interval	(2-Sided) 95%; -0.12 to 0.47
	Parameter Dispersion	Type: Value:
	Estimation Comments	MMRM model was fitted from Baseline up to Week 52 with factors for treatment, time, dialysis type, dialysis start manner, Baseline value and Baseline value by time and treatment by time interactions.

21. Secondary Outcome

Title	Plasma Concentration of Daprodustat (GSK1278863) and Its Metabolites GSK2391220 (M2), GSK2506104 (M3), and GSK2531401 (M13)
Description	Pharmacokinetic samples were collected at pre-dose, 0.5, 1, 2 and 3 hours post-dose on Week 4 or 8 or 12 for pharmacokinetic (PK) analysis of daprodustat (GSK1278863) and its metabolites GSK2391220 (M2), GSK2506104 (M3), and GSK2531401 (M13). GSK2391220, GSK2506104 and GSK2531401 are the metabolites of Daprodustat (GSK1278863). Protocol allowed participants to provide pharmacokinetic samples on Week 4 or 8 or 12. Pharmacokinetic Population comprised of participants for whom a pharmacokinetic sample was obtained and analyzed.
Time Frame	Pre-dose, 0.5, 1, 2 and 3 hours post-dose; each pharmacokinetic sample was taken at Week 4 or 8 or 12

Outcome Measure Data

Analysis Population Description

Pharmacokinetic Population. Only those participants with data available at the indicated time points were analyzed (represented by n=X in the category titles). Blood samples were not collected for PK analysis of daprodustat 12, 16 and 24 mg arms.

