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    Clinical Trial Results:
    A Phase 3, Randomized, Open-Label, Active-Controlled Study to Evaluate the Efficacy and Safety of Roxadustat in the Treatment of Anemia in Chronic Kidney Disease Patients Not on Dialysis

    Summary
    EudraCT number
    2013-000951-42
    Trial protocol
    GB   DE   ES   NL   CZ   SK   SI   PT   AT   IE   DK   FI   LV   SE   FR   HR   HU   BG  
    Global end of trial date
    15 Nov 2019

    Results information
    Results version number
    v1(current)
    This version publication date
    04 Nov 2020
    First version publication date
    04 Nov 2020
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    1517-CL-0610
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02021318
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Astellas Pharma Europe B.V.
    Sponsor organisation address
    Sylviusweg 62, Leiden, Netherlands, 2333 BE
    Public contact
    Clinical Trial Disclosure, Astellas Pharma Europe B.V., 31 71 5455 050, astellas.resultsdisclosure@astellas.com
    Scientific contact
    Clinical Trial Disclosure, Astellas Pharma Europe B.V., 31 71 5455 050, astellas.resultsdisclosure@astellas.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
    15 Nov 2019
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    15 Nov 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main objective of this study was to evaluate the efficacy of roxadustat compared to darbepoetin alfa in the treatment of anemia in nondialysis-dependent chronic kidney disease participants.
    Protection of trial subjects
    This clinical study was written, conducted and reported in accordance with the protocol, International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) Good Clinical Practice (GCP) Guidelines, and applicable local regulations, including the European Directive 2001/20/EC, on the protection of human rights, and with the ethical principles that have their origin in the Declaration of Helsinki. Astellas ensures that the use and disclosure of protected health information (PHI) obtained during a research study complies with the federal, national and/or regional legislation related to the privacy and protection of personal information.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    12 Mar 2014
    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
    Austria: 3
    Country: Number of subjects enrolled
    Belarus: 17
    Country: Number of subjects enrolled
    Bulgaria: 19
    Country: Number of subjects enrolled
    Croatia: 73
    Country: Number of subjects enrolled
    Czech Republic: 33
    Country: Number of subjects enrolled
    Finland: 3
    Country: Number of subjects enrolled
    France: 18
    Country: Number of subjects enrolled
    Georgia: 19
    Country: Number of subjects enrolled
    Germany: 37
    Country: Number of subjects enrolled
    Hungary: 32
    Country: Number of subjects enrolled
    Ireland: 8
    Country: Number of subjects enrolled
    Israel: 3
    Country: Number of subjects enrolled
    Latvia: 4
    Country: Number of subjects enrolled
    Macedonia, the former Yugoslav Republic of: 12
    Country: Number of subjects enrolled
    Montenegro: 4
    Country: Number of subjects enrolled
    Netherlands: 1
    Country: Number of subjects enrolled
    Poland: 30
    Country: Number of subjects enrolled
    Portugal: 17
    Country: Number of subjects enrolled
    Romania: 16
    Country: Number of subjects enrolled
    Russian Federation: 48
    Country: Number of subjects enrolled
    Serbia: 48
    Country: Number of subjects enrolled
    Slovakia: 26
    Country: Number of subjects enrolled
    Slovenia: 15
    Country: Number of subjects enrolled
    Spain: 33
    Country: Number of subjects enrolled
    Ukraine: 36
    Country: Number of subjects enrolled
    United Kingdom: 61
    Worldwide total number of subjects
    616
    EEA total number of subjects
    429
    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)
    237
    From 65 to 84 years
    349
    85 years and over
    30

    Subject disposition

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    Recruitment
    Recruitment details
    Participants of ≥18 years of age with a diagnosis of chronic kidney disease, with kidney disease outcomes quality initiative stage 3, 4 or 5, anaemic and not receiving dialysis; with an estimated glomerular filtration rate (eGFR) < 60 milliliter per minute per 1.73 meter square (mL/min/1.73 m^2) were enrolled in this study.

    Pre-assignment
    Screening details
    Participants were randomized in a 1:1 ratio to roxadustat or darbepoetin alfa. Randomization was stratified by 4 factors: region, screening hemoglobin (Hb) values (Hb ≤ 8.0 g/dL versus > 8.0 g/dL), history of cardiovascular, cerebrovascular or thromboembolic diseases and screening eGFR (<30 mL/min/1.73 m^2 versus ≥30 mL/min/1.73 m^2 ).

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Darbepoetin alfa
    Arm description
    Participants received initial dose of darbepoetin alfa based upon the weight (either 0.45 microgram per kilogram [μg/kg] of body weight, as a single subcutaneous or intravenous [IV] injection once weekly or 0.75 μg/kg of body weight, as a single subcutaneous injection once every 2 weeks) as per European Summary of Product Characteristics (EU SmPC) along with IV iron supplementation according to the standard of care. Dose-adjustment was performed based upon regular measurement of Hb levels until participants achieved central Hb value of ≥ 11.0 grams per deciliter (g/dL) and Hb increase from baseline of ≥ 1.0 g/dL at two consecutive study visits, separated by at least 5 days. Once target Hb level was reached participants entered maintenance period during which darbepoetin alfa dosage was adjusted every 4 weeks to maintain participants Hb level within the target range of 10.0 g/dL and 12.0 g/dL. Participants received darbepoetin alfa for up to a maximum of 104 weeks.
    Arm type
    Active comparator

    Investigational medicinal product name
    Darbepoetin alfa
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Intravenous use, Subcutaneous use
    Dosage and administration details
    Participants received initial dose of darbepoetin alfa based upon the weight (either 0.45 μg/kg of body weight, as a single subcutaneous or IV injection once weekly or 0.75 μg/kg of body weight, as a single subcutaneous injection once every 2 weeks) as per EU SmPC along with IV iron supplementation according to the standard of care.

    Arm title
    Roxadustat
    Arm description
    Participants received roxadustat orally according to the tiered weight-based approach, with starting dose of 70 milligram (mg) given three times weekly (TIW) to participants weighing between 45 kilogram (kg) up to 70 kg and 100 mg given TIW to participants weighing more than 70 kg up to 160 kg. Dose-titration was performed based upon regular measurement of Hb levels until participants achieved central Hb value of ≥ 11.0 g/dL and Hb increase from baseline of ≥ 1.0 g/dL at two consecutive study visits, separated by at least 5 days. Once target Hb level was reached participants entered maintenance period during which roxadustat dosage was adjusted every 4 weeks to maintain participants Hb level within the target range of 10.0 g/dL and 12.0 g/dL. Participants received roxadustat for up to a maximum of 104 weeks.
    Arm type
    Experimental

    Investigational medicinal product name
    Roxadustat
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received roxadustat orally according to the tiered weight-based approach, with starting dose of 70 mg given TIW to participants weighing between 45 kg up to 70 kg and 100 mg given TIW to participants weighing more than 70 kg up to 160 kg.

    Number of subjects in period 1
    Darbepoetin alfa Roxadustat
    Started
    293
    323
    Completed
    230
    250
    Not completed
    63
    73
         Progressive disease
    1
    -
         Death
    34
    33
         Miscellaneous
    3
    2
         Physician decision
    3
    3
         Withdrawal by Subject
    18
    30
         Adverse Event
    1
    2
         Lost to follow-up
    3
    3

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Darbepoetin alfa
    Reporting group description
    Participants received initial dose of darbepoetin alfa based upon the weight (either 0.45 microgram per kilogram [μg/kg] of body weight, as a single subcutaneous or intravenous [IV] injection once weekly or 0.75 μg/kg of body weight, as a single subcutaneous injection once every 2 weeks) as per European Summary of Product Characteristics (EU SmPC) along with IV iron supplementation according to the standard of care. Dose-adjustment was performed based upon regular measurement of Hb levels until participants achieved central Hb value of ≥ 11.0 grams per deciliter (g/dL) and Hb increase from baseline of ≥ 1.0 g/dL at two consecutive study visits, separated by at least 5 days. Once target Hb level was reached participants entered maintenance period during which darbepoetin alfa dosage was adjusted every 4 weeks to maintain participants Hb level within the target range of 10.0 g/dL and 12.0 g/dL. Participants received darbepoetin alfa for up to a maximum of 104 weeks.

    Reporting group title
    Roxadustat
    Reporting group description
    Participants received roxadustat orally according to the tiered weight-based approach, with starting dose of 70 milligram (mg) given three times weekly (TIW) to participants weighing between 45 kilogram (kg) up to 70 kg and 100 mg given TIW to participants weighing more than 70 kg up to 160 kg. Dose-titration was performed based upon regular measurement of Hb levels until participants achieved central Hb value of ≥ 11.0 g/dL and Hb increase from baseline of ≥ 1.0 g/dL at two consecutive study visits, separated by at least 5 days. Once target Hb level was reached participants entered maintenance period during which roxadustat dosage was adjusted every 4 weeks to maintain participants Hb level within the target range of 10.0 g/dL and 12.0 g/dL. Participants received roxadustat for up to a maximum of 104 weeks.

    Reporting group values
    Darbepoetin alfa Roxadustat Total
    Number of subjects
    293 323
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    65.7 ± 14.4 66.8 ± 13.6 -
    Gender categorical
    Units: Subjects
        M
    129 145 274
        F
    164 178 342
    Analysis Race
    Units: Subjects
        White
    281 306 587
        Black or African American
    2 8 10
        Asian
    10 9 19
    Baseline Hb Value
    Units: Subjects
        <=8.0 g/dL
    10 11 21
        >8.0 g/dL
    283 312 595

    End points

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    End points reporting groups
    Reporting group title
    Darbepoetin alfa
    Reporting group description
    Participants received initial dose of darbepoetin alfa based upon the weight (either 0.45 microgram per kilogram [μg/kg] of body weight, as a single subcutaneous or intravenous [IV] injection once weekly or 0.75 μg/kg of body weight, as a single subcutaneous injection once every 2 weeks) as per European Summary of Product Characteristics (EU SmPC) along with IV iron supplementation according to the standard of care. Dose-adjustment was performed based upon regular measurement of Hb levels until participants achieved central Hb value of ≥ 11.0 grams per deciliter (g/dL) and Hb increase from baseline of ≥ 1.0 g/dL at two consecutive study visits, separated by at least 5 days. Once target Hb level was reached participants entered maintenance period during which darbepoetin alfa dosage was adjusted every 4 weeks to maintain participants Hb level within the target range of 10.0 g/dL and 12.0 g/dL. Participants received darbepoetin alfa for up to a maximum of 104 weeks.

    Reporting group title
    Roxadustat
    Reporting group description
    Participants received roxadustat orally according to the tiered weight-based approach, with starting dose of 70 milligram (mg) given three times weekly (TIW) to participants weighing between 45 kilogram (kg) up to 70 kg and 100 mg given TIW to participants weighing more than 70 kg up to 160 kg. Dose-titration was performed based upon regular measurement of Hb levels until participants achieved central Hb value of ≥ 11.0 g/dL and Hb increase from baseline of ≥ 1.0 g/dL at two consecutive study visits, separated by at least 5 days. Once target Hb level was reached participants entered maintenance period during which roxadustat dosage was adjusted every 4 weeks to maintain participants Hb level within the target range of 10.0 g/dL and 12.0 g/dL. Participants received roxadustat for up to a maximum of 104 weeks.

    Primary: Percentage of Participants With a Hb Response to Treatment at Two Consecutive Visits During the First 24 Weeks of Treatment Without Rescue Therapy

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    End point title
    Percentage of Participants With a Hb Response to Treatment at Two Consecutive Visits During the First 24 Weeks of Treatment Without Rescue Therapy
    End point description
    Hb response was measured as Yes or No. Response Yes (responders) was defined as: Hb ≥11.0 g/dL and Hb change from baseline by ≥ 1.0 g/dL, for participants with baseline Hb > 8.0 g/dL; or Hb change from baseline by ≥ 2.0 g/dL, for participants with baseline Hb ≤ 8.0 g/dL at two consecutive visits with available data separated by at least 5 days during the first 24 weeks of treatment without having received rescue therapy (red blood cell [RBC] transfusion for all participants or darbepoetin for roxadustat treated participant). The analysis population was the Per Protocol Set (PPS) which consisted of all Full Analysis Set (FAS) participants who did not meet any of exclusion criteria from the PPS. The FAS consisted of all randomized participants who received at least one dose of study drug and had at least one post-dose valid Hb assessment.
    End point type
    Primary
    End point timeframe
    Baseline to week 24
    End point values
    Darbepoetin alfa Roxadustat
    Number of subjects analysed
    273
    286
    Units: Percentage of participants
        number (not applicable)
    78.0
    89.5
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    A generalized linear model as an approximation for the Miettinen and Nurminen method, adjusted for stratification factors (actual) was used to estimate the difference of proportions and 95% confidence interval (CI).
    Comparison groups
    Roxadustat v Darbepoetin alfa
    Number of subjects included in analysis
    559
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority [1]
    Method
    Parameter type
    Difference in percentage
    Point estimate
    11.51
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    5.66
         upper limit
    17.36
    Notes
    [1] - Non-inferiority of roxadustat versus darbepoetin alfa, margin = -15% (non-inferiority is concluded if the lower limit of the 95% confidence interval of the difference was >-15%).

    Secondary: Change from Baseline in Hb to the Average Hb of Weeks 28 to 36 Without Rescue Therapy Within 6 Weeks Prior to and During This 8-Week Evaluation Period

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    End point title
    Change from Baseline in Hb to the Average Hb of Weeks 28 to 36 Without Rescue Therapy Within 6 Weeks Prior to and During This 8-Week Evaluation Period
    End point description
    Baseline Hb was defined as the mean of all available central laboratory Hb values collected before or including the date of first study drug intake (predose). The analysis population was the PPS, with participants who had available data.
    End point type
    Secondary
    End point timeframe
    Baseline and weeks 28 to 36
    End point values
    Darbepoetin alfa Roxadustat
    Number of subjects analysed
    249
    258
    Units: g/dL
        arithmetic mean (standard deviation)
    1.839 ± 0.973
    1.848 ± 1.079
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    The model included treatment, visit, visit by treatment interaction, region and history of cardiovascular (CV) disease as fixed class factors and baseline Hb, baseline estimated glomerular filtration rate and baseline Hb by visit as continuous covariates.
    Comparison groups
    Roxadustat v Darbepoetin alfa
    Number of subjects included in analysis
    507
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority [2]
    P-value
    = 0.839
    Method
    Mixed models analysis
    Parameter type
    LSM Difference
    Point estimate
    0.015
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.131
         upper limit
    0.162
    Notes
    [2] - Non-Inferiority, margin = -0.75 (non-inferiority is concluded if the lower bound of the 95% confidence interval of the least square mean difference (LSM) is > -0.75 g/dL).

