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Clinical Trial Results:
A 52-week open-label (sponsor-blind), randomized, active controlled, parallel-group, multi-center study to evaluate the efficacy and safety of daprodustat compared to recombinant human erythropoietin in subjects with anemia associated with chronic kidney disease who are initiating dialysis

Summary
EudraCT number	2016-000507-86
Trial protocol	ES DE PL GB IT
Global end of trial date	24 Sep 2020

Results information
Results version number	v1(current)
This version publication date	08 Oct 2021
First version publication date	08 Oct 2021
Other versions

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

201410

ISRCTN number

US NCT number

WHO universal trial number (UTN)

Sponsor organisation name

GlaxoSmithKline

Sponsor organisation address

980 Great West Road, Brentford, Middlesex, United Kingdom, TW8 9GS

Public contact

GSK Response Center, GlaxoSmithKline, 1 8664357343, GSKClinicalSupportHD@gsk.com

Scientific contact

GSK Response Center, GlaxoSmithKline, 1 8664357343, GSKClinicalSupportHD@gsk.com

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

12 Mar 2021

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

24 Sep 2020

Was the trial ended prematurely?

Main objective of the trial

To compare daprodustat to recombinant human erythropoietin (rhEPO) for hemoglobin (Hgb) efficacy (non-inferiority)

Protection of trial subjects

Not applicable

Background therapy

Evidence for comparator

Actual start date of recruitment

11 May 2017

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

United States: 54

Country: Number of subjects enrolled

Germany: 5

Country: Number of subjects enrolled

Italy: 3

Country: Number of subjects enrolled

Poland: 22

Country: Number of subjects enrolled

Russian Federation: 72

Country: Number of subjects enrolled

Spain: 7

Country: Number of subjects enrolled

United Kingdom: 14

Country: Number of subjects enrolled

Argentina: 56

Country: Number of subjects enrolled

Australia: 7

Country: Number of subjects enrolled

Canada: 2

Country: Number of subjects enrolled

India: 14

Country: Number of subjects enrolled

Korea, Republic of: 22

Country: Number of subjects enrolled

Malaysia: 14

Country: Number of subjects enrolled

Mexico: 20

Worldwide total number of subjects

312

EEA total number of subjects

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

229

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

This was a multicenter study conducted across 14 countries. Participants were randomized to receive either Daprodustat or Darbepoetin alfa.

Screening details

A total of 312 participants were randomized in the study.

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Daprodustat

Arm description

Participants received daprodustat film-coated tablets with titrated dose levels ranging from 1, 2, 4, 6, 8, 10, 12, 16, and 24 milligrams (mg) orally once daily for up to 52 weeks. Study treatment was dose-titrated to achieve and maintain hemoglobin (Hgb) in the target range (10 to 11 grams per deciliter [g/dL]).

Arm type

Experimental

Investigational medicinal product name

Daprodustat

Investigational medicinal product code

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

Participants received daprodustat film-coated tablets with dose levels ranging from 1, 2, 4, 6, 8, 10, 12, 16 or 24 mg orally once daily for 52 weeks.

Darbepoetin alfa

Arm description

Participants received darbepoetin alfa as prefilled syringes (PFS) for subcutaneous or intravenous (IV) injection with 4-weekly total dose levels ranging from 20, 30, 40, 60, 80, 120, 160, 200, 300 and 400 microgram (mcg) for 52 weeks. Study treatment was dose-titrated to achieve and maintain Hgb in the target range (10 to 11 g/dL).

Arm type

Active comparator

Investigational medicinal product name

Darbepoetin alfa

Investigational medicinal product code

Other name

Pharmaceutical forms

Injection

Routes of administration

Subcutaneous use, Intravenous use

Dosage and administration details

Participants received darbepoetin alfa as PFS for subcutaneous or IV injection with 4-weekly total dose levels ranging from 20, 30, 40, 60, 80, 120, 160, 200, 300 and 400 mcg for 52 weeks.

Number of subjects in period 1	Daprodustat	Darbepoetin alfa
Started	157	155
Completed	155	151
Not completed	2	4
Consent withdrawn by subject	2	3
Lost to follow-up	-	1

Baseline characteristics

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Reporting group title

Daprodustat

Reporting group description

Reporting group title

Darbepoetin alfa

Reporting group description

Reporting group values	Daprodustat	Darbepoetin alfa	Total
Number of subjects	157	155	312
Age categorical
Units: Subjects
In utero	0	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0	0
Newborns (0-27 days)	0	0	0
Infants and toddlers (28 days-23 months)	0	0	0
Children (2-11 years)	0	0	0
Adolescents (12-17 years)	0	0	0
Adults (18-64 years)	119	110	229
From 65-84 years	38	43	81
85 years and over	0	2	2
Age Continuous
Units: Years
arithmetic mean (standard deviation)	53.7 ( 14.31 )	55.8 ( 15.70 )	-
Sex: Female, Male
Units: Participants
Female	61	57	118
Male	96	98	194
Race/Ethnicity, Customized
Units: Subjects
American Indian (AI) or Alaskan Native (AN)	5	2	7
Asian: Central/South Asian Heritage	7	6	13
Asian: East Asian Heritage	8	16	24
Asian: South East Asian Heritage	11	9	20
Black or African American	16	13	29
White: Arabic/North African Heritage	1	0	1
White: White/Caucasian/European Heritage	109	107	216
Mixed race: AI or AN and White	0	2	2

End points

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Reporting group title

Daprodustat

Reporting group description

Reporting group title

Darbepoetin alfa

Reporting group description

Subject analysis set title

Daprodustat 1 mg

Subject analysis set type

Sub-group analysis

Subject analysis set description

Participants received film-coated tablets of daprodustat 1 mg orally once daily for 52 weeks.

Subject analysis set title

Daprodustat 2 mg

Subject analysis set type

Sub-group analysis

Subject analysis set description

Participants received film-coated tablets of daprodustat 2 mg orally once daily for 52 weeks.

Subject analysis set title

Daprodustat 4 mg

Subject analysis set type

Sub-group analysis

Subject analysis set description

Participants received film-coated tablets of daprodustat 4 mg orally once daily for 52 weeks.

Subject analysis set title

Daprodustat 6 mg

Subject analysis set type

Sub-group analysis

Subject analysis set description

Participants received film-coated tablets of daprodustat 6 mg orally once daily for 52 weeks.

Subject analysis set title

Daprodustat 8 mg

Subject analysis set type

Sub-group analysis

Subject analysis set description

Participants received film-coated tablets of daprodustat 8 mg orally once daily for 52 weeks.

Subject analysis set title

Daprodustat 10 mg

Subject analysis set type

Sub-group analysis

Subject analysis set description

Participants received film-coated tablets of daprodustat 10 mg orally once daily for 52 weeks.

Primary: Mean Change from Baseline in Hemoglobin (Hgb) During Evaluation Period (Week 28 to Week 52)

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End point title

Mean Change from Baseline in Hemoglobin (Hgb) During Evaluation Period (Week 28 to Week 52)

End point description

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

End point type

Primary

End point timeframe

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

End point values	Daprodustat	Darbepoetin alfa
Number of subjects analysed	157 ^[1]	155 ^[2]
Units: Grams per deciliter
least squares mean (standard error)	1.02 ( 0.086 )	1.12 ( 0.085 )

Notes
[1] - ITT Population.
[2] - ITT Population.

Statistical analysis

Statistical analysis description

An ANCOVA model including randomization stratification factors Baseline Hgb and treatment was performed to obtain a point estimate and two-sided 95% CI for the treatment difference (daprodustat-darbepoetin alfa).

Comparison groups

Daprodustat v Darbepoetin alfa

Number of subjects included in analysis

312

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[3]

Method

Parameter type

Least square (LS) mean difference

Point estimate

-0.1

Confidence interval

level

95%

sides

2-sided

lower limit

-0.34

upper limit

0.14

Notes
[3] - Non-inferiority was to be established if the lower limit of the two-sided 95% CI for the treatment difference was greater than the pre-specified non-inferiority margin of -0.75 g/dL.

Secondary: Average Monthly Intravenous Iron Dose (milligrams) from Baseline to Week 52

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End point title

Average Monthly Intravenous Iron Dose (milligrams) from Baseline to Week 52

End point description

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

End point type

Secondary

End point timeframe

Baseline (Day 1) to Week 52

End point values	Daprodustat	Darbepoetin alfa
Number of subjects analysed	156 ^[4]	154 ^[5]
Units: Milligram
least squares mean (standard error)	144.7 ( 10.90 )	125.3 ( 10.97 )

Notes
[4] - ITT Population.
[5] - ITT Population.

Statistical analysis

Statistical analysis description

An ANCOVA model was used to compare the difference in this average monthly IV iron dose between arms, including factors for Baseline dose, treatment and the randomization stratification factors.

Comparison groups

Daprodustat v Darbepoetin alfa

Number of subjects included in analysis

310

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.8949

Method

ANCOVA

Parameter type

LS mean difference

Point estimate

19.4

Confidence interval

level

95%

sides

2-sided

lower limit

-11

upper limit

49.9

Secondary: Change from Baseline in Systolic Blood Pressure (SBP), Diastolic Blood Pressure (DBP), Mean Arterial Blood Pressure (MAP) at Week 52

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End point title

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

End point description

SBP, DBP and MAP were measured in a semi-supine or seated position in the dialysis chair after at least a 5-minutes of rest. MAP is an average BP in an individual's arteries during a single cardiac cycle. Change from Baseline was calculated as post-dose visit value minus Baseline value. Baseline was defined as the latest non-missing pre-dose assessment on or before the randomization date. This analysis was carried out by using mixed model repeated measures (MMRM) model. Only those participants with data available at the indicated time points were analyzed.

End point type

Secondary

End point timeframe

Baseline (Day 1) and Week 52

End point values	Daprodustat	Darbepoetin alfa
Number of subjects analysed	153 ^[6]	149 ^[7]
Units: Millimeter of mercury
least squares mean (standard error)
SBP	-3.57 ( 2.063 )	-6.80 ( 2.931 )
DBP	0.21 ( 1.216 )	-4.01 ( 1.650 )
MAP	-0.95 ( 1.364 )	-5.05 ( 1.894 )

Notes
[6] - ITT Population.
[7] - ITT Population.

Statistical analysis 1

Statistical analysis description

The difference in change from Baseline in SBP at Week 52 was analyzed with a MMRM approach with an unstructured covariance matrix to compare the difference in LS means between arms.

Comparison groups

Daprodustat v Darbepoetin alfa

Number of subjects included in analysis

302

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.8168

Method

Mixed model repeated measures (MMRM)

Parameter type

LS mean difference

Point estimate

3.23

Confidence interval

level

95%

sides

2-sided

lower limit

-3.82

upper limit

10.27

Statistical analysis 2

Statistical analysis description

The difference in change from Baseline in DBP at Week 52 was analyzed with a MMRM approach with an unstructured covariance matrix to compare the difference in LS means between arms.

Comparison groups

Daprodustat v Darbepoetin alfa

Number of subjects included in analysis

302

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.9793

Method

MMRM

Parameter type

LS mean difference

Point estimate

4.21

Confidence interval

level

95%

sides

2-sided

lower limit

0.17

upper limit

8.26

Statistical analysis 3

Statistical analysis description

The difference in change from Baseline in MAP at Week 52 was analyzed with a MMRM approach with an unstructured covariance matrix to compare the difference in LS means between arms.

Comparison groups

Daprodustat v Darbepoetin alfa

Number of subjects included in analysis

302

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.9597

Method

MMRM

Parameter type

LS mean difference

Point estimate

4.1

Confidence interval

level

95%

sides

2-sided

lower limit

-0.51

upper limit

8.7

Secondary: Change from Baseline in SBP, DBP, MAP at End of Treatment

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End point title

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

End point description

SBP, DBP and MAP were measured in a semi-supine or seated position in the dialysis chair after at least a 5-minutes of rest. MAP is an average BP in an individual's arteries during a single cardiac cycle. End of treatment value for the blood pressure parameters were defined as the latest value on or before the last non-zero dose date plus (+) 1 day. Change from Baseline was calculated as post-dose visit value minus Baseline value. Baseline was defined as the latest non-missing pre-dose assessment on or before the randomization date. This analysis was carried out by using ANCOVA model. Only those participants with data available at the indicated time points were analyzed.

