A Study to Evaluate Efficacy and Safety of Daprodustat Compared to Darbepoetin Alfa in Japanese Hemodialysis (HD)-Dependent Subjects With Anemia Associated With Chronic Kidney Disease (CKD)

• Sponsor: GlaxoSmithKline (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02969655
• Collaborator: (none)
• Enrollment: 271
• Locations: 50
• Arms: 2
• Actual Duration (Months): 19.3
• Patients Per Site: 5.4
• Patients Per Site Per Month: 0.3

Study Details

Study Description

Brief Summary

Daprodustat is a drug that is currently being developed as a treatment for renal anemia . This study is to evaluate the efficacy and safety of daprodustat following a switch from erythropoiesis-stimulating agent (ESA) in Japanese HD subjects with renal anemia who are currently treated with ESA. The primary objective is to demonstrate non-inferiority of daprodustat to darbepoetin alfa. This study is a 52-week, Phase III, double-blind, active-controlled, parallel-group, multi-center study. The total duration of the study will be approximately 58 weeks including screening and follow-up.

Condition or Disease	Intervention/Treatment	Phase
Anaemia	Drug: Daprodustat small; Drug: Daprodustat small placebo; Drug: Daprodustat large; Drug: Daprodustat large placebo; Drug: Darbepoetin alfa; Drug: Darbepoetin alfa placebo	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 271 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A 52-week, Phase III, Double-blind, Active-controlled, Parallel-group, Multi-center Study to Evaluate Efficacy and Safety of Daprodustat Compared to Darbepoetin Alfa in Japanese Hemodialysis-dependent Subjects With Anemia Associated With Chronic Kidney Disease Who Are Currently ESA Users
• Actual Study Start Date: Nov 21, 2016
• Actual Primary Completion Date: Jul 2, 2018
• Actual Study Completion Date: Jul 2, 2018

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Daprodustat Subjects will receive oral daprodustat once daily and intravenous (IV) darbepoetin alfa placebo once weekly for 52 weeks	Drug: Daprodustat small; Available as 7.0 millimeter (mm) round, standard biconvex, white film coated tablets containing 1 mg, 2 mg, or 4 mg of daprodustat as active ingredient; Drug: Daprodustat large; Available as 9.0 mm round, standard biconvex, white film coated tablets containing 6 mg of daprodustat as active ingredient; Drug: Darbepoetin alfa placebo; Available as 0.5 mL plastic PFS for IV injection containing no darbepoetin alfa in a clear and colorless solution.
Active Comparator: Darbepoetin alfa Subjects will receive IV darbepoetin alfa once weekly and oral daprodustat placebo once daily for 52 weeks	Drug: Daprodustat small placebo; Available as 7.0 mm round, standard biconvex, white film coated tablets containing no daprodustat; Drug: Daprodustat large placebo; Available as 9.0 mm round, standard biconvex, white film coated tablets containing no daprodustat; Drug: Darbepoetin alfa; Available as 0.5 mL plastic prefilled syringes (PFS) for IV injection each containing 10, 15, 20, 30, 40 or 60 mcg of darbepoetin alfa in a clear and colorless solution.

Outcome Measures

Primary Outcome Measures

1. Mean Hemoglobin (Hgb) During the Primary Efficacy Evaluation Period (Weeks 40 to 52) [Weeks 40 to 52]

   The mean hemoglobin during the Evaluation Period was estimated by a statistical model.

Secondary Outcome Measures

1. Percentage of Participants With Mean Hgb in the Target Range (10.0-12.0 g/dL) During the Primary Efficacy Evaluation Period (Weeks 40 to 52) [Weeks 40 to 52]

   The percentage of participants with observed mean Hgb within the target range during the primary efficacy evaluation period was summarized. Odds ratio was estimated using a logistic regression and provided along with its 95% CI and a one-sided p-value.

2. Change From Baseline in Hgb (Hgb Increase Rate) at Week 4 [Baseline and Week 4]

   Change from Baseline was calculated as the post-dose Week 4 visit value minus the Baseline value.

3. Percentage of Participants by Hgb Change From Baseline Category at Week 4 [Week 4]

   Percentage of participants within each category were provided only for daprodustat and the categories were classified into 6 (i.e., <=-2, >-2 to -1, >-1 to 0, >0 to 1, >1 to 2, >2 grams per deciliter [g/dL]). In addition, 'within 1.0 g/dL (i.e., <=-1 and >=1) and over 2.0 g/dL (i.e., <-2 and >2) categories were provided.

4. Distribution of Daprodustat Dose Level by Visit [Day 1, Weeks 4,8,12,16,20,24,28,32,36,40,44, and 48)]

   Distribution of dose level by visit for hemodialysis-dependent participants with anemia associated with chronic kidney disease who were currently ESA users has been presented for Daprodustat. Median along with the interquartile range (25th and 75th percentile) has been presented.

5. Distribution of Darbepoetin Alfa Dose Level by Visit [Day 1, Weeks 2,4,6,8,10,12,14,16,18,20,22,24,26,28,30,32,34,36,38,40,42,44,46,48, and 50]

   Distribution of dose level by visit for hemodialysis-dependent participants with anemia associated with chronic kidney disease who were currently ESA users has been presented for Darbepoetin Alfa. Median along with the interquartile range (25th and 75th percentile) has been presented.

6. Duration of Treatment Interruption Due to Hgb >13 g/dL [Up to Week 52]

   Duration of treatment interruption due to Hgb >13 g/dL for hemodialysis-dependent participants with anemia associated with chronic kidney disease who were currently ESA users has been presented for the daprodustat group.

7. Number of Dose Adjustments for Daprodustat [Up to Week 52]

   Number of dose adjustments has been presented only for daprodustat.

8. Hgb Values at Each Assessment Visit [Baseline (Day 1), Weeks 4,8,12,16,20,24,28,32,36,40,44,48 and Week 52]

   Hgb values at each assessment visit for hemodialysis-dependent participants with anemia associated with chronic kidney disease who were currently ESA users has been presented.

9. Change From Baseline in Hgb Values at Each Assessment Visit [Baseline (Day 1) and Weeks 4,8,12,16,20,24,28,32,36,40,44,48 and Week 52]

   Baseline Hgb value was the value from the Day 1 visit. Change from Baseline was calcuated as the post-dose visit value minus the Baseline value. Change from Baseline Hgb values at each assessment visit for hemodialysis-dependent participants with anemia associated with chronic kidney disease who were currently ESA users has been presented.

10. Percentage of Participants Who Had Hgb Level Within the Target Range (10.0-12.0 g/dL) at Each Assessment Visit [Baseline (Day 1) and Weeks 4,8,12,16,20,24,28,32,36,40,44,48 and Week 52]

    Percentage of participants with Hgb within the target range was summarized at each assessment visit by treatment group have been presented.

