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    Clinical Trial Results:
    A 28-week, randomized, double-blind, placebo-controlled, parallel-group, multi-center, study in recombinant human erythropoietin (rhEPO) naïve non-dialysis participants with anemia associated with chronic kidney disease to evaluate the efficacy, safety and effects on quality of life of daprodustat compared to placebo

    Summary
    EudraCT number
    		 2017-002270-39
    Trial protocol
    		 GB   ES   PL   IT   RO  
    Global end of trial date
    07 Oct 2020

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

    Trial information

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    Trial identification
    Sponsor protocol code
    205270
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    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
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    22 Feb 2021
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    07 Oct 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To compare the efficacy of daprodustat to placebo on mean change in hemoglobin (Hgb) levels Secondary objectives of the trial: To compare the proportion of participants achieving increases in Hgb when treated with daprodustat versus placebo; To compare daprodustat to placebo for health related quality-of-life; To compare daprodustat to placebo on additional Hgb endpoints; To compare daprodustat to placebo on the time to rescue; To compare daprodustat to placebo for improving symptoms of anemia of chronic kidney disease (CKD); To compare daprodustat to placebo on the severity and change in symptoms; To compare daprodustat to placebo for improving health related quality-of-life; To compare daprodustat to placebo on improving work productivity and regular daily activity impairment; To compare daprodustat to placebo on improving health status; To compare daprodustat to placebo on blood pressure (BP)
    Protection of trial subjects
    Not applicable
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    05 Mar 2018
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Argentina: 26
    Country: Number of subjects enrolled
    Australia: 21
    Country: Number of subjects enrolled
    Brazil: 39
    Country: Number of subjects enrolled
    Canada: 39
    Country: Number of subjects enrolled
    France: 15
    Country: Number of subjects enrolled
    Italy: 21
    Country: Number of subjects enrolled
    Mexico: 105
    Country: Number of subjects enrolled
    Poland: 31
    Country: Number of subjects enrolled
    Romania: 47
    Country: Number of subjects enrolled
    Russian Federation: 40
    Country: Number of subjects enrolled
    Korea, Republic of: 39
    Country: Number of subjects enrolled
    Spain: 1
    Country: Number of subjects enrolled
    United Kingdom: 18
    Country: Number of subjects enrolled
    United States: 172
    Worldwide total number of subjects
    614
    EEA total number of subjects
    115
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    256
    From 65 to 84 years
    321
    85 years and over
    37

    Subject disposition

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    Recruitment
    Recruitment details
    		 This was a multicenter study conducted at 142 centers in 14 countries. Participants were randomized to receive either Daprodustat or Placebo.

    Pre-assignment
    Screening details
    		 A total of 1336 participants were screened, of which 722 were screen failures. A total of 614 participants were enrolled in the study.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo
    Arm description
    		 Participants received matching placebo once daily orally for up to 28 weeks followed by 4 weeks of follow-up.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received matching placebo orally once daily.

    Arm title
    		 Daprodustat
    Arm description
    		 Participants received daprodustat film-coated tablets with titrated dose levels ranging from 1, 2, 4, 6, 8, 10, 12, 16 milligrams (mg) once daily orally for up to 28 weeks, followed by 4 weeks of follow-up. Study treatment was dose-titrated to achieve and maintain hemoglobin in the target range (11 to 12 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 titrated dose levels ranging from 1, 2, 4, 6, 8, 10, 12, 16 milligrams (mg) once daily orally.

    Number of subjects in period 1
    		Placebo Daprodustat
    Started
    307
    307
    Completed
    290
    300
    Not completed
    17
    7
         Consent withdrawn by subject
    4
    2
         Physician decision
    1
    -
         Adverse event, non-fatal
    5
    3
         Lost to follow-up
    7
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Participants received matching placebo once daily orally for up to 28 weeks followed by 4 weeks of follow-up.

    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 milligrams (mg) once daily orally for up to 28 weeks, followed by 4 weeks of follow-up. Study treatment was dose-titrated to achieve and maintain hemoglobin in the target range (11 to 12 grams per deciliter [g/dL])

    Reporting group values
    		 Placebo Daprodustat Total
    Number of subjects
    		 307 307 614
    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)
    		 121 135 256
        From 65-84 years
    		 165 156 321
        85 years and over
    		 21 16 37
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 66.6 ± 12.93 65.3 ± 13.43 -
    Sex: Female, Male
    Units: Participants
        Female
    		 178 176 354
        Male
    		 129 131 260
    Race/Ethnicity, Customized
    Units: Subjects
        AMERICAN INDIAN OR ALASKA NATIVE
    		 34 34 68
        ASIAN: CENTRAL/SOUTH ASIAN HERITAGE
    		 3 6 9
        ASIAN:JAPANESE/EAST(E).ASIAN/SOUTH E.ASIA HERITAGE
    		 24 24 48
        ASIAN: MIXED ASIAN RACE
    		 1 0 1
        BLACK OR AFRICAN AMERICAN
    		 47 44 91
        NATIVE HAWAIIAN/OTHER PACIFIC ISLANDER
    		 1 0 1
        WHITE
    		 195 197 392
        BLACK OR AFRICAN AMERICAN AND WHITE
    		 2 2 4

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Participants received matching placebo once daily orally for up to 28 weeks followed by 4 weeks of follow-up.

    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 milligrams (mg) once daily orally for up to 28 weeks, followed by 4 weeks of follow-up. Study treatment was dose-titrated to achieve and maintain hemoglobin in the target range (11 to 12 grams per deciliter [g/dL])

    Primary: Mean change in hemoglobin from Baseline and over the evaluation period (mean over Week 24 and 28)

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    End point title
    		 Mean change in hemoglobin from Baseline and over the evaluation period (mean over Week 24 and 28)
    End point description
    Blood samples were collected at given time points from participants for hemoglobin measurements. Evaluation period hemoglobin value was defined as the mean of all available post-randomization hemoglobin values (on and off-treatment) during the evaluation period (Week 24 to Week 28 inclusive). For the primary analysis, the missing post-Baseline hemoglobin 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 value was the latest non-missing pre-dose assessment on or before the randomization date. Analysis was performed using the Analysis of Covariance (ANCOVA) model with terms for treatment, Baseline hemoglobin, and region. Intent-to-Treat (ITT) Population comprised all randomized participants regardless of whether they took study drug.
    End point type
    Primary
    End point timeframe
    Baseline (Day 1) and Week 24 to Week 28
    End point values
    		 Placebo Daprodustat
    Number of subjects analysed
    307 [1]
    307 [2]
    Units: Grams per deciliter
        least squares mean (standard error)
    0.19 ± 0.062
    1.58 ± 0.061
    Notes
    [1] - ITT Population
    [2] - ITT Population
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Treatment group comparisons were based on a ANCOVA model with terms for treatment, Baseline hemoglobin, and region.
    Comparison groups
    Placebo v Daprodustat
    Number of subjects included in analysis
    614
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [3]
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean difference
    Point estimate
    1.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.23
         upper limit
    		 1.56
    Notes
    [3] - One-sided p-value based on test of null hypothesis: (Daprodustat - Placebo) <= 0 versus alternative: difference > 0.

