A Study to Evaluate Efficacy and Safety of Daprodustat Co... | NCT02969655

Label	Type	Description	Intervention Names
Daprodustat	Experimental	Subjects will receive oral daprodustat once daily and intravenous (IV) darbepoetin alfa placebo once weekly for 52 weeks	Drug: Daprodustat small Drug: Daprodustat large Drug: Darbepoetin alfa placebo
Darbepoetin alfa	Active Comparator	Subjects will receive IV darbepoetin alfa once weekly and oral daprodustat placebo once daily for 52 weeks	Drug: Daprodustat small placebo Drug: Daprodustat large placebo Drug: Darbepoetin alfa

Name	Type	Description	Arm Group Labels	Other Names
Daprodustat small	Drug	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	Daprodustat

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

Measure	Description	Time Frame
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)	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.	Weeks 40 to 52

Eligibility Module

Eligibility Criteria

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.

Name	Affiliation	Role
GSK Clinical Trials	GlaxoSmithKline	Study Director

Facility	Status	City	State	ZIP	Country	Contacts
GSK Investigational Site		Aichi		441-8023	Japan
GSK Investigational Site

PubMed Identifier	Type	Citation	Retractions
32723804	Background	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.
36005278

ID	Title	Description
FG000	Daprodustat	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.
FG001

Type	Includes Protocol	Includes SAP	Includes ICF	Document Label	Document Date	Document Uploaded Date	Document File Name
SAP	No	Yes	No	Statistical Analysis Plan	Aug 6, 2018	May 20, 2019

Type

Title

Description

Population Description

Reporting Status

Anticipated Posting Date

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Time Frame

Units Analyzed

Denominator Units Selected

Arm/Group Information

Denominators

Classes

Analyses

Primary

Mean Hemoglobin (Hgb) During the Primary Efficacy Evaluation Period (Weeks 40 to 52)

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

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

Posted

Least Squares Mean

Standard Error

Grams per deciliter (g/dL)

Weeks 40 to 52

ID	Title	Description
OG000	Daprodustat	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.
OG001	Darbepoetin Alfa	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.

Units	Counts
Participants	OG000133 OG001134

Title

Denominators

Categories

Title	Measurements
	OG00010.89± 0.062 OG00110.83± 0.060

Group IDs	Group Description	Statistical Method	Statistical Comment	P-Value	P-Value Comment	Parameter Type	Parameter Value	Dispersion Type	Dispersion Value	Confidence Interval Sides	Confidence Interval %	CI Lower Limit	CI Upper Limit	CI Lower Limit Comment	CI Upper Limit Comment	Estimate Comment	Tested Non-Inferiority	Non-Inferiority Type	Non-Inferiority Comment	Other Analysis Description
OG000 OG001		Mixed model repeated measures (MMRM)		<.0001	The p value on this table is one-sided and calculated for the non-inferiority assessment.	Mean Difference (Final Values)	0.06			2-Sided	95	-0.11	0.23			Analysis was performed by a MMRM with covariates of treatment, Baseline Hgb, visit, treatment-by-visit interaction, Baseline-by-visit interaction.		Non-Inferiority	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.

Secondary

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)

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.

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

Posted

Number

Percentage of participants

Weeks 40 to 52

ID	Title	Description
OG000	Daprodustat	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.
OG001	Darbepoetin Alfa	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.

Units	Counts

Secondary

Change From Baseline in Hgb (Hgb Increase Rate) at Week 4

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

ITT Population

Posted

Mean

Standard Deviation

g/dL

Baseline and Week 4

ID	Title	Description
OG000	Daprodustat	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.
OG001	Darbepoetin Alfa	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.

Units	Counts
Participants	OG000

Secondary

Percentage of Participants by Hgb Change From Baseline Category at 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.

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

Posted

Number

Percentage of participants

Week 4

ID	Title	Description
OG000	Daprodustat	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.

Units	Counts
Participants	OG000

Secondary

Distribution of Daprodustat Dose Level by Visit

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.

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

Posted

Median

Inter-Quartile Range

milligrams per day (mg/day)

Day 1, Weeks 4,8,12,16,20,24,28,32,36,40,44, and 48)

ID	Title	Description
OG000	Daprodustat	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.

Units	Counts
Participants	OG000

Secondary

Distribution of Darbepoetin Alfa Dose Level by Visit

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.

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

Posted

Median

Inter-Quartile Range

micrograms per week (ug/week)

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

ID	Title	Description
OG000	Darbepoetin Alfa	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.

Units	Counts
Participants	OG000

Secondary

Duration of Treatment Interruption Due to Hgb >13 g/dL

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.