Arm/Group Title	Daprodustat 1 mg	Daprodustat 2 mg	Daprodustat 4 mg	Daprodustat 6 mg	Daprodustat 8 mg	Daprodustat 10 mg	Daprodustat 12 mg	Daprodustat 16 mg	Daprodustat 24 mg
Arm/Group Description	Participants received film-coated tablets of daprodustat 1 mg orally once daily for 52 weeks.	Participants received film-coated tablets of daprodustat 2 mg orally once daily for 52 weeks.	Participants received film-coated tablets of daprodustat 4 mg orally once daily for 52 weeks.	Participants received film-coated tablets of daprodustat 6 mg orally once daily for 52 weeks.	Participants received film-coated tablets of daprodustat 8 mg orally once daily for 52 weeks.	Participants received film-coated tablets of daprodustat 10 mg orally once daily for 52 weeks.	Participants received film-coated tablets of daprodustat 12 mg orally once daily for 52 weeks.	Participants received film-coated tablets of daprodustat 16 mg orally once daily for 52 weeks.	Participants received film-coated tablets of daprodustat 24 mg orally once daily for 52 weeks.
Measure Participants	19	26	20	18	1	1	0	0	0
Daprodustat: Pre-Dose, n=19,26,20,18,1,1,0,0,0	2.118 (5.0030)	1.015 (3.1451)	0.5787 (1.5718)	2.867 (6.6142)	0.1030 (NA)	0.1090 (NA)
Daprodustat: 0.5 hour, n=19,26,20,18,0,1,0,0,0	5.675 (8.4998)	4.664 (8.7508)	10.27 (20.425)	12.58 (23.742)	145.0 (NA)
Daprodustat: 1 hour, n=19,26,20,18,1,1,0,0,0	12.34 (13.435)	21.45 (42.160)	36.78 (62.497)	45.48 (48.765)	0.9120 (NA)	79.60 (NA)
Daprodustat: 2 hours, n=19,26,20,18,1,1,0,0,0	12.74 (9.9019)	20.36 (22.210)	54.68 (80.284)	55.62 (51.471)	32.00 (NA)	27.60 (NA)
Daprodustat: 3 hours, n=19,26,19,18,1,1,0,0,0	7.719 (5.9144)	15.58 (13.694)	43.34 (66.295)	56.49 (74.357)	25.30 (NA)	11.00 (NA)
GSK2391220: Pre-Dose, n=19,26,20,18,1,1,0,0,0	0.7106 (0.64028)	2.124 (2.8721)	2.087 (2.1371)	3.560 (4.2255)	4.450 (NA)	6.560 (NA)
GSK2391220: 0.5 hour, n=19,25,20,18,1,1,0,0,0	0.7602 (0.67950)	1.807 (2.2007)	1.822 (2.1355)	2.410 (2.8243)	3.950 (NA)	6.740 (NA)
GSK2391220: 1 hour, n=18,26,20,18,1,1,0,0,0	1.123 (0.76920)	1.752 (1.8589)	1.965 (2.2830)	3.140 (2.4856)	3.900 (NA)	10.00 (NA)
GSK2391220: 2 hours, n=19,26,20,18,1,1,0,0,0	1.745 (1.3160)	2.969 (2.4659)	4.008 (4.4522)	6.336 (4.3723)	4.700 (NA)	16.20 (NA)
GSK2391220: 3 hours, n=19,26,19,18,1,1,0,0,0	1.911 (1.2274)	3.535 (2.7203)	5.553 (6.5157)	9.372 (6.6452)	6.090 (NA)	16.60 (NA)
GSK2506104: Pre-Dose, n=19,26,20,18,1,1,0,0,0	1.270 (0.96071)	3.508 (4.2066)	3.879 (3.4207)	5.921 (5.8981)	8.710 (NA)	9.500 (NA)
GSK2506104: 0.5 hour, n=19,26,20,18,1,1,0,0,0	1.197 (0.85104)	2.788 (2.9893)	3.315 (3.4249)	4.015 (3.7385)	7.740 (NA)	8.110 (NA)
GSK2506104: 1 hour, n=19,26,20,18,1,1,0,0,0	1.364 (0.96292)	2.610 (2.4761)	3.268 (3.4808)	4.333 (3.0505)	7.460 (NA)	12.40 (NA)
GSK2506104: 2 hours, n=19,26,20,18,1,1,0,0,0	1.966 (1.3440)	3.583 (2.8427)	4.989 (5.2109)	7.130 (4.5105)	8.930 (NA)	19.60 (NA)
GSK2506104: 3 hours, n=19,26,19,18,1,1,0,0,0	2.190 (1.3898)	4.145 (3.1757)	6.503 (7.5130)	9.942 (7.0616)	10.10 (NA)	22.00 (NA)
GSK2531401: Pre-Dose, n=19,26,20,18,1,1,0,0,0	1.642 (1.4836)	2.729 (1.8934)	3.750 (3.8006)	5.111 (4.0632)	5.660 (NA)	7.760 (NA)
GSK2531401: 0.5 hour, n=19,26,20,18,1,1,0,0,0	1.427 (1.2870)	2.170 (1.6621)	3.263 (3.8737)	3.800 (2.8722)	4.960 (NA)	6.460 (NA)
GSK2531401: 1 hour, n=19,26,20,18,1,1,0,0,0	1.399 (1.4595)	1.979 (1.6316)	3.146 (4.0334)	3.776 (3.4411)	4.810 (NA)	6.630 (NA)
GSK2531401: 2 hours, n=19,26,20,18,1,1,0,0,0	1.690 (1.6309)	2.338 (2.1467)	3.711 (5.0223)	4.892 (4.7877)	5.190 (NA)	8.290 (NA)
GSK2531401: 3 hours, n=19,26,19,18,1,1,0,0,0	1.847 (1.7376)	2.734 (2.6846)	4.715 (7.2788)	6.631 (7.1049)	5.760 (NA)	10.20 (NA)

22. Secondary Outcome

Title	Observed Concentration at Dosing Interval (Ctau) of Daprodustat (GSK1278863) and Its Metabolites GSK2391220 (M2), GSK2506104 (M3), and GSK2531401 (M13)
Description	Pharmacokinetic samples were collected at pre-dose, 0.5, 1, 2 and 3 hours post-dose on Week 4 or 8 or 12 for pharmacokinetic analysis of daprodustat (GSK1278863) and its metabolites GSK2391220 (M2), GSK2506104 (M3), and GSK2531401 (M13). GSK2391220, GSK2506104 and GSK2531401 are the metabolites of Daprodustat (GSK1278863). Protocol allowed participants to provide pharmacokinetic samples on Week 4 or 8 or 12.
Time Frame	Pre-Dose, 0.5, 1, 2 and 3 hours post-dose; each pharmacokinetic sample was taken at Week 4 or 8 or 12