    Secondary: Percentage of participants with hemoglobin increase of >=1.0 grams per deciliter from Baseline to evaluation period

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    End point title
    		 Percentage of participants with hemoglobin increase of >=1.0 grams per deciliter from Baseline to evaluation period
    End point description
    Blood samples were collected at given time points for hemoglobin measurements. Evaluation period hemoglobin value was defined as the mean of all available post-randomization hemoglobin values (on and off-treatment) during the evaluation period (Week 24 to Week 28 inclusive). For the primary analysis, the missing post-Baseline hemoglobin values were imputed using pre-specified multiple imputations. Baseline value was the latest non-missing pre-dose assessment on or before the randomization date. Percentage of participants with hemoglobin increase of >=1.0 grams per deciliter from Baseline to evaluation period was analyzed using Cochran-Mantel-Haenszel (CMH) chi-squared test. The percentage values presented has been rounded off.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1) and Week 24 to Week 28
    End point values
    		 Placebo Daprodustat
    Number of subjects analysed
    307 [4]
    307 [5]
    Units: Percentage of participants
    18
    77
    Notes
    [4] - ITT Population
    [5] - ITT Population
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Treatment group comparisons were based on a Cochran-Mantel-Haenszel test adjusted for treatment group and region.
    Comparison groups
    Placebo v Daprodustat
    Number of subjects included in analysis
    614
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [6]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Difference in Response rate
    Point estimate
    0.56
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.49
         upper limit
    		 0.63
    Notes
    [6] - One-sided p-value was based on test of null hypothesis: (Daprodustat - Placebo) <=0 versus alternative: difference > 0

    Secondary: Change from Baseline in short form-36 (SF-36) questionnaire vitality domain score by traditional scoring at Week 28

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    End point title
    		 Change from Baseline in short form-36 (SF-36) questionnaire vitality domain score by traditional scoring at Week 28
    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 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 Perception of Health.Each domain is scored from 0 (poorer health) to 100 (better health). Vitality domain score ranges from 0-100; higher score indicates a better health state & better functioning. Change from Baseline was calculated as Post-Dose Visit Value at Week 28 minus Baseline. For primary analysis, the missing on-treatment Week 28 SF-36 Vitality domain scores were imputed using pre-specified multiple imputations. Baseline value was latest non-missing pre-dose assessment on or before randomization date. Analysis was performed using ANCOVA model with terms for treatment, Baseline score, and region.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1) and Week 28
    End point values
    		 Placebo Daprodustat
    Number of subjects analysed
    307 [7]
    307 [8]
    Units: Scores on a scale
        least squares mean (standard error)
    1.93 ± 1.161
    7.29 ± 1.121
    Notes
    [7] - ITT Population
    [8] - ITT Population
    Statistical analysis title
    		 Statistical Analysis
    Statistical analysis description
    Treatment group comparisons were based on ANCOVA model with terms for treatment, Baseline score, and region.
    Comparison groups
    Placebo v Daprodustat
    Number of subjects included in analysis
    614
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0005 [9]
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean Difference
    Point estimate
    5.36
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 2.17
         upper limit
    		 8.56
    Notes
    [9] - One-sided p-value based on test of null hypothesis:(Daprodustat-Placebo) <= 0 vs alternative: difference >0.

    Secondary: Percentage of participants with Hgb response (Hgb in the 11-12 grams/deciliter range) During Evaluation Period (Week 24 to Week 28 inclusive)

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    End point title
    		 Percentage of participants with Hgb response (Hgb in the 11-12 grams/deciliter range) During Evaluation Period (Week 24 to Week 28 inclusive)
    End point description
    Mean hemoglobin during the evaluation period was defined as the mean of all evaluable hemoglobin values during the evaluation period (Week 24 to Week 28 inclusive) including any evaluable unscheduled hemoglobin values that were taken during this period. Percentage of participants with Hgb response was defined as participants with mean Hgb within range (11-12 grams per deciliter during the evaluation period (Week 24 to Week 28 inclusive) and it was analyzed using Cochran-Mantel-Haenszel (CMH) chi-squared test. The percentage values presented has been rounded off.
    End point type
    Secondary
    End point timeframe
    Week 24 to Week 28
    End point values
    		 Placebo Daprodustat
    Number of subjects analysed
    307 [10]
    307 [11]
    Units: Percentage of participants
    8
    52
    Notes
    [10] - ITT Population
    [11] - ITT Population
    Statistical analysis title
    		 Statistical Analysis
    Statistical analysis description
    Treatment group comparisons are based on a Cochran-Mantel-Haenszel test adjusted for treatment group, and region
    Comparison groups
    Placebo v Daprodustat
    Number of subjects included in analysis
    614
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [12]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Difference in Response rate
    Point estimate
    0.45
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.37
         upper limit
    		 0.52
    Notes
    [12] - One-sided p-value was based on test of null hypothesis: (Daprodustat-Placebo) <=0 versus alternative: difference >0.

    Secondary: Percentage of time with Hgb within the target range (11-12 grams per deciliter) During Evaluation Period (Week 24 to Week 28 inclusive) (Hodges-Lehmann Estimate)

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    End point title
    		 Percentage of time with Hgb within the target range (11-12 grams per deciliter) During Evaluation Period (Week 24 to Week 28 inclusive) (Hodges-Lehmann Estimate)
    End point description
    Percentage of days for which participant’s Hgb was within the target range of 11-12 grams per deciliter during the evaluation period (Week 24 to Week 28 inclusive), including any unscheduled evaluable Hgb values that were taken during this time period. Percentage of time for which Hgb was within the target range (11-12 grams per deciliter) for a participant was calculated by dividing ‘the total number of days that Hgb was within range during Week 24 to 28’ by ‘the total number of days the participant remained on treatment during Week 24 to 28’. Only those participants with data available at the indicated time points were analyzed.
    End point type
    Secondary
    End point timeframe
    Week 24 to Week 28
    End point values
    		 Placebo Daprodustat
    Number of subjects analysed
    216 [13]
    252 [14]
    Units: Percentage of days
        median (full range (min-max))
    0.00 (0.0 to 100.0)
    53.59 (0.0 to 100.0)
    Notes
    [13] - ITT Population
    [14] - ITT Population
    Statistical analysis title
    		 Statistical Analysis
    Statistical analysis description
    Hodges-Lehmann Estimate of treatment difference has been reported.
    Comparison groups
    Placebo v Daprodustat
    Number of subjects included in analysis
    468
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    		 Hodges-Lehmann Estimate
    Parameter type
    		 Difference in treatment effect
    Point estimate
    38.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 25
         upper limit
    		 54.55

    Secondary: Percentage of participants with Hgb response (Hgb in the 11-12 grams/deciliter range) During Evaluation Period (Week 24 to Week 28 inclusive) (Mann-Whitney Estimate)

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    End point title
    		 Percentage of participants with Hgb response (Hgb in the 11-12 grams/deciliter range) During Evaluation Period (Week 24 to Week 28 inclusive) (Mann-Whitney Estimate)
    End point description
    Percentage of days for which participant’s Hgb was within the target range of 11-12 grams per deciliter during the evaluation period (Week 24 to Week 28 inclusive), including any unscheduled evaluable Hgb values that were taken during this time period. Percentage of time for which Hgb was within the target range (11-12 grams per deciliter) for a participant was calculated by dividing ‘the total number of days that Hgb was within range during Week 24 to 28’ by ‘the total number of days the participant remained on treatment during Week 24 to 28’. Only those participants with data available at the indicated time points were analyzed.
    End point type
    Secondary
    End point timeframe
    Week 24 to Week 28
    End point values
    		 Placebo Daprodustat
    Number of subjects analysed
    216 [15]
    252 [16]
    Units: Percentage of days
        median (full range (min-max))
    0.00 (0.0 to 100.0)
    53.59 (0.0 to 100.0)
    Notes
    [15] - ITT Population
    [16] - ITT Population
    Statistical analysis title
    		 Statistical Analysis
    Statistical analysis description
    Mann-Whitney estimate of the treatment difference stratified by region has been presented.
    Comparison groups
    Placebo v Daprodustat
    Number of subjects included in analysis
    468
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [17]
    Method
    		 van Elteren test
    Parameter type
    		 Difference in treatment effect
    Point estimate
    0.768
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.729
         upper limit
    		 0.806
    Notes
    [17] - One-sided superiority p-value from the van Elteren test