11. Percentage of Time in Hgb Target Range (10.0 to 12.0 g/dL) During the Primary Efficacy Evaluation Period (Weeks 40 to 52) [Weeks 40 to 52]

    Percentage of time in Hgb target range (10.0 to 12.0 g/dL) during the primary efficacy evaluation period (Weeks 40 to 52) for hemodialysis-dependent participants with anemia associated with chronic kidney disease who were currently ESA users has been presented.

12. Number of Participants Who Had an Hgb Level of Less Than 7.5 g/dL [Up to Week 52]

    If an initial Hgb value was less than 7.5 g/dL, measurement was repeated at the same study visit (using the same sample) to calculate the average. If the average met the Hgb stopping criteria, study treatment was permanently discontinued. Number of participants who had an Hgb level of less than 7.5 g/dL has been presented.

13. Number of Participants Who Had an Hgb Increase of More Than 2 g/dL Over Any 4 Weeks [Up to Week 52]

    Number of participants who had an Hgb increase of more than 2 g/dL over any 4 weeks for hemodialysis-dependent participants with anemia associated with chronic kidney disease who were currently ESA users have been presented.

14. Number of Participants Who Had an Hgb Level of More Than 13.0 g/dL [Up to Week 52]

    Number of participants who had an Hgb increase of more than 13 g/dL for hemodialysis-dependent participants with anemia associated with chronic kidney disease who were currently ESA users have been presented.

15. Number of Episodes With Hgb Level of More Than 13.0 g/dL [Up to Week 52]

    Number of episodes with Hgb level of more than 13.0 g/dL for hemodialysis-dependent participants with anemia associated with chronic kidney disease who were currently ESA users have been presented.

16. Area Under Plasma Concentration Curve From Time Zero to 4 Hours (AUC [0 - 4]) of Plasma Daprodustat [0, 1, 2, 3, and 4 hours post-dose at Week 12 and Week 24]

    Blood samples for Pharmacokinetic (PK) analysis of daprodustat were collected as the time points provided. PK parameters were calculated by standard non-compartmental analysis according to current working practices and using the currently supported version of WinNonlin (version 6.3 or higher). NA indicates geometric co-efficient of variation could not be calculated as a single participant was analyzed. Data has been provided as a consolidated values for at all time-points (0,1,2,3,and 4 hours post-dose) as provided for a single value at Weeks 12 and 24 respectively. PK population comprised of all daprodustat-treated participants from whom PK samples were collected and analyzed. Data was not calculated for darbepoetin alfa group as the primary interest of analysis was Daprodustat and not comparator drug (darbepoetin alfa). Data is combined from Week 12 and Week 24 data.

17. Maximum Concentration (Cmax) of Plasma Daprodustat [0, 1, 2, 3, and 4 hours post-dose at Week 12 and Week 24]

    Blood samples for PK analysis of daprodustat were collected as the time points provided. PK parameters were calculated by standard non-compartmental analysis according to current working practices and using the currently supported version of WinNonlin (version 6.3 or higher). Data has been provided as a consolidated values for at all time-points (0,1,2,3,and 4 hours post-dose) as provided for a single value at Weeks 12 and 24 respectively. Data was not calculated for darbepoetin alfa group as the primary interest of analysis was Daprodustat and not comparator drug (darbepoetin alfa). Data is combined from Week 12 and Week 24 data.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 20 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria

• Age (informed consent): >=20 years of age

• Dialysis: On HD or hemodiafiltration (HDF) given three times weekly for at least 12 weeks prior to screening

• ESAs: Use of one and the same ESA for 10 weeks prior to screening

• ESA dose: Darbepoetin alfa 10 to 60 μg per week, epoetin (including biosimilars) <=9000 international units (IU) per week, or epoetin beta pegol <=250 μg per 4 weeks

• Hgb:>=9.5 g/dL and <=12.5 g/dL. Determined at the site using an Hgb analyzer

• Iron parameters: Ferritin >100 nanogram (ng)/millilitre (mL) or transferrin saturation (TSAT) >20 percent (screening verification only)

• Gender (screening verification only): Female or male

Females: Not pregnant [demonstrated to be negative for human chorionic gonadotropin (hCG) in serum], not breast-feeding, and meet at least one of the following:

• Females of non-childbearing potential are defined as follows:

Pre-menopausal with at least one of the following and no plans to utilise assisted reproductive techniques (e.g., in vitro fertilisation or donor embryo transfer):

• History of bilateral tubal ligation or salpingectomy

• History of hysteroscopic tubal occlusion and postoperatively documented bilateral tubal obstruction

• History of hysterectomy

• History of bilateral oophorectomy Postmenopausal defined as A) females 60 years of age or older or B) In females < 60 years of age, 12 months of spontaneous amenorrhea [in questionable cases a blood sample with postmenopausal follicle stimulating hormone (FSH) and estradiol concentrations is confirmatory (see separately specified reference ranges)]. Females on hormone replacement therapy (HRT) whose menopausal status is in doubt will be required to use one of the most effective contraception methods if they wish to continue their HRT during the study. Otherwise they must discontinue HRT to allow confirmation of post-menopausal status prior to study enrolment.

• Females of childbearing potential must agree to comply with one of the contraception methods listed as requirements in "GlaxoSmithKline (GSK) Listing of Most Effective Contraceptive Methods for Females of Childbearing Potential from 28 days prior to the first dose of study medication until the completion of the follow-up visit.

• Informed consent: Written informed consent, including adherence to the requirements and conditions specified in the consent form and the protocol, must be obtained from each subject.

Exclusion Criteria

CKD-related criteria

• Kidney transplant: Planned living-related kidney transplant during the study

Anemia-related criteria

• Aplasia: History of bone-marrow hypoplasia or pure red cell aplasia

• Other causes of anemia: pernicious anemia, thalassemia, sickle cell anemia, or myelodysplastic syndromes

• Gastrointestinal (GI) bleeding: Evidence of actively bleeding gastric, duodenal, or esophageal ulcer disease OR clinically significant GI bleeding within 10 weeks prior to screening or during a period from screening to Day 1

Cardiovascular disease-related criteria

• Myocardial infarction, acute coronary syndrome, stroke, or transient ischemic attack: Diagnosed within 10 weeks prior to screening or during a period from screening to Day 1

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

• Corrected QT (QTc) Interval (screening verification only): QTc >500 milliseconds (msec); or QTc >530 msec in subjects with bundle branch block Note: QT interval corrected using the Bazett's formula (QTcB) will be used, and electrocardiogram (ECG) can be mechanically or manually read

Other disease-related criteria:

• Liver disease (if any of the following occurs):

• Alanine transaminase (ALT) >2 upper limit of normal (ULN)

• Bilirubin >1.5×ULN (isolated bilirubin >1.5 ULN is acceptable if bilirubin is fractionated and direct bilirubin is <35 percent)

• Current unstable active liver or biliary disease (generally defined by the onset of ascites, encephalopathy, coagulopathy, hypoalbuminemia, esophageal/gastric varices, persistent jaundice, or cirrhosis)

• Malignancy: History of malignancy within 2 years prior to screening, currently receiving treatment for cancer, or complex kidney cyst >3 centimeters (cm) (II F, III or IV based on the Bosniak classification)

Concomitant medication and other study treatment-related criteria

• Iron: Planned use of intravenous iron during the screening phase or during a period from Day 1 to Week 4

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

• Drugs and supplements: Use or planned use of any prescription or non-prescription drugs or dietary supplements that are prohibited during the study period [prohibited medications: strong inducers and inhibitor of Cytochrome P450 (CYP) 2C8].