    Secondary: Change from Baseline in Low Density Lipoprotein Cholesterol (LDL-C) to the Average LDL-C of Weeks 12 to 28

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    End point title
    Change from Baseline in Low Density Lipoprotein Cholesterol (LDL-C) to the Average LDL-C of Weeks 12 to 28
    End point description
    Baseline LDL was defined as the LDL value on day 1. If this value was missing, the latest value prior to first study drug administration was used. The analysis population was the FAS, with participants who had available data.
    End point type
    Secondary
    End point timeframe
    Baseline and weeks 12 to 28
    End point values
    Darbepoetin alfa Roxadustat
    Number of subjects analysed
    277
    307
    Units: Millimoles per liter (mmol/L)
        arithmetic mean (standard deviation)
    0.049 ± 0.705
    -0.352 ± 0.772
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    The model included treatment, visit, visit by treatment interaction, region and history of cardiovascular disease as fixed class factors and baseline LDL, baseline Hb, baseline estimated glomerular filtration rate as continuous covariates.
    Comparison groups
    Darbepoetin alfa v Roxadustat
    Number of subjects included in analysis
    584
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001
    Method
    Mixed models analysis
    Parameter type
    LSM Difference
    Point estimate
    -0.403
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.51
         upper limit
    -0.296

    Secondary: Time to First Intavenous Iron use

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    End point title
    Time to First Intavenous Iron use
    End point description
    Participants were analyzed during the efficacy emergent period. The efficacy emergent period was defined as the evaluation period from the analysis date of first dose intake up to end of treatment (EOT) Visit or last non-missing Hb assessment (for participants who died during the treatment period). For participants who had received more than one intravenous iron, only their first event following study treatment was used. Data reported was analyzed by Kaplan-Meier estimate for cumulative proportion and the 95% confidence interval was calculated with Greenwood's formula. Percentage of participants were reported in this outcome measure. The analysis population was the FAS. Here, N is the number of participants with available data at each time point.
    End point type
    Secondary
    End point timeframe
    Weeks 6, 12, 18, 24, 30 and 36
    End point values
    Darbepoetin alfa Roxadustat
    Number of subjects analysed
    292
    322
    Units: Percentage of participants
    number (confidence interval 95%)
        Week 6 (N=318, 280)
    2.8 (0.9 to 4.6)
    0 (0 to 0)
        Week 12 (N=307, 259)
    6.7 (3.8 to 9.6)
    1.3 (0 to 2.5)
        Week 18 (N=290, 247)
    9.2 (5.8 to 12.6)
    3.3 (1.3 to 5.2)
        Week 24 (N=281, 243)
    10.7 (7.1 to 14.3)
    4.3 (2 to 6.5)
        Week 30 (N=272, 231)
    12.6 (8.7 to 16.5)
    5.3 (2.8 to 7.8)
        Week 36 (N=263, 226)
    13.3 (9.3 to 17.3)
    6.7 (3.9 to 9.6)
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Hazard Ratio was calculated using stratified Cox Proportional Hazards regression stratifying on cardiovascular history and Region and adjusting on Hb and eGFR at baseline as continuous covariate. Superiority was declared if the upper bound of the 95% CI was below 1.0.
    Comparison groups
    Roxadustat v Darbepoetin alfa
    Number of subjects included in analysis
    614
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.004
    Method
    Regression, Cox
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.45
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.26
         upper limit
    0.78

    Secondary: Change from Baseline in Short Form-36 (SF-36) Physical Functioning (PF) Sub-Score to the Average PF Sub-Score in Weeks 12 to 28

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    End point title
    Change from Baseline in Short Form-36 (SF-36) Physical Functioning (PF) Sub-Score to the Average PF Sub-Score in Weeks 12 to 28
    End point description
    Baseline SF-36 PF was defined as the SF-36 PF value on day 1.The SF-36 is a Quality of Life (QoL) instrument designed to assess generic health concepts relevant across age, disease, and treatment groups. The SF-36 contains 36 items that measured eight scales: (1) physical functioning; (2) role limitations due to physical health problems; (3) bodily pain; (4) social functioning; (5) general health perceptions; (6) role limitations due to emotional problems; (7) vitality, energy or fatigue; and (8) mental health. Each scale is transformed into 0-100 score, with higher scores indicating better health status. The SF-36 PF consisted of 11 questions that focused on health and ability to do usual activities, with higher scores indicating better health status. The analysis population was the PPS, with participants who had available data.
    End point type
    Secondary
    End point timeframe
    Baseline and weeks 12 to 28
    End point values
    Darbepoetin alfa Roxadustat
    Number of subjects analysed
    256
    274
    Units: Units on a scale
        arithmetic mean (standard deviation)
    2.062 ± 7.838
    0.913 ± 7.182
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    The model included treatment, visit (weeks 8, 12 and 28) visit by treatment interaction, region and history of cardiovascular disease as fixed class factors and baseline SF-36 PF, baseline Hb, baseline estimated glomerular filtration rate as continuous covariates.
    Comparison groups
    Roxadustat v Darbepoetin alfa
    Number of subjects included in analysis
    530
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority [3]
    P-value
    = 0.027
    Method
    Mixed models analysis
    Parameter type
    LSM Difference
    Point estimate
    -1.284
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.423
         upper limit
    -0.145
    Notes
    [3] - Non-Inferiority, margin = -3 (non-inferiority is concluded if the lower bound of the 95% confidence interval of the LSM difference is > - 3 points).

    Secondary: Change from Baseline in SF-36 Vitality (VT) Sub-Score to the Average VT Sub-Score in Weeks 12 to 28

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    End point title
    Change from Baseline in SF-36 Vitality (VT) Sub-Score to the Average VT Sub-Score in Weeks 12 to 28
    End point description
    Baseline VT Subscore was defined as the VT value on day 1. The SF-36 is a QoL instrument designed to assess generic health concepts relevant across age, disease, and treatment groups. The SF-36 vitality has four questions with score range from 0-100 with higher scores indicating better vitality status. The analysis population was the PPS, with participants who had available data.
    End point type
    Secondary
    End point timeframe
    Baseline and weeks 12 to 28
    End point values
    Darbepoetin alfa Roxadustat
    Number of subjects analysed
    256
    274
    Units: Units on a scale
        arithmetic mean (standard deviation)
    3.881 ± 8.76
    4.077 ± 8.657
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    The model included treatment, visit (weeks 8, 12 and 28), visit by treatment interaction, region and history of cardiovascular disease as fixed class factors and baseline SF-36 VT, baseline Hb, baseline eGFR as continuous covariates.
    Comparison groups
    Roxadustat v Darbepoetin alfa
    Number of subjects included in analysis
    530
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority [4]
    P-value
    = 0.454
    Method
    Mixed models analysis
    Parameter type
    LSM Difference
    Point estimate
    -0.457
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.656
         upper limit
    0.742
    Notes
    [4] - Non-Inferiority, margin = -3 (non-inferiority is concluded if the lower bound of the 95% confidence interval of the LSM difference is > - 3 points).

    Secondary: Change from Baseline in Mean Arterial Pressure (MAP) to the Average MAP Value in Weeks 20 to 28: Per Protocol Set

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    End point title
    Change from Baseline in Mean Arterial Pressure (MAP) to the Average MAP Value in Weeks 20 to 28: Per Protocol Set
    End point description
    Baseline MAP was defined as the MAP value on day 1. If this value was missing, the latest value prior to first study drug administration was used. MAP was derived as: MAP = (2/3)*diastolic blood pressure (DBP) + (1/3)*systolic blood pressure (SBP). The analysis population was the PPS, with participants who had available data.
    End point type
    Secondary
    End point timeframe
    Baseline and weeks 20 to 28
    End point values
    Darbepoetin alfa Roxadustat
    Number of subjects analysed
    252
    265
    Units: Millimeters of mercury (mmHg)
        arithmetic mean (standard deviation)
    0.588 ± 8.779
    0.541 ± 8.549
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    The model included treatment, visit, visit by treatment interaction, region and history of CV disease as fixed class factors and baseline MAP, baseline Hb, baseline eGFR as continuous covariates.
    Comparison groups
    Roxadustat v Darbepoetin alfa
    Number of subjects included in analysis
    517
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority [5]
    P-value
    = 0.547
    Method
    Mixed models analysis
    Parameter type
    LSM Difference
    Point estimate
    -0.372
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.587
         upper limit
    0.842
    Notes
    [5] - Non-Inferiority, margin = 1 mmHg (non-inferiority is concluded if the upper bound of the 95% confidence interval of the LSM difference is < 1).

    Secondary: Time to First Occurrence of Hypertension During Weeks 1 to 36: Per Protocol Set

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    End point title
    Time to First Occurrence of Hypertension During Weeks 1 to 36: Per Protocol Set
    End point description
    Hypertension was defined as either SBP ≥ 170 mmHg and an increase from baseline ≥ 20 mmHg or as DBP ≥ 110 mmHg and an increase from baseline ≥ 15 mmHg. For participants who had experienced more than one event, only their first event following study treatment was used. Data reported was analyzed by Kaplan-Meier estimate for cumulative proportion. Percentage of participants were reported in this outcome measure. The analysis population was the PPS.
    End point type
    Secondary
    End point timeframe
    Weeks 1 to 36
    End point values
    Darbepoetin alfa Roxadustat
    Number of subjects analysed
    273
    286
    Units: Percentage of participants
        number (not applicable)
    19.4
    17.5
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Hazard Ratio was calculated using stratified Cox Proportional Hazards regression stratifying on CV history and region and adjusting on Hb and eGFR at baseline as continuous covariates.
    Comparison groups
    Roxadustat v Darbepoetin alfa
    Number of subjects included in analysis
    559
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority [6]
    P-value
    = 0.336
    Method
    Regression, Cox
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.83
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.56
         upper limit
    1.22
    Notes
    [6] - Non-Inferiority, hazard ratio margin = 1.3 (non-inferiority is concluded if the upper bound of the 95% confidence interval of the hazard ratio is < 1.3).

    Secondary: Change from Baseline in MAP to the Average MAP Value in Weeks 20 to 28: Full Analysis Set

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    End point title
    Change from Baseline in MAP to the Average MAP Value in Weeks 20 to 28: Full Analysis Set
    End point description
    Baseline MAP was defined as the MAP value on day 1. If this value was missing, the latest value prior to first study drug administration was used. MAP was derived as: MAP = (2/3)*DBP + (1/3)*SBP. The analysis population was the FAS, with participants who had available data.
    End point type
    Secondary
    End point timeframe
    Baseline and weeks 20 to 28
    End point values
    Darbepoetin alfa Roxadustat
    Number of subjects analysed
    269
    294
    Units: mmHg
        arithmetic mean (standard deviation)
    0.457 ± 8.741
    0.635 ± 8.529
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    The model included treatment, visit, visit by treatment interaction, region and history of CV disease as fixed class factors and baseline MAP, baseline Hb, baseline eGFR as continuous covariates.
    Comparison groups
    Roxadustat v Darbepoetin alfa
    Number of subjects included in analysis
    563
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.818
    Method
    Mixed models analysis
    Parameter type
    LSM Difference
    Point estimate
    -0.136
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.299
         upper limit
    1.026

    Secondary: Time to First Occurrence of Hypertension During Weeks 1 to 36: Full Analysis Set

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    End point title
    Time to First Occurrence of Hypertension During Weeks 1 to 36: Full Analysis Set
    End point description
    Hypertension was defined as either SBP ≥ 170 mmHg and an increase from baseline ≥ 20 mmHg or as DBP ≥ 110 mmHg and an increase from baseline ≥ 15 mmHg. For participants who had experienced more than one event, only their first event following study treatment was used. Data reported was analyzed by Kaplan-Meier estimate for cumulative proportion. Percentage of participants were reported in this outcome measure. The analysis population was the FAS.
    End point type
    Secondary
    End point timeframe
    Weeks 1 to 36
    End point values
    Darbepoetin alfa Roxadustat
    Number of subjects analysed
    292
    322
    Units: Percentage of Participants
        number (not applicable)
    18.8
    17.4
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Hazard Ratio was calculated using stratified Cox Proportional Hazards regression stratifying on CV history and Region and adjusting on Hb and eGFR at baseline as continuous covariates. Superiority was declared if the upper bound of the 95% CI is lower than 1.
    Comparison groups
    Roxadustat v Darbepoetin alfa
    Number of subjects included in analysis
    614
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.452
    Method
    Regression, Cox
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.87
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.6
         upper limit
    1.26

    Secondary: Change From Baseline in Hb to the Average Hb Value of Weeks 28 to 52 Regardless Use of Rescue Therapy

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    End point title
    Change From Baseline in Hb to the Average Hb Value of Weeks 28 to 52 Regardless Use of Rescue Therapy
    End point description
    Baseline Hb was defined as the mean of all available central laboratory Hb values collected before or including the date of first study drug intake (pre-dose). The analysis population was the FAS, with participants who had available data.
    End point type
    Secondary
    End point timeframe
    Baseline and weeks 28 to 52
    End point values
    Darbepoetin alfa Roxadustat
    Number of subjects analysed
    266
    287
    Units: g/dL
        arithmetic mean (standard deviation)
    1.673 ± 0.923
    1.718 ± 0.958
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    The model included treatment, visit, visit by treatment interaction, region and history of CV disease as fixed class factors and baseline Hb, baseline eGFR and baseline Hb by visit as continuous covariates.
    Comparison groups
    Roxadustat v Darbepoetin alfa
    Number of subjects included in analysis
    553
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.529
    Method
    Mixed models analysis
    Parameter type
    LSM Difference
    Point estimate
    0.038
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.081
         upper limit
    0.157

    Secondary: Time to First Hb Response During First 24 Weeks of Treatment Regardless of Administration of Rescue Therapy

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    End point title
    Time to First Hb Response During First 24 Weeks of Treatment Regardless of Administration of Rescue Therapy
    End point description
    Participants were analyzed during the efficacy emergent period. The efficacy emergent period was defined as the evaluation period from the analysis date of first dose intake up to EOT Visit or last non-missing Hb assessment (for participants who died during the treatment period). For participants who had experienced more than one event, only their first event was used. Data reported was analyzed by Kaplan-Meier estimate for cumulative proportion. Percentage of participants were reported in this outcome measure. The analysis population was the FAS.
    End point type
    Secondary
    End point timeframe
    Weeks 1 to 24
    End point values
    Darbepoetin alfa Roxadustat
    Number of subjects analysed
    292
    322
    Units: Percentage of participants
        number (not applicable)
    77.7
    88.8
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Hazard Ratio was calculated using stratified Cox Proportional Hazards regression stratifying on CV history and Region and adjusting on Hb and eGFR at baseline as continuous covariates.
    Comparison groups
    Roxadustat v Darbepoetin alfa
    Number of subjects included in analysis
    614
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001
    Method
    Regression, Cox
    Parameter type
    Hazard ratio (HR)
    Point estimate
    1.64
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.38
         upper limit
    1.96