End point type

Secondary

End point timeframe

Baseline (Day 1) and end of treatment (last on-treatment value until Week 52)

End point values	Daprodustat	Darbepoetin alfa
Number of subjects analysed	154 ^[8]	153 ^[9]
Units: Millimeter of mercury
least squares mean (standard error)
SBP	-3.23 ( 1.659 )	-3.14 ( 1.664 )
DBP	0.60 ( 1.016 )	-1.39 ( 1.020 )
MAP	-0.68 ( 1.092 )	-1.97 ( 1.096 )

Notes
[8] - ITT Population.
[9] - ITT Population.

Statistical analysis 1

Statistical analysis description

The difference in change from Baseline in SBP at the derived end of treatment was analyzed with an ANCOVA model including terms for treatment, prognostic randomization stratification factors.

Comparison groups

Daprodustat v Darbepoetin alfa

Number of subjects included in analysis

307

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.484

Method

ANCOVA

Parameter type

LS mean difference

Point estimate

-0.09

Confidence interval

level

95%

sides

2-sided

lower limit

-4.72

upper limit

4.53

Statistical analysis 2

Statistical analysis description

The difference in change from Baseline in DBP at the derived end of treatment was analyzed with an ANCOVA model including terms for treatment, prognostic randomization stratification factors.

Comparison groups

Daprodustat v Darbepoetin alfa

Number of subjects included in analysis

307

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.9156

Method

ANCOVA

Parameter type

LS mean difference

Point estimate

1.99

Confidence interval

level

95%

sides

2-sided

lower limit

-0.85

upper limit

4.82

Statistical analysis 3

Statistical analysis description

The difference in change from Baseline in MAP at the derived end of treatment was analyzed with an ANCOVA model including terms for treatment, prognostic randomization stratification factors.

Comparison groups

Daprodustat v Darbepoetin alfa

Number of subjects included in analysis

307

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.7966

Method

ANCOVA

Parameter type

LS mean difference

Point estimate

1.29

Confidence interval

level

95%

sides

2-sided

lower limit

-1.76

upper limit

4.33

Secondary: Blood Pressure (BP) Exacerbation Events Rate per 100 Participant Years

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End point title

Blood Pressure (BP) Exacerbation Events Rate per 100 Participant Years

End point description

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

End point type

Secondary

End point timeframe

Up to Week 52

End point values	Daprodustat	Darbepoetin alfa
Number of subjects analysed	155 ^[10]	154 ^[11]
Units: Events per 100 participant year
number (confidence interval 95%)	352.50 (268.89 to 462.09)	350.00 (267.72 to 457.56)

Notes
[10] - ITT Population.
[11] - ITT Population.

Statistical analysis

Statistical analysis description

Model estimated exacerbation rates, ratio of model estimated exacerbation rates and CIs were estimated using a negative binomial model for the treatment group comparison.

Comparison groups

Daprodustat v Darbepoetin alfa

Number of subjects included in analysis

309

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.5174

Method

Negative binomial model

Parameter type

Ratio of exacerbation rate

Point estimate

1.01

Confidence interval

level

95%

sides

2-sided

lower limit

0.73

upper limit

1.39

Secondary: Number of Participants with at Least one Blood Pressure Exacerbation Event During Study

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End point title

Number of Participants with at Least one Blood Pressure Exacerbation Event During Study

End point description

BP exacerbation was defined (based on post-dialysis BP) as: SBP >=25 mmHg increased from Baseline or SBP >=180 mmHg; DBP >=15 mmHg increased from Baseline or DBP >=110 mmHg. Number of participants with at least one blood pressure exacerbation event is presented. Only those participants with data available at the indicated time points were analyzed.

End point type

Secondary

End point timeframe

Up to Week 52

End point values	Daprodustat	Darbepoetin alfa
Number of subjects analysed	155 ^[12]	154 ^[13]
Units: Participants	91	100

Notes
[12] - ITT Population.
[13] - ITT Population.

No statistical analyses for this end point

Secondary: Change From Baseline in Post-randomization Hgb at Week 52

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End point title

Change From Baseline in Post-randomization Hgb at Week 52

End point description

Blood samples were collected from participants for Hgb measurements. Change from Baseline was calculated as post-dose visit value minus Baseline value. Baseline was defined as the latest non-missing pre-dose assessment on or before the randomization date. Only those participants with data available at the indicated time points were analyzed.

End point type

Secondary

End point timeframe

Baseline (Day 1) and Week 52

End point values	Daprodustat	Darbepoetin alfa
Number of subjects analysed	139 ^[14]	141 ^[15]
Units: Grams per deciliter
least squares mean (standard error)	1.17 ( 0.117 )	1.13 ( 0.115 )

Notes
[14] - ITT Population.
[15] - ITT Population.

Statistical analysis

Statistical analysis description

The difference in change from Baseline in post-randomization Hgb at Week 52 was analyzed with a MMRM approach with an unstructured covariance matrix to compare the difference in LS means between arms.

Comparison groups

Daprodustat v Darbepoetin alfa

Number of subjects included in analysis

280

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[16]

Method

Parameter type

LS mean difference

Point estimate

0.04

Confidence interval

level

95%

sides

2-sided

lower limit

-0.29

upper limit

0.36

Notes
[16] - Non-inferiority was to be established if the lower limit of the two-sided 95% CI for the treatment difference was greater than the pre-specified non-inferiority margin of -0.75 g/dL.

Secondary: Number of Hgb Responders (Hgb in the Analysis Range of 10 to 11.5 grams/deciliter) During Evaluation Period (Week 28 to Week 52)

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End point title

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

End point description

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

End point type

Secondary

End point timeframe

Weeks 28 to 52

End point values	Daprodustat	Darbepoetin alfa
Number of subjects analysed	133 ^[17]	133 ^[18]
Units: Participants	86	87

Notes
[17] - ITT Population.
[18] - ITT Population.

Statistical analysis

Statistical analysis description

A Cochran-Mantel-Haenszel (CMH) test adjusted for treatment and randomization stratification factors were used to compare the number of responders between the treatment groups.

Comparison groups

Daprodustat v Darbepoetin alfa

Number of subjects included in analysis

266

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.5411

Method

Cochran-Mantel-Haenszel

Parameter type

Difference in response rate

Point estimate

-0.8

Confidence interval

level

95%

sides

2-sided

lower limit

-12.2

upper limit

10.7

Secondary: Percentage of Time for which Hgb was within the Analysis Range (10 to 11.5 g/dL) During Evaluation Period (Week 28 to Week 52): Non-inferiority analysis

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End point title

Percentage of Time for which Hgb was within the Analysis Range (10 to 11.5 g/dL) During Evaluation Period (Week 28 to Week 52): Non-inferiority analysis

End point description

Percentage of days for which a participant's Hgb was within the analysis range of 10-11.5 g/dL (both inclusive) during the evaluation period (Week 28 to Week 52), including any unscheduled evaluable Hgb values that were taken during this time period was calculated. Percentage of time for which Hgb was within range for a participant was calculated by dividing 'the total number of days that Hgb was within range during Weeks 28 to 52' by 'the total number of days the participant remained on treatment during Weeks 28 to 52'. Only those participants with data available at the indicated time points were analyzed.

End point type

Secondary

End point timeframe

Weeks 28 to 52

End point values	Daprodustat	Darbepoetin alfa
Number of subjects analysed	128 ^[19]	129 ^[20]
Units: Percentage of days
median (full range (min-max))	57.0 (0.0 to 100.0)	54.7 (0.0 to 100.0)

Notes
[19] - ITT Population.
[20] - ITT Population.

Statistical analysis

Statistical analysis description

Hodges-Lehmann Estimate of Treatment Difference has been reported.

Comparison groups

Daprodustat v Darbepoetin alfa

Number of subjects included in analysis

257

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[21]

Method

Parameter type

Median difference (final values)

Point estimate

2.05

Confidence interval

level

95%

sides

2-sided

lower limit

-4.45

upper limit

11.27

Notes
[21] - Non-inferiority was to be established if the lower limit of the two-sided 95% confidence interval for the treatment difference was greater than non-inferiority margin of -15%.

Secondary: Percentage of Time for which Hgb was within the Analysis Range (10 to 11.5 g/dL) During Evaluation Period (Week 28 to Week 52): Superiority analysis

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End point title

Percentage of Time for which Hgb was within the Analysis Range (10 to 11.5 g/dL) During Evaluation Period (Week 28 to Week 52): Superiority analysis

End point description

End point type

Secondary

End point timeframe

Weeks 28 to 52

End point values	Daprodustat	Darbepoetin alfa
Number of subjects analysed	128 ^[22]	129 ^[23]
Units: Percentage of days
median (full range (min-max))	57.0 (0.0 to 100.0)	54.7 (0.0 to 100.0)

Notes
[22] - ITT Population.
[23] - ITT Population.

Statistical analysis

Statistical analysis description

Mann-Whitney estimate (Probability) of the treatment effect has been presented.

Comparison groups

Daprodustat v Darbepoetin alfa

Number of subjects included in analysis

257

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.1538

Method

van Elteren test

Parameter type

Probability

Point estimate

0.54

Confidence interval

level

95%

sides

2-sided

lower limit

0.46

upper limit

0.61

Secondary: Number of Participants Permanently Stopping Randomized Treatment Due to Meeting Rescue Criteria

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End point title

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

End point description

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

End point type

Secondary

End point timeframe

Up to Week 52

End point values	Daprodustat	Darbepoetin alfa
Number of subjects analysed	157 ^[24]	155 ^[25]
Units: Participants	5	5

Notes
[24] - ITT Population
[25] - ITT Population

Statistical analysis

Statistical analysis description

Hazard ratio was estimated using a Cox proportional hazard regression model adjusted for treatment group, dialysis type and dialysis start manner.

Comparison groups

Daprodustat v Darbepoetin alfa

Number of subjects included in analysis

312

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.5348

Method

Wald test

Parameter type

Hazard ratio (HR)

Point estimate

1.06

Confidence interval

level

95%

sides

2-sided

lower limit

0.31

upper limit

3.66

Secondary: Change from Baseline in Physical Component Score (PCS) using Short Form (SF)-36 Health-related Quality of Life (HRQoL) Questionnaire at Weeks 8, 12, 28, 52

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End point title

Change from Baseline in Physical Component Score (PCS) using Short Form (SF)-36 Health-related Quality of Life (HRQoL) Questionnaire at Weeks 8, 12, 28, 52

End point description

SF-36 acute version2 is 36-item generic quality of life instrument designed to measure participant’s level of performance in following 8 health domains:physical functioning,role-physical(role limitations caused by physical problems),social functioning,bodily pain,mental health,role-emotional(role limitations caused by emotional problems),vitality/general health.Each domain is scored from 0(poorer health) to 100(better health). PCS is average score derived from 4domains(physical functioning,role-physical, bodily pain/general health) representing overall physical health.PCS ranges from 0 to 100;higher scores represent better health.Change from Baseline was calculated as post-dose visit value minus Baseline value.Baseline was defined as latest non-missing pre-dose assessment on or before randomization date. Only those participants with data available at indicated time points were analyzed (represented by n=X in the category titles)

End point type

Secondary

End point timeframe

Baseline (Day 1), Weeks 8, 12, 28 and 52

End point values	Daprodustat	Darbepoetin alfa
Number of subjects analysed	88 ^[26]	88 ^[27]
Units: Scores on a scale
least squares mean (standard error)
Week 8, n=88,86	0.79 ( 0.648 )	1.18 ( 0.658 )
Week 12, n=88,88	1.67 ( 0.627 )	0.54 ( 0.631 )
Week 28, n=80,74	0.94 ( 0.697 )	0.45 ( 0.725 )
Week 52, n=67,65	0.61 ( 0.755 )	1.93 ( 0.774 )

Notes
[26] - ITT Population.
[27] - ITT Population.

Statistical analysis 1

Statistical analysis description

SF-36 HRQoL PCS domain score was analyzed using an MMRM approach with an unstructured covariance matrix to compare the difference in LS means between arms at Week 8.

Comparison groups

Daprodustat v Darbepoetin alfa

Number of subjects included in analysis

176

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.6641

Method

MMRM

Parameter type

LS mean difference

Point estimate

-0.39

Confidence interval

level

95%

sides

2-sided

lower limit

-2.22

upper limit

1.44

Statistical analysis 2

Statistical analysis description

SF-36 HRQoL PCS domain score was analyzed using an MMRM approach with an unstructured covariance matrix to compare the difference in LS means between arms at Week 12.