• Prior investigational product exposure: Use of an investigational agent within 30 days or five half lives of the investigational agent (whichever is longer)

• Prior treatment with daprodustat: Any prior treatment with daprodustat for a treatment duration of >30 days

General health-related criteria

• Other conditions: Any other condition, clinical or laboratory abnormality, or examination finding that the investigator (or subinvestigator) considers would put the subject at unacceptable risk, which may affect study compliance 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	Aichi		Japan	441-8023
2	GSK Investigational Site	Aichi		Japan	446-0053
3	GSK Investigational Site	Aichi		Japan	446-0065
4	GSK Investigational Site	Aichi		Japan	454-0932
5	GSK Investigational Site	Aichi		Japan	455-0021
6	GSK Investigational Site	Aichi		Japan	462-0802
7	GSK Investigational Site	Aichi		Japan	486-8510
8	GSK Investigational Site	Chiba		Japan	276-0031
9	GSK Investigational Site	Ehime		Japan	790-0962
10	GSK Investigational Site	Ehime		Japan	792-0812
11	GSK Investigational Site	Fukui		Japan	918-8503
12	GSK Investigational Site	Fukuoka		Japan	804-0094
13	GSK Investigational Site	Fukuoka		Japan	811-0120
14	GSK Investigational Site	Fukuoka		Japan	811-0213
15	GSK Investigational Site	Fukuoka		Japan	818-0083
16	GSK Investigational Site	Fukushima		Japan	963-8002
17	GSK Investigational Site	Fukushima		Japan	963-8071
18	GSK Investigational Site	Gunma		Japan	370-0615
19	GSK Investigational Site	Gunma		Japan	372-0817
20	GSK Investigational Site	Gunma		Japan	375-0024
21	GSK Investigational Site	Hokkaido		Japan	004-0814
22	GSK Investigational Site	Hokkaido		Japan	007-0803
23	GSK Investigational Site	Hokkaido		Japan	073-0022
24	GSK Investigational Site	Hokkaido		Japan	073-0196
25	GSK Investigational Site	Ibaraki		Japan	300-0062
26	GSK Investigational Site	Ibaraki		Japan	302-0011
27	GSK Investigational Site	Ibaraki		Japan	305-0861
28	GSK Investigational Site	Kagawa		Japan	761-8024
29	GSK Investigational Site	Kanagawa		Japan	224-0032
30	GSK Investigational Site	Kanagawa		Japan	227-0046
31	GSK Investigational Site	Kanagawa		Japan	234-0054
32	GSK Investigational Site	Kanagawa		Japan	235-0045
33	GSK Investigational Site	Kyoto		Japan	613-0034
34	GSK Investigational Site	Miyagi		Japan	981-0954
35	GSK Investigational Site	Nagano		Japan	390-0821
36	GSK Investigational Site	Nagano		Japan	390-1401
37	GSK Investigational Site	Nagano		Japan	399-8292
38	GSK Investigational Site	Okayama		Japan	714-0043
39	GSK Investigational Site	Osaka		Japan	543-0052
40	GSK Investigational Site	Osaka		Japan	547-0024
41	GSK Investigational Site	Osaka		Japan	584-0082
42	GSK Investigational Site	Osaka		Japan	594-0076
43	GSK Investigational Site	Saitama		Japan	348-0045
44	GSK Investigational Site	Shizuoka		Japan	424-0012
45	GSK Investigational Site	Tokyo		Japan	158-0094
46	GSK Investigational Site	Tokyo		Japan	169-0075
47	GSK Investigational Site	Toyama		Japan	930-0065
48	GSK Investigational Site	Toyama		Japan	938-8502
49	GSK Investigational Site	Yamagata		Japan	990-0834
50	GSK Investigational Site	Yamaguchi		Japan	755-0155

Sponsors and Collaborators

• GlaxoSmithKline

Investigators

• Study Director: GSK Clinical Trials, GlaxoSmithKline

Study Documents (Full-Text)

• Statistical Analysis Plan - Aug 6, 2018
• Study Protocol - Jul 19, 2017

More Information

Publications

• Akizawa T, Nangaku M, Yonekawa T, Okuda N, Kawamatsu S, Onoue T, Endo Y, Hara K, Cobitz AR. Efficacy and Safety of Daprodustat Compared with Darbepoetin Alfa in Japanese Hemodialysis Patients with Anemia: A Randomized, Double-Blind, Phase 3 Trial. Clin J Am Soc Nephrol. 2020 Aug 7;15(8):1155-1165. doi: 10.2215/CJN.16011219. Epub 2020 Jul 28.

• Responsible Party: GlaxoSmithKline
• ClinicalTrials.gov Identifier: NCT02969655
• Other Study ID Numbers: 201754
• First Posted: Nov 21, 2016
• Last Update Posted: Nov 27, 2020
• Last Verified: Nov 1, 2020

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Keywords provided by GlaxoSmithKline: Safety; Efficacy; Daprodustat; Chronic kidney disease
• Additional relevant MeSH terms: Kidney Diseases; Renal Insufficiency, Chronic; Anemia; Darbepoetin alfa; Glycine

Study Results

Participant Flow

Recruitment Details	A total of 50 centers, contracted in Japan, enrolled and randomized participants. A total of 271 participants were enrolled and randomized in this study.
Pre-assignment Detail	A total of 332 participants were screened of which 61 failed screening reasons being participants did not meet inclusion/exclusion criteria (48), physician decision (3) and withdrawn by participant (10), hence 271 participants were enrolled and randomized.

Arm/Group Title	Daprodustat	Darbepoetin Alfa
Arm/Group Description	Participants received oral daprodustat tablets (1, 2, 4, 6, 8, 12, 18 and 24 milligrams [mg] as recommended) once daily and intravenous (IV) darbepoetin alfa placebo injection (0.5 milliliter prefilled syringes containing no darbepoetin alfa) once weekly for 52 weeks.	Participant received IV darbepoetin alfa injection (10,15,20,30,40 and 60 micrograms [ug] as recommended) once weekly and oral daprodustat placebo tablets (small and large tablets containing no daprodustat) once daily for 52 weeks.
Period Title: Overall Study
STARTED	136	135
COMPLETED	115	120
NOT COMPLETED	21	15