    Secondary: Time to First Hb Response During First 24 Weeks of Treatment Without Rescue Therapy

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    End point title
    Time to First Hb Response During First 24 Weeks of Treatment Without Rescue Therapy
    End point description
    Participants were analyzed during the efficacy emergent period. The efficacy emergent period was defined as the evaluation period from the analysis date of first dose intake up to EOT Visit or last non-missing Hb assessment (for participants who died during the treatment period). For participants who had experienced more than one event, only their first event was used. Data reported was analyzed by Kaplan-Meier estimate for cumulative proportion. Percentage of participants were reported in this outcome measure. The analysis population was the FAS.
    End point type
    Secondary
    End point timeframe
    Weeks 1 to 24
    End point values
    Darbepoetin alfa Roxadustat
    Number of subjects analysed
    292
    322
    Units: Percentage of participants
        number (not applicable)
    77.4
    88.2
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Hazard Ratio was calculated using stratified Cox Proportional Hazards regression stratifying on CV history and Region and adjusting on Hb and eGFR at baseline as continuous covariates.
    Comparison groups
    Roxadustat v Darbepoetin alfa
    Number of subjects included in analysis
    614
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001
    Method
    Regression, Cox
    Parameter type
    Hazard ratio (HR)
    Point estimate
    1.66
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.39
         upper limit
    1.98

    Secondary: Hb Level Averaged Over Weeks 28 to 36, Weeks 44 to 52, Weeks 72 to 80 and Weeks 96 to 104 Without Rescue Therapy

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    End point title
    Hb Level Averaged Over Weeks 28 to 36, Weeks 44 to 52, Weeks 72 to 80 and Weeks 96 to 104 Without Rescue Therapy
    End point description
    Baseline Hb was defined as the mean of all available central laboratory Hb values collected before or including the date of first study drug intake (predose). The analysis population was the FAS. Here, N signifies participants with available data at specified time points.
    End point type
    Secondary
    End point timeframe
    Weeks 28 to 36, 44 to 52, 72 to 80 and 96 to 104
    End point values
    Darbepoetin alfa Roxadustat
    Number of subjects analysed
    292
    322
    Units: g/dL
    least squares mean (confidence interval 95%)
        Weeks 28-36 (N=286, 266)
    11.351 (11.247 to 11.455)
    11.403 (11.302 to 11.503)
        Weeks 44-52 (N=266, 251)
    11.188 (11.082 to 11.294)
    11.185 (11.082 to 11.289)
        Weeks 72-80 (N=241, 233)
    11.217 (11.110 to 11.324)
    11.225 (11.120 to 11.331)
        Weeks 96-104 (N=218, 215)
    11.078 (10.960 to 11.196)
    11.102 (10.986 to 11.219)
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Weeks 28-36 - The model included treatment, visit, visit by treatment interaction, region and history of CV disease as fixed class factors and baseline Hb, baseline estimated glomerular filtration rate and baseline Hb by visit as continuous covariates.
    Comparison groups
    Roxadustat v Darbepoetin alfa
    Number of subjects included in analysis
    614
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.478
    Method
    Mixed models analysis
    Parameter type
    LSM Difference
    Point estimate
    0.051
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.091
         upper limit
    0.194
    Statistical analysis title
    Statistical Analysis 2
    Statistical analysis description
    Weeks 44-52 - The model included treatment, visit, visit by treatment interaction, region and history of CV disease as fixed class factors and baseline Hb, baseline estimated glomerular filtration rate and baseline Hb by visit as continuous covariates.
    Comparison groups
    Roxadustat v Darbepoetin alfa
    Number of subjects included in analysis
    614
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.969
    Method
    Mixed models analysis
    Parameter type
    LSM Difference
    Point estimate
    -0.003
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.149
         upper limit
    0.143
    Statistical analysis title
    Statistical Analysis 3
    Statistical analysis description
    Weeks 72-80 - The model included treatment, visit, visit by treatment interaction, region and history of CV disease as fixed class factors and baseline Hb, baseline estimated glomerular filtration rate and baseline Hb by visit as continuous covariates.
    Comparison groups
    Roxadustat v Darbepoetin alfa
    Number of subjects included in analysis
    614
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.91
    Method
    Mixed models analysis
    Parameter type
    LSM Difference
    Point estimate
    0.009
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.14
         upper limit
    0.157
    Statistical analysis title
    Statistical Analysis 4
    Statistical analysis description
    Weeks 96-104 - The model included treatment, visit, visit by treatment interaction, region and history of CV disease as fixed class factors and baseline Hb, baseline estimated glomerular filtration rate and baseline Hb by visit as continuous covariates
    Comparison groups
    Roxadustat v Darbepoetin alfa
    Number of subjects included in analysis
    614
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.775
    Method
    Mixed models analysis
    Parameter type
    LSM Difference
    Point estimate
    0.024
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.14
         upper limit
    0.188

    Secondary: Change From Baseline in Hb to Each Postdosing Time Point Regardless Use of rescue Therapy

