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    Clinical Trial Results:
    A Phase 3 randomized, double-blind, active-controlled, parallel-group, multi-center study in hemodialysis participants with anemia of chronic kidney disease to evaluate the efficacy, safety and pharmacokinetics of three-times weekly dosing of daprodustat compared to recombinant human erythropoietin, following a switch from recombinant human erythropoietin or its analogs

    Summary
    EudraCT number
    		 2017-004372-56
    Trial protocol
    		 ES   FR   GB   PL   IT   RO  
    Global end of trial date
    19 Jun 2020

    Results information
    Results version number
    		 v1(current)
    This version publication date
    04 Jul 2021
    First version publication date
    04 Jul 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    204837
    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,
    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
    17 Nov 2020
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    19 Jun 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To compare the effect of daprodustat to epoetin alfa on hemoglobin (Hgb) efficacy when administered three-times weekly to hemodialysis-dependent participants (noninferiority).
    Protection of trial subjects
    Not applicable
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    05 Sep 2018
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Korea, Republic of: 23
    Country: Number of subjects enrolled
    Romania: 9
    Country: Number of subjects enrolled
    Poland: 24
    Country: Number of subjects enrolled
    Russian Federation: 98
    Country: Number of subjects enrolled
    Australia: 8
    Country: Number of subjects enrolled
    Canada: 2
    Country: Number of subjects enrolled
    France: 10
    Country: Number of subjects enrolled
    Italy: 12
    Country: Number of subjects enrolled
    Spain: 32
    Country: Number of subjects enrolled
    United Kingdom: 9
    Country: Number of subjects enrolled
    Argentina: 42
    Country: Number of subjects enrolled
    Brazil: 31
    Country: Number of subjects enrolled
    United States: 107
    Worldwide total number of subjects
    407
    EEA total number of subjects
    87
    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)
    263
    From 65 to 84 years
    133
    85 years and over
    11

    Subject disposition

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    Recruitment
    Recruitment details
    		 This was a multicenter study conducted at 90 centers in 13 countries. Participants were randomized to receive either Daprodustat or Epoetin alfa.

    Pre-assignment
    Screening details
    		 A total of 595 participants were screened, of which 188 were screen failures. A total of 407 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, Monitor, Data analyst, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Daprodustat
    Arm description
    		 Participants received daprodustat tablets with titrated dose levels ranging from 2, 4, 8, 12, 16, 20, 24, 32 and 48 milligrams (mg) orally three-times weekly up to 52 weeks. Study treatment was dose-titrated to achieve and maintain hemoglobin in the target range (10 to 11 grams per deciliter [g/dL]). In order to maintain the study blind, participants also received saline intravenous (IV) injection once weekly or three-times weekly depending on dose level, up to 52 weeks as an inactive treatment for the IV formulation. All participants were followed up at 4 to 6 weeks after last dose.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Daprodustat
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Daprodustat tablets were given with titrated dose levels ranging from 2, 4, 8, 12, 16, 20, 24, 32 and 48 milligrams (mg) orally three-times weekly for 52 weeks.

    Investigational medicinal product name
    Saline
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Saline was administered as an IV injection once weekly or three-times weekly, depending on dose level for 52 weeks.

    Arm title
    		 Epoetin alfa
    Arm description
    		 Participants received epoetin alfa with titrated dose levels ranging from 1500 Units to 60,000 Units total weekly dose and administered as IV injection once weekly or three-times weekly depending on dose level up to 52 weeks. Study treatment was dose-titrated to achieve and maintain hemoglobin in the target range (10 to 11 g/dL). In order to maintain the study blind, participants also received placebo tablets matching to daprodustat orally three-times weekly up to 52 weeks as an inactive treatment for the tablet formulation. All participants were followed up at 4 to 6 weeks after last dose.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Epoetin alfa
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Epoetin alfa doses ranging from 1500 units to 60,000 units were administered as intravenous (IV) injections once weekly or three-times weekly, depending on dose level for 52 weeks.

    Investigational medicinal product name
    Placebo matching daprodustat
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo tablets matching daprodustat were given orally three-times weekly for 52 weeks.

    Number of subjects in period 1
    		Daprodustat Epoetin alfa
    Started
    270
    137
    Completed
    269
    135
    Not completed
    1
    2
         Consent withdrawn by subject
    1
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Daprodustat
    Reporting group description
    		 Participants received daprodustat tablets with titrated dose levels ranging from 2, 4, 8, 12, 16, 20, 24, 32 and 48 milligrams (mg) orally three-times weekly up to 52 weeks. Study treatment was dose-titrated to achieve and maintain hemoglobin in the target range (10 to 11 grams per deciliter [g/dL]). In order to maintain the study blind, participants also received saline intravenous (IV) injection once weekly or three-times weekly depending on dose level, up to 52 weeks as an inactive treatment for the IV formulation. All participants were followed up at 4 to 6 weeks after last dose.

    Reporting group title
    Epoetin alfa
    Reporting group description
    		 Participants received epoetin alfa with titrated dose levels ranging from 1500 Units to 60,000 Units total weekly dose and administered as IV injection once weekly or three-times weekly depending on dose level up to 52 weeks. Study treatment was dose-titrated to achieve and maintain hemoglobin in the target range (10 to 11 g/dL). In order to maintain the study blind, participants also received placebo tablets matching to daprodustat orally three-times weekly up to 52 weeks as an inactive treatment for the tablet formulation. All participants were followed up at 4 to 6 weeks after last dose.

    Reporting group values
    		 Daprodustat Epoetin alfa Total
    Number of subjects
    		 270 137 407
    Age Categorical
    Units: Participants
        19-64 Years
    		 167 96 263
        >= 65 Years
    		 103 41 144
    Sex: Female, Male
    Units: Participants
        Female
    		 121 56 177
        Male
    		 149 81 230
    Race/Ethnicity, Customized
    Units: Subjects
        BLACK OR AFRICAN AMERICAN
    		 49 32 81
        AMERICAN INDIAN OR ALASKAN NATIVE
    		 1 1 2
        ASIAN - CENTRAL/SOUTH ASIAN HERITAGE
    		 1 0 1
        ASIAN - EAST ASIAN HERITAGE
    		 16 9 25
        ASIAN - SOUTH EAST ASIAN HERITAGE
    		 3 0 3
        NATIVE HAWAIIAN OR OTHER PACIFIC ISLANDER
    		 1 0 1
        WHITE - ARABIC/NORTH AFRICAN HERITAGE
    		 1 4 5
        WHITE - WHITE/CAUCASIAN/EUROPEAN HERITAGE
    		 193 90 283
        MIXED WHITE RACE
    		 1 0 1
        MIXED RACE
    		 1 1 2
        UNKNOWN
    		 3 0 3

    End points

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    End points reporting groups
    Reporting group title
    Daprodustat
    Reporting group description
    		 Participants received daprodustat tablets with titrated dose levels ranging from 2, 4, 8, 12, 16, 20, 24, 32 and 48 milligrams (mg) orally three-times weekly up to 52 weeks. Study treatment was dose-titrated to achieve and maintain hemoglobin in the target range (10 to 11 grams per deciliter [g/dL]). In order to maintain the study blind, participants also received saline intravenous (IV) injection once weekly or three-times weekly depending on dose level, up to 52 weeks as an inactive treatment for the IV formulation. All participants were followed up at 4 to 6 weeks after last dose.