    Secondary: Change from Baseline in Post-randomization Hgb at Week 28

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    End point title
    		 Change from Baseline in Post-randomization Hgb at Week 28
    End point description
    Blood samples were collected at given time points for hemoglobin measurements. Change from Baseline in Hgb was analyzed using a mixed model repeated measures (MMRM) approach. Change from Baseline was calculated as Post-dose visit value minus Baseline. Baseline value was 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 28
    End point values
    		 Placebo Daprodustat
    Number of subjects analysed
    301 [18]
    299 [19]
    Units: Grams per deciliter
        least squares mean (standard error)
    0.20 ± 0.070
    1.56 ± 0.069
    Notes
    [18] - ITT Population
    [19] - ITT Population
    Statistical analysis title
    		 Statistical Analysis
    Statistical analysis description
    Treatment group comparisons were based on MMRM fitted from baseline up to Week 28, with factors for treatment, time, region, Baseline Hb and Baseline Hb by time and treatment by time interactions.
    Comparison groups
    Placebo v Daprodustat
    Number of subjects included in analysis
    600
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [20]
    Method
    		 MMRM
    Parameter type
    		 LS Mean difference
    Point estimate
    1.36
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.16
         upper limit
    		 1.55
    Notes
    [20] - One-sided superiority p-value from the MMRM model

    Secondary: Rate of participants permanently stopping randomized treatment due to meeting rescue criteria

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    End point title
    		 Rate of participants permanently stopping randomized treatment due to meeting rescue criteria
    End point description
    The incidence rate of participants permanently stopping randomized treatment due to meeting rescue criteria is presented.
    End point type
    Secondary
    End point timeframe
    Up to Week 28
    End point values
    		 Placebo Daprodustat
    Number of subjects analysed
    307 [21]
    307 [22]
    Units: Events per 100 person year
        number (confidence interval 95%)
    18.88 (12.33 to 27.66)
    1.33 (0.16 to 4.82)
    Notes
    [21] - ITT Population
    [22] - ITT Population
    Statistical analysis title
    		 Statistical Analysis
    Statistical analysis description
    Hazard ratio was estimated using a Cox proportional hazard regression model adjusted for treatment group and region.
    Comparison groups
    Placebo v Daprodustat
    Number of subjects included in analysis
    614
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0002 [23]
    Method
    		 Wald test
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.07
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.02
         upper limit
    		 0.3
    Notes
    [23] - One-sided p-value was based on Wald test of null hypothesis: (Daprodustat/Placebo) >=1 versus alternative: ratio<1.

    Secondary: Change from Baseline by domain and single item scores on the Chronic Kidney Disease -Anemia Questionnaire (CKD-AQ) symptom questionnaire

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    End point title
    		 Change from Baseline by domain and single item scores on the Chronic Kidney Disease -Anemia Questionnaire (CKD-AQ) symptom questionnaire
    End point description
    CKD-AQ is 21-item patient reported outcomes measure assessing symptoms & symptom impact in participants with anemia associated with CKD.CKD-AQ identified 3 domains:1.Tired/Low Energy/Weak scale consisting of 10items;2.Chest Pain/Shortness of Breath scale consisting of 4items;3.Cognitive scale consisting of 3items;&single items;4.Difficulty Sleeping;5.Difficulty Standing for long periods of time;6.Severity of Shortness of breath while sitting/resting;7.Time with Shortness of breath while not doing activity.Single-item measures were recorded based on 0-100 scoring:0 is worst possible&100 is best possible score.Total domain score is calculated as average of items in each domain &ranged from 0-100:0 is worst possible &100 is best possible score.Change from Baseline was calculated as post-dose visit value minus Baseline.Baseline value was latest non-missing pre-dose assessment on/before 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 28
    End point values
    		 Placebo Daprodustat
    Number of subjects analysed
    193 [24]
    212 [25]
    Units: Scores on a scale
    arithmetic mean (standard error)
        Tired/Low Energy/Weak Domain
    2.81 ± 1.132
    8.72 ± 1.086
        Chest Pain/Shortness of Breath Domain
    0.62 ± 0.971
    3.55 ± 0.932
        Cognitive Domain
    0.48 ± 1.042
    4.27 ± 0.999
        Difficulty in Sleeping
    2.61 ± 1.643
    5.22 ± 1.577
        Difficulty Standing for Long Periods of Time
    1.55 ± 1.630
    6.19 ± 1.563
        Severity of Shortness of Breath While Sitting/Rest
    0.43 ± 0.995
    3.11 ± 0.954
        Time with Shortness of BreathnotDoingActivity
    0.29 ± 1.083
    2.30 ± 1.037
    Notes
    [24] - ITT Population
    [25] - ITT Population
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Analysis was performed by MMRM with factors for treatment, time, region, Baseline value and Baseline value by time and treatment by time interactions for Tired/Low Energy/Weak domain.
    Comparison groups
    Placebo v Daprodustat
    Number of subjects included in analysis
    405
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [26]
    Method
    		 MMRM
    Parameter type
    		 Mean difference (net)
    Point estimate
    5.91
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 2.83
         upper limit
    		 9
    Notes
    [26] - One-sided p-value was based on test of null hypothesis: (Daprodustat-Placebo) <=0 versus alternative: difference >0.
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    Analysis was performed by MMRM with factors for treatment, time, region, Baseline value and Baseline value by time and treatment by time interactions for Chest Pain/Shortness of Breath Domain.
    Comparison groups
    Placebo v Daprodustat
    Number of subjects included in analysis
    405
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0152 [27]
    Method
    		 MMRM
    Parameter type
    		 Mean difference (net)
    Point estimate
    2.93
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.28
         upper limit
    		 5.57
    Notes
    [27] - One-sided p-value was based on test of null hypothesis: (Daprodustat-Placebo) <=0 versus alternative: difference >0.
    Statistical analysis title
    		 Statistical Analysis 3
    Statistical analysis description
    Analysis was performed by MMRM with factors for treatment, time, region, Baseline value and Baseline value by time and treatment by time interactions for Cognitive Domain.
    Comparison groups
    Placebo v Daprodustat
    Number of subjects included in analysis
    405
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0045 [28]
    Method
    		 MMRM
    Parameter type
    		 Mean difference (net)
    Point estimate
    3.79
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.95
         upper limit
    		 6.63
    Notes
    [28] - One-sided p-value was based on test of null hypothesis: (Daprodustat-Placebo) <=0 versus alternative: difference >0.
    Statistical analysis title
    		 Statistical Analysis 4
    Statistical analysis description
    Analysis was performed by MMRM with factors for treatment, time, region, Baseline value and Baseline value by time and treatment by time interactions for Difficulty Sleeping
    Comparison groups
    Placebo v Daprodustat
    Number of subjects included in analysis
    405
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1267 [29]
    Method
    		 MMRM
    Parameter type
    		 Mean difference (net)
    Point estimate
    2.61
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.87
         upper limit
    		 7.09
    Notes
    [29] - One-sided p-value was based on test of null hypothesis: (Daprodustat-Placebo) <=0 versus alternative: difference >0.
    Statistical analysis title
    		 Statistical Analysis 5
    Statistical analysis description
    Analysis was performed by MMRM with factors for treatment, time, region, Baseline value and Baseline value by time and treatment by time interactions for Difficulty Standing for Long Periods of Time
    Comparison groups
    Placebo v Daprodustat
    Number of subjects included in analysis
    405
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0203 [30]
    Method
    		 MMRM
    Parameter type
    		 Mean difference (net)
    Point estimate
    4.64
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.2
         upper limit
    		 9.09
    Notes
    [30] - One-sided p-value was based on test of null hypothesis: (Daprodustat-Placebo) <=0 versus alternative: difference >0.
    Statistical analysis title
    		 Statistical Analysis 6
    Statistical analysis description
    Analysis was performed by MMRM with factors for treatment, time, region, Baseline value and Baseline value by time and treatment by time interactions for Severity of Shortness of Breath While Sitting or Resting
    Comparison groups
    Placebo v Daprodustat
    Number of subjects included in analysis
    405
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0266 [31]
    Method
    		 MMRM
    Parameter type
    		 Mean difference (net)
    Point estimate
    2.68
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.04
         upper limit
    		 5.39
    Notes
    [31] - One-sided p-value was based on test of null hypothesis: (Daprodustat-Placebo) <=0 versus alternative: difference >0.
    Statistical analysis title
    		 Statistical Analysis 7
    Statistical analysis description
    Analysis was performed by MMRM with factors for treatment, time, region, Baseline value and Baseline value by time and treatment by time interactions for Time with Shortness of Breath While not Doing an Activity
    Comparison groups
    Placebo v Daprodustat
    Number of subjects included in analysis
    405
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0907 [32]
    Method
    		 MMRM
    Parameter type
    		 Mean difference (net)
    Point estimate
    2.01
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.94
         upper limit
    		 4.96
    Notes
    [32] - One-sided p-value was based on test of null hypothesis: (Daprodustat-Placebo) <=0 versus alternative: difference >0.