Comparison groups

Daprodustat v Darbepoetin alfa

Number of subjects included in analysis

176

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.103

Method

MMRM

Parameter type

LS mean difference

Point estimate

1.13

Confidence interval

level

95%

sides

2-sided

lower limit

-0.63

upper limit

2.89

Statistical analysis 3

Statistical analysis description

SF-36 HRQoL PCS domain score was analyzed using an MMRM approach with an unstructured covariance matrix to compare the difference in LS means between arms at Week 28.

Comparison groups

Daprodustat v Darbepoetin alfa

Number of subjects included in analysis

176

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.3157

Method

MMRM

Parameter type

LS mean difference

Point estimate

0.49

Confidence interval

level

95%

sides

2-sided

lower limit

-1.51

upper limit

2.48

Statistical analysis 4

Statistical analysis description

SF-36 HRQoL PCS domain score was analyzed using an MMRM approach with an unstructured covariance matrix to compare the difference in LS means between arms at Week 52.

Comparison groups

Daprodustat v Darbepoetin alfa

Number of subjects included in analysis

176

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.8855

Method

MMRM

Parameter type

LS mean difference

Point estimate

-1.31

Confidence interval

level

95%

sides

2-sided

lower limit

-3.46

upper limit

0.84

Secondary: Change from Baseline in Mental Component Score (MCS) using SF-36 HRQoL Questionnaire at Weeks 8, 12, 28, 52

Top of page

End point title

Change from Baseline in Mental Component Score (MCS) using SF-36 HRQoL Questionnaire at Weeks 8, 12, 28, 52

End point description

End point type

Secondary

End point timeframe

Baseline (Day 1), Weeks 8, 12, 28 and 52

End point values	Daprodustat	Darbepoetin alfa
Number of subjects analysed	88 ^[28]	88 ^[29]
Units: Scores on a scale
least squares mean (standard error)
Week 8, n=88,86	0.10 ( 0.822 )	0.76 ( 0.839 )
Week 12, n=88,88	0.08 ( 0.813 )	1.60 ( 0.824 )
Week 28, n=80,74	-0.02 ( 0.905 )	0.30 ( 0.942 )
Week 52, n=67,65	-0.95 ( 1.029 )	-0.72 ( 1.051 )

Notes
[28] - ITT Population.
[29] - ITT Population.

Statistical analysis 1

Statistical analysis description

SF-36 HRQoL MCS domain score was analyzed using an MMRM approach with an unstructured covariance matrix to compare the difference in LS means between arms at Week 8.

Comparison groups

Daprodustat v Darbepoetin alfa

Number of subjects included in analysis

176

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.7146

Method

MMRM

Parameter type

LS mean difference

Point estimate

-0.67

Confidence interval

level

95%

sides

2-sided

lower limit

-2.99

upper limit

1.66

Statistical analysis 2

Statistical analysis description

SF-36 HRQoL MCS domain score was analyzed using an MMRM approach with an unstructured covariance matrix to compare the difference in LS means between arms at Week 12.

Comparison groups

Daprodustat v Darbepoetin alfa

Number of subjects included in analysis

176

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.905

Method

MMRM

Parameter type

LS mean difference

Point estimate

-1.53

Confidence interval

level

95%

sides

2-sided

lower limit

-3.82

upper limit

0.76

Statistical analysis 3

Statistical analysis description

SF-36 HRQoL MCS domain score was analyzed using an MMRM approach with an unstructured covariance matrix to compare the difference in LS means between arms at Week 28.

Comparison groups

Daprodustat v Darbepoetin alfa

Number of subjects included in analysis

176

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.595

Method

MMRM

Parameter type

LS mean difference

Point estimate

-0.32

Confidence interval

level

95%

sides

2-sided

lower limit

-2.91

upper limit

2.28

Statistical analysis 4

Statistical analysis description

SF-36 HRQoL MCS domain score was analyzed using an MMRM approach with an unstructured covariance matrix to compare the difference in LS means between arms at Week 52.

Comparison groups

Daprodustat v Darbepoetin alfa

Number of subjects included in analysis

176

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.5619

Method

MMRM

Parameter type

LS mean difference

Point estimate

-0.23

Confidence interval

level

95%

sides

2-sided

lower limit

-3.17

upper limit

2.7

Secondary: Change from Baseline in SF-36 HRQoL Scores for Bodily Pain, General Health, Mental Health, Role-Emotional, Role-Physical, Social Functioning at Weeks 8, 12, 28, 52

Top of page

End point title

Change from Baseline in SF-36 HRQoL Scores for Bodily Pain, General Health, Mental Health, Role-Emotional, Role-Physical, Social Functioning at Weeks 8, 12, 28, 52

End point description

The SF-36 acute version 2 is a 36-item generic quality of life instrument designed to measure a participant’s level of performance in the following 8 health domains: bodily pain, general health, mental health, role-emotional (role limitations caused by emotional problems), role-physical (role limitations caused by physical problems), social functioning, physical functioning and vitality. Each domain is scored from 0 (poorer health) to 100 (better health). Each domain score ranges from 0 to 100, higher score indicates a better health state and better functioning. Change from Baseline was calculated as post-dose visit value minus Baseline value. Baseline was defined as the latest non-missing pre-dose assessment on or before the randomization date. Only those participants with data available at the indicated time points were analyzed (represented by n=X in the category titles).

End point type

Secondary

End point timeframe

Baseline (Day 1), Weeks 8, 12, 28 and 52

End point values	Daprodustat	Darbepoetin alfa
Number of subjects analysed	88 ^[30]	88 ^[31]
Units: Scores on a scale
least squares mean (standard error)
Bodily pain: Week 8, n=88,86	-0.41 ( 0.833 )	-0.55 ( 0.843 )
Bodily pain: Week 12, n=88,88	-0.13 ( 0.892 )	-0.06 ( 0.895 )
Bodily pain: Week 28, n=80,74	1.08 ( 0.941 )	-1.26 ( 0.976 )
Bodily pain: Week 52, n=67,65	-2.00 ( 1.084 )	0.61 ( 1.109 )
General health: Week 8, n=88,86	0.80 ( 0.662 )	0.75 ( 0.674 )
General health: Week 12, n=88,88	0.87 ( 0.651 )	0.59 ( 0.658 )
General health: Week 28, n=80,74	0.63 ( 0.693 )	0.37 ( 0.720 )
General health: Week 52, n=67,65	0.40 ( 0.823 )	0.58 ( 0.841 )
Mental health: Week 8, n=88,86	-0.90 ( 0.825 )	0.25 ( 0.841 )
Mental health: Week 12, n=88,88	0.01 ( 0.707 )	1.42 ( 0.712 )
Mental health: Week 28, n=80,74	-0.69 ( 0.866 )	-0.21 ( 0.902 )
Mental health: Week 52, n=67,65	-0.53 ( 0.994 )	-0.27 ( 1.013 )
Role-emotional: Week 8, n=88,86	0.83 ( 0.880 )	0.50 ( 0.896 )
Role-emotional: Week 12, n=88,88	0.55 ( 0.934 )	-0.07 ( 0.946 )
Role-emotional: Week 28, n=80,74	0.91 ( 0.929 )	0.39 ( 0.964 )
Role-emotional: Week 52, n=67,65	-1.60 ( 1.193 )	-0.11 ( 1.216 )
Role-physical: Week 8, n=88,86	1.34 ( 0.806 )	2.64 ( 0.818 )
Role-physical: Week 12, n=88,88	2.39 ( 0.712 )	1.69 ( 0.716 )
Role-physical: Week 28, n=80,74	0.62 ( 0.799 )	1.49 ( 0.829 )
Role-physical: Week 52, n=67,65	1.49 ( 0.895 )	2.22 ( 0.913 )
Social functioning: Week 8, n=88,86	0.52 ( 0.929 )	1.55 ( 0.947 )
Social functioning: Week 12, n=88,88	0.98 ( 0.774 )	2.15 ( 0.783 )
Social functioning: Week 28, n=80,74	1.03 ( 0.943 )	0.95 ( 0.980 )
Social functioning: Week 52, n=67,65	0.39 ( 1.085 )	-0.33 ( 1.105 )

Notes
[30] - ITT Population.
[31] - ITT Population.

Statistical analysis 1

Statistical analysis description

SF-36 HRQoL bodily pain domain score was analyzed using an MMRM approach with an unstructured covariance matrix to compare the difference in LS means between arms at Week 8.

Comparison groups

Daprodustat v Darbepoetin alfa

Number of subjects included in analysis

176

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.4523

Method

MMRM

Parameter type

LS mean difference

Point estimate

0.14

Confidence interval

level

95%

sides

2-sided

lower limit

-2.21

upper limit

2.49

Statistical analysis 2

Statistical analysis description

SF-36 HRQoL bodily pain domain score was analyzed using an MMRM approach with an unstructured covariance matrix to compare the difference in LS means between arms at Week 12.

Comparison groups

Daprodustat v Darbepoetin alfa

Number of subjects included in analysis

176

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.5222

Method

MMRM

Parameter type

LS mean difference

Point estimate

-0.07

Confidence interval

level

95%

sides

2-sided

lower limit

-2.57

upper limit

2.43

Statistical analysis 3

Statistical analysis description

SF-36 HRQoL bodily pain domain score was analyzed using an MMRM approach with an unstructured covariance matrix to compare the difference in LS means between arms at Week 28.

Comparison groups

Daprodustat v Darbepoetin alfa

Number of subjects included in analysis

176

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.044

Method

MMRM

Parameter type

LS mean difference

Point estimate

2.33

Confidence interval

level

95%

sides

2-sided

lower limit

-0.35

upper limit

5.02

Statistical analysis 4

Statistical analysis description

SF-36 HRQoL bodily pain domain score was analyzed using an MMRM approach with an unstructured covariance matrix to compare the difference in LS means between arms at Week 52.

Comparison groups

Daprodustat v Darbepoetin alfa

Number of subjects included in analysis

176

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.9523

Method

MMRM

Parameter type

LS mean difference

Point estimate

-2.61

Confidence interval

level

95%

sides

2-sided

lower limit

-5.68

upper limit

0.46

Statistical analysis 5

Statistical analysis description

SF-36 HRQoL general health domain score was analyzed using an MMRM approach with an unstructured covariance matrix to compare the difference in LS means between arms at Week 8.

Comparison groups

Daprodustat v Darbepoetin alfa

Number of subjects included in analysis

176

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.4811

Method

MMRM

Parameter type

LS mean difference

Point estimate

0.05

Confidence interval

level

95%

sides

2-sided

lower limit

-1.82

upper limit

1.91

Statistical analysis 6

Statistical analysis description

SF-36 HRQoL general health domain score was analyzed using an MMRM approach with an unstructured covariance matrix to compare the difference in LS means between arms at Week 12

Comparison groups

Daprodustat v Darbepoetin alfa

Number of subjects included in analysis

176

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.3834

Method

MMRM

Parameter type

LS mean difference

Point estimate

0.28

Confidence interval

level

95%

sides

2-sided

lower limit

-1.56

upper limit

2.11

Statistical analysis 7

Statistical analysis description

SF-36 HRQoL general health domain score was analyzed using an MMRM approach with an unstructured covariance matrix to compare the difference in LS means between arms at Week 28.

Comparison groups

Daprodustat v Darbepoetin alfa

Number of subjects included in analysis

176

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.3983

Method

MMRM

Parameter type

LS mean difference

Point estimate

0.26

Confidence interval

level

95%

sides

2-sided

lower limit

-1.72

upper limit

2.24

Statistical analysis 8

Statistical analysis description

SF-36 HRQoL general health domain score was analyzed using an MMRM approach with an unstructured covariance matrix to compare the difference in LS means between arms at Week 52.

Comparison groups

Daprodustat v Darbepoetin alfa

Number of subjects included in analysis

176

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.5617

Method

MMRM

Parameter type

LS mean difference

Point estimate

-0.18

Confidence interval

level

95%

sides

2-sided

lower limit

-2.51

upper limit

2.15

Statistical analysis 9

Statistical analysis description

SF-36 HRQoL mental health domain score was analyzed using an MMRM approach with an unstructured covariance matrix to compare the difference in LS means between arms at Week 8.

Comparison groups

Daprodustat v Darbepoetin alfa

Number of subjects included in analysis

176

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.8336

Method

MMRM

Parameter type

LS mean difference

Point estimate

-1.15

Confidence interval

level

95%

sides

2-sided

lower limit

-3.48

upper limit

1.18

Statistical analysis 10

Statistical analysis description

SF-36 HRQoL mental health domain score was analyzed using an MMRM approach with an unstructured covariance matrix to compare the difference in LS means between arms at Week 12.