    Reporting group title
    Epoetin alfa
    Reporting group description
    		 Participants received epoetin alfa with titrated dose levels ranging from 1500 Units to 60,000 Units total weekly dose and administered as IV injection once weekly or three-times weekly depending on dose level up to 52 weeks. Study treatment was dose-titrated to achieve and maintain hemoglobin in the target range (10 to 11 g/dL). In order to maintain the study blind, participants also received placebo tablets matching to daprodustat orally three-times weekly up to 52 weeks as an inactive treatment for the tablet formulation. All participants were followed up at 4 to 6 weeks after last dose.

    Subject analysis set title
    Daprodustat 2 mg
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants received daprodustat tablets 2 mg orally three-times weekly at the time of the pharmacokinetic visit.

    Subject analysis set title
    Daprodustat 4 mg
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants received daprodustat tablets 4 mg orally three-times weekly at the time of the pharmacokinetic visit.

    Subject analysis set title
    Daprodustat 8 mg
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants received daprodustat tablets 8 mg orally three-times weekly at the time of the pharmacokinetic visit.

    Subject analysis set title
    Daprodustat 12 mg
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants received daprodustat tablets 12 mg orally three-times weekly at the time of the pharmacokinetic visit.

    Subject analysis set title
    Daprodustat 16 mg
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants received daprodustat tablets 16 mg orally three-times weekly at the time of the pharmacokinetic visit.

    Subject analysis set title
    Daprodustat 20 mg
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants received daprodustat tablets 20 mg orally three-times weekly at the time of the pharmacokinetic visit.

    Subject analysis set title
    Daprodustat 24 mg
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants received daprodustat tablets 24 mg orally three-times weekly at the time of the pharmacokinetic visit.

    Subject analysis set title
    Daprodustat 32 mg
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants received daprodustat tablets 32 mg orally three-times weekly at the time of the pharmacokinetic visit.

    Subject analysis set title
    Daprodustat 48 mg
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants received daprodustat tablets 48 mg orally three-times weekly at the time of the pharmacokinetic visit.

    Primary: Mean change from Baseline in hemoglobin levels over the evaluation period (Week 28 to Week 52)

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    End point title
    		 Mean change from Baseline in hemoglobin levels over the evaluation period (Week 28 to Week 52)
    End point description
    Blood samples were collected from participants for hemoglobin measurements. Hemoglobin during the evaluation period was defined as the mean of all available post-randomization hemoglobin values (on and off-treatment) during the evaluation period (Week 28 to Week 52). 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, including those from unscheduled visits. Change from Baseline was defined as the average of post-randomization values during the evaluation period minus Baseline value. Analysis was performed using the Analysis of Covariance (ANCOVA) model with terms for treatment, Baseline hemoglobin, and region. All Randomized (Intent-to-treat [ITT]) Population comprised of all randomized participants. Any participant who received a treatment randomization number was considered to have been randomized.
    End point type
    Primary
    End point timeframe
    Baseline (Pre-dose on Day 1) and evaluation period (Week 28 to Week 52)
    End point values
    		 Daprodustat Epoetin alfa
    Number of subjects analysed
    270 [1]
    137 [2]
    Units: Grams per deciliter (g/dL)
        least squares mean (standard error)
    -0.04 ( 0.045 )
    0.02 ( 0.066 )
    Notes
    [1] - All Randomized (ITT) Population
    [2] - All Randomized (ITT) Population
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Epoetin alfa v Daprodustat
    Number of subjects included in analysis
    407
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [3]
    Method
    Parameter type
    		 Least square (LS) mean difference
    Point estimate
    -0.05
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.21
         upper limit
    		 0.1
    Notes
    [3] - Non-inferiority was to be established if the lower limit of the two-sided 95 percent (%) confidence interval (CI) for the treatment difference is greater than the pre-specified non-inferiority margin of -0.75 g/dL.

    Secondary: Mean average monthly on-treatment intravenous (IV) iron dose per participant

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    End point title
    		 Mean average monthly on-treatment intravenous (IV) iron dose per participant
    End point description
    Average monthly IV iron dose (mg) per participant during Day 1 to Week 52 was determined by calculating the total IV iron dose per participant from Day 1 to Week 52 while the participant was on study treatment and dividing by (the number of days the participant was on study treatment divided by 30.4375 days). Analysis was performed using the ANCOVA model with terms for treatment, Baseline monthly IV iron dose, and region. Only those participants with data available at specified time points were analyzed.
    End point type
    Secondary
    End point timeframe
    Day 1 to Week 52
    End point values
    		 Daprodustat Epoetin alfa
    Number of subjects analysed
    270 [4]
    136 [5]
    Units: Milligrams
        least squares mean (standard error)
    98.11 ( 11.049 )
    106.23 ( 15.569 )
    Notes
    [4] - All Randomized (ITT) Population
    [5] - All Randomized (ITT) Population
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Daprodustat v Epoetin alfa
    Number of subjects included in analysis
    406
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.3354
    Method
    		 ANCOVA
    Parameter type
    		 LS mean difference
    Point estimate
    -8.12
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -45.66
         upper limit
    		 29.41

    Secondary: Change from Baseline in hemoglobin levels at Week 52

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    End point title
    		 Change from Baseline in hemoglobin levels at Week 52
    End point description
    Blood samples were collected from participants for hemoglobin measurements. Baseline value was the latest non-missing pre-dose assessment on or before the randomization date, including those from unscheduled visits. Change from Baseline was defined as the post-randomization visit value minus Baseline value. Analysis was performed using a mixed model repeated measures (MMRM) model fitted to hemoglobin data collected after Baseline up to Week 52, excluding values collected during the stabilization period (Day 1 to Week 28). The model included factors for treatment, time, region, Baseline hemoglobin and Baseline hemoglobin by time and treatment by time interaction terms. Only those participants with data available at specified time points were analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline (Pre-dose on Day 1) and Week 52
    End point values
    		 Daprodustat Epoetin alfa
    Number of subjects analysed
    252 [6]
    128 [7]
    Units: Grams per deciliter
        least squares mean (standard error)
    -0.03 ( 0.069 )
    0.11 ( 0.098 )
    Notes
    [6] - All Randomized (ITT) Population
    [7] - All Randomized (ITT) Population
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Daprodustat v Epoetin alfa
    Number of subjects included in analysis
    380
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [8]
    Method
    Parameter type
    		 LS mean difference
    Point estimate
    -0.14
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.37
         upper limit
    		 0.1
    Notes
    [8] - Non-inferiority was to be established if the lower limit of the two-sided 95 % CI for the treatment difference is greater than the pre-specified non-inferiority margin of -0.75 g/dL.