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.

Posted

Median

Inter-Quartile Range

Days

Up to Week 52

ID	Title	Description
OG000	Daprodustat	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.

Units	Counts
Participants	OG000

Secondary

Number of Dose Adjustments for Daprodustat

Number of dose adjustments has been presented only for daprodustat.

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.

Posted

Median

Full Range

Dose adjustments

Up to Week 52

ID	Title	Description
OG000	Daprodustat	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.

Units	Counts
Participants	OG000

Secondary

Hgb Values at Each Assessment Visit

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.

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

Posted

Mean

Standard Deviation

g/dL

Baseline (Day 1), Weeks 4,8,12,16,20,24,28,32,36,40,44,48 and Week 52

ID	Title	Description
OG000	Daprodustat	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.
OG001	Darbepoetin Alfa	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.

Units	Counts
Participants

Secondary

Change From Baseline in Hgb Values at Each Assessment Visit

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.

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

Posted

Mean

Standard Deviation

g/dL

Baseline (Day 1) and Weeks 4,8,12,16,20,24,28,32,36,40,44,48 and Week 52

ID	Title	Description
OG000	Daprodustat	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.
OG001	Darbepoetin Alfa	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.

Secondary

Percentage of Participants Who Had Hgb Level Within the Target Range (10.0-12.0 g/dL) at Each Assessment Visit

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

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

Posted

Number

Percentage of participants

Baseline (Day 1) and Weeks 4,8,12,16,20,24,28,32,36,40,44,48 and Week 52

ID	Title	Description
OG000	Daprodustat	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.
OG001	Darbepoetin Alfa	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.

Units	Counts
Participants

Secondary

Percentage of Time in Hgb Target Range (10.0 to 12.0 g/dL) During the Primary Efficacy Evaluation Period (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.

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

Posted

Mean

Standard Deviation

Percentage of time

Weeks 40 to 52

ID	Title	Description
OG000	Daprodustat	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.
OG001	Darbepoetin Alfa	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.

Units	Counts

Secondary

Number of Participants Who Had an Hgb Level of Less Than 7.5 g/dL

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.

ITT Population

Posted

Number

Percentage of participants

Up to Week 52

ID	Title	Description
OG000	Daprodustat	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.
OG001	Darbepoetin Alfa	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.

Units	Counts
Participants

Secondary

Number of Participants Who Had an Hgb Increase of More Than 2 g/dL Over Any 4 Weeks

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.

ITT Population

Posted

Count of Participants

Participants

Up to Week 52

ID	Title	Description
OG000	Daprodustat	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.
OG001	Darbepoetin Alfa	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.

Units	Counts
Participants

Secondary

Number of Participants Who Had an Hgb Level of More Than 13.0 g/dL

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.

ITT Population

Posted

Number

Percentage of participants

Up to Week 52

ID	Title	Description
OG000	Daprodustat	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.
OG001	Darbepoetin Alfa	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.

Units	Counts
Participants

Secondary

Number of Episodes With Hgb Level of More Than 13.0 g/dL

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.

ITT Population

Posted

Number

Episodes

Up to Week 52

ID	Title	Description
OG000	Daprodustat	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.
OG001	Darbepoetin Alfa	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.

Units	Counts
Participants	OG000

Secondary

Area Under Plasma Concentration Curve From Time Zero to 4 Hours (AUC [0 - 4]) of Plasma Daprodustat

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.

PK Population

Posted

Geometric Mean

Geometric Coefficient of Variation

Hours*nanograms per milliliter

0, 1, 2, 3, and 4 hours post-dose at Week 12 and Week 24

ID	Title	Description
OG000	Daprodustat	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.

Units

Secondary

Maximum Concentration (Cmax) of Plasma Daprodustat

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.

PK Population

Posted

Geometric Mean

Geometric Coefficient of Variation

Nanograms per milliliter

0, 1, 2, 3, and 4 hours post-dose at Week 12 and Week 24

ID	Title	Description
OG000	Daprodustat	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.