Comparison groups

Daprodustat v Darbepoetin alfa

Number of subjects included in analysis

176

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.9188

Method

MMRM

Parameter type

LS mean difference

Point estimate

-1.41

Confidence interval

level

95%

sides

2-sided

lower limit

-3.4

upper limit

0.57

Statistical analysis 11

Statistical analysis description

SF-36 HRQoL mental health domain score was analyzed using an MMRM approach with an unstructured covariance matrix to compare the difference in LS means between arms at Week 28.

Comparison groups

Daprodustat v Darbepoetin alfa

Number of subjects included in analysis

176

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.6495

Method

MMRM

Parameter type

LS mean difference

Point estimate

-0.48

Confidence interval

level

95%

sides

2-sided

lower limit

-2.96

upper limit

1.99

Statistical analysis 12

Statistical analysis description

SF-36 HRQoL mental health domain score was analyzed using an MMRM approach with an unstructured covariance matrix to compare the difference in LS means between arms at Week 52.

Comparison groups

Daprodustat v Darbepoetin alfa

Number of subjects included in analysis

176

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.5737

Method

MMRM

Parameter type

LS mean difference

Point estimate

-0.27

Confidence interval

level

95%

sides

2-sided

lower limit

-3.09

upper limit

2.56

Statistical analysis 13

Statistical analysis description

SF-36 HRQoL role-emotional domain score was analyzed using an MMRM approach with an unstructured covariance matrix to compare the difference in LS means between arms at Week 8.

Comparison groups

Daprodustat v Darbepoetin alfa

Number of subjects included in analysis

176

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.3963

Method

MMRM

Parameter type

LS mean difference

Point estimate

0.33

Confidence interval

level

95%

sides

2-sided

lower limit

-2.15

upper limit

2.82

Statistical analysis 14

Statistical analysis description

SF-36 HRQoL role-emotional domain score was analyzed using an MMRM approach with an unstructured covariance matrix to compare the difference in LS means between arms at Week 12.

Comparison groups

Daprodustat v Darbepoetin alfa

Number of subjects included in analysis

176

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.322

Method

MMRM

Parameter type

LS mean difference

Point estimate

0.62

Confidence interval

level

95%

sides

2-sided

lower limit

-2.01

upper limit

3.25

Statistical analysis 15

Statistical analysis description

SF-36 HRQoL role-emotional domain score was analyzed using an MMRM approach with an unstructured covariance matrix to compare the difference in LS means between arms at Week 28.

Comparison groups

Daprodustat v Darbepoetin alfa

Number of subjects included in analysis

176

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.3485

Method

MMRM

Parameter type

LS mean difference

Point estimate

0.53

Confidence interval

level

95%

sides

2-sided

lower limit

-2.13

upper limit

3.18

Statistical analysis 16

Statistical analysis description

SF-36 HRQoL role-emotional domain score was analyzed using an MMRM approach with an unstructured covariance matrix to compare the difference in LS means between arms at Week 52.

Comparison groups

Daprodustat v Darbepoetin alfa

Number of subjects included in analysis

176

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.8064

Method

MMRM

Parameter type

LS mean difference

Point estimate

-1.49

Confidence interval

level

95%

sides

2-sided

lower limit

-4.87

upper limit

1.9

Statistical analysis 17

Statistical analysis description

SF-36 HRQoL role-physical domain score was analyzed using an MMRM approach with an unstructured covariance matrix to compare the difference in LS means between arms at Week 8.

Comparison groups

Daprodustat v Darbepoetin alfa

Number of subjects included in analysis

176

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.8687

Method

MMRM

Parameter type

LS mean difference

Point estimate

-1.29

Confidence interval

level

95%

sides

2-sided

lower limit

-3.57

upper limit

0.98

Statistical analysis 18

Statistical analysis description

SF-36 HRQoL role-physical domain score was analyzed using an MMRM approach with an unstructured covariance matrix to compare the difference in LS means between arms at Week 12.

Comparison groups

Daprodustat v Darbepoetin alfa

Number of subjects included in analysis

176

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.2435

Method

MMRM

Parameter type

LS mean difference

Point estimate

0.71

Confidence interval

level

95%

sides

2-sided

lower limit

-1.29

upper limit

2.7

Statistical analysis 19

Statistical analysis description

SF-36 HRQoL role-physical domain score was analyzed using an MMRM approach with an unstructured covariance matrix to compare the difference in LS means between arms at Week 28.

Comparison groups

Daprodustat v Darbepoetin alfa

Number of subjects included in analysis

176

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.7747

Method

MMRM

Parameter type

LS mean difference

Point estimate

-0.87

Confidence interval

level

95%

sides

2-sided

lower limit

-3.15

upper limit

1.41

Statistical analysis 20

Statistical analysis description

SF-36 HRQoL role-physical domain score was analyzed using an MMRM approach with an unstructured covariance matrix to compare the difference in LS means between arms at Week 52.

Comparison groups

Daprodustat v Darbepoetin alfa

Number of subjects included in analysis

176

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.7141

Method

MMRM

Parameter type

LS mean difference

Point estimate

-0.73

Confidence interval

level

95%

sides

2-sided

lower limit

-3.26

upper limit

1.81

Statistical analysis 21

Statistical analysis description

SF-36 HRQoL social functioning domain score was analyzed using an MMRM approach with an unstructured covariance matrix to compare the difference in LS means between arms at Week 8.

Comparison groups

Daprodustat v Darbepoetin alfa

Number of subjects included in analysis

176

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.7803

Method

MMRM

Parameter type

LS mean difference

Point estimate

-1.03

Confidence interval

level

95%

sides

2-sided

lower limit

-3.65

upper limit

1.59

Statistical analysis 22

Statistical analysis description

SF-36 HRQoL social functioning domain score was analyzed using an MMRM approach with an unstructured covariance matrix to compare the difference in LS means between arms at Week 12.

Comparison groups

Daprodustat v Darbepoetin alfa

Number of subjects included in analysis

176

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.8556

Method

MMRM

Parameter type

LS mean difference

Point estimate

-1.18

Confidence interval

level

95%

sides

2-sided

lower limit

-3.35

upper limit

Statistical analysis 23

Statistical analysis description

SF-36 HRQoL social functioning domain score was analyzed using an MMRM approach with an unstructured covariance matrix to compare the difference in LS means between arms at Week 28.

Comparison groups

Daprodustat v Darbepoetin alfa

Number of subjects included in analysis

176

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.4763

Method

MMRM

Parameter type

LS mean difference

Point estimate

0.08

Confidence interval

level

95%

sides

2-sided

lower limit

-2.61

upper limit

2.77

Statistical analysis 24

Statistical analysis description

SF-36 HRQoL social functioning domain score was analyzed using an MMRM approach with an unstructured covariance matrix to compare the difference in LS means between arms at Week 52.

Comparison groups

Daprodustat v Darbepoetin alfa

Number of subjects included in analysis

176

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.3208

Method

MMRM

Parameter type

LS mean difference

Point estimate

0.73

Confidence interval

level

95%

sides

2-sided

lower limit

-2.35

upper limit

3.8

Secondary: Change from Baseline in Vitality scores using SF-36 HRQoL Questionnaire at Weeks 28, 52

Top of page

End point title

Change from Baseline in Vitality scores using SF-36 HRQoL Questionnaire at Weeks 28, 52

End point description

The SF-36 acute version 2 is a 36-item generic quality of life instrument designed to measure a participant’s level of performance in the following 8 health domains: physical functioning, role-physical (role limitations caused by physical problems), social functioning, bodily pain, mental health, role-emotional (role limitations caused by emotional problems), vitality and general health. Each domain is scored from 0 (poorer health) to 100 (better health). Vitality ranges from 0 to 100; higher scores represent better health. Change from Baseline was calculated as post-dose visit value minus Baseline value. Baseline was defined as the latest non-missing pre-dose assessment on or before the randomization date. Only those participants with data available at the indicated time points were analyzed (represented by n=X in the category titles).

End point type

Secondary

End point timeframe

Baseline (Day 1), Weeks 28 and 52

End point values	Daprodustat	Darbepoetin alfa
Number of subjects analysed	80 ^[32]	74 ^[33]
Units: Scores on a scale
least squares mean (standard error)
Week 28, n=80,74	-0.08 ( 0.866 )	0.95 ( 0.902 )
Week 52, n=67,65	0.16 ( 0.907 )	1.61 ( 0.925 )

Notes
[32] - ITT Population.
[33] - ITT Population.

Statistical analysis 2

Statistical analysis description

SF-36 HRQoL vitality domain score was analyzed using an MMRM approach with an unstructured covariance matrix to compare the difference in LS means between arms at Week 52.

Comparison groups

Daprodustat v Darbepoetin alfa

Number of subjects included in analysis

154

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.8648

Method

MMRM

Parameter type

LS mean difference

Point estimate

-1.45

Confidence interval

level

95%

sides

2-sided

lower limit

-4.03

upper limit

1.14

Statistical analysis 1

Statistical analysis description

SF-36 HRQoL vitality domain score was analyzed using an MMRM approach with an unstructured covariance matrix to compare the difference in LS means between arms at Week 28.

Comparison groups

Daprodustat v Darbepoetin alfa

Number of subjects included in analysis

154

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.791

Method

MMRM

Parameter type

LS mean difference

Point estimate

-1.02

Confidence interval

level

95%

sides

2-sided

lower limit

-3.5

upper limit

1.46

Secondary: Change from Baseline in Physical Functioning domain scores using SF-36 HRQoL Questionnaire at Weeks 28, 52

Top of page

End point title

Change from Baseline in Physical Functioning domain scores using SF-36 HRQoL Questionnaire at Weeks 28, 52

End point description

The SF-36 acute version 2 is a 36-item generic quality of life instrument designed to measure a participant’s level of performance in the following 8 health domains: physical functioning, role-physical (role limitations caused by physical problems), social functioning, bodily pain, mental health, role-emotional (role limitations caused by emotional problems), vitality and general health. Each domain is scored from 0 (poorer health) to 100 (better health). Physical functioning ranges from 0 to 100; higher scores represent better health. Change from Baseline was calculated as post-dose visit value minus (-) Baseline value. Baseline was defined as the latest non-missing pre-dose assessment on or before the randomization date. Only those participants with data available at the indicated time points were analyzed (represented by n=X in the category titles).

End point type

Secondary

End point timeframe

Baseline (Day 1), Weeks 28 and 52

End point values	Daprodustat	Darbepoetin alfa
Number of subjects analysed	80 ^[34]	74 ^[35]
Units: Scores on a scale
least squares mean (standard error)
Week 28, n=80,74	0.55 ( 0.863 )	0.83 ( 0.898 )
Week 52, n=67,65	0.14 ( 0.947 )	1.58 ( 0.973 )

Notes
[34] - ITT Population.
[35] - ITT Population.

Statistical analysis 2

Statistical analysis description

SF-36 HRQoL physical functioning domain scor was analyzed using an MMRM approach with an unstructured covariance matrix to compare the difference in LS means between arms at Week 52.

Comparison groups

Daprodustat v Darbepoetin alfa

Number of subjects included in analysis

154

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.8525

Method

MMRM

Parameter type

LS mean difference

Point estimate

-1.43

Confidence interval

level

95%

sides

2-sided

lower limit

-4.12

upper limit

1.26

Statistical analysis 1

Statistical analysis description

SF-36 HRQoL physical functioning domain score was analyzed using an MMRM approach with an unstructured covariance matrix to compare the difference in LS means between arms at Week 28.

Comparison groups

Daprodustat v Darbepoetin alfa

Number of subjects included in analysis

154

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.5879

Method

MMRM

Parameter type

LS mean difference

Point estimate

-0.28

Confidence interval

level

95%

sides

2-sided

lower limit

-2.75

upper limit

2.19

Secondary: Change from Baseline in Health Utility EuroQol 5 Dimensions 5 Level (EQ-5D-5L) Questionnaire Score at Week 52

Top of page

End point title

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

End point description

EQ-5D-5L consists of 2concepts–EQ-5D-5L descriptive system and EQ Visual Analogue Scale(EQ-VAS).EQ-5D-5L is self-assessment questionnaire,consisting of 5items covering 5dimensions(mobility,self care,usual activities,pain/discomfort and anxiety/depression).Each dimension is measured by 5-point Likert scale(no problems,slight problems,moderate problems,severe problems and extreme problems).Responses for 5 dimensions together formed a 5-figure description of health state(e.g.11111 indicates no problems in all 5dimensions).Each of these 5 figure health states were converted to a single index score by applying country-specific value set formula that attaches weights to dimensions and levels.Range for EQ-5D-5L index score is -0.594(worst health) to 1(full health),higher score better health status.Change from Baseline was calculated as post-dose visit value-Baseline value.Baseline was latest non-missing pre-dose assessment on or before randomization date.