    Secondary: Percentage of time with hemoglobin in the analysis range (10 to 11.5 grams/deciliter) over evaluation period (Week 28 to Week 52)

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    End point title
    		 Percentage of time with hemoglobin in the analysis range (10 to 11.5 grams/deciliter) over evaluation period (Week 28 to Week 52)
    End point description
    Participants received treatment during the study to achieve or maintain hemoglobin level in the target range. Percentage of time for which hemoglobin level was maintained within the analysis range (10 to 11.5 grams/deciliter) has been presented. Only those participants with at least one evaluable hemoglobin value during the evaluation period were analyzed.
    End point type
    Secondary
    End point timeframe
    Week 28 to Week 52
    End point values
    		 Daprodustat Epoetin alfa
    Number of subjects analysed
    215 [9]
    107 [10]
    Units: Percentage of days
        median (inter-quartile range (Q1-Q3))
    70.83 (50.98 to 91.07)
    61.76 (29.69 to 85.19)
    Notes
    [9] - All Randomized (ITT) Population
    [10] - All Randomized (ITT) Population
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Hodges-Lehmann Estimate of Treatment Difference has been reported.
    Comparison groups
    Daprodustat v Epoetin alfa
    Number of subjects included in analysis
    322
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [11]
    P-value
    		 = 0.0034
    Method
    		 Van Elteren's test
    Parameter type
    		 Median difference (final values)
    Point estimate
    11.18
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 2.83
         upper limit
    		 19.56
    Notes
    [11] - Non-inferiority was to be established if the lower limit of the two-sided 95% CI for the treatment difference was above the non-inferiority margin of - 15%.

    Secondary: Number of hemoglobin responders in the hemoglobin analysis range (10 to 11.5 grams/deciliter) over evaluation period (Week 28 to Week 52)

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    End point title
    		 Number of hemoglobin responders in the hemoglobin analysis range (10 to 11.5 grams/deciliter) over evaluation period (Week 28 to Week 52)
    End point description
    Mean hemoglobin during the evaluation period was defined as the mean of all evaluable hemoglobin values during the evaluation period (Week 28 to Week 52) including any evaluable unscheduled hemoglobin values that were taken during this time period. Hemoglobin responders were defined as the number of participants with a mean hemoglobin during the evaluation period that falls within the hemoglobin analysis range of 10-11.5 grams/deciliter. Only those participants with at least one evaluable hemoglobin value during the evaluation period were analyzed.
    End point type
    Secondary
    End point timeframe
    Week 28 to Week 52
    End point values
    		 Daprodustat Epoetin alfa
    Number of subjects analysed
    215 [12]
    107 [13]
    Units: Participants
    172
    68
    Notes
    [12] - All Randomized (ITT) Population
    [13] - All Randomized (ITT) Population
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Daprodustat v Epoetin alfa
    Number of subjects included in analysis
    322
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.0007
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Difference in response rate
    Point estimate
    0.1645
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.06
         upper limit
    		 0.27

    Secondary: Percentage of participants permanently stopping study treatment due to meeting rescue criteria

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    End point title
    		 Percentage of participants permanently stopping study treatment due to meeting rescue criteria
    End point description
    Percentage of participants permanently stopping study treatment due to meeting rescue criteria has been presented.
    End point type
    Secondary
    End point timeframe
    Up to Week 52
    End point values
    		 Daprodustat Epoetin alfa
    Number of subjects analysed
    270 [14]
    137 [15]
    Units: Percentage of participants
        number (not applicable)
    2.2
    2.2
    Notes
    [14] - All Randomized (ITT) Population
    [15] - All Randomized (ITT) Population
    Statistical analysis title
    		 Statistical Analysis
    Statistical analysis description
    Hazard ratio is estimated using a Cox proportional hazard regression model adjusted for treatment group and region.
    Comparison groups
    Daprodustat v Epoetin alfa
    Number of subjects included in analysis
    407
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.5308
    Method
    		 Wald test
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.06
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.26
         upper limit
    		 4.22

    Secondary: Change from Baseline in systolic blood pressure (SBP), diastolic blood pressure (DBP) and mean arterial pressure (MAP) at Week 52

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    End point title
    		 Change from Baseline in systolic blood pressure (SBP), diastolic blood pressure (DBP) and mean arterial pressure (MAP) at Week 52
    End point description
    Measurements for SBP, DBP and MAP were taken with the participant in a semi-supine or seated position in the dialysis chair after at least a 5-minute rest period. MAP is the average BP in an individual's arteries during a single cardiac cycle. Baseline value was the latest non-missing pre-dose assessment on or before the randomization date, including those from unscheduled visits. Change from Baseline was defined as the on-treatment visit value minus Baseline value. Analysis was performed using MMRM model with treatment group, time, region, Baseline value, Baseline value*time, treatment group*time as variables. Only those participants with data available at specified time points were analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline (Week -4 ) and Week 52
    End point values
    		 Daprodustat Epoetin alfa
    Number of subjects analysed
    266 [16]
    133 [17]
    Units: Millimeter of mercury (mmHg)
    least squares mean (standard error)
        SBP
    -3.18 ( 1.470 )
    0.55 ( 2.252 )
        DBP
    -2.52 ( 0.764 )
    -0.29 ( 1.176 )
        MAP
    -2.72 ( 0.907 )
    -0.12 ( 1.389 )
    Notes
    [16] - All Randomized (ITT) Population
    [17] - All Randomized (ITT) Population
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    SBP
    Comparison groups
    Daprodustat v Epoetin alfa
    Number of subjects included in analysis
    399
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.083
    Method
    		 MMRM
    Parameter type
    		 LS mean difference
    Point estimate
    -3.73
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -9.03
         upper limit
    		 1.56
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    DBP
    Comparison groups
    Daprodustat v Epoetin alfa
    Number of subjects included in analysis
    399
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.057
    Method
    		 MMRM
    Parameter type
    		 LS mean difference
    Point estimate
    -2.23
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.99
         upper limit
    		 0.54
    Statistical analysis title
    		 Statistical Analysis 3
    Statistical analysis description
    MAP
    Comparison groups
    Daprodustat v Epoetin alfa
    Number of subjects included in analysis
    399
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.059
    Method
    		 MMRM
    Parameter type
    		 LS mean difference
    Point estimate
    -2.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.86
         upper limit
    		 0.67