Outcome Measure Data

Analysis Population Description

Pharmacokinetic Population. Only those participants with data available at the indicated time points were analyzed. Blood samples were not collected for PK analysis of daprodustat 12, 16 and 24 mg arms.

Arm/Group Title	Daprodustat 1 mg	Daprodustat 2 mg	Daprodustat 4 mg	Daprodustat 6 mg	Daprodustat 8 mg	Daprodustat 10 mg	Daprodustat 12 mg	Daprodustat 16 mg	Daprodustat 24 mg
Arm/Group Description	Participants received film-coated tablets of daprodustat 1 mg orally once daily for 52 weeks.	Participants received film-coated tablets of daprodustat 2 mg orally once daily for 52 weeks.	Participants received film-coated tablets of daprodustat 4 mg orally once daily for 52 weeks.	Participants received film-coated tablets of daprodustat 6 mg orally once daily for 52 weeks.	Participants received film-coated tablets of daprodustat 8 mg orally once daily for 52 weeks.	Participants received film-coated tablets of daprodustat 10 mg orally once daily for 52 weeks.	Participants received film-coated tablets of daprodustat 12 mg orally once daily for 52 weeks.	Participants received film-coated tablets of daprodustat 16 mg orally once daily for 52 weeks.	Participants received film-coated tablets of daprodustat 24 mg orally once daily for 52 weeks.
Measure Participants	19	26	20	18	1	1	0	0	0
Daprodustat	2.118 (5.0030)	1.015 (3.1451)	0.5787 (1.5718)	2.867 (6.6142)	0.1030 (NA)	0.1090 (NA)
GSK2391220	0.7106 (0.64028)	2.124 (2.8721)	2.087 (2.1371)	3.560 (4.2255)	4.450 (NA)	6.560 (NA)
GSK2506104	1.270 (0.96071)	3.508 (4.2066)	3.879 (3.4207)	5.921 (5.8981)	8.710 (NA)	9.500 (NA)
GSK2531401	1.642 (1.4836)	2.729 (1.8934)	3.750 (3.8006)	5.111 (4.0632)	5.660 (NA)	7.760 (NA)

23. Secondary Outcome

Title	Maximum Observed Concentration (Cmax) of Daprodustat (GSK1278863) and Its Metabolites GSK2391220 (M2), GSK2506104 (M3), and GSK2531401 (M13)
Description	Pharmacokinetic samples were collected at pre-dose, 0.5, 1, 2 and 3 hours post-dose on Week 4 or 8 or 12 for pharmacokinetic analysis of daprodustat (GSK1278863) and its metabolites GSK2391220 (M2), GSK2506104 (M3), and GSK2531401 (M13). GSK2391220, GSK2506104 and GSK2531401 are the metabolites of Daprodustat (GSK1278863). Protocol allowed participants to provide pharmacokinetic samples on Week 4 or 8 or 12.
Time Frame	Pre-Dose, 0.5, 1, 2 and 3 hours post-dose; each pharmacokinetic sample was taken at Week 4 or 8 or 12

Outcome Measure Data

Analysis Population Description

Pharmacokinetic Population. Only those participants with data available at the indicated time points were analyzed. Blood samples were not collected for PK analysis of daprodustat 12, 16 and 24 mg arms.