End point type

Secondary

End point timeframe

Baseline (Day 1) and Week 52

End point values	Daprodustat	Darbepoetin alfa
Number of subjects analysed	24 ^[36]	25 ^[37]
Units: Scores on a scale
least squares mean (standard error)	0.00 ( 0.041 )	-0.03 ( 0.040 )

Notes
[36] - ITT Population.
[37] - ITT Population.

Statistical analysis

Statistical analysis description

MMRM model was fitted from Baseline up to Week 52 with factors for treatment, time, dialysis type, dialysis start manner, Baseline value and Baseline value by time and treatment by time interactions.

Comparison groups

Daprodustat v Darbepoetin alfa

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.3154

Method

MMRM

Parameter type

LS mean difference

Point estimate

0.03

Confidence interval

level

95%

sides

2-sided

lower limit

-0.09

upper limit

0.14

Secondary: Change from Baseline in EQ Visual Analogue Scale (EQ-VAS) at Week 52

Top of page

End point title

Change from Baseline in EQ Visual Analogue Scale (EQ-VAS) at Week 52

End point description

EQ-5D-5L consists of 2 concepts –EQ-5D-5L descriptive system and EQ-VAS. The EQ-5D-5L is a self-assessment questionnaire, consisting of 5 items covering five dimensions (mobility, self care, usual activities, pain/discomfort and anxiety/depression). Each dimension is measured by 5-point Likert scale (no problems, slight problems, moderate problems, severe problems, and extreme problems). The range for EQ-5D-5L index score is 0 to 1 with '0' is worst health and '1' is full health. EQ VAS records respondent’s self-rated health on a vertical VAS, ranging from 0 to 100, where 0 represents worst health one can imagine and 100 represents best health one can imagine. Change from Baseline was calculated as post-dose visit value minus Baseline value. Baseline was defined as the latest non-missing pre-dose assessment on or before the randomization date. Only those participants with data available at indicated time points were analyzed.

End point type

Secondary

End point timeframe

Baseline (Day 1) and Week 52

End point values	Daprodustat	Darbepoetin alfa
Number of subjects analysed	24 ^[38]	25 ^[39]
Units: Scores on a scale
least squares mean (standard error)	3.4 ( 3.27 )	6.8 ( 3.28 )

Notes
[38] - ITT Population.
[39] - ITT Population.

Statistical analysis

Statistical analysis description

MMRM model was fitted from Baseline up to Week 52 with factors for treatment, time, dialysis type, dialysis start manner, Baseline value and Baseline value by time and treatment by time interactions.

Comparison groups

Daprodustat v Darbepoetin alfa

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.7651

Method

MMRM

Parameter type

LS mean difference

Point estimate

-3.4

Confidence interval

level

95%

sides

2-sided

lower limit

-12.7

upper limit

5.9

Secondary: Change from Baseline in Chronic Kidney Disease- Anemia Symptoms Questionnaire (CKD-AQ) at Week 52

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End point title

Change from Baseline in Chronic Kidney Disease- Anemia Symptoms Questionnaire (CKD-AQ) at Week 52

End point description

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

End point type

Secondary

End point timeframe

Baseline (Day 1) and Week 52

End point values	Daprodustat	Darbepoetin alfa
Number of subjects analysed	76 ^[40]	80 ^[41]
Units: Scores on a scale
least squares mean (standard error)
Tired/Low energy/Weak domain	-2.36 ( 2.007 )	4.07 ( 1.990 )
Chest pain/Shortness of breath domain	-1.83 ( 1.593 )	2.28 ( 1.557 )
Cognitive domain	-4.17 ( 1.893 )	2.43 ( 1.852 )
Shortness of breath, no activity	-1.90 ( 1.861 )	1.14 ( 1.826 )
Severity-short breath, Resting	-4.16 ( 1.869 )	0.12 ( 1.836 )
Difficulty standing for long time	-2.00 ( 2.812 )	3.30 ( 2.754 )
Difficulty sleeping	-5.27 ( 2.667 )	1.26 ( 2.611 )

Notes
[40] - ITT Population.
[41] - ITT Population.

Statistical analysis 1

Statistical analysis description

Tired/Low energy/Weak domain: MMRM model was fitted from Baseline up to Week 52 with factors for treatment, time, dialysis type, dialysis start manner, Baseline value and Baseline value by time and treatment by time interactions.

Comparison groups

Daprodustat v Darbepoetin alfa

Number of subjects included in analysis

156

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.9875

Method

MMRM

Parameter type

LS mean difference

Point estimate

-6.43

Confidence interval

level

95%

sides

2-sided

lower limit

-12.05

upper limit

-0.82

Statistical analysis 2

Statistical analysis description

Chest pain/Shortness of breath domain: MMRM model was fitted from Baseline up to Week 52 with factors for treatment, time, dialysis type, dialysis start manner, Baseline value and Baseline value by time and treatment by time interactions.

Comparison groups

Daprodustat v Darbepoetin alfa

Number of subjects included in analysis

156

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.9663

Method

MMRM

Parameter type

LS mean difference

Point estimate

-4.11

Confidence interval

level

95%

sides

2-sided

lower limit

-8.52

upper limit

0.3

Statistical analysis 3

Statistical analysis description

Cognitive domain: MMRM model was fitted from Baseline up to Week 52 with factors for treatment, time, dialysis type, dialysis start manner, Baseline value and Baseline value by time and treatment by time interactions.

Comparison groups

Daprodustat v Darbepoetin alfa

Number of subjects included in analysis

156

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.993

Method

MMRM

Parameter type

LS mean difference

Point estimate

-6.6

Confidence interval

level

95%

sides

2-sided

lower limit

-11.84

upper limit

-1.35

Statistical analysis 4

Statistical analysis description

Shortness of breath, no activity: MMRM model was fitted from Baseline up to Week 52 with factors for treatment, time, dialysis type, dialysis start manner, Baseline value and Baseline value by time and treatment by time interactions.

Comparison groups

Daprodustat v Darbepoetin alfa

Number of subjects included in analysis

156

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.8765

Method

MMRM

Parameter type

LS mean difference

Point estimate

-3.03

Confidence interval

level

95%

sides

2-sided

lower limit

-8.19

upper limit

2.12

Statistical analysis 5

Statistical analysis description

Severity-short breath, Resting: MMRM model was fitted from Baseline up to Week 52 with factors for treatment, time, dialysis type, dialysis start manner, Baseline value and Baseline value by time and treatment by time interactions.

Comparison groups

Daprodustat v Darbepoetin alfa

Number of subjects included in analysis

156

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.9464

Method

MMRM

Parameter type

LS mean difference

Point estimate

-4.27

Confidence interval

level

95%

sides

2-sided

lower limit

-9.48

upper limit

0.94

Statistical analysis 6

Statistical analysis description

Difficulty standing for long time: MMRM model was fitted from Baseline up to Week 52 with factors for treatment, time, dialysis type, dialysis start manner, Baseline value and Baseline value by time and treatment by time interactions.

Comparison groups

Daprodustat v Darbepoetin alfa

Number of subjects included in analysis

156

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.9101

Method

MMRM

Parameter type

LS mean difference

Point estimate

-5.31

Confidence interval

level

95%

sides

2-sided

lower limit

-13.09

upper limit

2.47

Statistical analysis 7

Statistical analysis description

Difficulty sleeping: MMRM model was fitted from Baseline up to Week 52 with factors for treatment, time, dialysis type, dialysis start manner, Baseline value and Baseline value by time and treatment by time interactions.

Comparison groups

Daprodustat v Darbepoetin alfa

Number of subjects included in analysis

156

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.9586

Method

MMRM

Parameter type

LS mean difference

Point estimate

-6.52

Confidence interval

level

95%

sides

2-sided

lower limit

-13.9

upper limit

0.86

Secondary: Change from Baseline in Patient Global Impression of Severity (PGI-S)

Top of page

End point title

Change from Baseline in Patient Global Impression of Severity (PGI-S)

End point description

The PGI-S is a 1-item questionnaire designed to assess participant’s impression of disease severity on a 5-point disease severity scale (0=absent, 1=mild, 2=moderate, 3=severe, or 4=very severe). A higher score indicated worse outcome. Change from Baseline was calculated as post-dose visit value minus Baseline value. Baseline was defined as the latest non-missing pre-dose assessment on or before the randomization date. Only those participants with data available at the indicated time points were analyzed (represented by n=X in the category titles).

End point type

Secondary

End point timeframe

Baseline (Day 1), Weeks 8, 12, 28 and 52

End point values	Daprodustat	Darbepoetin alfa
Number of subjects analysed	100 ^[42]	103 ^[43]
Units: Scores on a scale
least squares mean (standard error)
Week 8, n=100,100	0.16 ( 0.091 )	-0.11 ( 0.092 )
Week 12, n=100,103	0.02 ( 0.077 )	-0.03 ( 0.077 )
Week 28, n=92,85	0.09 ( 0.086 )	-0.07 ( 0.089 )
Week 52, n=75,77	0.22 ( 0.106 )	0.04 ( 0.105 )

Notes
[42] - ITT Population.
[43] - ITT Population.

Statistical analysis 1

Statistical analysis description

MMRM model was fitted from Baseline up to Week 8 with factors for treatment, time, dialysis type, dialysis start manner, Baseline value and Baseline value by time and treatment by time interactions.

Comparison groups

Daprodustat v Darbepoetin alfa

Number of subjects included in analysis

203

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.981

Method

MMRM

Parameter type

LS mean difference

Point estimate

0.27

Confidence interval

level

95%

sides

2-sided

lower limit

0.02

upper limit

0.53

Statistical analysis 2

Statistical analysis description

MMRM model was fitted from Baseline up to Week 12 with factors for treatment, time, dialysis type, dialysis start manner, Baseline value and Baseline value by time and treatment by time interactions.

Comparison groups

Daprodustat v Darbepoetin alfa

Number of subjects included in analysis

203

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.6743

Method

MMRM

Parameter type

LS mean difference

Point estimate

0.05

Confidence interval

level

95%

sides

2-sided

lower limit

-0.17

upper limit

0.26

Statistical analysis 3

Statistical analysis description

MMRM model was fitted from Baseline up to Week 28 with factors for treatment, time, dialysis type, dialysis start manner, Baseline value and Baseline value by time and treatment by time interactions.

Comparison groups

Daprodustat v Darbepoetin alfa

Number of subjects included in analysis

203

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.8997

Method

MMRM

Parameter type

LS mean difference

Point estimate

0.16

Confidence interval

level

95%

sides

2-sided

lower limit

-0.09

upper limit

0.4

Statistical analysis 4

Statistical analysis description

MMRM model was fitted from Baseline up to Week 52 with factors for treatment, time, dialysis type, dialysis start manner, Baseline value and Baseline value by time and treatment by time interactions.

Comparison groups

Daprodustat v Darbepoetin alfa

Number of subjects included in analysis

203

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.8835

Method

MMRM

Parameter type

LS mean difference

Point estimate

0.18

Confidence interval

level

95%

sides

2-sided

lower limit

-0.12

upper limit

0.47

Secondary: Plasma Concentration of Daprodustat (GSK1278863) and its Metabolites GSK2391220 (M2), GSK2506104 (M3), and GSK2531401 (M13)

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End point title

Plasma Concentration of Daprodustat (GSK1278863) and its Metabolites GSK2391220 (M2), GSK2506104 (M3), and GSK2531401 (M13)

End point description

Pharmacokinetic samples were collected at pre-dose, 0.5, 1, 2 and 3 hours post-dose on Week 4 or 8 or 12 for pharmacokinetic (PK) analysis of daprodustat (GSK1278863) and its metabolites GSK2391220 (M2), GSK2506104 (M3), and GSK2531401 (M13). GSK2391220, GSK2506104 and GSK2531401 are the metabolites of Daprodustat (GSK1278863). Protocol allowed participants to provide pharmacokinetic samples on Week 4 or 8 or 12. Pharmacokinetic Population comprised of participants for whom a pharmacokinetic sample was obtained and analyzed. Only those participants with data available at the indicated time points were analyzed (represented by n=X in the category titles). Blood samples were not collected for PK analysis of daprodustat 12, 16 and 24 mg arms. 99999 indicates, Standard deviation could not be calculated for single participant. 88888 indicates, data is not available.