Baseline Characteristics

Arm/Group Title	Daprodustat	Darbepoetin Alfa	Total
Arm/Group Description	Participants received oral daprodustat tablets (1, 2, 4, 6, 8, 12, 18 and 24 milligrams [mg] as recommended) once daily and intravenous (IV) darbepoetin alfa placebo injection (0.5 milliliter prefilled syringes containing no darbepoetin alfa) once weekly for 52 weeks.	Participant received IV darbepoetin alfa injection (10,15,20,30,40 and 60 micrograms [ug] as recommended) once weekly and oral daprodustat placebo tablets (small and large tablets containing no daprodustat) once daily for 52 weeks.	Total of all reporting groups
Overall Participants	136	135	271
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	64.1 (10.30)	63.5 (10.54)	63.8 (10.40)
Sex: Female, Male (Count of Participants)
Female	45 33.1%	46 34.1%	91 33.6%
Male	91 66.9%	89 65.9%	180 66.4%
Race/Ethnicity, Customized (Count of participants) [Number]
Asian - Japanese heritage	136 100%	135 100%	271 100%

Outcome Measures

1. Primary Outcome

Title	Mean Hemoglobin (Hgb) During the Primary Efficacy Evaluation Period (Weeks 40 to 52)
Description	The mean hemoglobin during the Evaluation Period was estimated by a statistical model.
Time Frame	Weeks 40 to 52

Outcome Measure Data

Analysis Population Description

Intent to treat (ITT) Population comprised of all randomized participants who had a Baseline and at least one post Baseline schedule Hgb assessment.

Arm/Group Title	Daprodustat	Darbepoetin Alfa
Arm/Group Description	Participants received oral daprodustat tablets (1, 2, 4, 6, 8, 12, 18 and 24 milligrams [mg] as recommended) once daily and intravenous (IV) darbepoetin alfa placebo injection (0.5 milliliter prefilled syringes containing no darbepoetin alfa) once weekly for 52 weeks.	Participant received IV darbepoetin alfa injection (10,15,20,30,40 and 60 micrograms [ug] as recommended) once weekly and oral daprodustat placebo tablets (small and large tablets containing no daprodustat) once daily for 52 weeks.
Measure Participants	133	134
Least Squares Mean (Standard Error) [Grams per deciliter (g/dL)]	10.89 (0.062)	10.83 (0.060)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Daprodustat, Darbepoetin Alfa
	Comments
	Type of Statistical Test	Non-Inferiority
	Comments	Non-inferiority was established if the lower limit of the 95% CI was greater than -1.0 g/dL. Even if the 95% CI for the difference was completely negative (i.e. lied fully within the range -1.0 to <0 g/dL) non-inferiority was concluded on condition that the mean Hgb estimated in the daprodustat group was within the target range.
Statistical Test of Hypothesis	p-Value	<.0001
	Comments	The p value on this table is one-sided and calculated for the non-inferiority assessment.
	Method	Mixed model repeated measures (MMRM)
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.06
	Confidence Interval	(2-Sided) 95%; -0.11 to 0.23
	Parameter Dispersion	Type: Value:
	Estimation Comments	Analysis was performed by a MMRM with covariates of treatment, Baseline Hgb, visit, treatment-by-visit interaction, Baseline-by-visit interaction.

2. Secondary Outcome

Title	Percentage of Participants With Mean Hgb in the Target Range (10.0-12.0 g/dL) During the Primary Efficacy Evaluation Period (Weeks 40 to 52)
Description	The percentage of participants with observed mean Hgb within the target range during the primary efficacy evaluation period was summarized. Odds ratio was estimated using a logistic regression and provided along with its 95% CI and a one-sided p-value.
Time Frame	Weeks 40 to 52

Outcome Measure Data

Analysis Population Description

Modified Intent to treat (mITT) comprised of all ITT participants who had at least one Hgb measurement during the evaluation period.

Arm/Group Title	Daprodustat	Darbepoetin Alfa
Arm/Group Description	Participants received oral daprodustat tablets (1, 2, 4, 6, 8, 12, 18 and 24 milligrams [mg] as recommended) once daily and intravenous (IV) darbepoetin alfa placebo injection (0.5 milliliter prefilled syringes containing no darbepoetin alfa) once weekly for 52 weeks.	Participant received IV darbepoetin alfa injection (10,15,20,30,40 and 60 micrograms [ug] as recommended) once weekly and oral daprodustat placebo tablets (small and large tablets containing no daprodustat) once daily for 52 weeks.
Measure Participants	120	125
Responder	88 64.7%	90 66.7%
Non-responder	13 9.6%	10 7.4%

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	0.7442
	Comments	The p value on this table is one-sided and calculated for the superiority assessment.
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.76
	Confidence Interval	(2-Sided) 95%; 0.34 to 1.71
	Parameter Dispersion	Type: Value:
	Estimation Comments	Analysis was performed by logistic regression with covariates of treatment and Baseline Hgb.

3. Secondary Outcome

Title	Change From Baseline in Hgb (Hgb Increase Rate) at Week 4
Description	Change from Baseline was calculated as the post-dose Week 4 visit value minus the Baseline value.
Time Frame	Baseline and Week 4

Outcome Measure Data

Analysis Population Description

ITT Population

Arm/Group Title	Daprodustat	Darbepoetin Alfa
Arm/Group Description	Participants received oral daprodustat tablets (1, 2, 4, 6, 8, 12, 18 and 24 milligrams [mg] as recommended) once daily and intravenous (IV) darbepoetin alfa placebo injection (0.5 milliliter prefilled syringes containing no darbepoetin alfa) once weekly for 52 weeks.	Participant received IV darbepoetin alfa injection (10,15,20,30,40 and 60 micrograms [ug] as recommended) once weekly and oral daprodustat placebo tablets (small and large tablets containing no daprodustat) once daily for 52 weeks.
Measure Participants	133	134
Mean (Standard Deviation) [g/dL]	-0.42 (0.898)	0.08 (0.525)

4. Secondary Outcome

Title	Percentage of Participants by Hgb Change From Baseline Category at Week 4
Description	Percentage of participants within each category were provided only for daprodustat and the categories were classified into 6 (i.e., <=-2, >-2 to -1, >-1 to 0, >0 to 1, >1 to 2, >2 grams per deciliter [g/dL]). In addition, 'within 1.0 g/dL (i.e., <=-1 and >=1) and over 2.0 g/dL (i.e., <-2 and >2) categories were provided.
Time Frame	Week 4

Outcome Measure Data

Analysis Population Description

ITT Population. Data for Darbepoetin alfa group could not be collected as comparison was not reasonable because of the difference in dose adjustment frequency.

Arm/Group Title	Daprodustat
Arm/Group Description	Participants received oral daprodustat tablets (1, 2, 4, 6, 8, 12, 18 and 24 milligrams [mg] as recommended) once daily and intravenous (IV) darbepoetin alfa placebo injection (0.5 milliliter prefilled syringes containing no darbepoetin alfa) once weekly for 52 weeks.
Measure Participants	133
<= -2.0	5 3.7%
> -2.0 and <= -1.0	21 15.4%
> -1.0 and <= 0	44 32.4%
> 0 and <= 1.0	27 19.9%
> 1.0 and <= 2.0	4 2.9%
> 2.0	0 0%
within +/- 1.0	75 55.1%
over +/- 2.0	5 3.7%

5. Secondary Outcome

Title	Distribution of Daprodustat Dose Level by Visit
Description	Distribution of dose level by visit for hemodialysis-dependent participants with anemia associated with chronic kidney disease who were currently ESA users has been presented for Daprodustat. Median along with the interquartile range (25th and 75th percentile) has been presented.
Time Frame	Day 1, Weeks 4,8,12,16,20,24,28,32,36,40,44, and 48)

Outcome Measure Data

Analysis Population Description

ITT Population. Only those participants available at the specified time points were analyzed (represented by n=x in the category titles).