    Secondary: Change from Baseline in SBP, DBP and MAP at end of treatment

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    End point title
    		 Change from Baseline in SBP, DBP and MAP at end of treatment
    End point description
    Measurements for SBP, DBP and MAP were taken with the participant in a semi-supine or seated position in the dialysis chair after at least a 5-minute rest period. MAP is the average BP in an individual's arteries during a single cardiac cycle. Baseline value was the latest non-missing pre-dose assessment on or before the randomization date, including those from unscheduled visits. Change from Baseline was defined as the last on-treatment visit value minus Baseline value. Analysis was performed using ANCOVA model with terms for treatment group, region and Baseline value. Adjusted mean and standard error have been presented. Only those participants with data available at specified time points were analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline (Week -4) and end of treatment (last on-treatment value until Week 52)
    End point values
    		 Daprodustat Epoetin alfa
    Number of subjects analysed
    270 [18]
    136 [19]
    Units: Millimeter of mercury (mmHg)
    arithmetic mean (standard error)
        SBP
    -1.4 ( 1.24 )
    -0.9 ( 1.75 )
        DBP
    -1.8 ( 0.66 )
    -0.8 ( 0.93 )
        MAP
    -1.7 ( 0.78 )
    -0.8 ( 1.09 )
    Notes
    [18] - All Randomized (ITT) Population
    [19] - All Randomized (ITT) Population
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    SBP
    Comparison groups
    Daprodustat v Epoetin alfa
    Number of subjects included in analysis
    406
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.407
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    -0.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.73
         upper limit
    		 3.72
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    DBP
    Comparison groups
    Daprodustat v Epoetin alfa
    Number of subjects included in analysis
    406
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.179
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    -1.05
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.29
         upper limit
    		 1.19
    Statistical analysis title
    		 Statistical Analysis 3
    Statistical analysis description
    MAP
    Comparison groups
    Daprodustat v Epoetin alfa
    Number of subjects included in analysis
    406
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.261
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    -0.86
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.5
         upper limit
    		 1.78

    Secondary: Blood pressure (BP) exacerbation event rate per 100 participant years

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    End point title
    		 Blood pressure (BP) exacerbation event rate per 100 participant years
    End point description
    BP exacerbation event is defined (based on post-dialysis BP) as SBP >=25 mmHg increased from Baseline or SBP >=180 mmHg; or DBP >=15 mmHg increased from Baseline or DBP >=110 mmHg. The BP exacerbation events per 100 participant years was estimated using the Negative Binomial Model. Only those participants with data available at specified time points were analyzed.
    End point type
    Secondary
    End point timeframe
    Up to 52 weeks
    End point values
    		 Daprodustat Epoetin alfa
    Number of subjects analysed
    270 [20]
    136 [21]
    Units: Events per 100 participant years
        number (confidence interval 95%)
    250.45 (210.69 to 297.72)
    356.91 (280.95 to 453.41)
    Notes
    [20] - All Randomized (ITT) Population
    [21] - All Randomized (ITT) Population
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Daprodustat v Epoetin alfa
    Number of subjects included in analysis
    406
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.0093
    Method
    		 Negative binomial model
    Parameter type
    		 Ratio of exacerbation rate
    Point estimate
    0.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.52
         upper limit
    		 0.94

    Secondary: Number of participants with at least one BP exacerbation event during the study

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    End point title
    		 Number of participants with at least one BP exacerbation event during the study
    End point description
    BP exacerbation (based on post-dialysis BP) is defined as: SBP >=25 mmHg increased from Baseline or SBP >=180mmHg; or DBP >=15 mmHg increase from Baseline or DBP >=110 mmHg. Number of participants with at least 1 BP exacerbation event have been reported. Only those participants with data available at specified time points were analyzed.
    End point type
    Secondary
    End point timeframe
    Up to 52 weeks
    End point values
    		 Daprodustat Epoetin alfa
    Number of subjects analysed
    270 [22]
    136 [23]
    Units: Participants
    151
    91
    Notes
    [22] - All Randomized (ITT) Population
    [23] - All Randomized (ITT) Population
    No statistical analyses for this end point

    Secondary: Change from Baseline at Weeks 8, 12, 28 and 52 in Patient Global Impression of Severity (PGI-S)

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    End point title
    		 Change from Baseline at Weeks 8, 12, 28 and 52 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 of their anemia of Chronic kidney disease (CKD). It is measured on a 5-point disease severity scale ranging from 0 (absent) to 4 (very severe), higher score indicates more disease severity. Baseline value was the latest non-missing pre-dose assessment on or before the randomization date, including those from unscheduled visits. Change from Baseline in on-treatment PGI-S scores was defined as the on-treatment visit value minus Baseline value. Analysis was performed using MMRM model fitted from Baseline up to Week 52 with factors for treatment, time, region, Baseline value and Baseline value by time and treatment by time interactions. Only those participants with data available at specified time points were analyzed (represented as n=X in the category titles).
    End point type
    Secondary
    End point timeframe
    Baseline (Pre-dose on Day 1) and Weeks 8, 12, 28, 52
    End point values
    		 Daprodustat Epoetin alfa
    Number of subjects analysed
    270 [24]
    137 [25]
    Units: Scores on a scale
    least squares mean (standard error)
        Week 8; n=248, 126
    -0.10 ( 0.048 )
    0.05 ( 0.068 )
        Week 12; n=243, 120
    -0.13 ( 0.050 )
    -0.01 ( 0.071 )
        Week 28; n=211, 106
    -0.07 ( 0.054 )
    0.03 ( 0.077 )
        Week 52; n=170, 85
    -0.11 ( 0.063 )
    0.04 ( 0.088 )
    Notes
    [24] - All Randomized (ITT) Population
    [25] - All Randomized (ITT) Population
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Week 8
    Comparison groups
    Daprodustat v Epoetin alfa
    Number of subjects included in analysis
    407
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0323
    Method
    		 MMRM
    Parameter type
    		 LS mean difference
    Point estimate
    -0.15
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.32
         upper limit
    		 0.01
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    Week 12
    Comparison groups
    Daprodustat v Epoetin alfa
    Number of subjects included in analysis
    407
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0921
    Method
    		 MMRM
    Parameter type
    		 LS mean difference
    Point estimate
    -0.12
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.29
         upper limit
    		 0.06
    Statistical analysis title
    		 Statistical Analysis 3
    Statistical analysis description
    Week 28
    Comparison groups
    Daprodustat v Epoetin alfa
    Number of subjects included in analysis
    407
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1291
    Method
    		 MMRM
    Parameter type
    		 LS mean difference
    Point estimate
    -0.11
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.29
         upper limit
    		 0.08
    Statistical analysis title
    		 Statistical Analysis 4
    Statistical analysis description
    Week 52
    Comparison groups
    Daprodustat v Epoetin alfa
    Number of subjects included in analysis
    407
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0859
    Method
    		 MMRM
    Parameter type
    		 LS mean difference
    Point estimate
    -0.15
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.36
         upper limit
    		 0.06

    Secondary: Pre-dose trough concentration (Ctau) of daprodustat (GSK1278863) and its metabolites GSK2391220 (M2), GSK2487818 (M4), GSK2506102 (M5), GSK2506104 (M3), GSK2531398 (M6) and GSK2531401 (M13)