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

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    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. Baseline value was the latest non-missing pre-dose assessment on or before the randomization date. Adjusted mean and standard error is presented. 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 28
    End point values
    		 Placebo Daprodustat
    Number of subjects analysed
    193 [33]
    212 [34]
    Units: Scores on a scale
        least squares mean (standard error)
    -0.04 ± 0.055
    -0.18 ± 0.052
    Notes
    [33] - ITT Population
    [34] - ITT Population
    Statistical analysis title
    		 Statistical Analysis
    Statistical analysis description
    MMRM fitted from Baseline up to Week 28 with factors for treatment, time, region, Baseline value and Baseline value by time and treatment by time interactions.
    Comparison groups
    Placebo v Daprodustat
    Number of subjects included in analysis
    405
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0391 [35]
    Method
    		 MMRM
    Parameter type
    		 Mean difference (net)
    Point estimate
    -0.13
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.28
         upper limit
    		 0.02
    Notes
    [35] - One-sided p-value was based on test of null hypothesis: (Daprodustat-rhEPO) >=0 versus alternative: difference <0

    Secondary: Change from Baseline in the SF-36 physical functioning Domain

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    End point title
    		 Change from Baseline in the SF-36 physical functioning Domain
    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 eight 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 perception of health. Each domain is scored from 0 (poorer health) to 100 (better health). Physical functioning domain score ranges from 0-100; higher score indicates a better health state and better functioning. Change from Baseline was calculated as post-dose visit value minus Baseline. Baseline value was 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 28
    End point values
    		 Placebo Daprodustat
    Number of subjects analysed
    190 [36]
    210 [37]
    Units: Scores on a scale
        least squares mean (standard error)
    1.23 ± 1.354
    3.80 ± 1.298
    Notes
    [36] - ITT Population
    [37] - ITT Population
    Statistical analysis title
    		 Statistical Analysis
    Statistical analysis description
    MMRM fitted from Baseline up to Week 28 with factors for treatment, time, region, Baseline value and Baseline value by time and treatment by time interactions.
    Comparison groups
    Placebo v Daprodustat
    Number of subjects included in analysis
    400
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0858 [38]
    Method
    		 MMRM
    Parameter type
    		 Mean difference (net)
    Point estimate
    2.57
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.12
         upper limit
    		 6.26
    Notes
    [38] - One sided p-value was based on test of null hypothesis: (Daprodustat-Placebo) <=0 vs. alternative: difference >0.

    Secondary: Change from Baseline of the SF-36 individual items in the vitality Domain

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    End point title
    		 Change from Baseline of the SF-36 individual items in the vitality Domain
    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 eight 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 perception of health. Individual vitality item includes: 1. Did you feel full of life?, 2. Did you have a lot of energy?, 3. Did you feel worn out?, 4. Did you feel tired?. Score of each item in the vitality domain ranges from 0-100; higher score indicates better health state and better functioning. Change from Baseline was calculated as post-dose visit value minus Baseline. Baseline value was 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 28
    End point values
    		 Placebo Daprodustat
    Number of subjects analysed
    190 [39]
    210 [40]
    Units: Scores on a scale
    least squares mean (standard error)
        Did you feel full of life?
    -0.02 ± 0.070
    0.16 ± 0.067
        Did you have a lot of energy?
    0.09 ± 0.066
    0.26 ± 0.063
        Did you feel worn out?
    0.16 ± 0.067
    0.34 ± 0.064
        Did you feel tired?
    0.08 ± 0.060
    0.34 ± 0.057
    Notes
    [39] - ITT Population
    [40] - ITT Population
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    MMRM fitted from Baseline up to Week 28 with factors for treatment, time, region, Baseline value and Baseline value by time and treatment by time interactions for Did you feel full of life?
    Comparison groups
    Placebo v Daprodustat
    Number of subjects included in analysis
    400
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0357 [41]
    Method
    		 MMRM
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.17
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.02
         upper limit
    		 0.36
    Notes
    [41] - One sided p-value based on test of null hypothesis: (Daprodustat-Placebo) <=0 versus alternative: difference >0.
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    MMRM fitted from Baseline up to Week 28 with factors for treatment, time, region, Baseline value and Baseline value by time and treatment by time interactions for Did you have a lot of energy?
    Comparison groups
    Placebo v Daprodustat
    Number of subjects included in analysis
    400
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0328 [42]
    Method
    		 MMRM
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.17
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.01
         upper limit
    		 0.35
    Notes
    [42] - One-sided p-value based on test of null hypothesis: (Daprodustat-Placebo) <=0 versus alternative: difference >0.
    Statistical analysis title
    		 Statistical Analysis 3
    Statistical analysis description
    MMRM fitted from Baseline up to Week 28 with factors for treatment, time, region, Baseline value and Baseline value by time and treatment by time interactions for Did you feel worn out?
    Comparison groups
    Placebo v Daprodustat
    Number of subjects included in analysis
    400
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0252 [43]
    Method
    		 MMRM
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.18
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0
         upper limit
    		 0.37
    Notes
    [43] - One-sided p-value based on test of null hypothesis: (Daprodustat-Placebo) <=0 versus alternative: difference >0.
    Statistical analysis title
    		 Statistical Analysis 4
    Statistical analysis description
    MMRM fitted from Baseline up to Week 28 with factors for treatment, time, region, Baseline value and Baseline value by time and treatment by time interactions for Did you feel tired?
    Comparison groups
    Placebo v Daprodustat
    Number of subjects included in analysis
    400
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.001 [44]
    Method
    		 MMRM
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.26
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.1
         upper limit
    		 0.42
    Notes
    [44] - One-sided p-value based on test of null hypothesis: (Daprodustat-Placebo) <=0 versus alternative: difference >0.