Arm/Group Title	Daprodustat 1 mg	Daprodustat 2 mg	Daprodustat 4 mg	Daprodustat 6 mg	Daprodustat 8 mg	Daprodustat 10 mg	Daprodustat 12 mg	Daprodustat 16 mg	Daprodustat 24 mg
Arm/Group Description	Participants received film-coated tablets of daprodustat 1 mg orally once daily for 52 weeks.	Participants received film-coated tablets of daprodustat 2 mg orally once daily for 52 weeks.	Participants received film-coated tablets of daprodustat 4 mg orally once daily for 52 weeks.	Participants received film-coated tablets of daprodustat 6 mg orally once daily for 52 weeks.	Participants received film-coated tablets of daprodustat 8 mg orally once daily for 52 weeks.	Participants received film-coated tablets of daprodustat 10 mg orally once daily for 52 weeks.	Participants received film-coated tablets of daprodustat 12 mg orally once daily for 52 weeks.	Participants received film-coated tablets of daprodustat 16 mg orally once daily for 52 weeks.	Participants received film-coated tablets of daprodustat 24 mg orally once daily for 52 weeks.
Measure Participants	19	26	20	18	1	1	0	0	0
Daprodustat	21.74 (10.998)	32.29 (40.166)	76.92 (81.867)	100.2 (74.086)	32.00 (NA)	145.0 (NA)
GSK2391220	2.160 (1.2596)	4.139 (3.3561)	5.780 (6.2840)	10.36 (6.3377)	6.090 (NA)	16.60 (NA)
GSK2506104	2.477 (1.3625)	5.212 (4.5562)	7.075 (7.1313)	11.60 (6.8731)	10.10 (NA)	22.00 (NA)
GSK2531401	2.283 (1.8210)	3.565 (2.6091)	5.328 (6.9034)	7.836 (6.6199)	5.760 (NA)	10.20 (NA)