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    End point title
    		 Pre-dose trough concentration (Ctau) of daprodustat (GSK1278863) and its metabolites GSK2391220 (M2), GSK2487818 (M4), GSK2506102 (M5), GSK2506104 (M3), GSK2531398 (M6) and GSK2531401 (M13)
    End point description
    Blood samples were collected at indicated time points for pharmacokinetic analysis of daprodustat (GSK1278863) and its metabolites: GSK2391220 (M2), GSK2487818 (M4), GSK2506102 (M5), GSK2506104 (M3), GSK2531398 (M6) and GSK2531401 (M13). Pharmacokinetic Population comprised of all randomized participants for whom a post-Baseline pharmacokinetic sample was obtained and analyzed. Only those participants with data available at specified time points were analyzed (represented as n=X in the category titles). 99999 indicates that data was not available as geometric coefficient of variation could not be calculated for single participant.
    End point type
    Secondary
    End point timeframe
    Pre-dose on Day 1; Pre-dose and at 0.5, 1, 2, 3 hours post-dose on any one post-Baseline visit day between Week 8 and Week 52
    End point values
    		 Daprodustat 2 mg Daprodustat 4 mg Daprodustat 8 mg Daprodustat 12 mg Daprodustat 16 mg Daprodustat 20 mg Daprodustat 24 mg Daprodustat 32 mg Daprodustat 48 mg
    Number of subjects analysed
    8 [26]
    20 [27]
    51 [28]
    59 [29]
    45 [30]
    28 [31]
    16 [32]
    3 [33]
    3 [34]
    Units: Nanograms per milliliter
    geometric mean (geometric coefficient of variation)
        Daprodustat; n=1, 2, 10, 18, 14, 9, 6, 3, 2
    6.2400 ( 99999 )
    1.1207 ( 494.71 )
    0.1786 ( 77.35 )
    0.3727 ( 277.88 )
    0.3443 ( 100.78 )
    0.3871 ( 161.05 )
    0.1621 ( 42.17 )
    0.2768 ( 140.82 )
    0.3486 ( 68.34 )
        GSK2391220; n=4, 17,42, 57, 40, 25, 16, 3, 3
    0.8623 ( 241.17 )
    0.5893 ( 255.59 )
    0.6341 ( 123.92 )
    1.1572 ( 184.51 )
    1.1654 ( 191.57 )
    1.1792 ( 168.59 )
    1.4987 ( 136.35 )
    1.6974 ( 6.82 )
    1.3531 ( 19.28 )
        GSK2487818; n=1, 4, 5, 20, 14, 7, 4, 3, 2
    0.3620 ( 99999 )
    0.2867 ( 111.67 )
    0.1594 ( 16.91 )
    0.2996 ( 105.55 )
    0.3027 ( 69.12 )
    0.2868 ( 109.23 )
    0.2585 ( 30.72 )
    0.2414 ( 29.66 )
    0.2111 ( 80.56 )
        GSK2506102; n=4, 17, 45, 59, 43, 27, 16, 3, 3
    0.9951 ( 122.94 )
    0.8372 ( 121.27 )
    0.9634 ( 95.99 )
    1.5100 ( 105.50 )
    1.5480 ( 122.95 )
    1.6555 ( 133.94 )
    3.2099 ( 67.36 )
    1.6892 ( 30.44 )
    1.8595 ( 48.36 )
        GSK2506104; n=6, 17, 45, 59, 43, 27, 16, 3, 3
    0.9750 ( 408.49 )
    1.9588 ( 163.27 )
    2.0381 ( 124.74 )
    3.5141 ( 136.72 )
    3.3872 ( 182.27 )
    3.6000 ( 173.62 )
    6.5730 ( 99.82 )
    4.2068 ( 15.44 )
    4.1894 ( 23.78 )
        GSK2531398; n=2, 7, 22, 41, 33, 20, 15, 3, 3
    1.1778 ( 20.55 )
    0.6069 ( 271.48 )
    0.2362 ( 76.76 )
    0.4444 ( 144.99 )
    0.3917 ( 169.77 )
    0.3728 ( 197.51 )
    0.3992 ( 153.15 )
    0.3963 ( 16.52 )
    0.2280 ( 56.68 )
        GSK2531401; n=6, 17, 45, 59, 44, 27, 16, 3, 3
    1.4466 ( 190.80 )
    3.5579 ( 102.68 )
    4.0910 ( 148.03 )
    6.8137 ( 102.34 )
    5.6037 ( 130.97 )
    8.4611 ( 128.74 )
    11.7372 ( 65.37 )
    6.0453 ( 140.63 )
    16.2584 ( 41.06 )
    Notes
    [26] - Pharmacokinetic Population
    [27] - Pharmacokinetic Population
    [28] - Pharmacokinetic Population
    [29] - Pharmacokinetic Population
    [30] - Pharmacokinetic Population
    [31] - Pharmacokinetic Population
    [32] - Pharmacokinetic Population
    [33] - Pharmacokinetic Population
    [34] - Pharmacokinetic Population
    No statistical analyses for this end point

    Secondary: Maximum observed concentration (Cmax) of daprodustat (GSK1278863) and its metabolites GSK2391220 (M2), GSK2487818 (M4), GSK2506102 (M5), GSK2506104 (M3), GSK2531398 (M6) and GSK2531401 (M13)