Arm/Group Title	Daprodustat
Arm/Group Description	Participants received oral daprodustat tablets (1, 2, 4, 6, 8, 12, 18 and 24 milligrams [mg] as recommended) once daily and intravenous (IV) darbepoetin alfa placebo injection (0.5 milliliter prefilled syringes containing no darbepoetin alfa) once weekly for 52 weeks.
Measure Participants	133
Day 1, n=133	4.0
Week 4, n=133	4.0
Week 8, n=126	4.0
Week 12, n=125	6.0
Week 16, n=123	6.0
Week 20, n=123	6.0
Week 24, n=123	6.0
Week 28, n=123	6.0
Week 32, n=122	6.0
Week 36, n=121	6.0
Week 40, n=119	6.0
Week 44, n=117	6.0
Week 48, n=117	6.0

6. Secondary Outcome

Title	Distribution of Darbepoetin Alfa Dose Level by Visit
Description	Distribution of dose level by visit for hemodialysis-dependent participants with anemia associated with chronic kidney disease who were currently ESA users has been presented for Darbepoetin Alfa. Median along with the interquartile range (25th and 75th percentile) has been presented.
Time Frame	Day 1, Weeks 2,4,6,8,10,12,14,16,18,20,22,24,26,28,30,32,34,36,38,40,42,44,46,48, and 50

Outcome Measure Data

Analysis Population Description

ITT Population. Only those participants available at the specified time points were analyzed (represented by n=x in the category titles).

Arm/Group Title	Darbepoetin Alfa
Arm/Group Description	Participant received IV darbepoetin alfa injection (10,15,20,30,40 and 60 micrograms [ug] as recommended) once weekly and oral daprodustat placebo tablets (small and large tablets containing no daprodustat) once daily for 52 weeks.
Measure Participants	134
Day 1, n=134	15.0
Week 2. n=134	15.0
Week 4, n=134	15.0
Week 6, n=133	15.0
Week 8, n=131	15.0
Week 10, n=129	15.0
Week 12, n=129	15.0
Week 14, n=129	15.0
Week 16, n=129	15.0
Week 18, n=129	15.0
Week 20, n=129	15.0
Week 22, n=128	15.0
Week 24, n=129	15.0
Week 26, n=129	15.0
Week 28, n=127	15.0
Week 30, n=128	15.0
Week 32, n=127	15.0
Week 34, n=127	15.0
Week 36, n=127	15.0
Week 38, n=127	15.0
Week 40, n=125	15.0
Week 42, n=125	15.0
Week 44, n=125	15.0
Week 46, n=125	15.0
Week 48, n=124	15.0
Week 50, n=122	15.0

7. Secondary Outcome

Title	Duration of Treatment Interruption Due to Hgb >13 g/dL
Description	Duration of treatment interruption due to Hgb >13 g/dL for hemodialysis-dependent participants with anemia associated with chronic kidney disease who were currently ESA users has been presented for the daprodustat group.
Time Frame	Up to Week 52

Outcome Measure Data

Analysis Population Description

ITT Population. Only those participants with data available at the time of assessment were used for analysis. Summary data for Darbepoetin alfa group could not be collected as comparison was not reasonable because of the difference in dose adjustment frequency. Median along with inter quartile range (25th and 75th percentile) have been presented.

Arm/Group Title	Daprodustat
Arm/Group Description	Participants received oral daprodustat tablets (1, 2, 4, 6, 8, 12, 18 and 24 milligrams [mg] as recommended) once daily and intravenous (IV) darbepoetin alfa placebo injection (0.5 milliliter prefilled syringes containing no darbepoetin alfa) once weekly for 52 weeks.
Measure Participants	3
Median (Inter-Quartile Range) [Days]	28.0

8. Secondary Outcome

Title	Number of Dose Adjustments for Daprodustat
Description	Number of dose adjustments has been presented only for daprodustat.
Time Frame	Up to Week 52

Outcome Measure Data

Analysis Population Description

ITT Population. Summary data for Darbepoetin alfa group could not be collected as comparison was not reasonable because of the difference in dose adjustment frequency.

Arm/Group Title	Daprodustat
Arm/Group Description	Participants received oral daprodustat tablets (1, 2, 4, 6, 8, 12, 18 and 24 milligrams [mg] as recommended) once daily and intravenous (IV) darbepoetin alfa placebo injection (0.5 milliliter prefilled syringes containing no darbepoetin alfa) once weekly for 52 weeks.
Measure Participants	133
Median (Full Range) [Dose adjustments]	2.0

9. Secondary Outcome

Title	Hgb Values at Each Assessment Visit
Description	Hgb values at each assessment visit for hemodialysis-dependent participants with anemia associated with chronic kidney disease who were currently ESA users has been presented.
Time Frame	Baseline (Day 1), Weeks 4,8,12,16,20,24,28,32,36,40,44,48 and Week 52

Outcome Measure Data

Analysis Population Description

ITT Population. Only those participants available at the specified time points were analyzed (represented by n=x in the category titles).

Arm/Group Title	Daprodustat	Darbepoetin Alfa
Arm/Group Description	Participants received oral daprodustat tablets (1, 2, 4, 6, 8, 12, 18 and 24 milligrams [mg] as recommended) once daily and intravenous (IV) darbepoetin alfa placebo injection (0.5 milliliter prefilled syringes containing no darbepoetin alfa) once weekly for 52 weeks.	Participant received IV darbepoetin alfa injection (10,15,20,30,40 and 60 micrograms [ug] as recommended) once weekly and oral daprodustat placebo tablets (small and large tablets containing no daprodustat) once daily for 52 weeks.
Measure Participants	133	134
Baseline (Day 1), n=133, 134	10.94 (0.770)	10.82 (0.732)
Week 4, n=133, 134	10.52 (0.984)	10.90 (0.829)
Week 8, n=127, 132	10.50 (1.069)	11.01 (0.824)
Week 12, n=125, 129	10.53 (0.989)	11.09 (0.753)
Week 16, n=124, 129	10.57 (0.970)	10.92 (0.862)
Week 20, n=123, 129	10.85 (0.784)	10.95 (0.830)
Week 24, n=123, 129	11.01 (0.718)	10.92 (0.859)
Week 28, n=123, 129	10.97 (0.748)	10.86 (0.872)
Week 32, n=122, 127	11.10 (0.829)	10.96 (0.820)
Week 36, n=121, 127	11.12 (0.827)	10.91 (0.847)
Week 40, n=120, 125	10.97 (0.860)	10.90 (0.835)
Week 44, n=117, 125	10.98 (0.912)	10.87 (0.904)
Week 48, n=117, 124	10.94 (0.893)	10.76 (0.830)
Week 52,n=115, 120	10.79 (0.807)	10.79 (0.841)

10. Secondary Outcome

Title	Change From Baseline in Hgb Values at Each Assessment Visit
Description	Baseline Hgb value was the value from the Day 1 visit. Change from Baseline was calcuated as the post-dose visit value minus the Baseline value. Change from Baseline Hgb values at each assessment visit for hemodialysis-dependent participants with anemia associated with chronic kidney disease who were currently ESA users has been presented.
Time Frame	Baseline (Day 1) and Weeks 4,8,12,16,20,24,28,32,36,40,44,48 and Week 52

Outcome Measure Data

Analysis Population Description

ITT Population. Only those participants available at the specified time points were analyzed (represented by n=x in the category titles).