Adverse Events

Time Frame	All-cause mortality, treatment emergent non-serious adverse events and serious adverse events were collected up to follow-up visit (Week 58)
Adverse Event Reporting Description	Safety Population comprised of all randomized participants who received at least one dose of randomized treatment.
Arm/Group Title	Daprodustat		Darbepoetin Alfa
Arm/Group Description	Participants received daprodustat film-coated tablets with titrated dose levels ranging from 1, 2, 4, 6, 8, 10, 12, 16, and 24 milligrams (mg) orally once daily for up to 52 weeks. Study treatment was dose-titrated to achieve and maintain hemoglobin (Hgb) in the target range (10 to 11 grams per deciliter [g/dL]).		Participants received darbepoetin alfa as prefilled syringes (PFS) for subcutaneous or intravenous (IV) injection with 4-weekly total dose levels ranging from 20, 30, 40, 60, 80, 120, 160, 200, 300 and 400 microgram (mcg) for 52 weeks. Study treatment was dose-titrated to achieve and maintain Hgb in the target range (10 to 11 g/dL).
All Cause Mortality
	Daprodustat		Darbepoetin Alfa
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	17/157 (10.8%)		12/155 (7.7%)
Serious Adverse Events
	Daprodustat		Darbepoetin Alfa
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	52/157 (33.1%)		51/155 (32.9%)
Blood and lymphatic system disorders
Pancytopenia	0/157 (0%)	0	1/155 (0.6%)	1
Cardiac disorders
Acute myocardial infarction	0/157 (0%)	0	3/155 (1.9%)	3
Cardiac failure	1/157 (0.6%)	1	2/155 (1.3%)	2
Myocardial infarction	1/157 (0.6%)	1	2/155 (1.3%)	2
Cardiac failure congestive	2/157 (1.3%)	2	0/155 (0%)	0
Acute coronary syndrome	1/157 (0.6%)	1	0/155 (0%)	0
Angina pectoris	1/157 (0.6%)	1	0/155 (0%)	0
Angina unstable	0/157 (0%)	0	1/155 (0.6%)	1
Aortic valve incompetence	1/157 (0.6%)	1	0/155 (0%)	0
Arteriosclerosis coronary artery	0/157 (0%)	0	1/155 (0.6%)	1
Atrial fibrillation	1/157 (0.6%)	1	0/155 (0%)	0
Atrioventricular block complete	0/157 (0%)	0	1/155 (0.6%)	1
Bradycardia	1/157 (0.6%)	1	0/155 (0%)	0
Cardiac failure acute	1/157 (0.6%)	1	0/155 (0%)	0
Cardiac failure chronic	1/157 (0.6%)	1	0/155 (0%)	0
Cardiogenic shock	1/157 (0.6%)	1	0/155 (0%)	0
Hypertensive heart disease	1/157 (0.6%)	1	0/155 (0%)	0
Pericardial effusion	0/157 (0%)	0	1/155 (0.6%)	1
Sinus bradycardia	1/157 (0.6%)	1	0/155 (0%)	0
Supraventricular tachycardia	1/157 (0.6%)	1	0/155 (0%)	0
Congenital, familial and genetic disorders
Hypertrophic cardiomyopathy	0/157 (0%)	0	1/155 (0.6%)	1
Eye disorders
Retinopathy hypertensive	1/157 (0.6%)	1	0/155 (0%)	0
Gastrointestinal disorders
Abdominal pain	0/157 (0%)	0	3/155 (1.9%)	3
Volvulus	1/157 (0.6%)	2	0/155 (0%)	0
Abdominal pain upper	0/157 (0%)	0	1/155 (0.6%)	1
Bloody peritoneal effluent	1/157 (0.6%)	1	0/155 (0%)	0
Diabetic gastropathy	1/157 (0.6%)	1	0/155 (0%)	0
Diarrhoea	0/157 (0%)	0	1/155 (0.6%)	1
Enteritis	0/157 (0%)	0	1/155 (0.6%)	1
Gastritis	0/157 (0%)	0	1/155 (0.6%)	1
Gastrooesophageal reflux disease	1/157 (0.6%)	1	0/155 (0%)	0
Impaired gastric emptying	0/157 (0%)	0	1/155 (0.6%)	1
Intestinal obstruction	1/157 (0.6%)	1	0/155 (0%)	0
Retroperitoneal haematoma	0/157 (0%)	0	1/155 (0.6%)	1