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    End point title
    Change From Baseline in Hb to Each Postdosing Time Point Regardless Use of rescue Therapy
    End point description
    Baseline Hb was defined as the mean of all available central laboratory Hb values collected before or including the date of first study drug intake (pre-dose). The analysis population was the FAS. Here, N signifies participants with available data at specified time points.
    End point type
    Secondary
    End point timeframe
    Baseline and weeks 1, 2, 4, 6, 8, 10, 12, 14, 16, 18,20, 22, 24, 28, 32, 36, 40, 44, 48, 52, 56, 60, 64, 68, 72,76, 80, 84, 88, 92, 96, 100, and 104
    End point values
    Darbepoetin alfa Roxadustat
    Number of subjects analysed
    292
    322
    Units: g/dL
    least squares mean (confidence interval 95%)
        Hb Change From BL to Week 1(N=308, 273)
    0.294 (0.221 to 0.368)
    0.381 (0.311 to 0.450)
        Hb Change From BL to Week 2 (N=314, 284)
    0.584 (0.500 to 0.667)
    0.862 (0.782 to 0.941)
        Hb Change From BL to Week 4 (N=311, 283)
    1.073 (0.962 to 1.183)
    1.508 (1.403 to 1.613)
        Hb Change From BL to Week 6 (N=306, 278)
    1.423 (1.3 to 1.546)
    1.845 (1.729 to 1.962)
        Hb Change From BL to Week 8 (N=301, 277)
    1.682 (1.554 to 1.810)
    2.063 (1.940 to 2.185)
        Hb Change From BL to Week 10 (N=301, 266)
    1.611 (1.483 to 1.739)
    1.941 (1.819 to 2.062)
        Hb Change From BL to Week 12 (N=288, 263)
    2.030 (1.897 to 2.162)
    2.330 (2.204 to 2.456)
        Hb Change From BL to Week 14 (N=293, 266)
    1.745 (1.616 to 1.875)
    1.904 (1.781 to 2.027)
        Hb Change From BL to Week 16 (N= 289, 264)
    1.994 (1.864 to 2.124)
    2.177 (2.053 to 2.301)
        Hb Change From BL to Week 18 (N=286, 260)
    1.609 (1.490 to 1.729)
    1.783 (1.699 to 1.896)
        Hb Change From BL to Week 20 (N=282, 262)
    1.900 (1.778 to 2.023)
    1.986 (1.869 to 2.103)
        Hb Change From BL to Week 22 (N=276, 260)
    1.615 (1.499 to 1.731)
    1.584 (1.473 to 1.696)
        Hb Change From BL to Week 24 (N=283, 254)
    1.554 (1.438 to 1.669)
    1.493 (1.383 to 1.603)
        Hb Change From BL to Week 28 (N=276, 252)
    1.869 (1.748 to 1.989)
    1.803 (1.688 to 1.919)
        Hb Change From BL to Week 32 (N=269, 252)
    1.673 (1.549 to 1.797)
    1.687 (1.568 to 1.806)
        Hb Change From BL to Week 36 (N=264, 247)
    1.781 (1.657 to 1.905)
    1.913 (1.793 to 2.032)
        Hb Change From BL to Week 40 (N=266, 254)
    1.438 (1.320 to 1.556)
    1.625 (1.510 to 1.740)
        Hb Change From BL to Week 44 (N=257, 248)
    1.628 (1.502 to 1.754)
    1.650 (1.527 to 1.773)
        Hb Change From BL to Week 48 (N=259, 245)
    1.447 (1.322 to 1.572)
    1.459 (1.338 to 1.581)
        Hb Change From BL to Week 52 (N=254, 242)
    1.710 (1.585 to 1.835)
    1.682 (1.560 to 1.803)
        Hb Change From BL to Week 56 (N=251, 243)
    1.444 (1.321 to 1.567)
    1.412 (1.292 to 1.533)
        Hb Change From BL to Week 60 (N=250, 242)
    1.670 (1.543 to 1.796)
    1.735 (1.611 to 1.859)
        Hb Change From BL to Week 64 (N=247, 236)
    1.547 (1.414 to 1.681)
    1.546 (1.415 to 1.676)
        Hb Change From BL to Week 68 (N=242, 229)
    1.747 (1.620 to 1.875)
    1.851 (1.726 to 1.976)
        Hb Change From BL to Week 72 (N=236, 227)
    1.548 (1.416 to 1.680)
    1.615 (1.486 to 1.745)
        Hb Change From BL to Week 76 (N=231, 225)
    1.767 (1.636 to 1.898)
    1.745 (1.616 to 1.873)
        Hb Change From BL to Week 80 (N=220, 220)
    1.579 (1.451 to 1.707)
    1.534 (1.408 to 1.661)
        Hb Change From BL to Week 84 (N=220, 219)
    1.679 (1.548 to 1.809)
    1.723 (1.594 to 1.853)
        Hb Change From BL to Week 88 (N=219, 220)
    1.370 (1.236 to 1.504)
    1.424 (1.291 to 1.557)
        Hb Change From BL to Week 92 (N=223, 215)
    1.643 (1.505 to 1.780)
    1.677 (1.541 to 1.812)
        Hb Change From BL to Week 96 (N=217, 213)
    1.404 (1.266 to 1.542)
    1.429 (1.293 to 1.566)
        Hb Change From BL to Week 100 (N=215, 204)
    1.598 (1.454 to 1.742)
    1.488 (1.346 to 1.629)
        Hb Change From BL to Week 104 (N=207, 201)
    1.452 (1.299 to 1.606)
    1.489 (1.339 to 1.640)
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Week 1- The model included treatment, visit, visit by treatment interaction, region and history of CV disease as fixed class factors and baseline Hb, baseline eGFR and baseline Hb by visit as continuous covariates.
    Comparison groups
    Roxadustat v Darbepoetin alfa
    Number of subjects included in analysis
    614
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.086
    Method
    Mixed models analysis
    Parameter type
    LSM Difference
    Point estimate
    0.087
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.012
         upper limit
    0.185
    Statistical analysis title
    Statistical Analysis 2
    Statistical analysis description
    Week 2- The model included treatment, visit, visit by treatment interaction, region and history of CV disease as fixed class factors and baseline Hb, baseline eGFR and baseline Hb by visit as continuous covariates.
    Comparison groups
    Roxadustat v Darbepoetin alfa
    Number of subjects included in analysis
    614
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001
    Method
    Mixed models analysis
    Parameter type
    LSM Difference
    Point estimate
    0.278
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.165
         upper limit
    0.391
    Statistical analysis title
    Statistical Analysis 3
    Statistical analysis description
    Week 4- The model included treatment, visit, visit by treatment interaction, region and history of CV disease as fixed class factors and baseline Hb, baseline eGFR and baseline Hb by visit as continuous covariates.
    Comparison groups
    Roxadustat v Darbepoetin alfa
    Number of subjects included in analysis
    614
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001
    Method
    Mixed models analysis
    Parameter type
    LSM Difference
    Point estimate
    0.435
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.284
         upper limit
    0.586
    Statistical analysis title
    Statistical Analysis 4
    Statistical analysis description
    Week 6- The model included treatment, visit, visit by treatment interaction, region and history of CV disease as fixed class factors and baseline Hb, baseline eGFR and baseline Hb by visit as continuous covariates.
    Comparison groups
    Roxadustat v Darbepoetin alfa
    Number of subjects included in analysis
    614
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001
    Method
    Mixed models analysis
    Parameter type
    LSM Difference
    Point estimate
    0.422
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.254
         upper limit
    0.59
    Statistical analysis title
    Statistical Analysis 5
    Statistical analysis description
    Week 8- The model included treatment, visit, visit by treatment interaction, region and history of CV disease as fixed class factors and baseline Hb, baseline eGFR and baseline Hb by visit as continuous covariates.
    Comparison groups
    Roxadustat v Darbepoetin alfa
    Number of subjects included in analysis
    614
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001
    Method
    Mixed models analysis
    Parameter type
    LSM Difference
    Point estimate
    0.38
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.205
         upper limit
    0.556
    Statistical analysis title
    Statistical Analysis 6
    Statistical analysis description
    Week 10- The model included treatment, visit, visit by treatment interaction, region and history of CV disease as fixed class factors and baseline Hb, baseline eGFR and baseline Hb by visit as continuous covariates.
    Comparison groups
    Roxadustat v Darbepoetin alfa
    Number of subjects included in analysis
    614
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001
    Method
    Mixed models analysis
    Parameter type
    LSM Difference
    Point estimate
    0.33
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.155
         upper limit
    0.505
    Statistical analysis title
    Statistical Analysis 7
    Statistical analysis description
    Week 12- The model included treatment, visit, visit by treatment interaction, region and history of CV disease as fixed class factors and baseline Hb, baseline eGFR and baseline Hb by visit as continuous covariates.
    Comparison groups
    Roxadustat v Darbepoetin alfa
    Number of subjects included in analysis
    614
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.001
    Method
    Mixed models analysis
    Parameter type
    LSM Difference
    Point estimate
    0.3
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.119
         upper limit
    0.482
    Statistical analysis title
    Statistical Analysis 8
    Statistical analysis description
    Week 14- The model included treatment, visit, visit by treatment interaction, region and history of CV disease as fixed class factors and baseline Hb, baseline eGFR and baseline Hb by visit as continuous covariates.
    Comparison groups
    Roxadustat v Darbepoetin alfa
    Number of subjects included in analysis
    614
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.079
    Method
    Mixed models analysis
    Parameter type
    LSM Difference
    Point estimate
    0.159
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.018
         upper limit
    0.336
    Statistical analysis title
    Statistical Analysis 9
    Statistical analysis description
    Week 16- The model included treatment, visit, visit by treatment interaction, region and history of CV disease as fixed class factors and baseline Hb, baseline eGFR and baseline Hb by visit as continuous covariates.
    Comparison groups
    Roxadustat v Darbepoetin alfa
    Number of subjects included in analysis
    614
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.044
    Method
    Mixed models analysis
    Parameter type
    LSM Difference
    Point estimate
    0.183
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.005
         upper limit
    0.361
    Statistical analysis title
    Statistical Analysis 10
    Statistical analysis description
    Week 18- The model included treatment, visit, visit by treatment interaction, region and history of CV disease as fixed class factors and baseline Hb, baseline eGFR and baseline Hb by visit as continuous covariates.
    Comparison groups
    Roxadustat v Darbepoetin alfa
    Number of subjects included in analysis
    614
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.037
    Method
    Mixed models analysis
    Parameter type
    LSM Difference
    Point estimate
    0.173
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.01
         upper limit
    0.336
    Statistical analysis title
    Statistical Analysis 11
    Statistical analysis description
    Week 20- The model included treatment, visit, visit by treatment interaction, region and history of CV disease as fixed class factors and baseline Hb, baseline eGFR and baseline Hb by visit as continuous covariates.
    Comparison groups
    Roxadustat v Darbepoetin alfa
    Number of subjects included in analysis
    614
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.319
    Method
    Mixed models analysis
    Parameter type
    LSM Difference
    Point estimate
    0.085
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.083
         upper limit
    0.253
    Statistical analysis title
    Statistical Analysis 12
    Statistical analysis description
    Week 22- The model included treatment, visit, visit by treatment interaction, region and history of CV disease as fixed class factors and baseline Hb, baseline eGFR and baseline Hb by visit as continuous covariates.
    Comparison groups
    Roxadustat v Darbepoetin alfa
    Number of subjects included in analysis
    614
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.709
    Method
    Mixed models analysis
    Parameter type
    LSM Difference
    Point estimate
    -0.03
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.19
         upper limit
    0.129
    Statistical analysis title
    Statistical Analysis 13
    Statistical analysis description
    Week 24- The model included treatment, visit, visit by treatment interaction, region and history of CV disease as fixed class factors and baseline Hb, baseline eGFR and baseline Hb by visit as continuous covariates.
    Comparison groups
    Roxadustat v Darbepoetin alfa
    Number of subjects included in analysis
    614
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.45
    Method
    Mixed models analysis
    Parameter type
    LSM Difference
    Point estimate
    -0.061
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.219
         upper limit
    0.097
    Statistical analysis title
    Statistical Analysis 14
    Statistical analysis description
    Week 28- The model included treatment, visit, visit by treatment interaction, region and history of CV disease as fixed class factors and baseline Hb, baseline eGFR and baseline Hb by visit as continuous covariates.
    Comparison groups
    Roxadustat v Darbepoetin alfa
    Number of subjects included in analysis
    614
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.44
    Method
    Mixed models analysis
    Parameter type
    LSM Difference
    Point estimate
    -0.065
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.231
         upper limit
    0.101
    Statistical analysis title
    Statistical Analysis 15
    Statistical analysis description
    Week 32- The model included treatment, visit, visit by treatment interaction, region and history of CV disease as fixed class factors and baseline Hb, baseline eGFR and baseline Hb by visit as continuous covariates.
    Comparison groups
    Roxadustat v Darbepoetin alfa
    Number of subjects included in analysis
    614
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.874
    Method
    Mixed models analysis
    Parameter type
    LSM Difference
    Point estimate
    0.014
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.157
         upper limit
    0.184
    Statistical analysis title
    Statistical Analysis 16
    Statistical analysis description
    Week 36- The model included treatment, visit, visit by treatment interaction, region and history of CV disease as fixed class factors and baseline Hb, baseline eGFR and baseline Hb by visit as continuous covariates.
    Comparison groups
    Roxadustat v Darbepoetin alfa
    Number of subjects included in analysis
    614
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.132
    Method
    Mixed models analysis
    Parameter type
    LSM Difference
    Point estimate
    0.131
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.039
         upper limit
    0.302
    Statistical analysis title
    Statistical Analysis 17
    Statistical analysis description
    Week 40- The model included treatment, visit, visit by treatment interaction, region and history of CV disease as fixed class factors and baseline Hb, baseline eGFR and baseline Hb by visit as continuous covariates.
    Comparison groups
    Roxadustat v Darbepoetin alfa
    Number of subjects included in analysis
    614
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.024
    Method
    Mixed models analysis
    Parameter type
    LSM Difference
    Point estimate
    0.187
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.024
         upper limit
    0.351
    Statistical analysis title
    Statistical Analysis 18
    Statistical analysis description
    Week 44- The model included treatment, visit, visit by treatment interaction, region and history of CV disease as fixed class factors and baseline Hb, baseline eGFR and baseline Hb by visit as continuous covariates.
    Comparison groups
    Roxadustat v Darbepoetin alfa
    Number of subjects included in analysis
    614
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.807
    Method
    Mixed models analysis
    Parameter type
    LSM Difference
    Point estimate
    0.022
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.153
         upper limit
    0.197
    Statistical analysis title
    Statistical Analysis 19
    Statistical analysis description
    Week 48- The model included treatment, visit, visit by treatment interaction, region and history of CV disease as fixed class factors and baseline Hb, baseline eGFR and baseline Hb by visit as continuous covariates.
    Comparison groups
    Roxadustat v Darbepoetin alfa
    Number of subjects included in analysis
    614
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.89
    Method
    Mixed models analysis
    Parameter type
    LSM Difference
    Point estimate
    0.012
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.16
         upper limit
    0.185
    Statistical analysis title
    Statistical Analysis 20
    Statistical analysis description
    Week 52- The model included treatment, visit, visit by treatment interaction, region and history of CV disease as fixed class factors and baseline Hb, baseline eGFR and baseline Hb by visit as continuous covariates.
    Comparison groups
    Roxadustat v Darbepoetin alfa
    Number of subjects included in analysis
    614
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.746
    Method
    Mixed models analysis
    Parameter type
    LSM Difference
    Point estimate
    -0.029
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.201
         upper limit
    0.144
    Statistical analysis title
    Statistical Analysis 21
    Statistical analysis description
    Week 56- The model included treatment, visit, visit by treatment interaction, region and history of CV disease as fixed class factors and baseline Hb, baseline eGFR and baseline Hb by visit as continuous covariates.
    Comparison groups
    Roxadustat v Darbepoetin alfa
    Number of subjects included in analysis
    614
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.715
    Method
    Mixed models analysis
    Parameter type
    LSM Difference
    Point estimate
    -0.032
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.202
         upper limit
    0.139
    Statistical analysis title
    Statistical Analysis 22
    Statistical analysis description
    Week 60- The model included treatment, visit, visit by treatment interaction, region and history of CV disease as fixed class factors and baseline Hb, baseline eGFR and baseline Hb by visit as continuous covariates.
    Comparison groups
    Roxadustat v Darbepoetin alfa
    Number of subjects included in analysis
    614
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.463
    Method
    Mixed models analysis
    Parameter type
    LSM Difference
    Point estimate
    0.066
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.11
         upper limit
    0.242
    Statistical analysis title
    Statistical Analysis 23
    Statistical analysis description
    Week 64- The model included treatment, visit, visit by treatment interaction, region and history of CV disease as fixed class factors and baseline Hb, baseline eGFR and baseline Hb by visit as continuous covariates.
    Comparison groups
    Roxadustat v Darbepoetin alfa
    Number of subjects included in analysis
    614
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.987
    Method
    Mixed models analysis
    Parameter type
    LSM Difference
    Point estimate
    -0.002
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.187
         upper limit
    0.184
    Statistical analysis title
    Statistical Analysis 24
    Statistical analysis description
    Week 68- The model included treatment, visit, visit by treatment interaction, region and history of CV disease as fixed class factors and baseline Hb, baseline eGFR and baseline Hb by visit as continuous covariates.
    Comparison groups
    Roxadustat v Darbepoetin alfa
    Number of subjects included in analysis
    614
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.251
    Method
    Mixed models analysis
    Parameter type
    LSM Difference
    Point estimate
    0.104
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.074
         upper limit
    0.281
    Statistical analysis title
    Statistical Analysis 25
    Statistical analysis description
    Week 72- The model included treatment, visit, visit by treatment interaction, region and history of CV disease as fixed class factors and baseline Hb, baseline eGFR and baseline Hb by visit as continuous covariates.
    Comparison groups
    Roxadustat v Darbepoetin alfa
    Number of subjects included in analysis
    614
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.473
    Method
    Mixed models analysis
    Parameter type
    LSM Difference
    Point estimate
    0.067
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.117
         upper limit
    0.251
    Statistical analysis title
    Statistical Analysis 26
    Statistical analysis description
    Week 76- The model included treatment, visit, visit by treatment interaction, region and history of CV disease as fixed class factors and baseline Hb, baseline eGFR and baseline Hb by visit as continuous covariates.
    Comparison groups
    Roxadustat v Darbepoetin alfa
    Number of subjects included in analysis
    614
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.813
    Method
    Mixed models analysis
    Parameter type
    LSM Difference
    Point estimate
    -0.022
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.204
         upper limit
    0.16
    Statistical analysis title
    Statistical Analysis 27
    Statistical analysis description
    Week 80- The model included treatment, visit, visit by treatment interaction, region and history of CV disease as fixed class factors and baseline Hb, baseline eGFR and baseline Hb by visit as continuous covariates.
    Comparison groups
    Roxadustat v Darbepoetin alfa
    Number of subjects included in analysis
    614
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.622
    Method
    Mixed models analysis
    Parameter type
    LSM Difference
    Point estimate
    -0.045
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.223
         upper limit
    0.134
    Statistical analysis title
    Statistical Analysis 28
    Statistical analysis description
    Week 84- The model included treatment, visit, visit by treatment interaction, region and history of CV disease as fixed class factors and baseline Hb, baseline eGFR and baseline Hb by visit as continuous covariates.
    Comparison groups
    Roxadustat v Darbepoetin alfa
    Number of subjects included in analysis
    614
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.632
    Method
    Mixed models analysis
    Parameter type
    LSM Difference
    Point estimate
    0.045
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.138
         upper limit
    0.227
    Statistical analysis title
    Statistical Analysis 29
    Statistical analysis description
    Week 88- The model included treatment, visit, visit by treatment interaction, region and history of CV disease as fixed class factors and baseline Hb, baseline eGFR and baseline Hb by visit as continuous covariates.
    Comparison groups
    Roxadustat v Darbepoetin alfa
    Number of subjects included in analysis
    614
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.568
    Method
    Mixed models analysis
    Parameter type
    LSM Difference
    Point estimate
    0.055
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.133
         upper limit
    0.242
    Statistical analysis title
    Statistical Analysis 30
    Statistical analysis description
    Week 92- The model included treatment, visit, visit by treatment interaction, region and history of CV disease as fixed class factors and baseline Hb, baseline eGFR and baseline Hb by visit as continuous covariates.
    Comparison groups
    Roxadustat v Darbepoetin alfa
    Number of subjects included in analysis
    614
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.729
    Method
    Mixed models analysis
    Parameter type
    LSM Difference
    Point estimate
    0.034
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.158
         upper limit
    0.226
    Statistical analysis title
    Statistical Analysis 31
    Statistical analysis description
    Week 96- The model included treatment, visit, visit by treatment interaction, region and history of CV disease as fixed class factors and baseline Hb, baseline eGFR and baseline Hb by visit as continuous covariates.
    Comparison groups
    Roxadustat v Darbepoetin alfa
    Number of subjects included in analysis
    614
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.797
    Method
    Mixed models analysis
    Parameter type
    LSM Difference
    Point estimate
    0.025
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.168
         upper limit
    0.218
    Statistical analysis title
    Statistical Analysis 32
    Statistical analysis description
    Week 100- The model included treatment, visit, visit by treatment interaction, region and history of CV disease as fixed class factors and baseline Hb, baseline eGFR and baseline Hb by visit as continuous covariates.
    Comparison groups
    Roxadustat v Darbepoetin alfa
    Number of subjects included in analysis
    614
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.28
    Method
    Mixed models analysis
    Parameter type
    LSM Difference
    Point estimate
    -0.11
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.31
         upper limit
    0.09
    Statistical analysis title
    Statistical Analysis 33
    Statistical analysis description
    Week 104- The model included treatment, visit, visit by treatment interaction, region and history of CV disease as fixed class factors and baseline Hb, baseline eGFR and baseline Hb by visit as continuous covariates.
    Comparison groups
    Roxadustat v Darbepoetin alfa
    Number of subjects included in analysis
    614
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.733
    Method
    Mixed models analysis
    Parameter type
    LSM Difference
    Point estimate
    0.037
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.177
         upper limit
    0.251

    Secondary: Change From Baseline in Hb to Average Hb Value of Weeks 28 to 36, Weeks 44 to 52, Weeks 72 to 80, Weeks 96 to 104 Regardless of Use of Rescue Therapy