Arm/Group Title	Daprodustat	Darbepoetin Alfa
Arm/Group Description	Participants received oral daprodustat tablets (1, 2, 4, 6, 8, 12, 18 and 24 milligrams [mg] as recommended) once daily and intravenous (IV) darbepoetin alfa placebo injection (0.5 milliliter prefilled syringes containing no darbepoetin alfa) once weekly for 52 weeks.	Participant received IV darbepoetin alfa injection (10,15,20,30,40 and 60 micrograms [ug] as recommended) once weekly and oral daprodustat placebo tablets (small and large tablets containing no daprodustat) once daily for 52 weeks.
Measure Participants	133	134
Week 4, n=133, 134	-0.42 (0.898)	0.08 (0.525)
Week 8, n=127, 132	-0.45 (1.178)	0.20 (0.821)
Week 12, n=125, 129	-0.42 (1.258)	0.27 (1.021)
Week 16, n=124, 129	-0.38 (1.348)	0.09 (1.146)
Week 20, n=123, 129	-0.09 (1.161)	0.12 (1.120)
Week 24, n=123, 129	0.07 (1.106)	0.10 (1.068)
Week 28, n=123, 129	0.03 (1.084)	0.04 (1.080)
Week 32, n=122, 127	0.16 (1.119)	0.14 (1.071)
Week 36, n=121, 127	0.17 (1.020)	0.09 (1.041)
Week 40, n=120, 125	0.03 (1.060)	0.10 (1.034)
Week 44, n=117, 125	0.03 (1.118)	0.07 (1.019)
Week 48, n=117, 124	-0.01 (1.164)	-0.04 (0.978)
Week 52,n=115, 120	-0.16 (1.169)	0.01 (1.019)

11. Secondary Outcome

Title	Percentage of Participants Who Had Hgb Level Within the Target Range (10.0-12.0 g/dL) at Each Assessment Visit
Description	Percentage of participants with Hgb within the target range was summarized at each assessment visit by treatment group have been presented.
Time Frame	Baseline (Day 1) and Weeks 4,8,12,16,20,24,28,32,36,40,44,48 and Week 52

Outcome Measure Data

Analysis Population Description

ITT Population. Only those participants available at the specified time points were analyzed (represented by n=x in the category titles).

Arm/Group Title	Daprodustat	Darbepoetin Alfa
Arm/Group Description	Participants received oral daprodustat tablets (1, 2, 4, 6, 8, 12, 18 and 24 milligrams [mg] as recommended) once daily and intravenous (IV) darbepoetin alfa placebo injection (0.5 milliliter prefilled syringes containing no darbepoetin alfa) once weekly for 52 weeks.	Participant received IV darbepoetin alfa injection (10,15,20,30,40 and 60 micrograms [ug] as recommended) once weekly and oral daprodustat placebo tablets (small and large tablets containing no daprodustat) once daily for 52 weeks.
Measure Participants	133	134
Baseline (Day 1), n=133, 134	79 58.1%	87 64.4%
Week 4, n=133,134	65 47.8%	80 59.3%
Week 8, n=127,132	65 47.8%	84 62.2%
Week 12, n=125,129	66 48.5%	86 63.7%
Week 16, n=124,129	64 47.1%	80 59.3%
Week 20, n=123,129	82 60.3%	81 60%
Week 24, n=123,129	85 62.5%	81 60%
Week 28, n=123,129	85 62.5%	82 60.7%
Week 32, n=122, 127	79 58.1%	80 59.3%
Week 36, n=121,127	78 57.4%	78 57.8%
Week 40, n=120,125	77 56.6%	80 59.3%
Week 44, n=117,125	74 54.4%	82 60.7%
Week 48, n=117,124	77 56.6%	79 58.5%
Week 52, n=115,120	77 56.6%	80 59.3%

12. Secondary Outcome

Title	Percentage of Time in Hgb Target Range (10.0 to 12.0 g/dL) During the Primary Efficacy Evaluation Period (Weeks 40 to 52)
Description	Percentage of time in Hgb target range (10.0 to 12.0 g/dL) during the primary efficacy evaluation period (Weeks 40 to 52) for hemodialysis-dependent participants with anemia associated with chronic kidney disease who were currently ESA users has been presented.
Time Frame	Weeks 40 to 52

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Daprodustat	Darbepoetin Alfa
Arm/Group Description	Participants received oral daprodustat tablets (1, 2, 4, 6, 8, 12, 18 and 24 milligrams [mg] as recommended) once daily and intravenous (IV) darbepoetin alfa placebo injection (0.5 milliliter prefilled syringes containing no darbepoetin alfa) once weekly for 52 weeks.	Participant received IV darbepoetin alfa injection (10,15,20,30,40 and 60 micrograms [ug] as recommended) once weekly and oral daprodustat placebo tablets (small and large tablets containing no daprodustat) once daily for 52 weeks.
Measure Participants	118	125
Mean (Standard Deviation) [Percentage of time]	76.81 (30.387)	80.23 (28.038)

13. Secondary Outcome

Title	Number of Participants Who Had an Hgb Level of Less Than 7.5 g/dL
Description	If an initial Hgb value was less than 7.5 g/dL, measurement was repeated at the same study visit (using the same sample) to calculate the average. If the average met the Hgb stopping criteria, study treatment was permanently discontinued. Number of participants who had an Hgb level of less than 7.5 g/dL 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 oral daprodustat tablets (1, 2, 4, 6, 8, 12, 18 and 24 milligrams [mg] as recommended) once daily and intravenous (IV) darbepoetin alfa placebo injection (0.5 milliliter prefilled syringes containing no darbepoetin alfa) once weekly for 52 weeks.	Participant received IV darbepoetin alfa injection (10,15,20,30,40 and 60 micrograms [ug] as recommended) once weekly and oral daprodustat placebo tablets (small and large tablets containing no daprodustat) once daily for 52 weeks.
Measure Participants	133	134
Number [Percentage of participants]	0 0%	0 0%