    Secondary: Number of participants currently employed as per work productivity and activity impairment questionnaire: Anemic symptoms clinical practice version (WPAI-ANS-CPV)

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    End point title
    		 Number of participants currently employed as per work productivity and activity impairment questionnaire: Anemic symptoms clinical practice version (WPAI-ANS-CPV)
    End point description
    WPAI-ANS-CPV is anemia specific questionnaire designed as self-reported quantitative assessment of social functioning related to work and regular daily activities. It contains 2 concepts-work productivity impairment measured via absenteeism (time missed from work), presenteeism (impairment at work) and regular daily activity impairment. WPAI questions (Q) were:1) currently employed, 2) work time missed due to problem, 3) impairment while working due to problem, 4) overall work impairment due to problem, 5) activity impairment due to problem. WPAI generates 4 domain scores:percent (%) of work time missed(absenteeism),% of impairment while working (presenteeism), % of overall work impairment (absenteeism and presenteeism combined), % of activity impairment. Number of participants currently employed as per WPAI-ANS-CPV is presented. Only those participants with data available at the indicated time points were analyzed (represented by n=X in category titles).
    End point type
    Secondary
    End point timeframe
    Week 8, Week 12 and Week 28
    End point values
    		 Placebo Daprodustat
    Number of subjects analysed
    249 [45]
    251 [46]
    Units: Participants
        Week 8, No, n=249, 250
    195
    204
        Week 8, Yes, n=249, 250
    54
    46
        Week 12, No, n=234, 251
    183
    212
        Week 12, Yes, n=234, 251
    51
    39
        Week 28, No, n=193, 213
    158
    178
        Week 28, Yes, n=193, 213
    35
    35
    Notes
    [45] - ITT Population
    [46] - ITT Population
    No statistical analyses for this end point

    Secondary: Change from Baseline in WPAI-ANS-CPV: Percent time missed from Work

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    End point title
    		 Change from Baseline in WPAI-ANS-CPV: Percent time missed from Work
    End point description
    WPAI-ANS-CPV is anemia specific questionnaire designed as self-reported quantitative assessment of social functioning related to work&regular daily activities.It contain concepts-work productivity impairment measured via absenteeism(time missed from work),presenteeism(impairment at work)&regular daily activity impairment.WPAI Qs were:1)currently employed,2)work time missed due to problem,3)impairment while working due to problem,4)overall work impairment due to problem,5)activity impairment due to problem.Percent work time missed due to problem was subscale&calculated as: Q2/(Q2+Q4) for those who were currently employed.Subscale score was expressed as impairment percentage (range:0-100%) where higher numbers indicate greater impairment&less productivity.Change from Baseline was calculated as post-dose visit minus Baseline.Baseline was latest non-missing predose assessment on/before randomization date.Only those participants with data available at indicated time points are presented.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1), Week 8, Week 12 and Week 28
    End point values
    		 Placebo Daprodustat
    Number of subjects analysed
    50 [47]
    39 [48]
    Units: Percentage of time
    arithmetic mean (standard deviation)
        Week 8, n=50, 39
    -2.4 ± 28.40
    -6.1 ± 24.92
        Week 12, n=46, 31
    0.9 ± 28.79
    4.2 ± 27.96
        Week 28, n=28, 25
    0.0 ± 33.59
    0.3 ± 31.01
    Notes
    [47] - ITT Population
    [48] - ITT Population
    No statistical analyses for this end point

    Secondary: Change from Baseline in WPAI-ANS-CPV: mean hours missed from work in the past 7 days

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    End point title
    		 Change from Baseline in WPAI-ANS-CPV: mean hours missed from work in the past 7 days
    End point description
    WPAI-ANS-CPV is anemia specific questionnaire designed as self-reported quantitative assessment of social functioning related to work and regular daily activities. It contains 2 concepts-work productivity impairment measured via absenteeism (time missed from work), presenteeism (impairment at work) and regular daily activity impairment. WPAI questions (Q) were: 1) currently employed, 2) work time missed due to problem, 3) impairment while working due to problem, 4) overall work impairment due to problem, 5) activity impairment due to problem. Change from Baseline was calculated as post-dose visit value minus Baseline. Baseline value was the latest non-missing pre-dose assessment on or before the randomization date. Only those participants with data available at indicated time points are presented (presented by n=X in category titles).
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1), Week 8, Week 12 and Week 28
    End point values
    		 Placebo Daprodustat
    Number of subjects analysed
    50 [49]
    39 [50]
    Units: Percentage of hours
    arithmetic mean (standard deviation)
        Week 8, n=50, 39
    0.1 ± 18.46
    -1.8 ± 11.88
        Week 12, n=46, 31
    1.4 ± 14.07
    2.4 ± 16.83
        Week 28, n=28, 25
    0.3 ± 19.90
    1.0 ± 14.24
    Notes
    [49] - ITT Population
    [50] - ITT Population
    No statistical analyses for this end point

    Secondary: Change from Baseline in WPAI: Percent Impairment at Work

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    End point title
    		 Change from Baseline in WPAI: Percent Impairment at Work
    End point description
    WPAI-ANS-CPV is anemia specific questionnaire designed as self-reported quantitative assessment of social functioning related to work&regular daily activities.It contains2concepts-work productivity impairment measured via absenteeism(time missed from work),presenteeism(impairment at work)&regular daily activity impairment.WPAI Qs:1)currently employed,2)work time missed due to problem,3)impairment while working due to problem,4)overall work impairment due to problem,5)activity impairment due to problem.% Impairment while Working due to Problem was subscale&calculated asQ5/10 for those who were currently employed,actually worked in past7day.Subscale score was expressed as impairment percentage(range:0-100%),higher number indicate greater impairment,less productivity.Change fromBaseline=post-dose visit value-Baseline.Baseline was latest non-missing pre-dose assessment on/before randomization date.Only participants with data available at indicated time point are presented(n=X)
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1), Week 8, Week 12 and Week 28
    End point values
    		 Placebo Daprodustat
    Number of subjects analysed
    45 [51]
    32 [52]
    Units: Percentage of impairment
    arithmetic mean (standard deviation)
        Week 8, n=45, 32
    -5.1 ± 18.42
    -11.3 ± 24.06
        Week 12, n=41, 26
    -4.6 ± 18.99
    -8.8 ± 23.38
        Week 28, n=24, 20
    -9.6 ± 25.62
    -9.0 ± 22.92
    Notes
    [51] - ITT Population
    [52] - ITT Population
    No statistical analyses for this end point

    Secondary: Change from Baseline in WPAI: Percent overall work impairment

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    End point title
    		 Change from Baseline in WPAI: Percent overall work impairment
    End point description
    WPAI-ANS-CPV is anemia specific questionnaire designed as self-reported quantitative assessment of social functioning related to work & regular daily activities. WPAI Questions(Q)were:1)currently employed,2)work time missed due to problem,3)impairment while working due to problem,4)overall work impairment due to problem,5)activity impairment due to problem.Percent overall work impairment due to problem was subscale & calculated as: Q2/(Q2+Q4)+[(1-Q2/(Q2+Q4))×(Q5/10)] for those who were currently employed.Subscale score was expressed as impairment percentage (range:0-100%) where higher numbers indicate greater impairment. Change from Baseline was calculated as post-dose visit value minus Baseline. Baseline was latest non-missing pre-dose assessment on/before randomization date. Only those participants with data available at indicated time points were analyzed (n=X).
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1), Week 8, Week 12 and Week 28
    End point values
    		 Placebo Daprodustat
    Number of subjects analysed
    45 [53]
    32 [54]
    Units: Percentage of impairment
    arithmetic mean (standard deviation)
        Week 8, n=45, 32
    -4.3 ± 24.04
    -12.0 ± 25.90
        Week 12, n=41, 26
    0.5 ± 25.81
    -3.2 ± 33.35
        Week 28, n=24, 20
    -9.3 ± 37.45
    -8.4 ± 19.12
    Notes
    [53] - ITT Population
    [54] - ITT Population
    No statistical analyses for this end point