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    End point title
    Change From Baseline in Hb to Average Hb Value of Weeks 28 to 36, Weeks 44 to 52, Weeks 72 to 80, Weeks 96 to 104 Regardless of Use of Rescue Therapy
    End point description
    Baseline Hb was defined as the mean of all available central laboratory Hb values collected before or including the date of first study drug intake (predose). The analysis population was the FAS. Here, N signifies participants with available data at specified time points.
    End point type
    Secondary
    End point timeframe
    Baseline and weeks 28 to 36, 44 to 52, 72 to 80 and 96 to 104
    End point values
    Darbepoetin alfa Roxadustat
    Number of subjects analysed
    292
    322
    Units: g/dL
    least squares mean (confidence interval 95%)
        Hb Change From BL to Weeks 28-36 (N=287, 266)
    1.799 (1.694 to 1.905)
    1.825 (1.723 to 1.926)
        Hb Change From BL to Weeks 44-52 (N=267, 252)
    1.620 (1.512 to 1.729)
    1.619 (1.513 to 1.724)
        Hb Change From BL to Weeks 72-80 (N=243, 233)
    1.649 (1.540 to 1.758)
    1.652 (1.545 to 1.759)
        Hb Change From BL to Weeks 96-104 (N=223, 217)
    1.502 (1.378 to 1.626)
    1.486 (1.363 to 1.608)
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Weeks 28-36 - The model included treatment, visit, visit by treatment interaction, region and history of CV disease as fixed class factors and baseline Hb, baseline estimated glomerular filtration rate and baseline Hb by visit as continuous covariates.
    Comparison groups
    Roxadustat v Darbepoetin alfa
    Number of subjects included in analysis
    614
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.727
    Method
    Mixed models analysis
    Parameter type
    LSM Difference
    Point estimate
    0.026
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.119
         upper limit
    0.17
    Statistical analysis title
    Statistical Analysis 2
    Statistical analysis description
    Weeks 44-52 - The model included treatment, visit, visit by treatment interaction, region and history of CV disease as fixed class factors and baseline Hb, baseline estimated glomerular filtration rate and baseline Hb by visit as continuous covariates.
    Comparison groups
    Roxadustat v Darbepoetin alfa
    Number of subjects included in analysis
    614
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.985
    Method
    Mixed models analysis
    Parameter type
    LSM Difference
    Point estimate
    -0.001
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.151
         upper limit
    0.148
    Statistical analysis title
    Statistical Analysis 3
    Statistical analysis description
    Weeks 72-80 - The model included treatment, visit, visit by treatment interaction, region and history of CV disease as fixed class factors and baseline Hb, baseline estimated glomerular filtration rate and baseline Hb by visit as continuous covariates.
    Comparison groups
    Roxadustat v Darbepoetin alfa
    Number of subjects included in analysis
    614
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.965
    Method
    Mixed models analysis
    Parameter type
    LSM Difference
    Point estimate
    0.003
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.148
         upper limit
    0.154
    Statistical analysis title
    Statistical Analysis 4
    Statistical analysis description
    Weeks 96-104 - The model included treatment, visit, visit by treatment interaction, region and history of CV disease as fixed class factors and baseline Hb, baseline estimated glomerular filtration rate and baseline Hb by visit as continuous covariates.
    Comparison groups
    Roxadustat v Darbepoetin alfa
    Number of subjects included in analysis
    614
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.856
    Method
    Mixed models analysis
    Parameter type
    LSM Difference
    Point estimate
    -0.016
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.188
         upper limit
    0.157

    Secondary: Percentage of Hb Values ≥ 10 g/dL and Within 10.0 to 12.0 g/dL in Weeks 28 to 36, Weeks 44 to 52, Weeks 72 to 80 and Weeks 96 to 104 Without Use of Rescue Therapy

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    End point title
    Percentage of Hb Values ≥ 10 g/dL and Within 10.0 to 12.0 g/dL in Weeks 28 to 36, Weeks 44 to 52, Weeks 72 to 80 and Weeks 96 to 104 Without Use of Rescue Therapy
    End point description
    Percentage for each participant was calculated from the number of Hb values within 10.0 to 12.0 g/dL / total number of Hb values*100 in weeks 28 to 36, 44 to 52, 72 to 80 and 96 to 104 without use of rescue therapy within 6 weeks prior to and during the 8 week evaluation period. The analysis population was the FAS. Here, N signifies participants with available data at specified time points.
    End point type
    Secondary
    End point timeframe
    Weeks 28 to 36, 44 to 52, 72 to 80 and 96 to 104
    End point values
    Darbepoetin alfa Roxadustat
    Number of subjects analysed
    292
    322
    Units: Percentage of Hb values
    arithmetic mean (standard deviation)
        Weeks 28-36, ≥ 10 (N=286, 266)
    92.481 ± 19.876
    93.078 ± 20.671
        Weeks 28-36, Within 10-12 (N=286, 266)
    69.217 ± 34.171
    67.896 ± 33.499
        Weeks 44-52, ≥ 10 (N=266, 251)
    89.416 ± 24.833
    90.921 ± 23.123
        Weeks 44-52, Within 10-12 (N=266, 251)
    68.931 ± 35.367
    74.104 ± 32.119
        Weeks 72-80, ≥ 10 (N=241, 233)
    90.343 ± 24.364
    91.494 ± 20.923
        Weeks 72-80, Within 10-12 (N=241, 233)
    67.861 ± 37.024
    69.710 ± 32.444
        Weeks 96-104, ≥10 (N=218, 215)
    87.777 ± 27.03
    90.436 ± 22.725
        Weeks 96-104, Within 10-12 (N=218, 215)
    68.629 ± 35.352
    72.393 ± 33.277
    No statistical analyses for this end point

    Secondary: Time to First Hb Rate of Rise > 2 g/dL Within 4 weeks

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    End point title
    Time to First Hb Rate of Rise > 2 g/dL Within 4 weeks
    End point description
    Participants were analyzed during the efficacy emergent period. The efficacy emergent period was defined as the evaluation period from the analysis date of first dose intake up to EOT Visit or last non-missing Hb assessment (for participants who died during the treatment period). For participants who had experienced more than one event, only their first event was used. Data reported was analyzed by Kaplan-Meier estimate for cumulative proportion and the 95% confidence interval was calculated with Greenwood's formula. Percentage of participants were reported in this outcome measure. The analysis population was the FAS. Here, N signifies participants with available data at specified time points.
    End point type
    Secondary
    End point timeframe
    Year 0.5, 1, 1.5 and 2
    End point values
    Darbepoetin alfa Roxadustat
    Number of subjects analysed
    292
    322
    Units: Percentage of participants
    number (confidence interval 95%)
        Year 0.5 (N=155, 188)
    28.9 (23.6 to 34.1)
    45.5 (40.0 to 51.0)
        Year 1 (N=131, 171)
    30.9 (25.4 to 36.3)
    48.8 (43.2 to 54.4)
        Year 1.5 (N=104, 145)
    35.0 (29.3 to 40.7)
    53.4 (47.7 to 59.1)
        Year 2 (N=10, 22)
    37.8 (31.9 to 43.7)
    55.3 (49.5 to 61.0)
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Hazard Ratio was calculated using stratified Cox Proportional Hazards regression stratifying on CV history and Region and adjusting on Hb and eGFR at baseline as continuous covariates.
    Comparison groups
    Roxadustat v Darbepoetin alfa
    Number of subjects included in analysis
    614
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001
    Method
    Regression, Cox
    Parameter type
    Hazard ratio (HR)
    Point estimate
    1.74
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.36
         upper limit
    2.22

    Secondary: Number of Hospitalizations

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    End point title
    Number of Hospitalizations
    End point description
    The number of hospitalizations per participant were calculated during the efficacy emergent period. The efficacy emergent period was defined as the evaluation period from the analysis date of first dose intake up to EOT Visit or last non-missing Hb assessment (for participants who died during the treatment period). The analysis population was the FAS.
    End point type
    Secondary
    End point timeframe
    Baseline to EOT (Up to week 104)
    End point values
    Darbepoetin alfa Roxadustat
    Number of subjects analysed
    292
    322
    Units: Hospitalizations
        arithmetic mean (standard deviation)
    1.4 ± 2.3
    1.5 ± 2.4
    No statistical analyses for this end point

    Secondary: Number of Days of Hospitalization per Year

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    End point title
    Number of Days of Hospitalization per Year
    End point description
    The number of days of hospitalization per year was calculated as the sum of the durations of all hospitalizations in days (minimum [date of discharge, end of efficacy of emergent period] - date of admission + 1) / (duration of efficacy emergent period in days / 365.25). The efficacy emergent period was defined as the evaluation period from the analysis date of first dose intake up to EOT Visit or last non-missing Hb assessment (for participants who died during the treatment period). The analysis population was the FAS.
    End point type
    Secondary
    End point timeframe
    Baseline to EOT (Up to week 104)
    End point values
    Darbepoetin alfa Roxadustat
    Number of subjects analysed
    292
    322
    Units: Days per year
        arithmetic mean (standard deviation)
    11.3 ± 27.7
    12.6 ± 22.0
    No statistical analyses for this end point

    Secondary: Time to First Hospitalization

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    End point title
    Time to First Hospitalization
    End point description
    Time to first hospitalization in years was defined in years as: (first event date during the efficacy emergent period – analysis date of first dose intake +1)/365.25, and the ‘first event date’ was defined as ‘date of first admission and ‘analysis date of first dose intake. Date of end of efficacy emergent period was defined as as the treatment period up to the EOT visit. For participants who have experienced more than one hospitalization, only their first event following study treatment was used. Data reported was analyzed by Kaplan-Meier estimate for cumulative proportion and the 95% confidence interval was calculated with Greenwood's formula. Percentage of participants were reported in this outcome measure. The analysis population was the FAS. Here, N signifies participants with available data at specified time points.
    End point type
    Secondary
    End point timeframe
    Year 0.5, 1, 1.5 and 2
    End point values
    Darbepoetin alfa Roxadustat
    Number of subjects analysed
    292
    322
    Units: Percentage of participants
    number (confidence interval 95%)
        Year 0.5 (N=207, 216)
    21.8 (17 to 26.7)
    31.7 (26.5 to 36.8)
        Year 1 (N=162, 158)
    40.4 (34.6 to 46.2)
    43.7 (38.2 to 49.3)
        Year 1.5 (N=122, 124)
    50.2 (44.2 to 56.1)
    55.2 (49.6 to 60.9)
        Year 2 (N=15, 24)
    56.7 (50.7 to 62.7)
    62.3 (56.7 to 67.9)
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Hazard Ratio was calculated using stratified Cox Proportional Hazards regression stratifying on CV history and Region and adjusting on Hb and eGFR at baseline as continuous covariates. Superiority was declared if the upper bound of the 95% CI is below 1.0.
    Comparison groups
    Roxadustat v Darbepoetin alfa
    Number of subjects included in analysis
    614
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.079
    Method
    Regression, Cox
    Parameter type
    Hazard ratio (HR)
    Point estimate
    1.21
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.98
         upper limit
    1.5

    Secondary: Time to First Use of RBC Transfusion

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    End point title
    Time to First Use of RBC Transfusion
    End point description
    Participants were analyzed during the efficacy emergent period. The efficacy emergent period was defined as the evaluation period from the analysis date of first dose intake up to EOT Visit or last non-missing Hb assessment (for participants who died during the treatment period). For participants who had experienced more than one RBC transfusion, only their first event was used. Data reported was analyzed by Kaplan-Meier estimate for cumulative proportion and the 95% confidence interval was calculated with Greenwood's formula. Percentage of participants were reported in this outcome measure. The analysis population was the FAS. Here, N signifies participants with available data at specified time points.
    End point type
    Secondary
    End point timeframe
    Year 0.5, 1, 1.5 and 2
    End point values
    Darbepoetin alfa Roxadustat
    Number of subjects analysed
    292
    322
    Units: Percentage of participants
    number (confidence interval 95%)
        Year 0.5 (N=281, 263)
    2.1 (0.4 to 3.8)
    3 (1.1 to 4.9)
        Year 1 (N=244, 233)
    6.5 (3.5 to 9.5)
    7.3 (4.3 to 10.3)
        Year 1.5 (N=214, 207)
    9.4 (5.8 to 13)
    10.9 (7.2 to 14.6)
        Year 2 (N=31, 34)
    11.2 (7.3 to 15.1)
    13.9 (9.7 to 18.2)
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Hazard Ratio was calculated using stratified Cox Proportional Hazards regression stratifying on CV history and Region and adjusting on Hb and eGFR at baseline as continuous covariates. Superiority was declared if the upper bound of the 95% CI is below 1.0.
    Comparison groups
    Roxadustat v Darbepoetin alfa
    Number of subjects included in analysis
    614
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.3
    Method
    Regression, Cox
    Parameter type
    Hazard ratio (HR)
    Point estimate
    1.3
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.79
         upper limit
    2.11

    Secondary: Number of RBC Packs

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    End point title
    Number of RBC Packs
    End point description
    The number of RBC packs were calculated as the sum of units transfused during the efficacy emergent period. The efficacy emergent period was defined as the evaluation period from the analysis date of first dose intake up to EOT Visit or last non-missing Hb assessment (for participants who died during the treatment period). Participants with no medication records of RBC have their number of RBC packs set to 0. The analysis population was the FAS.
    End point type
    Secondary
    End point timeframe
    Baseline to EOT (Up to week 104)
    End point values
    Darbepoetin alfa Roxadustat
    Number of subjects analysed
    292
    322
    Units: RBC packs
        arithmetic mean (standard deviation)
    0.4 ± 1.98
    0.4 ± 1.20
    No statistical analyses for this end point

    Secondary: Volume of RBC Transfused

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    End point title
    Volume of RBC Transfused
    End point description
    The volume of blood transfused was calculated as the sum of blood volume transfused during the efficacy emergent period. The efficacy emergent period was defined as the evaluation period from the analysis date of first dose intake up to EOT Visit or last non-missing Hb assessment (for participants who died during the treatment period). Participants with no medication records of RBC have their volume set to 0. The analysis population was the FAS.
    End point type
    Secondary
    End point timeframe
    Baseline to EOT (Up to week 104)
    End point values
    Darbepoetin alfa Roxadustat
    Number of subjects analysed
    292
    322
    Units: mL
        arithmetic mean (standard deviation)
    334.63 ± 508.40
    97.0 ± 112.2
    No statistical analyses for this end point

    Secondary: Number of Particpants who Received RBC Transfusions

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    End point title
    Number of Particpants who Received RBC Transfusions
    End point description
    Participants who received RBC transfusions during the efficacy emergent period were reported. The efficacy emergent period was defined as the evaluation period from the analysis date of first dose intake up to EOT Visit or last non-missing Hb assessment (for participants who died during the treatment period). The analysis population was the FAS.
    End point type
    Secondary
    End point timeframe
    Baseline to EOT (Up to week 104)
    End point values
    Darbepoetin alfa Roxadustat
    Number of subjects analysed
    292
    322
    Units: Participants
    28
    38
    No statistical analyses for this end point

    Secondary: Time to First Use of Rescue Therapy

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    End point title
    Time to First Use of Rescue Therapy
    End point description
    Rescue therapy for partcipants in the roxadustat group included RBC transfusion or ESA therapy and for partcipants in the darbepoetin alfa group included RBC transfusion only. Participants were analyzed during the efficacy emergent period. The efficacy emergent period was defined as the evaluation period from the analysis date of first dose intake up to EOT Visit or last non-missing Hb assessment (for participants who died during the treatment period). For participants who have experienced more than one use of rescue therapy (i.e. RBC and ESA), only their first event was used. Data reported was analyzed by Kaplan-Meier estimate for cumulative proportion and the 95% confidence interval was calculated with Greenwood's formula. Percentage of participants were reported in this outcome measure. The analysis population was the FAS. Here, N signifies participants with available data at specified time points.
    End point type
    Secondary
    End point timeframe
    Year 0.5, 1, 1.5 and 2
    End point values
    Darbepoetin alfa Roxadustat
    Number of subjects analysed
    292
    322
    Units: Percentage of participants
    number (confidence interval 95%)
        Year 0.5 (N=278, 263)
    2.1 (0.4 to 3.8)
    4 (1.8 to 6.2)
        Year 1 (N=241, 233)
    6.5 (3.5 to 9.5)
    9.3 (6 to 12.7)
        Year 1.5 (N=213, 207)
    9.4 (5.8 to 13)
    13.3 (9.3 to 17.3)
        Year 2 (N=31, 34)
    11.2 (7.3 to 15.1)
    16.7 (12.2 to 21.2)
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Hazard Ratio was calculated using stratified Cox Proportional Hazards regression stratifying on CV history and Region and adjusting on Hb and eGFR at baseline as continuous covariates. Superiority was declared if the upper bound of the 95% CI is below 1.0.
    Comparison groups
    Roxadustat v Darbepoetin alfa
    Number of subjects included in analysis
    614
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.055
    Method
    Regression, Cox
    Parameter type
    Hazard ratio (HR)
    Point estimate
    1.59
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.99
         upper limit
    2.54