End point type

Secondary

End point timeframe

Pre-dose, 0.5, 1, 2 and 3 hours post-dose; each pharmacokinetic sample was taken at Week 4 or 8 or 12

End point values	Daprodustat 1 mg	Daprodustat 2 mg	Daprodustat 4 mg	Daprodustat 6 mg	Daprodustat 8 mg	Daprodustat 10 mg
Number of subjects analysed	19 ^[44]	26 ^[45]	20 ^[46]	18 ^[47]	1 ^[48]	1 ^[49]
Units: Nanogram per milliliter
arithmetic mean (standard deviation)
Daprodustat: Pre-Dose, n=19,26,20,18,1,1	2.118 ( 5.0030 )	1.015 ( 3.1451 )	0.5787 ( 1.5718 )	2.867 ( 6.6142 )	0.1030 ( 99999 )	0.1090 ( 99999 )
Daprodustat: 0.5 hour, n=19,26,20,18,0,1	5.675 ( 8.4998 )	4.664 ( 8.7508 )	10.27 ( 20.425 )	12.58 ( 23.742 )	88888 ( 88888 )	145.0 ( 99999 )
Daprodustat: 1 hour, n=19,26,20,18,1,1	12.34 ( 13.435 )	21.45 ( 42.160 )	36.78 ( 62.497 )	45.48 ( 48.765 )	0.9120 ( 99999 )	79.60 ( 99999 )
Daprodustat: 2 hours, n=19,26,20,18,1,1	12.74 ( 9.9019 )	20.36 ( 22.210 )	54.68 ( 80.284 )	55.62 ( 51.471 )	32.00 ( 99999 )	27.60 ( 99999 )
Daprodustat: 3 hours, n=19,26,19,18,1,1	7.719 ( 5.9144 )	15.58 ( 13.694 )	43.34 ( 66.295 )	56.49 ( 74.357 )	25.30 ( 99999 )	11.00 ( 99999 )
GSK2391220: Pre-Dose, n=19,26,20,18,1,1	0.7106 ( 0.64028 )	2.124 ( 2.8721 )	2.087 ( 2.1371 )	3.560 ( 4.2255 )	4.450 ( 99999 )	6.560 ( 99999 )
GSK2391220: 0.5 hour, n=19,25,20,18,1,1	0.7602 ( 0.67950 )	1.807 ( 2.2007 )	1.822 ( 2.1355 )	2.410 ( 2.8243 )	3.950 ( 99999 )	6.740 ( 99999 )
GSK2391220: 1 hour, n=18,26,20,18,1,1	1.123 ( 0.76920 )	1.752 ( 1.8589 )	1.965 ( 2.2830 )	3.140 ( 2.4856 )	3.900 ( 99999 )	10.00 ( 99999 )
GSK2391220: 2 hours, n=19,26,20,18,1,1	1.745 ( 1.3160 )	2.969 ( 2.4659 )	4.008 ( 4.4522 )	6.336 ( 4.3723 )	4.700 ( 99999 )	16.20 ( 99999 )
GSK2391220: 3 hours, n=19,26,19,18,1,1	1.911 ( 1.2274 )	3.535 ( 2.7203 )	5.553 ( 6.5157 )	9.372 ( 6.6452 )	6.090 ( 99999 )	16.60 ( 99999 )
GSK2506104: Pre-Dose, n=19,26,20,18,1,1	1.270 ( 0.96071 )	3.508 ( 4.2066 )	3.879 ( 3.4207 )	5.921 ( 5.8981 )	8.710 ( 99999 )	9.500 ( 99999 )
GSK2506104: 0.5 hour, n=19,26,20,18,1,1	1.197 ( 0.85104 )	2.788 ( 2.9893 )	3.315 ( 3.4249 )	4.015 ( 3.7385 )	7.740 ( 99999 )	8.110 ( 99999 )
GSK2506104: 1 hour, n=19,26,20,18,1,1	1.364 ( 0.96292 )	2.610 ( 2.4761 )	3.268 ( 3.4808 )	4.333 ( 3.0505 )	7.460 ( 99999 )	12.40 ( 99999 )
GSK2506104: 2 hours, n=19,26,20,18,1,1	1.966 ( 1.3440 )	3.583 ( 2.8427 )	4.989 ( 5.2109 )	7.130 ( 4.5105 )	8.930 ( 99999 )	19.60 ( 99999 )
GSK2506104: 3 hours, n=19,26,19,18,1,1	2.190 ( 1.3898 )	4.145 ( 3.1757 )	6.503 ( 7.5130 )	9.942 ( 7.0616 )	10.10 ( 99999 )	22.00 ( 99999 )
GSK2531401: Pre-Dose, n=19,26,20,18,1,1	1.642 ( 1.4836 )	2.729 ( 1.8934 )	3.750 ( 3.8006 )	5.111 ( 4.0632 )	5.660 ( 99999 )	7.760 ( 99999 )
GSK2531401: 0.5 hour, n=19,26,20,18,1,1	1.427 ( 1.2870 )	2.170 ( 1.6621 )	3.263 ( 3.8737 )	3.800 ( 2.8722 )	4.960 ( 99999 )	6.460 ( 99999 )
GSK2531401: 1 hour, n=19,26,20,18,1,1	1.399 ( 1.4595 )	1.979 ( 1.6316 )	3.146 ( 4.0334 )	3.776 ( 3.4411 )	4.810 ( 99999 )	6.630 ( 99999 )
GSK2531401: 2 hours, n=19,26,20,18,1,1	1.690 ( 1.6309 )	2.338 ( 2.1467 )	3.711 ( 5.0223 )	4.892 ( 4.7877 )	5.190 ( 99999 )	8.290 ( 99999 )
GSK2531401: 3 hours, n=19,26,19,18,1,1	1.847 ( 1.7376 )	2.734 ( 2.6846 )	4.715 ( 7.2788 )	6.631 ( 7.1049 )	5.760 ( 99999 )	10.20 ( 99999 )

Notes
[44] - Pharmacokinetic Population.
[45] - Pharmacokinetic Population.
[46] - Pharmacokinetic Population.
[47] - Pharmacokinetic Population.
[48] - Pharmacokinetic Population.
[49] - Pharmacokinetic Population.

No statistical analyses for this end point

Secondary: Observed concentration at Dosing Interval (Ctau) of Daprodustat (GSK1278863) and its Metabolites GSK2391220 (M2), GSK2506104 (M3), and GSK2531401 (M13)

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End point title

Observed concentration at Dosing Interval (Ctau) of Daprodustat (GSK1278863) and its Metabolites GSK2391220 (M2), GSK2506104 (M3), and GSK2531401 (M13)

End point description

Pharmacokinetic samples were collected at pre-dose, 0.5, 1, 2 and 3 hours post-dose on Week 4 or 8 or 12 for pharmacokinetic analysis of daprodustat (GSK1278863) and its metabolites GSK2391220 (M2), GSK2506104 (M3), and GSK2531401 (M13). GSK2391220, GSK2506104 and GSK2531401 are the metabolites of Daprodustat (GSK1278863). Protocol allowed participants to provide pharmacokinetic samples on Week 4 or 8 or 12. Only those participants with data available at the indicated time points were analyzed. Blood samples were not collected for PK analysis of daprodustat 12, 16 and 24 mg arms. 99999 indicates, Standard deviation could not be calculated for single participant.

End point type

Secondary

End point timeframe

Pre-Dose, 0.5, 1, 2 and 3 hours post-dose; each pharmacokinetic sample was taken at Week 4 or 8 or 12

End point values	Daprodustat 1 mg	Daprodustat 2 mg	Daprodustat 4 mg	Daprodustat 6 mg	Daprodustat 8 mg	Daprodustat 10 mg
Number of subjects analysed	19 ^[50]	26 ^[51]	20 ^[52]	18 ^[53]	1 ^[54]	1 ^[55]
Units: Nanogram per milliliter
arithmetic mean (standard deviation)
Daprodustat	2.118 ( 5.0030 )	1.015 ( 3.1451 )	0.5787 ( 1.5718 )	2.867 ( 6.6142 )	0.1030 ( 99999 )	0.1090 ( 99999 )
GSK2391220	0.7106 ( 0.64028 )	2.124 ( 2.8721 )	2.087 ( 2.1371 )	3.560 ( 4.2255 )	4.450 ( 99999 )	6.560 ( 99999 )
GSK2506104	1.270 ( 0.96071 )	3.508 ( 4.2066 )	3.879 ( 3.4207 )	5.921 ( 5.8981 )	8.710 ( 99999 )	9.500 ( 99999 )
GSK2531401	1.642 ( 1.4836 )	2.729 ( 1.8934 )	3.750 ( 3.8006 )	5.111 ( 4.0632 )	5.660 ( 99999 )	7.760 ( 99999 )

Notes
[50] - Pharmacokinetic Population.
[51] - Pharmacokinetic Population.
[52] - Pharmacokinetic Population.
[53] - Pharmacokinetic Population.
[54] - Pharmacokinetic Population.
[55] - Pharmacokinetic Population.

No statistical analyses for this end point

Secondary: Maximum Observed Concentration (Cmax) of Daprodustat (GSK1278863) and its Metabolites GSK2391220 (M2), GSK2506104 (M3), and GSK2531401 (M13)

Top of page

End point title

Maximum Observed Concentration (Cmax) of Daprodustat (GSK1278863) and its Metabolites GSK2391220 (M2), GSK2506104 (M3), and GSK2531401 (M13)

End point description

End point type

Secondary

End point timeframe

Pre-Dose, 0.5, 1, 2 and 3 hours post-dose; each pharmacokinetic sample was taken at Week 4 or 8 or 12

End point values	Daprodustat 1 mg	Daprodustat 2 mg	Daprodustat 4 mg	Daprodustat 6 mg	Daprodustat 8 mg	Daprodustat 10 mg
Number of subjects analysed	19 ^[56]	26 ^[57]	20 ^[58]	18 ^[59]	1 ^[60]	1 ^[61]
Units: Nanogram per milliliter
arithmetic mean (standard deviation)
Daprodustat	21.74 ( 10.998 )	32.29 ( 40.166 )	76.92 ( 81.867 )	100.2 ( 74.086 )	32.00 ( 99999 )	145.0 ( 99999 )
GSK2391220	2.160 ( 1.2596 )	4.139 ( 3.3561 )	5.780 ( 6.2840 )	10.36 ( 6.3377 )	6.090 ( 99999 )	16.60 ( 99999 )
GSK2506104	2.477 ( 1.3625 )	5.212 ( 4.5562 )	7.075 ( 7.1313 )	11.60 ( 6.8731 )	10.10 ( 99999 )	22.00 ( 99999 )
GSK2531401	2.283 ( 1.8210 )	3.565 ( 2.6091 )	5.328 ( 6.9034 )	7.836 ( 6.6199 )	5.760 ( 99999 )	10.20 ( 99999 )

Notes
[56] - Pharmacokinetic Population.
[57] - Pharmacokinetic Population.
[58] - Pharmacokinetic Population.
[59] - Pharmacokinetic Population.
[60] - Pharmacokinetic Population.
[61] - Pharmacokinetic Population.

No statistical analyses for this end point

Adverse events

Top of page

Timeframe for reporting adverse events

All-cause mortality, treatment emergent non-serious adverse events and serious adverse events were collected up to follow-up visit (Week 58)

Adverse event reporting additional description

Safety Population comprised of all randomized participants who received at least one dose of randomized treatment.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

23.1

Reporting group title

Daprodustat

Reporting group description

Participants received daprodustat film-coated tablets with titrated dose levels ranging from 1, 2, 4, 6, 8, 10, 12, 16, and 24 milligrams (mg) orally once daily for up to 52 weeks. Study treatment was dose-titrated to achieve and maintain hemoglobin in the target range (10 to 11 grams per deciliter [g/dL]).