Units	Counts
Participants

Serious Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Shunt stenosis	Injury, poisoning and procedural complications	MedDRA 21.0	Systematic Assessment	EG0004 events4 affected136 at risk EG0016 events6 affected135 at risk
Shunt occlusion	Injury, poisoning and procedural complications	MedDRA 21.0	Systematic Assessment	EG0001 events1 affected136 at risk EG0013 events3 affected135 at risk
Shunt malfunction	Injury, poisoning and procedural complications	MedDRA 21.0	Systematic Assessment	EG0000 events0 affected136 at risk EG0012 events2 affected135 at risk
Arteriovenous fistula aneurysm	Injury, poisoning and procedural complications	MedDRA 21.0	Systematic Assessment	EG0000 events0 affected136 at risk EG0011 events1 affected135 at risk
Contusion	Injury, poisoning and procedural complications	MedDRA 21.0	Systematic Assessment	EG0000 events0 affected136 at risk EG0011 events1 affected135 at risk
Femur fracture	Injury, poisoning and procedural complications	MedDRA 21.0	Systematic Assessment	EG0000 events0 affected136 at risk EG0011 events1 affected135 at risk
Rib fracture	Injury, poisoning and procedural complications	MedDRA 21.0	Systematic Assessment	EG0000 events0 affected136 at risk EG0011 events1 affected135 at risk
Spinal compression fracture	Injury, poisoning and procedural complications	MedDRA 21.0	Systematic Assessment	EG0000 events0 affected136 at risk EG0011 events1 affected135 at risk
Forearm fracture	Injury, poisoning and procedural complications	MedDRA 21.0	Systematic Assessment	EG0001 events1 affected136 at risk EG0010 events0 affected135 at risk
Humerus fracture	Injury, poisoning and procedural complications	MedDRA 21.0	Systematic Assessment	EG0001 events1 affected136 at risk EG0010 events0 affected135 at risk
Pelvic fracture	Injury, poisoning and procedural complications	MedDRA 21.0	Systematic Assessment	EG0001 events1 affected136 at risk EG0010 events0 affected135 at risk
Procedural hypertension	Injury, poisoning and procedural complications	MedDRA 21.0	Systematic Assessment	EG0001 events1 affected136 at risk EG0010 events0 affected135 at risk
Pneumonia	Infections and infestations	MedDRA 21.0	Systematic Assessment	EG0001 events1 affected136 at risk EG0013 events2 affected135 at risk
Sepsis	Infections and infestations	MedDRA 21.0	Systematic Assessment	EG0000 events0 affected136 at risk EG0012 events2 affected135 at risk
Bacteraemia	Infections and infestations	MedDRA 21.0	Systematic Assessment	EG0000 events0 affected136 at risk EG0011 events1 affected135 at risk
Diverticulitis	Infections and infestations	MedDRA 21.0	Systematic Assessment	EG0000 events0 affected136 at risk EG0011 events1 affected135 at risk
Enteritis infectious	Infections and infestations	MedDRA 21.0	Systematic Assessment	EG0000 events0 affected136 at risk EG0011 events1 affected135 at risk
Gangrene	Infections and infestations	MedDRA 21.0	Systematic Assessment	EG0000 events0 affected136 at risk EG0011 events1 affected135 at risk
Herpes zoster	Infections and infestations	MedDRA 21.0	Systematic Assessment	EG0000 events0 affected136 at risk EG0011 events1 affected135 at risk
Shunt infection	Infections and infestations	MedDRA 21.0	Systematic Assessment	EG0000 events0 affected136 at risk EG0011 events1 affected135 at risk
Urinary tract infection	Infections and infestations	MedDRA 21.0	Systematic Assessment	EG0001 events1 affected136 at risk EG0010 events0 affected135 at risk
Cardiac failure congestive	Cardiac disorders	MedDRA 21.0	Systematic Assessment	EG0000 events0 affected136 at risk EG0012 events2 affected135 at risk
Angina pectoris	Cardiac disorders	MedDRA 21.0	Systematic Assessment	EG0001 events1 affected136 at risk EG0011 events1 affected135 at risk
Coronary artery stenosis	Cardiac disorders	MedDRA 21.0	Systematic Assessment	EG0001 events1 affected136 at risk EG0011 events1 affected135 at risk
Arrhythmia	Cardiac disorders	MedDRA 21.0	Systematic Assessment	EG0000 events0 affected136 at risk EG0011 events1 affected135 at risk
Arteriosclerosis coronary artery	Cardiac disorders	MedDRA 21.0	Systematic Assessment	EG0000 events0 affected136 at risk EG0011 events1 affected135 at risk
Cardiac valve disease	Cardiac disorders	MedDRA 21.0	Systematic Assessment	EG0000 events0 affected136 at risk EG0011 events1 affected135 at risk