    Secondary: Number of Participants who Received Rescue Therapy (Composite of RBC Transfusions (all Participants) and Darbepoetin alfa use (Roxadustat Treated Participants only)

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    End point title
    Number of Participants who Received Rescue Therapy (Composite of RBC Transfusions (all Participants) and Darbepoetin alfa use (Roxadustat Treated Participants only)
    End point description
    Rescue therapy for participants in the roxadustat group included RBC transfusion or ESA therapy and for participants in the darbepoetin alfa group included RBC transfusion only. Participants were analyzed during the efficacy emergent period. The efficacy emergent period was defined as the evaluation period from the analysis date of first dose intake up to EOT Visit or last non-missing Hb assessment (for participants who died during the treatment period). For participants who have experienced more than one use of rescue therapy (i.e. RBC and ESA), only their first event was used. The analysis population was the FAS.
    End point type
    Secondary
    End point timeframe
    Baseline to EOT (Up to week 104)
    End point values
    Darbepoetin alfa Roxadustat
    Number of subjects analysed
    292
    322
    Units: Participants
    28
    46
    No statistical analyses for this end point

    Secondary: Mean Monthly Intravenous Iron per Participant During Weeks 37 to 52 and Weeks 53 to 104

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    End point title
    Mean Monthly Intravenous Iron per Participant During Weeks 37 to 52 and Weeks 53 to 104
    End point description
    Participants with no or missing medication records of IV Iron had their monthly IV Iron use set to 0 mg. The analysis population was the FAS. Here, N signifies participants with available data at specified time points.
    End point type
    Secondary
    End point timeframe
    Weeks 37 to 52 and 53 to 104
    End point values
    Darbepoetin alfa Roxadustat
    Number of subjects analysed
    292
    322
    Units: mg per month
    arithmetic mean (standard deviation)
        Weeks 37 to 52 (N=275, 258)
    13.208 ± 46.408
    11.208 ± 64.282
        Weeks 53 to 104 (N=259, 248)
    31.315 ± 95.306
    18.702 ± 68.074
    No statistical analyses for this end point

    Secondary: Time to First Use of IV Iron Supplementation

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    End point title
    Time to First Use of IV Iron Supplementation
    End point description
    Participants were analyzed during the efficacy emergent period. The efficacy emergent period was defined as the evaluation period from the analysis date of first dose intake up to EOT Visit or last non-missing Hb assessment (for participants who died during the treatment period). For participants who had received more than one IV iron, only their first event following study treatment was used. Data reported was analyzed by Kaplan-Meier estimate for cumulative proportion and the 95% confidence interval was calculated with Greenwood's formula. Percentage of participants were reported in this outcome measure. The analysis population was the FAS. Here, N signifies participants with available data at specified time points.
    End point type
    Secondary
    End point timeframe
    Year 0.5, 1, 1.5 and 2
    End point values
    Darbepoetin alfa Roxadustat
    Number of subjects analysed
    292
    322
    Units: Percentage of participants
    number (confidence interval 95%)
        Year 0.5 (N=278, 238)
    11.8 (8 to 15.6)
    4.3 (2 to 6.5)
        Year 1 (N=240, 201)
    19.2 (14.5 to 23.9)
    10 (6.5 to 13.5)
        Year 1.5 (N=206, 176)
    24.2 (19 to 29.4)
    15.9 (11.5 to 20.2)
        Year 2 (N=26, 30)
    29.1 (23.1 to 35.1)
    24.9 (18.8 to 31)
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Hazard Ratio was calculated using stratified Cox Proportional Hazards regression stratifying on CV history and Region and adjusting on Hb and eGFR at baseline as continuous covariate. Superiority was declared if the upper bound of the 95% CI is below 1.0.
    Comparison groups
    Roxadustat v Darbepoetin alfa
    Number of subjects included in analysis
    614
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.052
    Method
    Regression, Cox
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.71
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.51
         upper limit
    1

    Secondary: Percentage of Participants with Oral Iron Use Only

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    End point title
    Percentage of Participants with Oral Iron Use Only
    End point description
    Percentage of participants with oral iron use only were calculated based on total number of participants within the efficacy emergent period. The efficacy emergent period was defined as the evaluation period from the analysis date of first dose intake up to EOT Visit or last non-missing Hb assessment (for participants who died during the treatment period). The analysis population was the FAS.
    End point type
    Secondary
    End point timeframe
    Day 1 to week 36, weeks 37 to 52, weeks 53 to 104, efficacy emergent period (up to week 104)
    End point values
    Darbepoetin alfa Roxadustat
    Number of subjects analysed
    292
    322
    Units: Percentage of participants
    number (not applicable)
        During efficacy emergent period
    52.7
    50.6
        During day 1 to week 36
    55.1
    55.3
        During week 37 to 52
    55.4
    55.6
        During week 53 to 104
    50.6
    53.1
    No statistical analyses for this end point

    Secondary: Change From Baseline to Weeks 8, 28, 52 and 104 in Total Cholesterol

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    End point title
    Change From Baseline to Weeks 8, 28, 52 and 104 in Total Cholesterol
    End point description
    Baseline was defined as the value on day 1. If baseline value was missing, the latest value prior to first study drug administration was used regardless of fasting. The analysis population was the FAS. Here, N signifies participants with available data at specified time points.
    End point type
    Secondary
    End point timeframe
    Baseline and weeks 8, 28, 52, 104
    End point values
    Darbepoetin alfa Roxadustat
    Number of subjects analysed
    292
    322
    Units: mmol/L
    arithmetic mean (standard deviation)
        Change from BL to week 8 (N=311, 282)
    -0.046 ± 0.836
    -0.92 ± 0.98
        Change from BL to week 28 (N=285, 264)
    0.016 ± 0.953
    -0.531 ± 1.153
        Change from BL to week 52 (N=256, 245)
    -0.111 ± 1.097
    -0.524 ± 1.232
        Change from BL to week 104 (N=215, 212)
    -0.197 ± 1.171
    -0.695 ± 1.284
    No statistical analyses for this end point

    Secondary: Change From Baseline to Weeks 8, 28, 52 and 104 in LDL-C/High-Density Lipoprotein cholesterol (HDL-C) Ratio

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    End point title
    Change From Baseline to Weeks 8, 28, 52 and 104 in LDL-C/High-Density Lipoprotein cholesterol (HDL-C) Ratio
    End point description
    Baseline was defined as the value on day 1. If baseline value was missing, the latest value prior to first study drug administration was used regardless of fasting. The analysis population was the FAS. Here, N signifies participants with available data at specified time points.
    End point type
    Secondary
    End point timeframe
    Baseline and weeks 8, 28, 52, 104
    End point values
    Darbepoetin alfa Roxadustat
    Number of subjects analysed
    292
    322
    Units: Ratio
    arithmetic mean (standard deviation)
        Change from BL to week 8 (N=310, 282)
    -0.049 ± 0.629
    -0.209 ± 0.665
        Change from BL to week 28 (N=284, 262)
    0.053 ± 0.747
    0.016 ± 0.893
        Change from BL to week 52 (N=256, 245)
    -0.065 ± 0.871
    0.014 ± 1.095
        Change from BL to week 104 (N=215, 209)
    0.012 ± 1.06
    -0.069 ± 1.579
    No statistical analyses for this end point

    Secondary: Change From Baseline to Weeks 8, 28, 52 and 104 in Non-HDL Cholesterol

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    End point title
    Change From Baseline to Weeks 8, 28, 52 and 104 in Non-HDL Cholesterol
    End point description
    Baseline was defined as the value on day 1. If baseline value was missing, the latest value prior to first study drug administration was used regardless of fasting. The analysis population was the FAS. Here, N signifies participants with available data at specified time points.
    End point type
    Secondary
    End point timeframe
    Baseline and weeks 8, 28, 52, 104
    End point values
    Darbepoetin alfa Roxadustat
    Number of subjects analysed
    292
    322
    Units: mmoL/L
    arithmetic mean (standard deviation)
        Change from BL to week 8 (N=310, 282)
    -0.045 ± 0.787
    -0.729 ± 0.9
        Change from BL to week 28 (N=284, 262)
    0.02 ± 0.911
    -0.392 ± 1.098
        Change from BL to week 52 (N=256, 245)
    -0.114 ± 1.062
    -0.383 ± 1.19
        Change from BL to week 104 (N=215, 211)
    -0.15 ± 1.151
    -0.562 ± 1.162
    No statistical analyses for this end point

    Secondary: Change From Baseline to Weeks 8, 28, 52 and 104 in Apolipoproteins A1 (ApoA1)

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    End point title
    Change From Baseline to Weeks 8, 28, 52 and 104 in Apolipoproteins A1 (ApoA1)
    End point description
    Baseline was defined as the value on day 1. If baseline value was missing, the latest value prior to first study drug administration was used regardless of fasting. The analysis population was the FAS. Here, N signifies participants with available data at specified time points.
    End point type
    Secondary
    End point timeframe
    Baseline and weeks 8, 28, 52, 104
    End point values
    Darbepoetin alfa Roxadustat
    Number of subjects analysed
    292
    322
    Units: Grams per liter (g/L)
    arithmetic mean (standard deviation)
        Change from BL to week 8 (N=310, 283)
    0.026 ± 0.204
    -0.184 ± 0.222
        Change from BL to week 28 (N=287, 264)
    0.055 ± 0.217
    -0.104 ± 0.258
        Change from BL to week 52 (N=254, 243)
    0.027 ± 0.229
    -0.12 ± 0.254
        Change from BL to week 104 (N=214, 212)
    -0.018 ± 0.242
    -0.116 ± 0.311
    No statistical analyses for this end point

    Secondary: Change From Baseline to Weeks 8, 28, 52 and 104 in Apolipoproteins B (ApoB)

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    End point title
    Change From Baseline to Weeks 8, 28, 52 and 104 in Apolipoproteins B (ApoB)
    End point description
    Baseline was defined as the value on day 1. If baseline value was missing, the latest value prior to first study drug administration was used regardless of fasting. The analysis population was the FAS. Here, N signifies participants with available data at specified time points.
    End point type
    Secondary
    End point timeframe
    Baseline and weeks 8, 28, 52, 104
    End point values
    Darbepoetin alfa Roxadustat
    Number of subjects analysed
    292
    322
    Units: Milligrams per deciliter (mg/dL)
    arithmetic mean (standard deviation)
        Change from BL to week 8 (N=310, 283)
    -0.71 ± 17.791
    -16.5 ± 19.581
        Change from BL to week 28 (N=287, 264)
    0.091 ± 19.672
    -10.659 ± 23.644
        Change from BL to week 52 (N=254, 243)
    -3.539 ± 23.811
    -10.74 ± 25.155
        Change from BL to week 104 (N=214, 212)
    -2.038 ± 25.857
    -13.561 ± 25.461
    No statistical analyses for this end point

    Secondary: Change From Baseline to Weeks 8, 28, 52 and 104 in ApoB/ApoA1 Ratio

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    End point title
    Change From Baseline to Weeks 8, 28, 52 and 104 in ApoB/ApoA1 Ratio
    End point description
    Baseline was defined as the value on day 1. If baseline value was missing, the latest value prior to first study drug administration was used regardless of fasting. The analysis population was the FAS. Here, N signifies participants with available data at specified time points.
    End point type
    Secondary
    End point timeframe
    Baseline and weeks 8, 28, 52, 104
    End point values
    Darbepoetin alfa Roxadustat
    Number of subjects analysed
    292
    322
    Units: Ratio
    arithmetic mean (standard deviation)
        Change from BL to week 8 (N=252, 252)
    -0.019 ± 0.13
    -0.031 ± 0.185
        Change from BL to week 28 (N=231, 234)
    -0.034 ± 0.159
    -0.026 ± 0.208
        Change from BL to week 52 (N=204, 217)
    -0.038 ± 0.191
    -0.025 ± 0.254
        Change from BL to week 104 (N=170, 187)
    -0.009 ± 0.218
    -0.044 ± 0.238
    No statistical analyses for this end point

    Secondary: Number of Participants with Mean LDL Cholesterol < 100 mg/dL

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    End point title
    Number of Participants with Mean LDL Cholesterol < 100 mg/dL
    End point description
    Missing category for fasting only includes non-fasting participants and the participants with missing values. The analysis population was the FAS.
    End point type
    Secondary
    End point timeframe
    Weeks 12 to 28 and 36 to 52
    End point values
    Darbepoetin alfa Roxadustat
    Number of subjects analysed
    292
    322
    Units: Participants
        Weeks 12-28: Yes (Regardless Fasting Status)
    111
    147
        Weeks 12-28: No (Regardless Fasting Status)
    33
    20
        Weeks 12-28: Missing (Regardless Fasting Status)
    8
    10
        Weeks 12-28: Yes (Fasting only)
    69
    90
        Weeks 12-28: No (Fasting only)
    18
    11
        Weeks 12-28: Missing (Fasting only)
    65
    76
        Weeks 36-52: Yes (Regardless Fasting Status)
    104
    129
        Weeks 36-52: No (Regardless Fasting Status)
    31
    26
        Weeks 36-52: Missing (Regardless Fasting Status)
    17
    22
        Weeks 36-52: Yes (Fasting only)
    57
    78
        Weeks 36-52: No (Fasting only)
    22
    15
        Weeks 36-52: Missing (Fasting only)
    73
    84
    No statistical analyses for this end point

    Secondary: Number of Participants who Had Achieved Antihypertensive Treatment Goal