14. Secondary Outcome

Title	Number of Participants Who Had an Hgb Increase of More Than 2 g/dL Over Any 4 Weeks
Description	Number of participants who had an Hgb increase of more than 2 g/dL over any 4 weeks for hemodialysis-dependent participants with anemia associated with chronic kidney disease who were currently ESA users have 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 oral daprodustat tablets (1, 2, 4, 6, 8, 12, 18 and 24 milligrams [mg] as recommended) once daily and intravenous (IV) darbepoetin alfa placebo injection (0.5 milliliter prefilled syringes containing no darbepoetin alfa) once weekly for 52 weeks.	Participant received IV darbepoetin alfa injection (10,15,20,30,40 and 60 micrograms [ug] as recommended) once weekly and oral daprodustat placebo tablets (small and large tablets containing no daprodustat) once daily for 52 weeks.
Measure Participants	133	134
Count of Participants [Participants]	1 0.7%	2 1.5%

15. Secondary Outcome

Title	Number of Participants Who Had an Hgb Level of More Than 13.0 g/dL
Description	Number of participants who had an Hgb increase of more than 13 g/dL for hemodialysis-dependent participants with anemia associated with chronic kidney disease who were currently ESA users have 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 oral daprodustat tablets (1, 2, 4, 6, 8, 12, 18 and 24 milligrams [mg] as recommended) once daily and intravenous (IV) darbepoetin alfa placebo injection (0.5 milliliter prefilled syringes containing no darbepoetin alfa) once weekly for 52 weeks.	Participant received IV darbepoetin alfa injection (10,15,20,30,40 and 60 micrograms [ug] as recommended) once weekly and oral daprodustat placebo tablets (small and large tablets containing no daprodustat) once daily for 52 weeks.
Measure Participants	133	134
Number [Percentage of participants]	7 5.1%	8 5.9%

16. Secondary Outcome

Title	Number of Episodes With Hgb Level of More Than 13.0 g/dL
Description	Number of episodes with Hgb level of more than 13.0 g/dL for hemodialysis-dependent participants with anemia associated with chronic kidney disease who were currently ESA users have 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 oral daprodustat tablets (1, 2, 4, 6, 8, 12, 18 and 24 milligrams [mg] as recommended) once daily and intravenous (IV) darbepoetin alfa placebo injection (0.5 milliliter prefilled syringes containing no darbepoetin alfa) once weekly for 52 weeks.	Participant received IV darbepoetin alfa injection (10,15,20,30,40 and 60 micrograms [ug] as recommended) once weekly and oral daprodustat placebo tablets (small and large tablets containing no daprodustat) once daily for 52 weeks.
Measure Participants	133	134
Number [Episodes]	9	12

17. Secondary Outcome

Title	Area Under Plasma Concentration Curve From Time Zero to 4 Hours (AUC [0 - 4]) of Plasma Daprodustat
Description	Blood samples for Pharmacokinetic (PK) analysis of daprodustat were collected as the time points provided. PK parameters were calculated by standard non-compartmental analysis according to current working practices and using the currently supported version of WinNonlin (version 6.3 or higher). NA indicates geometric co-efficient of variation could not be calculated as a single participant was analyzed. Data has been provided as a consolidated values for at all time-points (0,1,2,3,and 4 hours post-dose) as provided for a single value at Weeks 12 and 24 respectively. PK population comprised of all daprodustat-treated participants from whom PK samples were collected and analyzed. Data was not calculated for darbepoetin alfa group as the primary interest of analysis was Daprodustat and not comparator drug (darbepoetin alfa). Data is combined from Week 12 and Week 24 data.
Time Frame	0, 1, 2, 3, and 4 hours post-dose at Week 12 and Week 24

Outcome Measure Data

Analysis Population Description

PK Population

Arm/Group Title	Daprodustat
Arm/Group Description	Participants received oral daprodustat tablets (1, 2, 4, 6, 8, 12, 18 and 24 milligrams [mg] as recommended) once daily and intravenous (IV) darbepoetin alfa placebo injection (0.5 milliliter prefilled syringes containing no darbepoetin alfa) once weekly for 52 weeks.
Measure Participants	125
1 mg, n=8	27.57 (147.6)
2 mg, n=24	44.52 (139.2)
4 mg, n=91	72.68 (242.2)
6 mg, n=61	140.58 (238.9)
8 mg, n=38	170.41 (136.1)
12 mg, n=17	150.53 (176.4)
18 mg, n=5	488.93 (89.2)

18. Secondary Outcome

Title	Maximum Concentration (Cmax) of Plasma Daprodustat
Description	Blood samples for PK analysis of daprodustat were collected as the time points provided. PK parameters were calculated by standard non-compartmental analysis according to current working practices and using the currently supported version of WinNonlin (version 6.3 or higher). Data has been provided as a consolidated values for at all time-points (0,1,2,3,and 4 hours post-dose) as provided for a single value at Weeks 12 and 24 respectively. Data was not calculated for darbepoetin alfa group as the primary interest of analysis was Daprodustat and not comparator drug (darbepoetin alfa). Data is combined from Week 12 and Week 24 data.
Time Frame	0, 1, 2, 3, and 4 hours post-dose at Week 12 and Week 24

Outcome Measure Data

Analysis Population Description

PK Population

Arm/Group Title	Daprodustat
Arm/Group Description	Participants received oral daprodustat tablets (1, 2, 4, 6, 8, 12, 18 and 24 milligrams [mg] as recommended) once daily and intravenous (IV) darbepoetin alfa placebo injection (0.5 milliliter prefilled syringes containing no darbepoetin alfa) once weekly for 52 weeks.
Measure Participants	125
1 mg, n=8	16.11 (105.7)
2 mg, n=24	25.16 (122.7)
4 mg, n=91	42.45 (237.9)
6 mg, n=61	83.60 (269.7)
8 mg, n=38	105.71 (110.9)
12 mg, n=17	108.58 (117.8)
18 mg, n=5	306.61 (61.0)