    Secondary: Change from Baseline in WPAI: Percent regular daily activity impairment

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    End point title
    		 Change from Baseline in WPAI: Percent regular daily activity impairment
    End point description
    WPAI-ANS-CPV is anemia specific questionnaire designed as self-reported quantitative assessment of social functioning related to work and regular daily activities.WPAI Questions (Q) were: 1) currently employed, 2) work time missed due to problem, 3) impairment while working due to problem, 4) overall work impairment due to problem, 5) activity impairment due to problem. Percent activity impairment due to problem was a subscale and calculated as: Q5/10 for all respondents. Subscale score was expressed as an impairment percentage (range: 0-100%) where higher numbers indicate greater impairment. Change from Baseline was calculated as post-dose visit value minus Baseline. Baseline value was the latest non-missing pre-dose assessment on or before randomization date.Only those participants with data available at the indicated time points were analyzed (represented by n=X in category titles).
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1), Week 8, Week 12 and Week 28
    End point values
    		 Placebo Daprodustat
    Number of subjects analysed
    246 [55]
    248 [56]
    Units: Percentage of impairment
    arithmetic mean (standard deviation)
        Week 8, n=243, 248
    -4.6 ± 23.67
    -7.7 ± 24.53
        Week 12, n=228, 246
    -5.2 ± 25.40
    -8.6 ± 24.58
        Week 28, n=187, 210
    -6.7 ± 28.93
    -12.2 ± 27.50
    Notes
    [55] - ITT Population
    [56] - ITT Population
    No statistical analyses for this end point

    Secondary: Change from Baseline in EuroQol 5 Dimension 5 Level Health Utility Index (EQ-5D-5L) utility score

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    End point title
    		 Change from Baseline in EuroQol 5 Dimension 5 Level Health Utility Index (EQ-5D-5L) utility score
    End point description
    The EQ-5D-5L is a self-assessment questionnaire, consisting of 5 items covering 5 dimensions (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression). Each dimension is measured by a 5-point Likert scale (1: no problems, 2: slight problems, 3: moderate problems, 4: severe problems, and 5: extreme problems). The responses for the five dimension together form a five-figure description of health state. Each of these five-figure health states has attached valuation (utility score), expressed as single index on a scale from 0-1, where 1 is full health and 0 is worst health. The higher the score the better the health status. Change from Baseline was calculated as post-dose visit value minus Baseline. Baseline value was the latest non-missing pre-dose assessment on or before the randomization date. Only those participants with data available at indicated time points are presented.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1) and Week 28
    End point values
    		 Placebo Daprodustat
    Number of subjects analysed
    106 [57]
    116 [58]
    Units: Scores on a scale
        least squares mean (standard error)
    0.01 ± 0.015
    0.03 ± 0.014
    Notes
    [57] - ITT Population
    [58] - ITT Population
    Statistical analysis title
    		 Statistical Analysis
    Statistical analysis description
    Based on MMRM model fitted from Baseline up to Week 28 with factors for treatment, time, region, Baseline value and Baseline value by time and treatment by time interactions.
    Comparison groups
    Placebo v Daprodustat
    Number of subjects included in analysis
    222
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1098 [59]
    Method
    		 MMRM
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.03
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.02
         upper limit
    		 0.07
    Notes
    [59] - One-sided p-value was based on test of null hypothesis: (Daprodustat-Placebo) <=0 versus. alternative: difference >0.

    Secondary: Change from Baseline in EuroQol visual analogue scale (EQ-VAS) score

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    End point title
    		 Change from Baseline in EuroQol visual analogue scale (EQ-VAS) score
    End point description
    The EQ VAS records the respondent’s self-rated health on a vertical, visual analogue scale where the endpoints are labeled ‘the best health you can imagine’ and ‘the worst health you can imagine’ at the time of completion. It is a self-assessment visual analogue scale, ranging from 0=worst imaginable to 100=best. Change from Baseline was calculated as post-dose visit value minus Baseline. Baseline value was the latest non-missing pre-dose assessment on or before the randomization date. Adjusted mean and standard error is presented. Only those participants with data available at indicated time points are presented.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1) and Week 28
    End point values
    		 Placebo Daprodustat
    Number of subjects analysed
    106 [60]
    116 [61]
    Units: Scores on a scale
        least squares mean (standard error)
    0.80 ± 1.427
    5.30 ± 1.373
    Notes
    [60] - ITT Population
    [61] - ITT Population
    Statistical analysis title
    		 Statistical Analysis
    Statistical analysis description
    Mixed model repeated measures model fitted from Baseline up to Week 28 with factors for treatment, time, region, Baseline value and Baseline value by time and treatment by time interactions.
    Comparison groups
    Placebo v Daprodustat
    Number of subjects included in analysis
    222
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.012 [62]
    Method
    		 MMRM
    Parameter type
    		 Mean difference (net)
    Point estimate
    4.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.6
         upper limit
    		 8.4
    Notes
    [62] - One-sided p-value was based on test of null hypothesis: (Daprodustat-Placebo) <=0 vs. alternative: difference >0.

    Secondary: Change from Baseline in systolic blood pressure (SBP), diastolic blood pressure (DBP), mean arterial pressure (MAP) at Week 28

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    End point title
    		 Change from Baseline in systolic blood pressure (SBP), diastolic blood pressure (DBP), mean arterial pressure (MAP) at Week 28
    End point description
    SBP, DBP and MAP were measured with participants in a seated position after at least a 5-minute of rest. MAP is the average BP in an individual’s arteries during a single cardiac cycle. Change from Baseline was calculated as post-dose visit value minus Baseline. Baseline value was 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 28
    End point values
    		 Placebo Daprodustat
    Number of subjects analysed
    202 [63]
    230 [64]
    Units: Millimeters of mercury (mmHg)
    least squares mean (standard error)
        SBP
    -0.63 ± 1.045
    -0.23 ± 0.981
        DBP
    -0.96 ± 0.625
    0.84 ± 0.587
        MAP
    -0.82 ± 0.674
    0.49 ± 0.632
    Notes
    [63] - ITT Population
    [64] - ITT Population
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    MMRM model fitted from Baseline up to Week 28, with factors for treatment, time, region, Baseline SBP and Baseline SBP by time and treatment by time interactions.
    Comparison groups
    Placebo v Daprodustat
    Number of subjects included in analysis
    432
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.6106 [65]
    Method
    		 MMRM
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.42
         upper limit
    		 3.22
    Notes
    [65] - One-sided p-value was based on test of null hypothesis: (Daprodustat - Placebo) >= 0 versus alternative: difference <0
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    MMRM model fitted from Baseline up to Week 28, with factors for treatment, time, region, Baseline DBP and Baseline DBP by time and treatment by time interactions.
    Comparison groups
    Placebo v Daprodustat
    Number of subjects included in analysis
    432
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.9819 [66]
    Method
    		 MMRM
    Parameter type
    		 Mean difference (net)
    Point estimate
    1.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.12
         upper limit
    		 3.49
    Notes
    [66] - One-sided p-value was based on test of null hypothesis: (Daprodustat - Placebo) >= 0 versus alternative: difference < 0
    Statistical analysis title
    		 Statistical Analysis 3
    Statistical analysis description
    MMRM model fitted from Baseline up to Week 28, with factors for treatment, time, region, Baseline MAP and Baseline MAP by time and treatment by time interactions.
    Comparison groups
    Placebo v Daprodustat
    Number of subjects included in analysis
    432
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.9215 [67]
    Method
    		 MMRM
    Parameter type
    		 Mean difference (net)
    Point estimate
    1.31
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.51
         upper limit
    		 3.13
    Notes
    [67] - One-sided p-value was based on test of null hypothesis: (Daprodustat - Placebo) >= 0 versus alternative: difference <0