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    End point title
    Number of Participants who Had Achieved Antihypertensive Treatment Goal
    End point description
    Achieved antihypertensive treatment goal was defined as SBP < 130 mmHg and DBP < 80 mmHg over an evaluation period defined as the average of available values in weeks 12 to 28 and 36 to 52. The analysis population was the FAS.
    End point type
    Secondary
    End point timeframe
    Weeks 12 to 28 and 36 to 52
    End point values
    Darbepoetin alfa Roxadustat
    Number of subjects analysed
    292
    322
    Units: Participants
        Weeks 12-28: Yes
    64
    76
        Weeks 12-28: No
    212
    228
        Week 12-28: Missing
    16
    18
        Weeks 36-52: Yes
    64
    80
        Weeks 36-52: No
    193
    196
        Weeks 36-52: Missing
    35
    46
    No statistical analyses for this end point

    Secondary: Change from Baseline to the Average of Weeks 12 to 28 and Weeks 36 to 52 in SF-36 Physical Component Score (PCS)

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    End point title
    Change from Baseline to the Average of Weeks 12 to 28 and Weeks 36 to 52 in SF-36 Physical Component Score (PCS)
    End point description
    Baseline SF-36 PCS was defined as the SF-36 PCS value on day 1.The SF-36 is a QoL instrument designed to assess generic health concepts relevant across age, disease, and treatment groups. The SF-36 contains 36 items that measured eight scales: (1) physical functioning; (2) role limitations due to physical health problems; (3) bodily pain; (4) social functioning; (5) general health perceptions; (6) role limitations due to emotional problems; (7) vitality, energy or fatigue; and (8) mental health. Each scale is transformed into 0-100 score, with higher scores indicating better health status. The PCS was calculated based on all 8 scales and ranged from 5.02-79.78. For each of these above scales, higher scores always indicated better health status. The analysis population was the FAS. Here, N signifies participants with available data at specified time points.
    End point type
    Secondary
    End point timeframe
    Baseline, weeks 12 to 28 and 36 to 52
    End point values
    Darbepoetin alfa Roxadustat
    Number of subjects analysed
    292
    322
    Units: Units on a scale
    least squares mean (confidence interval 95%)
        Change from BL to weeks 12-28 (N=303, 272)
    2.29 (1.576 to 3.004)
    1.222 (0.54 to 1.904)
        Change from BL to weeks 36-52 (N=271, 258)
    1.686 (0.939 to 2.433)
    1.083 (0.358 to 1.808)
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Weeks 12-28 - The model included treatment, visit, visit by treatment interaction, region and history of cardiovascular disease as fixed class factors and baseline SF-36 PCS, baseline Hb, baseline estimated glomerular filtration rate as continuous covariates.
    Comparison groups
    Roxadustat v Darbepoetin alfa
    Number of subjects included in analysis
    614
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.027
    Method
    Mixed models analysis
    Parameter type
    LSM Difference
    Point estimate
    -1.068
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.012
         upper limit
    -0.124
    Statistical analysis title
    Statistical Analysis 2
    Statistical analysis description
    Weeks 36-52 - The model included treatment, visit, visit by treatment interaction, region and history of cardiovascular disease as fixed class factors and baseline SF-36 PCS, baseline Hb, baseline estimated glomerular filtration rate as continuous covariates.
    Comparison groups
    Roxadustat v Darbepoetin alfa
    Number of subjects included in analysis
    614
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.239
    Method
    Mixed models analysis
    Parameter type
    LSM Difference
    Point estimate
    -0.603
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.606
         upper limit
    0.401

    Secondary: Change From Baseline to the Average of Weeks 12 to 28 and Weeks 36 to 52 in Anemia Subscale (AnS) (Additional Concerns) of Functional Assessment of Cancer Therapy-Anemia (FACT-An) Score

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    End point title
    Change From Baseline to the Average of Weeks 12 to 28 and Weeks 36 to 52 in Anemia Subscale (AnS) (Additional Concerns) of Functional Assessment of Cancer Therapy-Anemia (FACT-An) Score
    End point description
    Baseline FACT-An AnS was defined as the FACT-An AnS value on day 1. Together with the Functional Assessment of Cancer Therapy – General (FACT-G), the AnS is referred to as the FACT-An Total. The AnS scale contains 13 fatigue specific items (the fatigue score) plus 7 items related to anemia. The Anemia AnS score range is 0 to 80. Higher scores indicated better QoL. The analysis population was the FAS. Here, N signifies participants with available data at specified time points.
    End point type
    Secondary
    End point timeframe
    Baseline, weeks 12 to 28 and 36 to 52
    End point values
    Darbepoetin alfa Roxadustat
    Number of subjects analysed
    292
    322
    Units: Units on a scale
    least squares mean (confidence interval 95%)
        Change from BL to weeks 12-28 (N=303, 272)
    5.238 (4.029 to 6.446)
    4.71 (3.558 to 5.861)
        Change from BL to weeks 36-52 (N=272, 257)
    4.608 (3.252 to 5.964)
    3.661 (2.355 to 4.967)
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Weeks 12-28 - The model included treatment, visit, visit by treatment interaction, region and history of cardiovascular disease as fixed class factors and baseline FACT-An AnS, baseline Hb, baseline estimated glomerular filtration rate as continuous covariates.
    Comparison groups
    Roxadustat v Darbepoetin alfa
    Number of subjects included in analysis
    614
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.517
    Method
    Mixed models analysis
    Parameter type
    LSM Difference
    Point estimate
    -0.528
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.127
         upper limit
    1.072
    Statistical analysis title
    Statistical Analysis 2
    Statistical analysis description
    Weeks 36-52 - The model included treatment, visit, visit by treatment interaction, region and history of cardiovascular disease as fixed class factors and baseline FACT-An AnS, baseline Hb, baseline estimated glomerular filtration rate as continuous covariates.
    Comparison groups
    Roxadustat v Darbepoetin alfa
    Number of subjects included in analysis
    614
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.308
    Method
    Mixed models analysis
    Parameter type
    LSM Difference
    Point estimate
    -0.947
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.771
         upper limit
    0.877

    Secondary: Change from Baseline to the Average Value of Weeks 12 to 28 and Weeks 36 to 52 in FACT-An Total Score

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    End point title
    Change from Baseline to the Average Value of Weeks 12 to 28 and Weeks 36 to 52 in FACT-An Total Score
    End point description
    Baseline FACT-An total Score was defined on day 1. Total Fact-An score is composed of FACT-G and Ans scales. FACT-G contains 27 items that cover four dimensions of well-being: physical well being (PWB) – 7 items, functional well being (FWB) - 7 items, social/family well being (SWB) - 7 items, and emotional well being (EWB) - 6 items. The AnS scale contains 13 fatigue specific items (the Fatigue Score) plus 7 items related to anemia. The total score was obtained by summation of the scores from PWB, SWB, EWB, FWB and AnS. The FACT-An Total Score scale range was 0-188. A higher score indicated better QoL. The analysis population was the FAS. Here, N signifies participants with available data at specified time points.
    End point type
    Secondary
    End point timeframe
    Baseline, weeks 12 to 28 and 36 to 52
    End point values
    Darbepoetin alfa Roxadustat
    Number of subjects analysed
    292
    322
    Units: Units on a scale
    least squares mean (confidence interval 95%)
        Change from BL to weeks 12-28 (N=299, 270)
    8.665 (6.299 to 11.031)
    7.761 (5.501 to 10.02)
        Change from BL to weeks 36-52 (N=268, 255)
    7.259 (4.593 to 9.925)
    5.492 (2.915 to 8.069)
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Week 12-28 - The model included treatment, visit, visit by treatment interaction, region and history of cardiovascular disease as fixed class factors and baseline FACT-An total score, baseline Hb, baseline estimated glomerular filtration rate as continuous covariates.
    Comparison groups
    Roxadustat v Darbepoetin alfa
    Number of subjects included in analysis
    614
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.57
    Method
    Mixed models analysis
    Parameter type
    LSM Difference
    Point estimate
    -0.904
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -4.032
         upper limit
    2.224
    Statistical analysis title
    Statistical Analysis 2
    Statistical analysis description
    Weeks 36-52 -The model included treatment, visit, visit by treatment interaction, region and history of cardiovascular disease as fixed class factors and baseline FACT-An total score, baseline Hb, baseline estimated glomerular filtration rate as continuous covariates.
    Comparison groups
    Roxadustat v Darbepoetin alfa
    Number of subjects included in analysis
    614
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.334
    Method
    Mixed models analysis
    Parameter type
    LSM Difference
    Point estimate
    -1.767
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -5.354
         upper limit
    1.82

    Secondary: Change from Baseline to the Average Value of Weeks 12 to 28 and Weeks 36 to 52 in FACT-An Trial Outcome Index (TOI) Score

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    End point title
    Change from Baseline to the Average Value of Weeks 12 to 28 and Weeks 36 to 52 in FACT-An Trial Outcome Index (TOI) Score
    End point description
    Baseline FACT-An total TOI Score was defined on day 1. Total FACT-An TOI score is a sum of PWB subscale score, FWB subscale score and Ans scale score. Fact-An TOI scale contains 14 items that cover four dimensions of well-being: PWB -7 items, FWB -7 items, where score range for each PWB subscale and FWB subscale is 0-28. The AnS scale contains 13 fatigue specific items (the Fatigue Score) plus 7 items related to anemia, where score range for Ans scale is 0-80. The total score was obtained by summation of the scores from PWB, FWB and AnS. The FACT-An Total TOI score range was 0-136. A higher score indicated better QoL. The analysis population was the FAS. Here, N signifies participants with available data at specified time points.
    End point type
    Secondary
    End point timeframe
    Baseline, weeks 12 to 28 and 36 to 52
    End point values
    Darbepoetin alfa Roxadustat
    Number of subjects analysed
    292
    322
    Units: Units on a scale
    arithmetic mean (standard deviation)
        Weeks 12-28 (N=300, 270)
    6.876 ± 16.960
    6.798 ± 17.830
        Weeks 36-52 (N=269, 255)
    5.595 ± 19.922
    5.602 ± 19.302
    No statistical analyses for this end point

    Secondary: Change from Baseline to the Average Value of Weeks 12 to 28 in Euroqol Questionnaire-5 Dimensions 5 levels (EQ-5D 5L) Visual Analogue Scale (VAS) Score

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    End point title
    Change from Baseline to the Average Value of Weeks 12 to 28 in Euroqol Questionnaire-5 Dimensions 5 levels (EQ-5D 5L) Visual Analogue Scale (VAS) Score
    End point description
    Baseline assessment was defined as the value on day 1. The EuroQol Questionnaire -5 Dimensions -5 Levels (EQ-5D-5L) is a self-reported questionnaire, used as a measure of respondents' Health Related Quality of Life (HRQoL) and utility values. The EQ-5D consists of the descriptive system and the visual analogue scale (VAS). The EQ-5D descriptive system comprises 5 dimensions of health: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each dimension has 5 levels: no problems, slight problems, moderate problems, severe problems, extreme problems. The VAS records the respondent's self rated health status on a graduated (0–100) scale, where the endpoints are labeled ‘Best imaginable health state’ and ‘Worst imaginable health state’ with higher scores for higher HRQoL. The analysis population was the FAS, with participants who had available data.
    End point type
    Secondary
    End point timeframe
    Baseline and weeks 12 to 28
    End point values
    Darbepoetin alfa Roxadustat
    Number of subjects analysed
    271
    300
    Units: Units on a scale
        least squares mean (confidence interval 95%)
    4.353 (2.643 to 6.064)
    5.137 (3.498 to 6.776)
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    The model includes treatment, visit, visit by treatment interaction, region and history of CV disease as fixed class factors and baseline EQ-5D 5L VAS, baseline Hb, baseline eGFR as continuous covariates.
    Comparison groups
    Roxadustat v Darbepoetin alfa
    Number of subjects included in analysis
    571
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.497
    Method
    Mixed models analysis
    Parameter type
    LSM Difference
    Point estimate
    0.784
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.481
         upper limit
    3.049

    Secondary: Change from Baseline to the Average Value of Weeks 12 to 28 and Weeks 36 to 52 in Work Productivity and Activity Impairment-Anemic Symptoms (WPAI:ANS) Score: Percent Work Time Missed

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    End point title
    Change from Baseline to the Average Value of Weeks 12 to 28 and Weeks 36 to 52 in Work Productivity and Activity Impairment-Anemic Symptoms (WPAI:ANS) Score: Percent Work Time Missed
    End point description
    WPAI consisted of 6 questions (Q1=Employment status; Q2=Hours absent from work due to anaemic symptoms; Q3=Hours absent from work due to other reasons; Q4=Hours actually worked; Q5=Impact of the anaemic symptoms on productivity while working; Q6=Impact of the anaemic symptoms on productivity while doing regular daily activities other than work) and a 1-week recall period. Higher WPAI scores indicated greater activity impairment. Multiply scores by 100 to express in percentages. Percent work time missed due to problem: Q2/(Q2+Q4). The analysis population was the FAS. Here, N signifies participants with available data at specified time points.
    End point type
    Secondary
    End point timeframe
    Baseline, weeks 12 to 28 and 36 to 52
    End point values
    Darbepoetin alfa Roxadustat
    Number of subjects analysed
    292
    322
    Units: Percent work time
    arithmetic mean (standard deviation)
        Change from BL to weeks 12-28 (N=35,49)
    0.842 ± 21
    -3.793 ± 32.987
        Change from BL to weeks 36-52 (N=23,44)
    0.216 ± 23.483
    -0.078 ± 37.047
    No statistical analyses for this end point

    Secondary: Change from Baseline to the Average Value of Weeks 12 to 28 and Weeks 36 to 52 in WPAI:ANS Score: Percent Impairment While Working

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    End point title
    Change from Baseline to the Average Value of Weeks 12 to 28 and Weeks 36 to 52 in WPAI:ANS Score: Percent Impairment While Working
    End point description
    WPAI consisted of 6 questions (Q1=Employment status; Q2=Hours absent from work due to anaemic symptoms; Q3=Hours absent from work due to other reasons; Q4=Hours actually worked; Q5=Impact of the anaemic symptoms on productivity while working; Q6=Impact of the anaemic symptoms on productivity while doing regular daily activities other than work) and a 1-week recall period. Higher WPAI scores indicated greater activity impairment. Percent impairment while working due to problem: Q5/10. The analysis population was the FAS. Here, N signifies participants with available data at specified time points.
    End point type
    Secondary
    End point timeframe
    Baseline, weeks 12 to 28 and 36 to 52
    End point values
    Darbepoetin alfa Roxadustat
    Number of subjects analysed
    292
    322
    Units: Percent impairment
    arithmetic mean (standard deviation)
        Change from BL to weeks 12-28 (N=34,50)
    -2.433 ± 28.598
    -6.618 ± 22.419
        Change from BL to weeks 36-52 (N=22,48)
    1.083 ± 23.102
    -7.879 ± 25.872
    No statistical analyses for this end point