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    End point title
    		 Maximum observed concentration (Cmax) of daprodustat (GSK1278863) and its metabolites GSK2391220 (M2), GSK2487818 (M4), GSK2506102 (M5), GSK2506104 (M3), GSK2531398 (M6) and GSK2531401 (M13)
    End point description
    Blood samples were collected at indicated time points for pharmacokinetic analysis of daprodustat (GSK1278863) and its metabolites: GSK2391220 (M2), GSK2487818 (M4), GSK2506102 (M5), GSK2506104 (M3), GSK2531398 (M6) and GSK2531401 (M13). Only those participants with data available at specified time points were analyzed (represented as n=X in the category titles).
    End point type
    Secondary
    End point timeframe
    Pre-dose on Day 1; Pre-dose and at 0.5, 1, 2, 3 hours post-dose on any one post-Baseline visit day between Week 8 and Week 52
    End point values
    		 Daprodustat 2 mg Daprodustat 4 mg Daprodustat 8 mg Daprodustat 12 mg Daprodustat 16 mg Daprodustat 20 mg Daprodustat 24 mg Daprodustat 32 mg Daprodustat 48 mg
    Number of subjects analysed
    8 [35]
    20 [36]
    51 [37]
    59 [38]
    45 [39]
    28 [40]
    16 [41]
    3 [42]
    3 [43]
    Units: Nanograms per milliliter
    geometric mean (geometric coefficient of variation)
        Daprodustat; n=8, 20, 49, 57, 45, 28, 16, 3, 3
    44.5832 ( 227.65 )
    51.9261 ( 227.59 )
    113.4049 ( 179.69 )
    143.8790 ( 233.09 )
    126.6824 ( 288.50 )
    212.5087 ( 152.47 )
    290.3163 ( 87.39 )
    197.7071 ( 36.53 )
    310.1938 ( 190.69 )
        GSK2391220; n=8, 19, 50, 59, 45, 28, 16, 3, 3
    2.6298 ( 60.93 )
    4.0224 ( 134.91 )
    6.3826 ( 198.78 )
    8.9535 ( 126.76 )
    9.5131 ( 167.92 )
    11.8995 ( 172.35 )
    22.3378 ( 95.60 )
    9.3582 ( 71.78 )
    31.6698 ( 84.08 )
        GSK2487818; n=7, 18, 47, 56, 45, 28, 16, 3, 3
    2.0320 ( 73.45 )
    3.2703 ( 143.75 )
    6.3474 ( 175.79 )
    8.0134 ( 146.43 )
    6.4276 ( 278.04 )
    9.6617 ( 207.18 )
    19.9693 ( 94.09 )
    8.4327 ( 64.98 )
    29.3042 ( 72.06 )
        GSK2506102; n=8, 19, 51, 59, 45, 28, 16, 3, 3
    0.8328 ( 101.92 )
    1.4018 ( 84.93 )
    2.0385 ( 85.59 )
    2.8357 ( 68.15 )
    3.2007 ( 89.86 )
    3.5712 ( 96.48 )
    6.4555 ( 59.57 )
    2.4981 ( 71.38 )
    7.1245 ( 87.62 )
        GSK2506104; n=8, 19, 51, 59, 45, 28, 16, 3, 3
    3.2020 ( 81.23 )
    5.2039 ( 98.70 )
    7.5220 ( 131.81 )
    10.8186 ( 84.31 )
    11.5783 ( 130.74 )
    13.8509 ( 125.27 )
    24.4926 ( 84.96 )
    9.5457 ( 73.58 )
    30.4034 ( 79.13 )
        GSK2531398; n=8, 17, 46, 59, 45, 27, 16, 3, 3
    1.2731 ( 57.92 )
    2.3676 ( 84.23 )
    3.7348 ( 131.10 )
    3.8017 ( 177.36 )
    4.0850 ( 209.29 )
    6.1029 ( 137.40 )
    10.7532 ( 98.46 )
    4.6296 ( 72.00 )
    14.7844 ( 81.18 )
        GSK2531401; n=7, 19, 51, 59, 45, 28, 16, 3, 3
    2.0473 ( 100.05 )
    4.0012 ( 88.64 )
    5.4631 ( 120.63 )
    8.8488 ( 80.17 )
    8.4814 ( 93.83 )
    10.7368 ( 90.83 )
    14.7926 ( 59.24 )
    7.1458 ( 174.98 )
    20.1044 ( 67.56 )
    Notes
    [35] - Pharmacokinetic Population
    [36] - Pharmacokinetic Population
    [37] - Pharmacokinetic Population
    [38] - Pharmacokinetic Population
    [39] - Pharmacokinetic Population
    [40] - Pharmacokinetic Population
    [41] - Pharmacokinetic Population
    [42] - Pharmacokinetic Population
    [43] - Pharmacokinetic Population
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Treatment emergent serious adverse events (SAEs) and non-serious adverse events (non-serious AEs) were collected up to 52 weeks.
    Adverse event reporting additional description
    Safety Population was used to assess SAEs and non-serious AEs, which comprised of all randomized participants who have taken at least 1 dose of study treatment. One participant from Randomized (ITT) Population (N=407) did not receive study treatment, hence was not included in Safety Population (N=406).
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    23.0
    Reporting groups
    Reporting group title
    Daprodustat
    Reporting group description
    		 Participants received daprodustat tablets with titrated dose levels ranging from 2, 4, 8, 12, 16, 20, 24, 32 and 48 milligrams (mg) orally three-times weekly up to 52 weeks. Study treatment was dose-titrated to achieve and maintain hemoglobin in the target range (10 to 11 grams per deciliter [g/dL]). In order to maintain the study blind, participants also received saline intravenous (IV) injection once weekly or three-times weekly depending on dose level, up to 52 weeks as an inactive treatment for the IV formulation. All participants were followed up at 4 to 6 weeks after last dose.

    Reporting group title
    Epoetin alfa
    Reporting group description
    		 Participants received epoetin alfa with titrated dose levels ranging from 1500 Units to 60,000 Units total weekly dose and administered as IV injection once weekly or three-times weekly depending on dose level up to 52 weeks. Study treatment was dose-titrated to achieve and maintain hemoglobin in the target range (10 to 11 g/dL). In order to maintain the study blind, participants also received placebo tablets matching to daprodustat orally three-times weekly up to 52 weeks as an inactive treatment for the tablet formulation. All participants were followed up at 4 to 6 weeks after last dose.