    Secondary: Percentage of participants with at least one BP) exacerbation event

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    End point title
    		 Percentage of participants with at least one BP) exacerbation event
    End point description
    Percentage of participants with at least one BP exacerbation event is presented. BP exacerbation is defined as: SBP exacerbation: SBP >= 25 mmHg increase from Baseline or SBP >= 180 mmHg; DBP exacerbation: DBP >= 15 mmHg increase from Baseline or DBP >= 110 mmHg. Percentage of participants with at least one BP exacerbation event is presented. The percentage values presented has been rounded off.
    End point type
    Secondary
    End point timeframe
    Up to Week 28
    End point values
    		 Placebo Daprodustat
    Number of subjects analysed
    307
    307
    Units: Percentage of participants
    26
    32
    Statistical analysis title
    		 Statistical Analysis
    Statistical analysis description
    Cochran-Mantel-Haenszel test was performed for treatment group comparison.
    Comparison groups
    Placebo v Daprodustat
    Number of subjects included in analysis
    614
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.068 [68]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Difference in Response rate
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.02
         upper limit
    		 0.13
    Notes
    [68] - One-sided p-value based on test of null hypothesis: (Daprodustat - Placebo) <= 0 versus alternative: difference > 0.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All cause mortality, serious adverse events (SAEs) and non-serious AEs were collected up to follow-up (Week 32).
    Adverse event reporting additional description
    Safety Population comprised of all randomized participants who received at least 1 dose of study treatment.Treatment emergent non-serious adverse events & serious adverse events are reported.One participant who was randomized to placebo accidently received daprodustat during study & was evaluated in daprodustat treatment group for safety outcome.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    23.1
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Participants received matching placebo once daily orally for up to 28 weeks followed by 4 weeks of follow-up.

    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 milligrams (mg) once daily orally for up to 28 weeks, followed by 4 weeks of follow-up. Study treatment was dose-titrated to achieve and maintain hemoglobin in the target range (11 to 12 grams per deciliter [g/dL])

    Serious adverse events
    		 Placebo Daprodustat
    Total subjects affected by serious adverse events
         subjects affected / exposed
    68 / 306 (22.22%)
    62 / 308 (20.13%)
         number of deaths (all causes)
    16
    10
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Breast cancer
         subjects affected / exposed
    1 / 306 (0.33%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pituitary tumour benign
         subjects affected / exposed
    0 / 306 (0.00%)
    1 / 308 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Plasma cell myeloma
         subjects affected / exposed
    1 / 306 (0.33%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Hypertension
         subjects affected / exposed
    2 / 306 (0.65%)
    2 / 308 (0.65%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    3 / 306 (0.98%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertensive crisis
         subjects affected / exposed
    1 / 306 (0.33%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertensive emergency
         subjects affected / exposed
    1 / 306 (0.33%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypovolaemic shock
         subjects affected / exposed
    1 / 306 (0.33%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Peripheral arterial occlusive disease
         subjects affected / exposed
    0 / 306 (0.00%)
    1 / 308 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombophlebitis superficial
         subjects affected / exposed
    0 / 306 (0.00%)
    1 / 308 (0.32%)
         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
    Death
         subjects affected / exposed
    1 / 306 (0.33%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    1 / 306 (0.33%)
    0 / 308 (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
    Acute pulmonary oedema
         subjects affected / exposed
    1 / 306 (0.33%)
    3 / 308 (0.97%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary oedema
         subjects affected / exposed
    1 / 306 (0.33%)
    1 / 308 (0.32%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute interstitial pneumonitis
         subjects affected / exposed
    0 / 306 (0.00%)
    1 / 308 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchial hyperreactivity
         subjects affected / exposed
    1 / 306 (0.33%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    0 / 306 (0.00%)
    1 / 308 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Interstitial lung disease
         subjects affected / exposed
    1 / 306 (0.33%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    1 / 306 (0.33%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary hypertension
         subjects affected / exposed
    0 / 306 (0.00%)
    1 / 308 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Bipolar disorder
         subjects affected / exposed
    0 / 306 (0.00%)
    1 / 308 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Blood pressure increased
         subjects affected / exposed
    1 / 306 (0.33%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic enzyme increased
         subjects affected / exposed
    1 / 306 (0.33%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Liver function test abnormal
         subjects affected / exposed
    1 / 306 (0.33%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Femur fracture
         subjects affected / exposed
    0 / 306 (0.00%)
    2 / 308 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cervical vertebral fracture
         subjects affected / exposed
    0 / 306 (0.00%)
    1 / 308 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Craniocerebral injury
         subjects affected / exposed
    0 / 306 (0.00%)
    1 / 308 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Humerus fracture
         subjects affected / exposed
    1 / 306 (0.33%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Kidney rupture
         subjects affected / exposed
    1 / 306 (0.33%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ligament sprain
         subjects affected / exposed
    1 / 306 (0.33%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subdural haematoma
         subjects affected / exposed
    1 / 306 (0.33%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transplant dysfunction
         subjects affected / exposed
    0 / 306 (0.00%)
    1 / 308 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper limb fracture
         subjects affected / exposed
    1 / 306 (0.33%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular pseudoaneurysm
         subjects affected / exposed
    0 / 306 (0.00%)
    1 / 308 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Cardiac failure congestive
         subjects affected / exposed
    2 / 306 (0.65%)
    3 / 308 (0.97%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure acute
         subjects affected / exposed
    4 / 306 (1.31%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute coronary syndrome
         subjects affected / exposed
    2 / 306 (0.65%)
    1 / 308 (0.32%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    0 / 306 (0.00%)
    3 / 308 (0.97%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Bradycardia
         subjects affected / exposed
    2 / 306 (0.65%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Left ventricular failure
         subjects affected / exposed
    0 / 306 (0.00%)
    2 / 308 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute myocardial infarction
         subjects affected / exposed
    1 / 306 (0.33%)
    0 / 308 (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
    0 / 306 (0.00%)
    1 / 308 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Angina unstable
         subjects affected / exposed
    0 / 306 (0.00%)
    1 / 308 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arrhythmia
         subjects affected / exposed
    0 / 306 (0.00%)
    1 / 308 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Atrial flutter
         subjects affected / exposed
    0 / 306 (0.00%)
    1 / 308 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial thrombosis
         subjects affected / exposed
    0 / 306 (0.00%)
    1 / 308 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure chronic
         subjects affected / exposed
    1 / 306 (0.33%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    0 / 306 (0.00%)
    1 / 308 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mitral valve incompetence
         subjects affected / exposed
    1 / 306 (0.33%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    1 / 306 (0.33%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial ischaemia
         subjects affected / exposed
    0 / 306 (0.00%)
    1 / 308 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Right ventricular failure
         subjects affected / exposed
    0 / 306 (0.00%)
    1 / 308 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    1 / 306 (0.33%)
    4 / 308 (1.30%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Tricuspid valve incompetence
         subjects affected / exposed
    0 / 306 (0.00%)
    1 / 308 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Syncope
         subjects affected / exposed
    0 / 306 (0.00%)
    3 / 308 (0.97%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Autonomic nervous system imbalance
         subjects affected / exposed
    1 / 306 (0.33%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Encephalopathy
         subjects affected / exposed
    1 / 306 (0.33%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    0 / 306 (0.00%)
    1 / 308 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sciatica
         subjects affected / exposed
    1 / 306 (0.33%)
    0 / 308 (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
    Anaemia
         subjects affected / exposed
    8 / 306 (2.61%)
    2 / 308 (0.65%)
         occurrences causally related to treatment / all
    1 / 9
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Hypoacusis
         subjects affected / exposed
    1 / 306 (0.33%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tympanic membrane perforation
         subjects affected / exposed
    1 / 306 (0.33%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vertigo positional
         subjects affected / exposed
    0 / 306 (0.00%)
    1 / 308 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Ulcerative keratitis
         subjects affected / exposed
    1 / 306 (0.33%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vitreous haemorrhage
         subjects affected / exposed
    1 / 306 (0.33%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Gastrointestinal haemorrhage
         subjects affected / exposed
    2 / 306 (0.65%)
    1 / 308 (0.32%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 306 (0.33%)
    2 / 308 (0.65%)
         occurrences causally related to treatment / all
    0 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    2 / 306 (0.65%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 306 (0.33%)
    1 / 308 (0.32%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    0 / 306 (0.00%)
    1 / 308 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ascites
         subjects affected / exposed
    1 / 306 (0.33%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    1 / 306 (0.33%)
    0 / 308 (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 / 306 (0.33%)
    0 / 308 (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 / 306 (0.00%)
    1 / 308 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Large intestine polyp
         subjects affected / exposed
    1 / 306 (0.33%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    0 / 306 (0.00%)
    1 / 308 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Autoimmune hepatitis
         subjects affected / exposed
    0 / 306 (0.00%)
    1 / 308 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholangitis
         subjects affected / exposed
    1 / 306 (0.33%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    0 / 306 (0.00%)
    1 / 308 (0.32%)
         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
    Skin ulcer
         subjects affected / exposed
    0 / 306 (0.00%)
    1 / 308 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    5 / 306 (1.63%)
    5 / 308 (1.62%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    6 / 306 (1.96%)
    2 / 308 (0.65%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    End stage renal disease
         subjects affected / exposed
    2 / 306 (0.65%)
    2 / 308 (0.65%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Renal impairment
         subjects affected / exposed
    2 / 306 (0.65%)
    1 / 308 (0.32%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Azotaemia
         subjects affected / exposed
    1 / 306 (0.33%)
    1 / 308 (0.32%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Urinary retention
         subjects affected / exposed
    2 / 306 (0.65%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic kidney disease
         subjects affected / exposed
    1 / 306 (0.33%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    IgA nephropathy
         subjects affected / exposed
    0 / 306 (0.00%)
    1 / 308 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nephrolithiasis
         subjects affected / exposed
    0 / 306 (0.00%)
    1 / 308 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nephropathy toxic
         subjects affected / exposed
    0 / 306 (0.00%)
    1 / 308 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nephrotic syndrome
         subjects affected / exposed
    1 / 306 (0.33%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal haematoma
         subjects affected / exposed
    1 / 306 (0.33%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 306 (0.00%)
    1 / 308 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atlantoaxial instability
         subjects affected / exposed
    1 / 306 (0.33%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    1 / 306 (0.33%)
    0 / 308 (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
    Sepsis
         subjects affected / exposed
    2 / 306 (0.65%)
    2 / 308 (0.65%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    2 / 306 (0.65%)
    1 / 308 (0.32%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    4 / 306 (1.31%)
    2 / 308 (0.65%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    2 / 306 (0.65%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 306 (0.33%)
    2 / 308 (0.65%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    0 / 306 (0.00%)
    2 / 308 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    COVID-19
         subjects affected / exposed
    0 / 306 (0.00%)
    1 / 308 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetic foot infection
         subjects affected / exposed
    0 / 306 (0.00%)
    1 / 308 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear infection
         subjects affected / exposed
    1 / 306 (0.33%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endophthalmitis
         subjects affected / exposed
    1 / 306 (0.33%)
    0 / 308 (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 / 306 (0.00%)
    1 / 308 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    1 / 306 (0.33%)
    0 / 308 (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 / 306 (0.00%)
    1 / 308 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Otitis externa
         subjects affected / exposed
    1 / 306 (0.33%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Perirectal abscess
         subjects affected / exposed
    0 / 306 (0.00%)
    1 / 308 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia bacterial
         subjects affected / exposed
    0 / 306 (0.00%)
    1 / 308 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    0 / 306 (0.00%)
    1 / 308 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 306 (0.33%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hypoglycaemia
         subjects affected / exposed
    1 / 306 (0.33%)
    2 / 308 (0.65%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fluid overload
         subjects affected / exposed
    1 / 306 (0.33%)
    1 / 308 (0.32%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    0 / 306 (0.00%)
    1 / 308 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetic ketoacidosis
         subjects affected / exposed
    1 / 306 (0.33%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    1 / 306 (0.33%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperkalaemia
         subjects affected / exposed
    0 / 306 (0.00%)
    1 / 308 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    1 / 306 (0.33%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Placebo Daprodustat
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    44 / 306 (14.38%)
    49 / 308 (15.91%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    14 / 306 (4.58%)
    21 / 308 (6.82%)
         occurrences all number
    14
    27
    General disorders and administration site conditions
    Oedema peripheral
         subjects affected / exposed
    21 / 306 (6.86%)
    12 / 308 (3.90%)
         occurrences all number
    23
    14
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    17 / 306 (5.56%)
    24 / 308 (7.79%)
         occurrences all number
    22
    26