Adverse Events

Time Frame	Adverse events and serious adverse events were collected from the start of study treatment until the follow-up contact (Day 1 up to Follow-up Visit [Week 54])
Adverse Event Reporting Description	Safety population that comprised of all participants who received at least one dose of study treatment were used for the assessment of serious adverse events and non-serious adverse events.
Arm/Group Title	Daprodustat		Darbepoetin Alfa
Arm/Group Description	Participants received oral daprodustat tablets (1, 2, 4, 6, 8, 12, 18 and 24 milligrams [mg] as recommended) once daily and intravenous (IV) darbepoetin alfa placebo injection (0.5 milliliter prefilled syringes containing no darbepoetin alfa) once weekly for 52 weeks.		Participant received IV darbepoetin alfa injection (10,15,20,30,40 and 60 micrograms [ug] as recommended) once weekly and oral daprodustat placebo tablets (small and large tablets containing no daprodustat) once daily for 52 weeks.
All Cause Mortality
	Daprodustat		Darbepoetin Alfa
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/136 (0%)		1/135 (0.7%)
Serious Adverse Events
	Daprodustat		Darbepoetin Alfa
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	21/136 (15.4%)		37/135 (27.4%)
Cardiac disorders
Cardiac failure congestive	0/136 (0%)	0	2/135 (1.5%)	2
Angina pectoris	1/136 (0.7%)	1	1/135 (0.7%)	1
Coronary artery stenosis	1/136 (0.7%)	1	1/135 (0.7%)	1
Arrhythmia	0/136 (0%)	0	1/135 (0.7%)	1
Arteriosclerosis coronary artery	0/136 (0%)	0	1/135 (0.7%)	1
Cardiac valve disease	0/136 (0%)	0	1/135 (0.7%)	1
Palpitations	0/136 (0%)	0	1/135 (0.7%)	1
Sinus node dysfunction	0/136 (0%)	0	1/135 (0.7%)	1
Mitral valve incompetence	1/136 (0.7%)	1	0/135 (0%)	0
Ventricular extrasystoles	1/136 (0.7%)	1	0/135 (0%)	0
Gastrointestinal disorders
Ileus	0/136 (0%)	0	1/135 (0.7%)	1
Colitis ulcerative	0/136 (0%)	0	1/135 (0.7%)	1
Intestinal perforation	0/136 (0%)	0	1/135 (0.7%)	1
Lower gastrointestinal haemorrhage	0/136 (0%)	0	1/135 (0.7%)	1
Nausea	0/136 (0%)	0	1/135 (0.7%)	1
Duodenal perforation	1/136 (0.7%)	1	0/135 (0%)	0
Large intestine polyp	1/136 (0.7%)	1	0/135 (0%)	0
Upper gastrointestinal haemorrhage	1/136 (0.7%)	1	0/135 (0%)	0
General disorders
Vessel puncture site haemorrhage	0/136 (0%)	0	1/135 (0.7%)	1
Hepatobiliary disorders
Bile duct stone	1/136 (0.7%)	1	0/135 (0%)	0
Infections and infestations
Pneumonia	1/136 (0.7%)	1	2/135 (1.5%)	3
Sepsis	0/136 (0%)	0	2/135 (1.5%)	2
Bacteraemia	0/136 (0%)	0	1/135 (0.7%)	1
Diverticulitis	0/136 (0%)	0	1/135 (0.7%)	1
Enteritis infectious	0/136 (0%)	0	1/135 (0.7%)	1
Gangrene	0/136 (0%)	0	1/135 (0.7%)	1
Herpes zoster	0/136 (0%)	0	1/135 (0.7%)	1
Shunt infection	0/136 (0%)	0	1/135 (0.7%)	1
Urinary tract infection	1/136 (0.7%)	1	0/135 (0%)	0
Injury, poisoning and procedural complications
Shunt stenosis	4/136 (2.9%)	4	6/135 (4.4%)	6
Shunt occlusion	1/136 (0.7%)	1	3/135 (2.2%)	3
Shunt malfunction	0/136 (0%)	0	2/135 (1.5%)	2
Arteriovenous fistula aneurysm	0/136 (0%)	0	1/135 (0.7%)	1
Contusion	0/136 (0%)	0	1/135 (0.7%)	1
Femur fracture	0/136 (0%)	0	1/135 (0.7%)	1
Rib fracture	0/136 (0%)	0	1/135 (0.7%)	1
Spinal compression fracture	0/136 (0%)	0	1/135 (0.7%)	1
Forearm fracture	1/136 (0.7%)	1	0/135 (0%)	0
Humerus fracture	1/136 (0.7%)	1	0/135 (0%)	0
Pelvic fracture	1/136 (0.7%)	1	0/135 (0%)	0
Procedural hypertension	1/136 (0.7%)	1	0/135 (0%)	0
Investigations
Blood pressure increased	0/136 (0%)	0	1/135 (0.7%)	1
Metabolism and nutrition disorders
Hypoglycaemia	0/136 (0%)	0	1/135 (0.7%)	1
Musculoskeletal and connective tissue disorders
Pain in extremity	0/136 (0%)	0	1/135 (0.7%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Colon adenoma	0/136 (0%)	0	1/135 (0.7%)	1
Pancreatic carcinoma	0/136 (0%)	0	1/135 (0.7%)	1
Salivary gland neoplasm	1/136 (0.7%)	1	0/135 (0%)	0
Nervous system disorders
Spondylitic myelopathy	0/136 (0%)	0	1/135 (0.7%)	1
Renal and urinary disorders
Hydronephrosis	0/136 (0%)	0	1/135 (0.7%)	1
Reproductive system and breast disorders
Endometrial hyperplasia	1/136 (0.7%)	1	0/135 (0%)	0
Respiratory, thoracic and mediastinal disorders
Pulmonary oedema	0/136 (0%)	0	1/135 (0.7%)	2
Skin and subcutaneous tissue disorders
Pemphigoid	1/136 (0.7%)	1	0/135 (0%)	0
Vascular disorders
Aortic stenosis	1/136 (0.7%)	1	1/135 (0.7%)	1
Hypertensive emergency	0/136 (0%)	0	1/135 (0.7%)	1
Peripheral arterial occlusive disease	0/136 (0%)	0	1/135 (0.7%)	1
Other (Not Including Serious) Adverse Events
	Daprodustat		Darbepoetin Alfa
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	102/136 (75%)		102/135 (75.6%)
Gastrointestinal disorders
Diarrhoea	20/136 (14.7%)	24	12/135 (8.9%)	15
Vomiting	15/136 (11%)	20	11/135 (8.1%)	13
Nausea	9/136 (6.6%)	10	11/135 (8.1%)	13
Constipation	8/136 (5.9%)	10	6/135 (4.4%)	6
Abdominal discomfort	3/136 (2.2%)	3	7/135 (5.2%)	7
General disorders
Pyrexia	7/136 (5.1%)	8	3/135 (2.2%)	4
Infections and infestations
Nasopharyngitis	57/136 (41.9%)	110	73/135 (54.1%)	135
Pharyngitis	10/136 (7.4%)	11	6/135 (4.4%)	6
Gastroenteritis	7/136 (5.1%)	7	2/135 (1.5%)	2
Injury, poisoning and procedural complications
Shunt stenosis	16/136 (11.8%)	30	15/135 (11.1%)	28
Contusion	17/136 (12.5%)	21	10/135 (7.4%)	12
Skin abrasion	10/136 (7.4%)	14	7/135 (5.2%)	7
Procedural hypotension	11/136 (8.1%)	16	5/135 (3.7%)	6
Musculoskeletal and connective tissue disorders
Back pain	6/136 (4.4%)	6	10/135 (7.4%)	10
Arthralgia	5/136 (3.7%)	5	10/135 (7.4%)	13
Muscle spasms	7/136 (5.1%)	9	4/135 (3%)	5
Pain in extremity	1/136 (0.7%)	1	9/135 (6.7%)	10
Nervous system disorders
Headache	8/136 (5.9%)	8	6/135 (4.4%)	8
Vascular disorders
Hypertension	5/136 (3.7%)	9	8/135 (5.9%)	8

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.