    Serious adverse events
    		 Daprodustat Epoetin alfa
    Total subjects affected by serious adverse events
         subjects affected / exposed
    80 / 270 (29.63%)
    47 / 136 (34.56%)
         number of deaths (all causes)
    18
    10
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Lip and/or oral cavity cancer
         subjects affected / exposed
    1 / 270 (0.37%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oropharyngeal cancer
         subjects affected / exposed
    1 / 270 (0.37%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Smooth muscle cell neoplasm
         subjects affected / exposed
    1 / 270 (0.37%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Squamous cell carcinoma of lung
         subjects affected / exposed
    0 / 270 (0.00%)
    1 / 136 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Vascular disorders
    Hypertension
         subjects affected / exposed
    2 / 270 (0.74%)
    1 / 136 (0.74%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertensive crisis
         subjects affected / exposed
    2 / 270 (0.74%)
    1 / 136 (0.74%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    1 / 270 (0.37%)
    2 / 136 (1.47%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral ischaemia
         subjects affected / exposed
    2 / 270 (0.74%)
    1 / 136 (0.74%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Deep vein thrombosis
         subjects affected / exposed
    1 / 270 (0.37%)
    1 / 136 (0.74%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Extremity necrosis
         subjects affected / exposed
    2 / 270 (0.74%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhage
         subjects affected / exposed
    1 / 270 (0.37%)
    1 / 136 (0.74%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertensive emergency
         subjects affected / exposed
    1 / 270 (0.37%)
    1 / 136 (0.74%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arterial occlusive disease
         subjects affected / exposed
    1 / 270 (0.37%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Brachiocephalic vein stenosis
         subjects affected / exposed
    1 / 270 (0.37%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dialysis induced hypertension
         subjects affected / exposed
    1 / 270 (0.37%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematoma
         subjects affected / exposed
    1 / 270 (0.37%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ischaemia
         subjects affected / exposed
    0 / 270 (0.00%)
    1 / 136 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malignant hypertension
         subjects affected / exposed
    1 / 270 (0.37%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Orthostatic hypotension
         subjects affected / exposed
    1 / 270 (0.37%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral vascular disorder
         subjects affected / exposed
    0 / 270 (0.00%)
    1 / 136 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subclavian vein thrombosis
         subjects affected / exposed
    1 / 270 (0.37%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombophlebitis
         subjects affected / exposed
    0 / 270 (0.00%)
    1 / 136 (0.74%)
         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
    Pyrexia
         subjects affected / exposed
    2 / 270 (0.74%)
    1 / 136 (0.74%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Asthenia
         subjects affected / exposed
    1 / 270 (0.37%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Catheter site inflammation
         subjects affected / exposed
    0 / 270 (0.00%)
    1 / 136 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device related thrombosis
         subjects affected / exposed
    0 / 270 (0.00%)
    1 / 136 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    0 / 270 (0.00%)
    1 / 136 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 270 (0.00%)
    1 / 136 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thirst
         subjects affected / exposed
    1 / 270 (0.37%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Fatigue
         subjects affected / exposed
    1 / 270 (0.37%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Postmenopausal haemorrhage
         subjects affected / exposed
    0 / 270 (0.00%)
    1 / 136 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory failure
         subjects affected / exposed
    3 / 270 (1.11%)
    1 / 136 (0.74%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    1 / 270 (0.37%)
    3 / 136 (2.21%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    2 / 270 (0.74%)
    1 / 136 (0.74%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    1 / 270 (0.37%)
    1 / 136 (0.74%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    0 / 270 (0.00%)
    2 / 136 (1.47%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    1 / 270 (0.37%)
    1 / 136 (0.74%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Asthma
         subjects affected / exposed
    0 / 270 (0.00%)
    1 / 136 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epistaxis
         subjects affected / exposed
    0 / 270 (0.00%)
    1 / 136 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemoptysis
         subjects affected / exposed
    0 / 270 (0.00%)
    1 / 136 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary hypertension
         subjects affected / exposed
    1 / 270 (0.37%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary oedema
         subjects affected / exposed
    0 / 270 (0.00%)
    1 / 136 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Confusional state
         subjects affected / exposed
    0 / 270 (0.00%)
    1 / 136 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Product issues
    Thrombosis in device
         subjects affected / exposed
    0 / 270 (0.00%)
    1 / 136 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Arteriovenous fistula thrombosis
         subjects affected / exposed
    7 / 270 (2.59%)
    3 / 136 (2.21%)
         occurrences causally related to treatment / all
    0 / 9
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Head injury
         subjects affected / exposed
    2 / 270 (0.74%)
    2 / 136 (1.47%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arteriovenous fistula site complication
         subjects affected / exposed
    2 / 270 (0.74%)
    1 / 136 (0.74%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    1 / 270 (0.37%)
    2 / 136 (1.47%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular graft occlusion
         subjects affected / exposed
    1 / 270 (0.37%)
    1 / 136 (0.74%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arteriovenous fistula occlusion
         subjects affected / exposed
    0 / 270 (0.00%)
    1 / 136 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arteriovenous fistula site haematoma
         subjects affected / exposed
    1 / 270 (0.37%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arteriovenous fistula site haemorrhage
         subjects affected / exposed
    1 / 270 (0.37%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arteriovenous graft site stenosis
         subjects affected / exposed
    0 / 270 (0.00%)
    1 / 136 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arthropod bite
         subjects affected / exposed
    1 / 270 (0.37%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Joint injury
         subjects affected / exposed
    0 / 270 (0.00%)
    1 / 136 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multiple fractures
         subjects affected / exposed
    1 / 270 (0.37%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post procedural haematoma
         subjects affected / exposed
    0 / 270 (0.00%)
    1 / 136 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rib fracture
         subjects affected / exposed
    1 / 270 (0.37%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sternal fracture
         subjects affected / exposed
    1 / 270 (0.37%)
    0 / 136 (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
    0 / 270 (0.00%)
    1 / 136 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tibia fracture
         subjects affected / exposed
    1 / 270 (0.37%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular access complication
         subjects affected / exposed
    0 / 270 (0.00%)
    1 / 136 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular access malfunction
         subjects affected / exposed
    0 / 270 (0.00%)
    1 / 136 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular access site thrombosis
         subjects affected / exposed
    1 / 270 (0.37%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular access site pseudoaneurysm
         subjects affected / exposed
    1 / 270 (0.37%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Congenital cystic kidney disease
         subjects affected / exposed
    1 / 270 (0.37%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Angina unstable
         subjects affected / exposed
    0 / 270 (0.00%)
    3 / 136 (2.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    1 / 270 (0.37%)
    2 / 136 (1.47%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    3 / 270 (1.11%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Acute coronary syndrome
         subjects affected / exposed
    2 / 270 (0.74%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute myocardial infarction
         subjects affected / exposed
    1 / 270 (0.37%)
    1 / 136 (0.74%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Angina pectoris
         subjects affected / exposed
    1 / 270 (0.37%)
    1 / 136 (0.74%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    2 / 270 (0.74%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Atrioventricular block complete
         subjects affected / exposed
    0 / 270 (0.00%)
    1 / 136 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    0 / 270 (0.00%)
    1 / 136 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cardiac failure congestive
         subjects affected / exposed
    1 / 270 (0.37%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiomyopathy
         subjects affected / exposed
    0 / 270 (0.00%)
    1 / 136 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    1 / 270 (0.37%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Supraventricular tachycardia
         subjects affected / exposed
    1 / 270 (0.37%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebrovascular accident
         subjects affected / exposed
    4 / 270 (1.48%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    2 / 270 (0.74%)
    1 / 136 (0.74%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetic hyperglycaemic coma
         subjects affected / exposed
    0 / 270 (0.00%)
    1 / 136 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Generalised tonic-clonic seizure
         subjects affected / exposed
    0 / 270 (0.00%)
    1 / 136 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhagic stroke
         subjects affected / exposed
    1 / 270 (0.37%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Headache
         subjects affected / exposed
    1 / 270 (0.37%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertensive encephalopathy