Reporting group title

Darbepoetin alfa

Reporting group description

Serious adverse events	Daprodustat	Darbepoetin alfa
Total subjects affected by serious adverse events
subjects affected / exposed	52 / 157 (33.12%)	51 / 155 (32.90%)
number of deaths (all causes)	17	12
number of deaths resulting from adverse events
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Renal cell carcinoma
subjects affected / exposed	0 / 157 (0.00%)	1 / 155 (0.65%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Prostate cancer metastatic
subjects affected / exposed	1 / 157 (0.64%)	0 / 155 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Thyroid cancer stage I
subjects affected / exposed	0 / 157 (0.00%)	1 / 155 (0.65%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Vascular disorders
Hypertension
subjects affected / exposed	2 / 157 (1.27%)	1 / 155 (0.65%)
occurrences causally related to treatment / all	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hypertensive emergency
subjects affected / exposed	0 / 157 (0.00%)	1 / 155 (0.65%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Hypertensive urgency
subjects affected / exposed	1 / 157 (0.64%)	1 / 155 (0.65%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Lymphocele
subjects affected / exposed	1 / 157 (0.64%)	0 / 155 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Peripheral vascular disorder
subjects affected / exposed	1 / 157 (0.64%)	0 / 155 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Steal syndrome
subjects affected / exposed	0 / 157 (0.00%)	1 / 155 (0.65%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
General disorders and administration site conditions
Non-cardiac chest pain
subjects affected / exposed	0 / 157 (0.00%)	2 / 155 (1.29%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Pyrexia
subjects affected / exposed	1 / 157 (0.64%)	1 / 155 (0.65%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Catheter site haemorrhage
subjects affected / exposed	1 / 157 (0.64%)	0 / 155 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Sudden death
subjects affected / exposed	2 / 157 (1.27%)	0 / 155 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 2	0 / 0
Generalised oedema
subjects affected / exposed	0 / 157 (0.00%)	1 / 155 (0.65%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Multiple organ dysfunction syndrome
subjects affected / exposed	0 / 157 (0.00%)	1 / 155 (0.65%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Reproductive system and breast disorders
Benign prostatic hyperplasia
subjects affected / exposed	0 / 157 (0.00%)	1 / 155 (0.65%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Metrorrhagia
subjects affected / exposed	1 / 157 (0.64%)	0 / 155 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Chronic obstructive pulmonary disease
subjects affected / exposed	1 / 157 (0.64%)	0 / 155 (0.00%)
occurrences causally related to treatment / all	0 / 7	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Epistaxis
subjects affected / exposed	0 / 157 (0.00%)	2 / 155 (1.29%)
occurrences causally related to treatment / all	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Acute respiratory failure
subjects affected / exposed	1 / 157 (0.64%)	1 / 155 (0.65%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Dyspnoea
subjects affected / exposed	0 / 157 (0.00%)	1 / 155 (0.65%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Pleural effusion
subjects affected / exposed	0 / 157 (0.00%)	2 / 155 (1.29%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Respiratory failure
subjects affected / exposed	1 / 157 (0.64%)	1 / 155 (0.65%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 1	0 / 0
Asthma
subjects affected / exposed	1 / 157 (0.64%)	0 / 155 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Haemothorax
subjects affected / exposed	0 / 157 (0.00%)	1 / 155 (0.65%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pulmonary hypertension
subjects affected / exposed	1 / 157 (0.64%)	0 / 155 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Psychiatric disorders
Depression
subjects affected / exposed	0 / 157 (0.00%)	1 / 155 (0.65%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Product issues
Device malfunction
subjects affected / exposed	4 / 157 (2.55%)	0 / 155 (0.00%)
occurrences causally related to treatment / all	0 / 4	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Device dislocation
subjects affected / exposed	1 / 157 (0.64%)	2 / 155 (1.29%)
occurrences causally related to treatment / all	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Investigations
Hepatic enzyme increased
subjects affected / exposed	0 / 157 (0.00%)	1 / 155 (0.65%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Injury, poisoning and procedural complications
Arteriovenous fistula thrombosis
subjects affected / exposed	1 / 157 (0.64%)	4 / 155 (2.58%)
occurrences causally related to treatment / all	0 / 1	1 / 5
deaths causally related to treatment / all	0 / 0	0 / 0
Arteriovenous fistula site complication
subjects affected / exposed	0 / 157 (0.00%)	2 / 155 (1.29%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Humerus fracture
subjects affected / exposed	1 / 157 (0.64%)	0 / 155 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Anaemia postoperative
subjects affected / exposed	1 / 157 (0.64%)	0 / 155 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Arteriovenous graft thrombosis
subjects affected / exposed	0 / 157 (0.00%)	1 / 155 (0.65%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Fall
subjects affected / exposed	1 / 157 (0.64%)	0 / 155 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Femoral neck fracture
subjects affected / exposed	0 / 157 (0.00%)	1 / 155 (0.65%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Inadequate haemodialysis
subjects affected / exposed	0 / 157 (0.00%)	1 / 155 (0.65%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Open globe injury
subjects affected / exposed	1 / 157 (0.64%)	0 / 155 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Peritoneal dialysate leakage
subjects affected / exposed	0 / 157 (0.00%)	1 / 155 (0.65%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Peritoneal dialysis complication
subjects affected / exposed	0 / 157 (0.00%)	1 / 155 (0.65%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Procedural haemorrhage
subjects affected / exposed	1 / 157 (0.64%)	0 / 155 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Procedural pain
subjects affected / exposed	0 / 157 (0.00%)	1 / 155 (0.65%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Subdural haematoma
subjects affected / exposed	1 / 157 (0.64%)	0 / 155 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Unintentional medical device removal
subjects affected / exposed	1 / 157 (0.64%)	0 / 155 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Vascular access malfunction
subjects affected / exposed	0 / 157 (0.00%)	1 / 155 (0.65%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Congenital, familial and genetic disorders
Hypertrophic cardiomyopathy
subjects affected / exposed	0 / 157 (0.00%)	1 / 155 (0.65%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiac disorders
Acute myocardial infarction
subjects affected / exposed	0 / 157 (0.00%)	3 / 155 (1.94%)
occurrences causally related to treatment / all	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiac failure
subjects affected / exposed	1 / 157 (0.64%)	2 / 155 (1.29%)
occurrences causally related to treatment / all	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Myocardial infarction
subjects affected / exposed	1 / 157 (0.64%)	2 / 155 (1.29%)
occurrences causally related to treatment / all	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiac failure congestive
subjects affected / exposed	2 / 157 (1.27%)	0 / 155 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Acute coronary syndrome
subjects affected / exposed	1 / 157 (0.64%)	0 / 155 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Angina pectoris
subjects affected / exposed	1 / 157 (0.64%)	0 / 155 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Angina unstable
subjects affected / exposed	0 / 157 (0.00%)	1 / 155 (0.65%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Aortic valve incompetence
subjects affected / exposed	1 / 157 (0.64%)	0 / 155 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Arteriosclerosis coronary artery
subjects affected / exposed	0 / 157 (0.00%)	1 / 155 (0.65%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Atrial fibrillation
subjects affected / exposed	1 / 157 (0.64%)	0 / 155 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Atrioventricular block complete
subjects affected / exposed	0 / 157 (0.00%)	1 / 155 (0.65%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Bradycardia
subjects affected / exposed	1 / 157 (0.64%)	0 / 155 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiac failure acute
subjects affected / exposed	1 / 157 (0.64%)	0 / 155 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiac failure chronic
subjects affected / exposed	1 / 157 (0.64%)	0 / 155 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiogenic shock
subjects affected / exposed	1 / 157 (0.64%)	0 / 155 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hypertensive heart disease
subjects affected / exposed	1 / 157 (0.64%)	0 / 155 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pericardial effusion
subjects affected / exposed	0 / 157 (0.00%)	1 / 155 (0.65%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Sinus bradycardia
subjects affected / exposed	1 / 157 (0.64%)	0 / 155 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Supraventricular tachycardia
subjects affected / exposed	1 / 157 (0.64%)	0 / 155 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Nervous system disorders
Syncope
subjects affected / exposed	1 / 157 (0.64%)	1 / 155 (0.65%)
occurrences causally related to treatment / all	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Seizure
subjects affected / exposed	0 / 157 (0.00%)	2 / 155 (1.29%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Carpal tunnel syndrome
subjects affected / exposed	0 / 157 (0.00%)	1 / 155 (0.65%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hypertensive encephalopathy
subjects affected / exposed	1 / 157 (0.64%)	0 / 155 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Presyncope
subjects affected / exposed	0 / 157 (0.00%)	1 / 155 (0.65%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Transient ischaemic attack
subjects affected / exposed	0 / 157 (0.00%)	1 / 155 (0.65%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Uraemic encephalopathy
subjects affected / exposed	1 / 157 (0.64%)	0 / 155 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Blood and lymphatic system disorders
Pancytopenia
subjects affected / exposed	0 / 157 (0.00%)	1 / 155 (0.65%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Eye disorders
Retinopathy hypertensive
subjects affected / exposed	1 / 157 (0.64%)	0 / 155 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Gastrointestinal disorders
Abdominal pain
subjects affected / exposed	0 / 157 (0.00%)	3 / 155 (1.94%)
occurrences causally related to treatment / all	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Volvulus
subjects affected / exposed	1 / 157 (0.64%)	0 / 155 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Abdominal pain upper
subjects affected / exposed	0 / 157 (0.00%)	1 / 155 (0.65%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Bloody peritoneal effluent
subjects affected / exposed	1 / 157 (0.64%)	0 / 155 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Diabetic gastropathy
subjects affected / exposed	1 / 157 (0.64%)	0 / 155 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Diarrhoea
subjects affected / exposed	0 / 157 (0.00%)	1 / 155 (0.65%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Enteritis
subjects affected / exposed	0 / 157 (0.00%)	1 / 155 (0.65%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Gastritis
subjects affected / exposed	0 / 157 (0.00%)	1 / 155 (0.65%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Gastrooesophageal reflux disease
subjects affected / exposed	1 / 157 (0.64%)	0 / 155 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Impaired gastric emptying
subjects affected / exposed	0 / 157 (0.00%)	1 / 155 (0.65%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Intestinal obstruction
subjects affected / exposed	1 / 157 (0.64%)	0 / 155 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Retroperitoneal haematoma
subjects affected / exposed	0 / 157 (0.00%)	1 / 155 (0.65%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Subileus
subjects affected / exposed	1 / 157 (0.64%)	0 / 155 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Upper gastrointestinal haemorrhage
subjects affected / exposed	0 / 157 (0.00%)	1 / 155 (0.65%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hepatobiliary disorders
Hydrocholecystis
subjects affected / exposed	0 / 157 (0.00%)	1 / 155 (0.65%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
Diabetic foot
subjects affected / exposed	0 / 157 (0.00%)	1 / 155 (0.65%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Renal and urinary disorders
Azotaemia
subjects affected / exposed	1 / 157 (0.64%)	1 / 155 (0.65%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 1	0 / 0
Haematuria
subjects affected / exposed	1 / 157 (0.64%)	0 / 155 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Chronic kidney disease
subjects affected / exposed	1 / 157 (0.64%)	0 / 155 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Infections and infestations
Pneumonia
subjects affected / exposed	4 / 157 (2.55%)	7 / 155 (4.52%)
occurrences causally related to treatment / all	0 / 7	0 / 7
deaths causally related to treatment / all	0 / 0	0 / 1
Peritonitis
subjects affected / exposed	1 / 157 (0.64%)	3 / 155 (1.94%)
occurrences causally related to treatment / all	0 / 1	0 / 5
deaths causally related to treatment / all	0 / 0	0 / 0
Septic shock
subjects affected / exposed	2 / 157 (1.27%)	2 / 155 (1.29%)
occurrences causally related to treatment / all	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 2	0 / 0
Post procedural infection
subjects affected / exposed	3 / 157 (1.91%)	0 / 155 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Sepsis
subjects affected / exposed	0 / 157 (0.00%)	3 / 155 (1.94%)
occurrences causally related to treatment / all	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Clostridium difficile infection
subjects affected / exposed	1 / 157 (0.64%)	1 / 155 (0.65%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Gastroenteritis
subjects affected / exposed	1 / 157 (0.64%)	1 / 155 (0.65%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Localised infection
subjects affected / exposed	1 / 157 (0.64%)	1 / 155 (0.65%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Respiratory tract infection
subjects affected / exposed	1 / 157 (0.64%)	1 / 155 (0.65%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Staphylococcal infection
subjects affected / exposed	2 / 157 (1.27%)	0 / 155 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Urinary tract infection
subjects affected / exposed	1 / 157 (0.64%)	1 / 155 (0.65%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Urosepsis
subjects affected / exposed	1 / 157 (0.64%)	1 / 155 (0.65%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Bronchiolitis
subjects affected / exposed	1 / 157 (0.64%)	0 / 155 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
COVID-19
subjects affected / exposed	1 / 157 (0.64%)	0 / 155 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Clostridial sepsis
subjects affected / exposed	1 / 157 (0.64%)	0 / 155 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Clostridium difficile colitis
subjects affected / exposed	1 / 157 (0.64%)	0 / 155 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Device related bacteraemia
subjects affected / exposed	1 / 157 (0.64%)	0 / 155 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Device related infection
subjects affected / exposed	0 / 157 (0.00%)	1 / 155 (0.65%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Device related sepsis
subjects affected / exposed	0 / 157 (0.00%)	1 / 155 (0.65%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Escherichia infection
subjects affected / exposed	1 / 157 (0.64%)	0 / 155 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Escherichia urinary tract infection
subjects affected / exposed	0 / 157 (0.00%)	1 / 155 (0.65%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Helicobacter gastritis
subjects affected / exposed	0 / 157 (0.00%)	1 / 155 (0.65%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Infected skin ulcer
subjects affected / exposed	1 / 157 (0.64%)	0 / 155 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Leptospirosis
subjects affected / exposed	1 / 157 (0.64%)	0 / 155 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Lower respiratory tract infection
subjects affected / exposed	0 / 157 (0.00%)	1 / 155 (0.65%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Osteomyelitis
subjects affected / exposed	0 / 157 (0.00%)	1 / 155 (0.65%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Staphylococcal bacteraemia
subjects affected / exposed	1 / 157 (0.64%)	0 / 155 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Staphylococcal sepsis
subjects affected / exposed	1 / 157 (0.64%)	0 / 155 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Streptococcal infection
subjects affected / exposed	1 / 157 (0.64%)	0 / 155 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Subcutaneous abscess
subjects affected / exposed	1 / 157 (0.64%)	0 / 155 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Urinary tract infection bacterial
subjects affected / exposed	0 / 157 (0.00%)	1 / 155 (0.65%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Metabolism and nutrition disorders
Fluid overload
subjects affected / exposed	5 / 157 (3.18%)	3 / 155 (1.94%)
occurrences causally related to treatment / all	0 / 9	0 / 8
deaths causally related to treatment / all	0 / 0	0 / 0
Hyperkalaemia
subjects affected / exposed	2 / 157 (1.27%)	2 / 155 (1.29%)
occurrences causally related to treatment / all	0 / 2	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0
Hypoglycaemia
subjects affected / exposed	0 / 157 (0.00%)	3 / 155 (1.94%)
occurrences causally related to treatment / all	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Fluid retention
subjects affected / exposed	0 / 157 (0.00%)	1 / 155 (0.65%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	Daprodustat	Darbepoetin alfa
Total subjects affected by non serious adverse events
subjects affected / exposed	76 / 157 (48.41%)	74 / 155 (47.74%)
Injury, poisoning and procedural complications
Arteriovenous fistula site complication
subjects affected / exposed	4 / 157 (2.55%)	8 / 155 (5.16%)
occurrences all number	4	13
Vascular disorders
Hypertension
subjects affected / exposed	27 / 157 (17.20%)	24 / 155 (15.48%)
occurrences all number	51	35
Dialysis hypotension
subjects affected / exposed	21 / 157 (13.38%)	15 / 155 (9.68%)
occurrences all number	34	22
Hypotension
subjects affected / exposed	7 / 157 (4.46%)	9 / 155 (5.81%)
occurrences all number	8	9
Nervous system disorders
Headache
subjects affected / exposed	12 / 157 (7.64%)	9 / 155 (5.81%)
occurrences all number	14	10
Gastrointestinal disorders
Diarrhoea
subjects affected / exposed	14 / 157 (8.92%)	10 / 155 (6.45%)
occurrences all number	17	10
Vomiting
subjects affected / exposed	11 / 157 (7.01%)	5 / 155 (3.23%)
occurrences all number	16	5
Nausea
subjects affected / exposed	8 / 157 (5.10%)	6 / 155 (3.87%)
occurrences all number	13	6
Musculoskeletal and connective tissue disorders
Muscle spasms
subjects affected / exposed	7 / 157 (4.46%)	9 / 155 (5.81%)
occurrences all number	12	12
Infections and infestations
Nasopharyngitis
subjects affected / exposed	7 / 157 (4.46%)	9 / 155 (5.81%)
occurrences all number	12	9
Catheter site infection
subjects affected / exposed	5 / 157 (3.18%)	8 / 155 (5.16%)
occurrences all number	5	11
Upper respiratory tract infection
subjects affected / exposed	7 / 157 (4.46%)	11 / 155 (7.10%)
occurrences all number	9	12
Metabolism and nutrition disorders
Fluid overload
subjects affected / exposed	9 / 157 (5.73%)	6 / 155 (3.87%)
occurrences all number	9	7