Subileus	1/157 (0.6%)	1	0/155 (0%)	0
Upper gastrointestinal haemorrhage	0/157 (0%)	0	1/155 (0.6%)	1
General disorders
Non-cardiac chest pain	0/157 (0%)	0	2/155 (1.3%)	2
Pyrexia	1/157 (0.6%)	1	1/155 (0.6%)	1
Sudden death	2/157 (1.3%)	2	0/155 (0%)	0
Catheter site haemorrhage	1/157 (0.6%)	1	0/155 (0%)	0
Generalised oedema	0/157 (0%)	0	1/155 (0.6%)	1
Multiple organ dysfunction syndrome	0/157 (0%)	0	1/155 (0.6%)	1
Hepatobiliary disorders
Hydrocholecystis	0/157 (0%)	0	1/155 (0.6%)	1
Infections and infestations
Pneumonia	4/157 (2.5%)	7	7/155 (4.5%)	7
Peritonitis	1/157 (0.6%)	1	3/155 (1.9%)	5
Septic shock	2/157 (1.3%)	2	2/155 (1.3%)	2
Post procedural infection	3/157 (1.9%)	3	0/155 (0%)	0
Sepsis	0/157 (0%)	0	3/155 (1.9%)	3
Clostridium difficile infection	1/157 (0.6%)	1	1/155 (0.6%)	1
Gastroenteritis	1/157 (0.6%)	1	1/155 (0.6%)	1
Localised infection	1/157 (0.6%)	1	1/155 (0.6%)	1
Respiratory tract infection	1/157 (0.6%)	1	1/155 (0.6%)	1
Staphylococcal infection	2/157 (1.3%)	2	0/155 (0%)	0
Urinary tract infection	1/157 (0.6%)	1	1/155 (0.6%)	1
Urosepsis	1/157 (0.6%)	1	1/155 (0.6%)	1
Bronchiolitis	1/157 (0.6%)	1	0/155 (0%)	0
COVID-19	1/157 (0.6%)	1	0/155 (0%)	0
Clostridial sepsis	1/157 (0.6%)	1	0/155 (0%)	0
Clostridium difficile colitis	1/157 (0.6%)	1	0/155 (0%)	0
Device related bacteraemia	1/157 (0.6%)	1	0/155 (0%)	0
Device related infection	0/157 (0%)	0	1/155 (0.6%)	1
Device related sepsis	0/157 (0%)	0	1/155 (0.6%)	1
Escherichia infection	1/157 (0.6%)	1	0/155 (0%)	0
Escherichia urinary tract infection	0/157 (0%)	0	1/155 (0.6%)	1
Helicobacter gastritis	0/157 (0%)	0	1/155 (0.6%)	1
Infected skin ulcer	1/157 (0.6%)	1	0/155 (0%)	0
Leptospirosis	1/157 (0.6%)	1	0/155 (0%)	0
Lower respiratory tract infection	0/157 (0%)	0	1/155 (0.6%)	1
Osteomyelitis	0/157 (0%)	0	1/155 (0.6%)	1
Staphylococcal bacteraemia	1/157 (0.6%)	1	0/155 (0%)	0
Staphylococcal sepsis	1/157 (0.6%)	1	0/155 (0%)	0
Streptococcal infection	1/157 (0.6%)	1	0/155 (0%)	0
Subcutaneous abscess	1/157 (0.6%)	1	0/155 (0%)	0
Urinary tract infection bacterial	0/157 (0%)	0	1/155 (0.6%)	1
Injury, poisoning and procedural complications
Arteriovenous fistula thrombosis	1/157 (0.6%)	1	4/155 (2.6%)	5
Arteriovenous fistula site complication	0/157 (0%)	0	2/155 (1.3%)	2
Humerus fracture	1/157 (0.6%)	2	0/155 (0%)	0
Anaemia postoperative	1/157 (0.6%)	1	0/155 (0%)	0
Arteriovenous graft thrombosis	0/157 (0%)	0	1/155 (0.6%)	1
Fall	1/157 (0.6%)	1	0/155 (0%)	0
Femoral neck fracture	0/157 (0%)	0	1/155 (0.6%)	1
Inadequate haemodialysis	0/157 (0%)	0	1/155 (0.6%)	1
Open globe injury	1/157 (0.6%)	1	0/155 (0%)	0
Peritoneal dialysate leakage	0/157 (0%)	0	1/155 (0.6%)	1
Peritoneal dialysis complication	0/157 (0%)	0	1/155 (0.6%)	1
Procedural haemorrhage	1/157 (0.6%)	1	0/155 (0%)	0
Procedural pain	0/157 (0%)	0	1/155 (0.6%)	1
Subdural haematoma	1/157 (0.6%)	1	0/155 (0%)	0
Unintentional medical device removal	1/157 (0.6%)	1	0/155 (0%)	0
Vascular access malfunction	0/157 (0%)	0	1/155 (0.6%)	1
Investigations
Hepatic enzyme increased	0/157 (0%)	0	1/155 (0.6%)	1
Metabolism and nutrition disorders
Fluid overload	5/157 (3.2%)	9	3/155 (1.9%)	8