         subjects affected / exposed
    1 / 270 (0.37%)
    0 / 136 (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
    1 / 270 (0.37%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Loss of consciousness
         subjects affected / exposed
    1 / 270 (0.37%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lumbar radiculopathy
         subjects affected / exposed
    0 / 270 (0.00%)
    1 / 136 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myoclonus
         subjects affected / exposed
    1 / 270 (0.37%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 270 (0.00%)
    1 / 136 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    2 / 270 (0.74%)
    3 / 136 (2.21%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Normocytic anaemia
         subjects affected / exposed
    1 / 270 (0.37%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vertigo positional
         subjects affected / exposed
    1 / 270 (0.37%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Gastritis
         subjects affected / exposed
    1 / 270 (0.37%)
    2 / 136 (1.47%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    2 / 270 (0.74%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    1 / 270 (0.37%)
    1 / 136 (0.74%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Nausea
         subjects affected / exposed
    1 / 270 (0.37%)
    1 / 136 (0.74%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 270 (0.37%)
    1 / 136 (0.74%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    1 / 270 (0.37%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    1 / 270 (0.37%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic gastritis
         subjects affected / exposed
    1 / 270 (0.37%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetic gastroparesis
         subjects affected / exposed
    1 / 270 (0.37%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric antral vascular ectasia
         subjects affected / exposed
    1 / 270 (0.37%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric dilatation
         subjects affected / exposed
    1 / 270 (0.37%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric ulcer haemorrhage
         subjects affected / exposed
    1 / 270 (0.37%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 270 (0.00%)
    1 / 136 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Impaired gastric emptying
         subjects affected / exposed
    0 / 270 (0.00%)
    1 / 136 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    1 / 270 (0.37%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis relapsing
         subjects affected / exposed
    1 / 270 (0.37%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 270 (0.37%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Bile duct stone
         subjects affected / exposed
    0 / 270 (0.00%)
    1 / 136 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis
         subjects affected / exposed
    1 / 270 (0.37%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Diabetic foot
         subjects affected / exposed
    0 / 270 (0.00%)
    2 / 136 (1.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Erythema
         subjects affected / exposed
    1 / 270 (0.37%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin ulcer
         subjects affected / exposed
    1 / 270 (0.37%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    0 / 270 (0.00%)
    2 / 136 (1.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Calculus urethral
         subjects affected / exposed
    1 / 270 (0.37%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    Hyperparathyroidism
         subjects affected / exposed
    0 / 270 (0.00%)
    1 / 136 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthritis
         subjects affected / exposed
    0 / 270 (0.00%)
    1 / 136 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cervical spinal stenosis
         subjects affected / exposed
    1 / 270 (0.37%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal chest pain
         subjects affected / exposed
    1 / 270 (0.37%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neuropathic arthropathy
         subjects affected / exposed
    1 / 270 (0.37%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain in extremity
         subjects affected / exposed
    1 / 270 (0.37%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pathological fracture
         subjects affected / exposed
    1 / 270 (0.37%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    9 / 270 (3.33%)
    5 / 136 (3.68%)
         occurrences causally related to treatment / all
    0 / 9
    0 / 5
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Clostridium difficile colitis
         subjects affected / exposed
    2 / 270 (0.74%)
    1 / 136 (0.74%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arteriovenous fistula site infection
         subjects affected / exposed
    2 / 270 (0.74%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gangrene
         subjects affected / exposed
    1 / 270 (0.37%)
    1 / 136 (0.74%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    2 / 270 (0.74%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 270 (0.37%)
    1 / 136 (0.74%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    2 / 270 (0.74%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acinetobacter infection
         subjects affected / exposed
    1 / 270 (0.37%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atypical pneumonia
         subjects affected / exposed
    1 / 270 (0.37%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bacteraemia
         subjects affected / exposed
    0 / 270 (0.00%)
    1 / 136 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    1 / 270 (0.37%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Campylobacter colitis
         subjects affected / exposed
    1 / 270 (0.37%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Catheter bacteraemia
         subjects affected / exposed
    0 / 270 (0.00%)
    1 / 136 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    1 / 270 (0.37%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear infection
         subjects affected / exposed
    1 / 270 (0.37%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocarditis
         subjects affected / exposed
    0 / 270 (0.00%)
    1 / 136 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enteritis infectious
         subjects affected / exposed
    1 / 270 (0.37%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Enterococcal bacteraemia
         subjects affected / exposed
    1 / 270 (0.37%)
    0 / 136 (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
    1 / 270 (0.37%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    H1N1 influenza
         subjects affected / exposed
    1 / 270 (0.37%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infected skin ulcer
         subjects affected / exposed
    0 / 270 (0.00%)
    1 / 136 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    1 / 270 (0.37%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injection site cellulitis
         subjects affected / exposed
    1 / 270 (0.37%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Laryngitis
         subjects affected / exposed
    1 / 270 (0.37%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Localised infection
         subjects affected / exposed
    0 / 270 (0.00%)
    1 / 136 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteomyelitis
         subjects affected / exposed
    0 / 270 (0.00%)
    1 / 136 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pharyngitis
         subjects affected / exposed
    1 / 270 (0.37%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Postoperative wound infection
         subjects affected / exposed
    0 / 270 (0.00%)
    1 / 136 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Prostatitis Escherichia coli
         subjects affected / exposed
    1 / 270 (0.37%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Proteus infection
         subjects affected / exposed
    1 / 270 (0.37%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pseudomembranous colitis
         subjects affected / exposed
    1 / 270 (0.37%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    1 / 270 (0.37%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory syncytial virus infection
         subjects affected / exposed
    1 / 270 (0.37%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    0 / 270 (0.00%)
    1 / 136 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin bacterial infection
         subjects affected / exposed
    1 / 270 (0.37%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tubo-ovarian abscess
         subjects affected / exposed
    1 / 270 (0.37%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 270 (0.37%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    0 / 270 (0.00%)
    1 / 136 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 270 (0.37%)
    0 / 136 (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
    Fluid overload
         subjects affected / exposed
    2 / 270 (0.74%)
    2 / 136 (1.47%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperkalaemia
         subjects affected / exposed
    3 / 270 (1.11%)
    1 / 136 (0.74%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetic ketoacidosis
         subjects affected / exposed
    2 / 270 (0.74%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    1 / 270 (0.37%)
    1 / 136 (0.74%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetes mellitus
         subjects affected / exposed
    0 / 270 (0.00%)
    1 / 136 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Daprodustat Epoetin alfa
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    74 / 270 (27.41%)
    42 / 136 (30.88%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    22 / 270 (8.15%)
    14 / 136 (10.29%)
         occurrences all number
    35
    19
    Hypotension
         subjects affected / exposed
    12 / 270 (4.44%)
    9 / 136 (6.62%)
         occurrences all number
    16
    13
    Nervous system disorders
    Headache
         subjects affected / exposed
    11 / 270 (4.07%)
    13 / 136 (9.56%)
         occurrences all number
    13
    26
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    7 / 270 (2.59%)
    8 / 136 (5.88%)
         occurrences all number
    9
    9
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    23 / 270 (8.52%)
    14 / 136 (10.29%)
         occurrences all number
    36
    19
    Vomiting
         subjects affected / exposed
    15 / 270 (5.56%)
    13 / 136 (9.56%)
         occurrences all number
    16
    15
    Nausea
         subjects affected / exposed
    6 / 270 (2.22%)
    11 / 136 (8.09%)
         occurrences all number
    8
    21
    Abdominal pain
         subjects affected / exposed
    7 / 270 (2.59%)
    9 / 136 (6.62%)
         occurrences all number
    8
    9

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    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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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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