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    02 Apr 2018
    Country Specific Protocol ITA-1: Edited footnote 11 to include evaluation of all iron parameters at Week 4 in Section 2: Schedule of Activities; Exclude participants with a lower electrocardiogram (ECG) criteria based on Frederica’s QT Interval Corrected for Heart Rate (QTcF) and not Bazett’s QT Interval Corrected for Heart Rate (QTcB); exclude participants with second or third degree atrioventricular (AV) block in Exclusion Criteria (Crit) Exclusion 18; replaced QTcB with QTcF in Electrocardiograms section.
    23 Aug 2019
    Amendment 1:Added footnote17 to state when study treatment should be dispensed;Revised footnote9 to permit HemoCue Hgb retest with new blood sample; Revised footnote12 to clarify the purpose of participant reminder card;Edited footnote15 to add ultrasound assessments for ADPKD participants at end of treatment.Added row to conduct assessment regarding HCRU by participants at each visit starting with Day1 & after study treatment discontinuation;Added renal ultrasound for ADPKD participants upon discontinuation of study treatment ;Updated risk assessment table with language related to IB update;Added secondary & exploratory endpoints objectives related to BP exacerbations & concomitant medications;Revised secondary endpoints for work productivity& regular daily activity impairment captured on WPAI-ANS-CPV;Amended exploratory objectives for Hgb change to evaluate participants achieving Hgb increase of >=1.0 g/dL instead of >=1.2g/dL;Updated exploratory objective to capture time to first rhEPO Transfusion use;Edited inclusion Crit5 to provide clarity for requirements of compliance with oral iron dosing prior to Day1 & removed need for stable iron dose prior to screening;Edited ex crit 13 edited to include use of investigational device;Added ex crit22 for uncontrolled hypertension;Instructions to repeat & average HemoCue Hgb assessment for Hgb <8.5 g/dL;Added information regarding discontinuation of study treatment in participants with ADPKD;Added language related to alternative methods of follow-up;Added language regarding alternative methods of follow-up for participants potentially lost to follow-up;Added language regarding retests with new blood sample entering HemoCue Hgb values into IRT system;Added worsening of hypertension as additional AESI; Added guidance on conducting ultrasound for participants with ADPKD based on different clinical scenarios in study;Changes made to provide guidance regarding the conduct of study at French site only.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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