Palpitations	Cardiac disorders	MedDRA 21.0	Systematic Assessment	EG0000 events0 affected136 at risk EG0011 events1 affected135 at risk
Sinus node dysfunction	Cardiac disorders	MedDRA 21.0	Systematic Assessment	EG0000 events0 affected136 at risk EG0011 events1 affected135 at risk
Mitral valve incompetence	Cardiac disorders	MedDRA 21.0	Systematic Assessment	EG0001 events1 affected136 at risk EG0010 events0 affected135 at risk
Ventricular extrasystoles	Cardiac disorders	MedDRA 21.0	Systematic Assessment	EG0001 events1 affected136 at risk EG0010 events0 affected135 at risk
Ileus	Gastrointestinal disorders	MedDRA 21.0	Systematic Assessment	EG0000 events0 affected136 at risk EG0011 events1 affected135 at risk
Colitis ulcerative	Gastrointestinal disorders	MedDRA 21.0	Systematic Assessment	EG0000 events0 affected136 at risk EG0011 events1 affected135 at risk
Intestinal perforation	Gastrointestinal disorders	MedDRA 21.0	Systematic Assessment	EG0000 events0 affected136 at risk EG0011 events1 affected135 at risk
Lower gastrointestinal haemorrhage	Gastrointestinal disorders	MedDRA 21.0	Systematic Assessment	EG0000 events0 affected136 at risk EG0011 events1 affected135 at risk
Nausea	Gastrointestinal disorders	MedDRA 21.0	Systematic Assessment	EG0000 events0 affected136 at risk EG0011 events1 affected135 at risk
Duodenal perforation	Gastrointestinal disorders	MedDRA 21.0	Systematic Assessment	EG0001 events1 affected136 at risk EG0010 events0 affected135 at risk
Large intestine polyp	Gastrointestinal disorders	MedDRA 21.0	Systematic Assessment	EG0001 events1 affected136 at risk EG0010 events0 affected135 at risk
Upper gastrointestinal haemorrhage	Gastrointestinal disorders	MedDRA 21.0	Systematic Assessment	EG0001 events1 affected136 at risk EG0010 events0 affected135 at risk
Aortic stenosis	Vascular disorders	MedDRA 21.0	Systematic Assessment	EG0001 events1 affected136 at risk EG0011 events1 affected135 at risk
Hypertensive emergency	Vascular disorders	MedDRA 21.0	Systematic Assessment	EG0000 events0 affected136 at risk EG0011 events1 affected135 at risk
Peripheral arterial occlusive disease	Vascular disorders	MedDRA 21.0	Systematic Assessment	EG0000 events0 affected136 at risk EG0011 events1 affected135 at risk
Colon adenoma	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA 21.0	Systematic Assessment	EG0000 events0 affected136 at risk EG0011 events1 affected135 at risk
Pancreatic carcinoma	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA 21.0	Systematic Assessment	EG0000 events0 affected136 at risk EG0011 events1 affected135 at risk
Salivary gland neoplasm	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA 21.0	Systematic Assessment	EG0001 events1 affected136 at risk EG0010 events0 affected135 at risk
Vessel puncture site haemorrhage	General disorders	MedDRA 21.0	Systematic Assessment	EG0000 events0 affected136 at risk EG0011 events1 affected135 at risk
Bile duct stone	Hepatobiliary disorders	MedDRA 21.0	Systematic Assessment	EG0001 events1 affected136 at risk EG0010 events0 affected135 at risk
Blood pressure increased	Investigations	MedDRA 21.0	Systematic Assessment	EG0000 events0 affected136 at risk EG0011 events1 affected135 at risk
Hypoglycaemia	Metabolism and nutrition disorders	MedDRA 21.0	Systematic Assessment	EG0000 events0 affected136 at risk EG0011 events1 affected135 at risk
Pain in extremity	Musculoskeletal and connective tissue disorders	MedDRA 21.0	Systematic Assessment	EG0000 events0 affected136 at risk EG0011 events1 affected135 at risk
Spondylitic myelopathy	Nervous system disorders	MedDRA 21.0	Systematic Assessment	EG0000 events0 affected136 at risk EG0011 events1 affected135 at risk
Hydronephrosis	Renal and urinary disorders	MedDRA 21.0	Systematic Assessment	EG0000 events0 affected136 at risk EG0011 events1 affected135 at risk
Endometrial hyperplasia	Reproductive system and breast disorders	MedDRA 21.0	Systematic Assessment	EG0001 events1 affected136 at risk EG0010 events0 affected135 at risk
Pulmonary oedema	Respiratory, thoracic and mediastinal disorders	MedDRA 21.0	Systematic Assessment	EG0000 events0 affected136 at risk EG0012 events1 affected135 at risk
Pemphigoid	Skin and subcutaneous tissue disorders	MedDRA 21.0	Systematic Assessment	EG0001 events1 affected136 at risk EG0010 events0 affected135 at risk