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Were there any global substantial amendments to the protocol? Yes

06 Oct 2017

Amendment 1: Updated time period of planning to start dialysis from the screening to 6 weeks, when appropriate; Removed number of screening participants and stated only an approximate number of randomized participants required; Modified PD inclusion criteria to allow participants on >=4 times/week PD including an incremental schedule; Removed France country specific requirement for Informed Consent process from inclusion criteria; Broadened exclusion to include participation in an interventional study with an investigational agent or device; Removed option to have Early Treatment Discontinuation visit supersede the scheduled visit; Added a provision that in unexpected circumstances where the supply to the site is interrupted, local SOC for anemia management during this time period may be considered; Added direction regarding randomized treatment and study continuation for participants who will be away from the research site for an extended period of time; Added new darbepoetin alfa dose strengths (not available in all countries); Clarified timeframe for iron management criteria; Clarified timing of designated study visits for participants who have not yet initiated dialysis and for participants on dialysis; Shortened visit window for week 2 and 4; Changed time point for blinded data cut need for psychometric validation of the CKD Questionnaire; Revised statistical section to change from 2-sided testing at the 5% level to 1-sided testing at the 2.5% level; for secondary endpoints, to change significance levels to p-values and to correct the time point for various PRO;Provision for possible adjustment to the Dose Adjustment Algorithm triggers for Hgb values 7.5 grams per deciliter (g/dL) to <9.5 g/dL based on review of blinded instream Hgb data; Updated FSH level to confirm menopause in Appendix 5, Female Eligibility Criteria

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

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Clinical trials

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Mean Change from Baseline in Hemoglobin (Hgb) During Evaluation Period (Week 28 to Week 52)

Primary: Mean Change from Baseline in Hemoglobin (Hgb) During Evaluation Period (Week 28 to Week 52)

Secondary: Average Monthly Intravenous Iron Dose (milligrams) from Baseline to Week 52

Secondary: Average Monthly Intravenous Iron Dose (milligrams) from Baseline to Week 52

Secondary: Change from Baseline in Systolic Blood Pressure (SBP), Diastolic Blood Pressure (DBP), Mean Arterial Blood Pressure (MAP) at Week 52

Secondary: Change from Baseline in Systolic Blood Pressure (SBP), Diastolic Blood Pressure (DBP), Mean Arterial Blood Pressure (MAP) at Week 52

Secondary: Change from Baseline in SBP, DBP, MAP at End of Treatment

Secondary: Change from Baseline in SBP, DBP, MAP at End of Treatment

Secondary: Blood Pressure (BP) Exacerbation Events Rate per 100 Participant Years

Secondary: Blood Pressure (BP) Exacerbation Events Rate per 100 Participant Years

Secondary: Number of Participants with at Least one Blood Pressure Exacerbation Event During Study

Secondary: Number of Participants with at Least one Blood Pressure Exacerbation Event During Study

Secondary: Change From Baseline in Post-randomization Hgb at Week 52

Secondary: Change From Baseline in Post-randomization Hgb at Week 52

Secondary: Number of Hgb Responders (Hgb in the Analysis Range of 10 to 11.5 grams/deciliter) During Evaluation Period (Week 28 to Week 52)

Secondary: Number of Hgb Responders (Hgb in the Analysis Range of 10 to 11.5 grams/deciliter) During Evaluation Period (Week 28 to Week 52)

Secondary: Percentage of Time for which Hgb was within the Analysis Range (10 to 11.5 g/dL) During Evaluation Period (Week 28 to Week 52): Non-inferiority analysis

Secondary: Percentage of Time for which Hgb was within the Analysis Range (10 to 11.5 g/dL) During Evaluation Period (Week 28 to Week 52): Non-inferiority analysis

Secondary: Percentage of Time for which Hgb was within the Analysis Range (10 to 11.5 g/dL) During Evaluation Period (Week 28 to Week 52): Superiority analysis

Secondary: Percentage of Time for which Hgb was within the Analysis Range (10 to 11.5 g/dL) During Evaluation Period (Week 28 to Week 52): Superiority analysis

Secondary: Number of Participants Permanently Stopping Randomized Treatment Due to Meeting Rescue Criteria

Secondary: Number of Participants Permanently Stopping Randomized Treatment Due to Meeting Rescue Criteria

Secondary: Change from Baseline in Physical Component Score (PCS) using Short Form (SF)-36 Health-related Quality of Life (HRQoL) Questionnaire at Weeks 8, 12, 28, 52

Secondary: Change from Baseline in Physical Component Score (PCS) using Short Form (SF)-36 Health-related Quality of Life (HRQoL) Questionnaire at Weeks 8, 12, 28, 52

Secondary: Change from Baseline in Mental Component Score (MCS) using SF-36 HRQoL Questionnaire at Weeks 8, 12, 28, 52

Secondary: Change from Baseline in Mental Component Score (MCS) using SF-36 HRQoL Questionnaire at Weeks 8, 12, 28, 52

Secondary: Change from Baseline in SF-36 HRQoL Scores for Bodily Pain, General Health, Mental Health, Role-Emotional, Role-Physical, Social Functioning at Weeks 8, 12, 28, 52

Secondary: Change from Baseline in SF-36 HRQoL Scores for Bodily Pain, General Health, Mental Health, Role-Emotional, Role-Physical, Social Functioning at Weeks 8, 12, 28, 52

Secondary: Change from Baseline in Vitality scores using SF-36 HRQoL Questionnaire at Weeks 28, 52

Secondary: Change from Baseline in Vitality scores using SF-36 HRQoL Questionnaire at Weeks 28, 52

Secondary: Change from Baseline in Physical Functioning domain scores using SF-36 HRQoL Questionnaire at Weeks 28, 52

Secondary: Change from Baseline in Physical Functioning domain scores using SF-36 HRQoL Questionnaire at Weeks 28, 52

Secondary: Change from Baseline in Health Utility EuroQol 5 Dimensions 5 Level (EQ-5D-5L) Questionnaire Score at Week 52

Secondary: Change from Baseline in Health Utility EuroQol 5 Dimensions 5 Level (EQ-5D-5L) Questionnaire Score at Week 52

Secondary: Change from Baseline in EQ Visual Analogue Scale (EQ-VAS) at Week 52

Secondary: Change from Baseline in EQ Visual Analogue Scale (EQ-VAS) at Week 52

Secondary: Change from Baseline in Chronic Kidney Disease- Anemia Symptoms Questionnaire (CKD-AQ) at Week 52

Secondary: Change from Baseline in Chronic Kidney Disease- Anemia Symptoms Questionnaire (CKD-AQ) at Week 52

Secondary: Change from Baseline in Patient Global Impression of Severity (PGI-S)

Secondary: Change from Baseline in Patient Global Impression of Severity (PGI-S)

Secondary: Plasma Concentration of Daprodustat (GSK1278863) and its Metabolites GSK2391220 (M2), GSK2506104 (M3), and GSK2531401 (M13)

Secondary: Plasma Concentration of Daprodustat (GSK1278863) and its Metabolites GSK2391220 (M2), GSK2506104 (M3), and GSK2531401 (M13)

Secondary: Observed concentration at Dosing Interval (Ctau) of Daprodustat (GSK1278863) and its Metabolites GSK2391220 (M2), GSK2506104 (M3), and GSK2531401 (M13)

Secondary: Observed concentration at Dosing Interval (Ctau) of Daprodustat (GSK1278863) and its Metabolites GSK2391220 (M2), GSK2506104 (M3), and GSK2531401 (M13)

Secondary: Maximum Observed Concentration (Cmax) of Daprodustat (GSK1278863) and its Metabolites GSK2391220 (M2), GSK2506104 (M3), and GSK2531401 (M13)

Secondary: Maximum Observed Concentration (Cmax) of Daprodustat (GSK1278863) and its Metabolites GSK2391220 (M2), GSK2506104 (M3), and GSK2531401 (M13)

Adverse events

Adverse events

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Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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