Hyperkalaemia	2/157 (1.3%)	2	2/155 (1.3%)	4
Hypoglycaemia	0/157 (0%)	0	3/155 (1.9%)	3
Fluid retention	0/157 (0%)	0	1/155 (0.6%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Prostate cancer metastatic	1/157 (0.6%)	1	0/155 (0%)	0
Renal cell carcinoma	0/157 (0%)	0	1/155 (0.6%)	1
Thyroid cancer stage I	0/157 (0%)	0	1/155 (0.6%)	1
Nervous system disorders
Syncope	1/157 (0.6%)	2	1/155 (0.6%)	1
Seizure	0/157 (0%)	0	2/155 (1.3%)	2
Carpal tunnel syndrome	0/157 (0%)	0	1/155 (0.6%)	1
Hypertensive encephalopathy	1/157 (0.6%)	1	0/155 (0%)	0
Presyncope	0/157 (0%)	0	1/155 (0.6%)	1
Transient ischaemic attack	0/157 (0%)	0	1/155 (0.6%)	1
Uraemic encephalopathy	1/157 (0.6%)	1	0/155 (0%)	0
Product Issues
Device malfunction	4/157 (2.5%)	4	0/155 (0%)	0
Device dislocation	1/157 (0.6%)	1	2/155 (1.3%)	2
Psychiatric disorders
Depression	0/157 (0%)	0	1/155 (0.6%)	1
Renal and urinary disorders
Azotaemia	1/157 (0.6%)	1	1/155 (0.6%)	1
Chronic kidney disease	1/157 (0.6%)	1	0/155 (0%)	0
Haematuria	1/157 (0.6%)	1	0/155 (0%)	0
Reproductive system and breast disorders
Benign prostatic hyperplasia	0/157 (0%)	0	1/155 (0.6%)	1
Metrorrhagia	1/157 (0.6%)	1	0/155 (0%)	0
Respiratory, thoracic and mediastinal disorders
Chronic obstructive pulmonary disease	1/157 (0.6%)	7	0/155 (0%)	0
Epistaxis	0/157 (0%)	0	2/155 (1.3%)	3
Acute respiratory failure	1/157 (0.6%)	1	1/155 (0.6%)	1
Dyspnoea	0/157 (0%)	0	1/155 (0.6%)	2
Pleural effusion	0/157 (0%)	0	2/155 (1.3%)	2
Respiratory failure	1/157 (0.6%)	1	1/155 (0.6%)	1
Asthma	1/157 (0.6%)	1	0/155 (0%)	0
Haemothorax	0/157 (0%)	0	1/155 (0.6%)	1
Pulmonary hypertension	1/157 (0.6%)	1	0/155 (0%)	0
Skin and subcutaneous tissue disorders
Diabetic foot	0/157 (0%)	0	1/155 (0.6%)	1
Vascular disorders
Hypertension	2/157 (1.3%)	2	1/155 (0.6%)	1
Hypertensive emergency	0/157 (0%)	0	1/155 (0.6%)	2
Hypertensive urgency	1/157 (0.6%)	1	1/155 (0.6%)	1
Lymphocele	1/157 (0.6%)	1	0/155 (0%)	0
Peripheral vascular disorder	1/157 (0.6%)	1	0/155 (0%)	0
Steal syndrome	0/157 (0%)	0	1/155 (0.6%)	1
Other (Not Including Serious) Adverse Events
	Daprodustat		Darbepoetin Alfa
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	76/157 (48.4%)		74/155 (47.7%)
Gastrointestinal disorders
Diarrhoea	14/157 (8.9%)	17	10/155 (6.5%)	10
Vomiting	11/157 (7%)	16	5/155 (3.2%)	5
Nausea	8/157 (5.1%)	13	6/155 (3.9%)	6
Infections and infestations
Nasopharyngitis	7/157 (4.5%)	12	9/155 (5.8%)	9
Upper respiratory tract infection	7/157 (4.5%)	9	11/155 (7.1%)	12
Catheter site infection	5/157 (3.2%)	5	8/155 (5.2%)	11
Injury, poisoning and procedural complications
Arteriovenous fistula site complication	4/157 (2.5%)	4	8/155 (5.2%)	13
Metabolism and nutrition disorders
Fluid overload	9/157 (5.7%)	9	6/155 (3.9%)	7
Musculoskeletal and connective tissue disorders
Muscle spasms	7/157 (4.5%)	12	9/155 (5.8%)	12
Nervous system disorders
Headache	12/157 (7.6%)	14	9/155 (5.8%)	10
Vascular disorders
Hypertension	27/157 (17.2%)	51	24/155 (15.5%)	35
Dialysis hypotension	21/157 (13.4%)	34	15/155 (9.7%)	22
Hypotension	7/157 (4.5%)	8	9/155 (5.8%)	9

Limitations/Caveats

[Not Specified]

More Information

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.