Other Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Nasopharyngitis	Infections and infestations	MedDRA 21.0	Systematic Assessment	EG000110 events57 affected136 at risk EG001135 events73 affected135 at risk
Pharyngitis	Infections and infestations	MedDRA 21.0	Systematic Assessment	EG00011 events10 affected136 at risk EG0016 events6 affected135 at risk
Gastroenteritis	Infections and infestations	MedDRA 21.0	Systematic Assessment	EG0007 events7 affected136 at risk EG0012 events2 affected135 at risk
Shunt stenosis	Injury, poisoning and procedural complications	MedDRA 21.0	Systematic Assessment	EG00030 events16 affected136 at risk EG00128 events15 affected135 at risk
Contusion	Injury, poisoning and procedural complications	MedDRA 21.0	Systematic Assessment	EG00021 events17 affected136 at risk EG00112 events10 affected135 at risk
Skin abrasion	Injury, poisoning and procedural complications	MedDRA 21.0	Systematic Assessment	EG00014 events10 affected136 at risk EG0017 events7 affected135 at risk
Procedural hypotension	Injury, poisoning and procedural complications	MedDRA 21.0	Systematic Assessment	EG00016 events11 affected136 at risk EG0016 events5 affected135 at risk
Diarrhoea	Gastrointestinal disorders	MedDRA 21.0	Systematic Assessment	EG00024 events20 affected136 at risk EG00115 events12 affected135 at risk
Vomiting	Gastrointestinal disorders	MedDRA 21.0	Systematic Assessment	EG00020 events15 affected136 at risk EG00113 events11 affected135 at risk
Nausea	Gastrointestinal disorders	MedDRA 21.0	Systematic Assessment	EG00010 events9 affected136 at risk EG00113 events11 affected135 at risk
Constipation	Gastrointestinal disorders	MedDRA 21.0	Systematic Assessment	EG00010 events8 affected136 at risk EG0016 events6 affected135 at risk
Abdominal discomfort	Gastrointestinal disorders	MedDRA 21.0	Systematic Assessment	EG0003 events3 affected136 at risk EG0017 events7 affected135 at risk
Back pain	Musculoskeletal and connective tissue disorders	MedDRA 21.0	Systematic Assessment	EG0006 events6 affected136 at risk EG00110 events10 affected135 at risk
Arthralgia	Musculoskeletal and connective tissue disorders	MedDRA 21.0	Systematic Assessment	EG0005 events5 affected136 at risk EG00113 events10 affected135 at risk
Muscle spasms	Musculoskeletal and connective tissue disorders	MedDRA 21.0	Systematic Assessment	EG0009 events7 affected136 at risk EG0015 events4 affected135 at risk
Pain in extremity	Musculoskeletal and connective tissue disorders	MedDRA 21.0	Systematic Assessment	EG0001 events1 affected136 at risk EG00110 events9 affected135 at risk
Headache	Nervous system disorders	MedDRA 21.0	Systematic Assessment	EG0008 events8 affected136 at risk EG0018 events6 affected135 at risk
Hypertension	Vascular disorders	MedDRA 21.0	Systematic Assessment	EG0009 events5 affected136 at risk EG0018 events8 affected135 at risk
Pyrexia	General disorders	MedDRA 21.0	Systematic Assessment	EG0008 events7 affected136 at risk EG0014 events3 affected135 at risk

ID	Term
D006402	Hematologic Diseases
D006425	Hemic and Lymphatic Diseases
D051437	Renal Insufficiency
D007674	Kidney Diseases
D014570	Urologic Diseases
D052776	Female Urogenital Diseases
D005261	Female Urogenital Diseases and Pregnancy Complications
D000091642	Urogenital Diseases
D052801	Male Urogenital Diseases
D002908	Chronic Disease
D020969	Disease Attributes
D010335	Pathologic Processes
D013568	Pathological Conditions, Signs and Symptoms

ID	Term
D004921	Erythropoietin
D003115	Colony-Stimulating Factors
D006023	Glycoproteins
D006001	Glycoconjugates
D002241	Carbohydrates
D011506	Proteins
D000602	Amino Acids, Peptides, and Proteins

ID	Title	Description
BG000	Daprodustat	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.
BG001	Darbepoetin Alfa	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.
BG002	Total	Total of all reporting groups

ID	Title	Description	Deaths (Affected)	Deaths (At Risk)	Serious Events (Affected)	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	Daprodustat	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.	0	136	21	136	102	136
EG001	Darbepoetin Alfa	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.	1	135	37	135	102	135