    Secondary: Change from Baseline to the Average Value of Weeks 12 to 28 and Weeks 36 to 52 in WPAI:ANS Score: Percent Overall Work Impairment

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    End point title
    Change from Baseline to the Average Value of Weeks 12 to 28 and Weeks 36 to 52 in WPAI:ANS Score: Percent Overall Work Impairment
    End point description
    WPAI consisted of 6 questions (Q1=Employment status; Q2=Hours absent from work due to anaemic symptoms; Q3=Hours absent from work due to other reasons; Q4=Hours actually worked; Q5=Impact of the anaemic symptoms on productivity while working; Q6=Impact of the anaemic symptoms on productivity while doing regular daily activities other than work) and a 1-week recall period. Higher WPAI scores indicated greater activity impairment. Percent overall work impairment due to problem: Q2/(Q2+Q4)+[(1-(Q2/(Q2+Q4))x(Q5/10)]. The analysis population was the FAS. Here, N signifies participants with available data at specified time points.
    End point type
    Secondary
    End point timeframe
    Baseline, weeks 12 to 28 and 36 to 52
    End point values
    Darbepoetin alfa Roxadustat
    Number of subjects analysed
    292
    322
    Units: Percent impairment
    arithmetic mean (standard deviation)
        Change from BL to weeks 12-28 (N=32,49)
    -1.217 ± 20.743
    -6.112 ± 23.21
        Change From BL to weeks 36-52 (N=21,44)
    0.197 ± 23.431
    2.817 ± 30.432
    No statistical analyses for this end point

    Secondary: Change from Baseline to the Average Value of Weeks 12 to 28 and Weeks 36 to 52 in WPAI:ANS Score: Percent Activity Impairment

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    End point title
    Change from Baseline to the Average Value of Weeks 12 to 28 and Weeks 36 to 52 in WPAI:ANS Score: Percent Activity Impairment
    End point description
    WPAI consisted of 6 questions (Q1=Employment status; Q2=Hours absent from work due to anaemic symptoms; Q3=Hours absent from work due to other reasons; Q4=Hours actually worked; Q5=Impact of the anaemic symptoms on productivity while working; Q6=Impact of the anaemic symptoms on productivity while doing regular daily activities other than work) and a 1-week recall period. Higher WPAI scores indicated greater activity impairment. Percent activity impairment due to problem: Q6/10. The analysis population was the FAS. Here, N signifies participants with available data at specified time points.
    End point type
    Secondary
    End point timeframe
    Baseline, weeks 12 to 28 and 36 to 52
    End point values
    Darbepoetin alfa Roxadustat
    Number of subjects analysed
    292
    322
    Units: Percent impairment
    arithmetic mean (standard deviation)
        Change from BL to weeks 12-28 (N=300, 269)
    -9.34 ± 27.09
    -9.581 ± 27.367
        Change from BL to weeks 36-52 (N=270, 254)
    -8.17 ± 27.486
    -9.365 ± 28.956
    No statistical analyses for this end point

    Secondary: Percentage of Participants with Improvements Measured by Patients' Global Impression of Change (PGIC)

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    End point title
    Percentage of Participants with Improvements Measured by Patients' Global Impression of Change (PGIC)
    End point description
    The PGIC is a patient-rated instrument that measured change in participant's overall status on a 7-point scale ranging from 1 (very much improved) to 7 (very much worse), when compared to the start of treatment. The percentage of participants presented included very much improved, much improved and minimally improved. The analysis population was the FAS.
    End point type
    Secondary
    End point timeframe
    Weeks 8, 12, 28, 52, 76, 104, last assessment (week 108)
    End point values
    Darbepoetin alfa Roxadustat
    Number of subjects analysed
    292
    322
    Units: Percentage of participants
    number (not applicable)
        Week 8
    79.4
    76.1
        Week 12
    83.6
    83.7
        Week 28
    81
    83
        Week 52
    79.8
    79.3
        Week 76
    74.9
    73
        Week 104
    76
    71.8
        Last Assessment (week 108)
    71.4
    70.6
    No statistical analyses for this end point

    Secondary: Change from Baseline to Each Scheduled Measurement Serum Ferritin

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    End point title
    Change from Baseline to Each Scheduled Measurement Serum Ferritin
    End point description
    Baseline assessment was assessment from day 1 visit. If baseline value was missing, the value from screening visit was used. In case of missing data, no imputation rules were applied. The analysis population was the FAS. Here, N signifies participants with available data at specified time points.
    End point type
    Secondary
    End point timeframe
    Baseline and weeks 4, 8, 12, 20, 28, 36, 44, 52, 60, 68, 76, 84, 92, 100, 104 and end of study (EOS) (up to 108 weeks)
    End point values
    Darbepoetin alfa Roxadustat
    Number of subjects analysed
    292
    322
    Units: Picomoles per liter (pmol/L)
    arithmetic mean (standard deviation)
        Week 4 (N=316, 288)
    -159.174 ± 218.981
    -190.762 ± 241.695
        Week 8 (N=307, 280)
    -208.356 ± 309.893
    -229.471 ± 255.677
        Week 12 (N=300, 271)
    -201.587 ± 346.59
    -205.722 ± 271.752
        Week 20 (N=286, 265)
    -140.26 ± 338.512
    -99.86 ± 334.486
        Week 28 (N=286, 262)
    -121.574 ± 348.136
    -97.622 ± 366.153
        Week 36 (N=271, 256)
    -120.424 ± 362.08
    -131.801 ± 355.463
        Week 44 (N=261, 250)
    -60.149 ± 425.455
    -120.864 ± 368.902
        Week 52 (N=254, 241)
    -72.383 ± 459.342
    -93.074 ± 521.433
        Week 60 (N=252, 243)
    -47.714 ± 459.319
    -141.264 ± 355.419
        Week 68 (N=245, 239)
    -14.283 ± 464.714
    -110.907 ± 422.28
        Week 76 (N=235, 230)
    3.424 ± 615.735
    -99.697 ± 412.982
        Week 84 (N=224, 221)
    -1.351 ± 576.437
    -126.615 ± 403.693
        Week 92 (N=222, 219)
    -26.73 ± 547.371
    -98.025 ± 460.364
        Week 100 (N=216, 206)
    31.391 ± 750.432
    -95.513 ± 486.758
        Week 104 (N=212, 208)
    26.454 ± 730.126
    -89.276 ± 476.167
        EOS (N=245, 225)
    119.157 ± 697.39
    78.577 ± 680.524
    No statistical analyses for this end point

    Secondary: Change from Baseline to Each Scheduled Measurement in Transferrin Saturation (TSAT)

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    End point title
    Change from Baseline to Each Scheduled Measurement in Transferrin Saturation (TSAT)
    End point description
    Baseline assessment was assessment from day 1 visit. If baseline value was missing, the value from screening visit was used. In case of missing data, no imputation rules were applied. The analysis population was the FAS. Here, N signifies participants with available data at specified time points.
    End point type
    Secondary
    End point timeframe
    Baseline and weeks 4, 8, 12, 20, 28, 36, 44, 52, 60, 68, 76, 84, 92, 100, 104 and EOS (up to 108 weeks)
    End point values
    Darbepoetin alfa Roxadustat
    Number of subjects analysed
    292
    322
    Units: Percentage of saturation
    arithmetic mean (standard deviation)
        Week 4 (N=312, 287)
    -2.1 ± 11.5
    -6 ± 10.7
        Week 8 (N=304, 278)
    -2.4 ± 10.6
    -5.9 ± 11.5
        Week 12 (N=294, 268)
    -0.5 ± 12.3
    -2.4 ± 13.2
        Week 20 (N=286, 263)
    2.9 ± 11.6
    1.6 ± 13.9
        Week 28 (N=284, 263)
    4 ± 12.5
    1.1 ± 12.5
        Week 36 (N=270, 256)
    3.9 ± 11.5
    1.6 ± 12
        Week 44 (N=259, 247)
    4.9 ± 12.9
    0.6 ± 12
        Week 52 (N=252, 242)
    5.2 ± 13.2
    1.3 ± 11.8
        Week 60 (N=250, 238)
    4.8 ± 12.7
    0.4 ± 12.4
        Week 68 (N=245, 237)
    6.3 ± 13.1
    1 ± 13.4
        Week 76 (N=235, 228)
    6 ± 13.7
    0.1 ± 12.2
        Week 84 (N=222, 220)
    6.5 ± 13.9
    1.1 ± 12.5
        Week 92 (N=222, 216)
    5.6 ± 13.8
    -0.2 ± 11.7
        Week 100 (N=214, 201)
    5.8 ± 14
    0.6 ± 12.4
        Week 104 (N=210, 207)
    5 ± 13.3
    0.5 ± 11.9
        EOS (N=242, 222)
    4.7 ± 13.9
    5.3 ± 12.3
    No statistical analyses for this end point

    Secondary: Change from Baseline to Each Scheduled Measurement in Glycated Hemoglobin (HbA1c)

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    End point title
    Change from Baseline to Each Scheduled Measurement in Glycated Hemoglobin (HbA1c)
    End point description
    Percentage of change from baseline to each study visit were calculated for HbA1c. Baseline assessment was assessment from day 1 visit. If baseline value was missing, the value from screening visit was used. In case of missing data, no imputation rules were applied. The analysis population was the FAS. Here, N signifies participants with available data at specified time points.
    End point type
    Secondary
    End point timeframe
    Baseline and weeks 12, 28, 36, 44, 60, 84, 104 and EOS (up to 108 weeks)
    End point values
    Darbepoetin alfa Roxadustat
    Number of subjects analysed
    292
    322
    Units: Percentage of HbA1c
    arithmetic mean (standard deviation)
        Week 12 (N=296, 267)
    0.001 ± 0.0073
    0.0021 ± 0.0071
        Week 28 (N=277, 256)
    0.0015 ± 0.0067
    0.0009 ± 0.0072
        Week 36 (N=265, 252)
    0.0021 ± 0.0073
    0.0021 ± 0.0075
        Week 44 (N=254, 249)
    0.002 ± 0.0066
    0.0026 ± 0.0077
        Week 60 (N=250, 242)
    0.0019 ± 0.0074
    0.0025 ± 0.0083
        Week 84 (N=223, 222)
    0.0025 ± 0.0077
    0.0024 ± 0.0093
        Week 104 (N=212, 202)
    0.002 ± 0.008
    0.0018 ± 0.0086
        EOS (N=244, 225)
    0.0034 ± 0.0081
    0.0031 ± 0.0087
    No statistical analyses for this end point

    Secondary: Change from Baseline to Each Scheduled Measurement in Fasting Blood Glucose

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    End point title
    Change from Baseline to Each Scheduled Measurement in Fasting Blood Glucose
    End point description
    Baseline assessment was assessment from day 1 visit. If baseline value was missing, the value from screening visit was used. In case of missing data, no imputation rules were applied. The analysis population was the FAS. Here, N signifies participants with available data at specified time points.
    End point type
    Secondary
    End point timeframe
    Baseline and weeks 4, 8, 12, 20, 28, 36, 44, 52, 60, 68, 76, 84, 92, 100, 104, 106 and EOS (up to 108 weeks)
    End point values
    Darbepoetin alfa Roxadustat
    Number of subjects analysed
    292
    322
    Units: mg/dL
    arithmetic mean (standard deviation)
        Week 4 (N=169, 143)
    10.3 ± 76.9
    7 ± 62.8
        Week 8 (N=168, 136)
    1.3 ± 40.3
    4.1 ± 60.1
        Week 12 (N=156, 134)
    7.1 ± 58.2
    9.3 ± 64.5
        Week 20 (N=147, 131)
    4.3 ± 57.9
    6.9 ± 69.4
        Week 28 (N=137, 122)
    2.8 ± 37.7
    8.7 ± 66.9
        Week 36 (N=133, 126)
    3.6 ± 45.3
    6.4 ± 52.5
        Week 44 (N=129, 123)
    0.4 ± 45.1
    3.3 ± 44.7
        Week 52 (N=129, 115)
    1.1 ± 41.1
    7.1 ± 69.7
        Week 60 (N=121, 104)
    6.3 ± 43.1
    6.6 ± 65.6
        Week 68 (N=119, 109)
    5.5 ± 48.2
    3.8 ± 66.1
        Week 76 (N=113, 102)
    5.8 ± 55.2
    0.9 ± 41.9
        Week 84 (N=115, 101)
    12 ± 57.4
    1.4 ± 49.1
        Week 92 (N=107, 95)
    2.1 ± 46.5
    6 ± 69.5
        Week 100 (N=101, 87)
    4 ± 48.9
    2.7 ± 45.3
        Week 104 (N=104, 90)
    1 ± 48.6
    -2.6 ± 60.7
        Week 106 (N=106, 92)
    9.2 ± 53.3
    -2.4 ± 31.2
        EOS (N=116, 100)
    9.8 ± 43.6
    2.5 ± 58.2
    No statistical analyses for this end point

    Secondary: Change from Baseline to Each Scheduled Measurement in Estimated Glomerular Filtration Rate (eGFR)

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    End point title
    Change from Baseline to Each Scheduled Measurement in Estimated Glomerular Filtration Rate (eGFR)
    End point description
    Baseline assessment was assessment from day 1 visit. If baseline value was missing, the value from screening visit was used. In case of missing data, no imputation rules were applied. The analysis population was the FAS. Here, N signifies participants with available data at specified time points.
    End point type
    Secondary
    End point timeframe
    Baseline and weeks 4, 8, 12, 20, 28, 36, 44, 52, 60, 68, 76, 84, 92, 100, 104, 106 and EOS (up to 108 weeks)
    End point values
    Darbepoetin alfa Roxadustat
    Number of subjects analysed
    292
    322
    Units: Geometric mean ratio
    geometric mean (confidence interval 95%)
        Week 4 (N=311, 284)
    0.97 (0.95 to 0.99)
    1.01 (0.99 to 1.03)
        Week 8 (N=300, 272)
    0.96 (0.94 to 0.99)
    1.01 (0.98 to 1.03)
        Week 12 (N=286, 261)
    0.95 (0.93 to 0.98)
    1.02 (1.00 to 1.05)
        Week 20 (N=267, 249)
    0.93 (0.90 to 0.96)
    0.98 (0.95 to 1.01)
        Week 28 (N=252, 244)
    0.89 (0.86 to 0.93)
    0.93 (0.89 to 0.96)
        Week 36 (N=227, 227)
    0.89 (0.85 to 0.93)
    0.93 (0.89 to 0.97)
        Week 44 (N=211, 209)
    0.89 (0.84 to 0.93)
    0.90 (0.86 to 0.93)
        Week 52 (N=200, 191)
    0.88 (0.83 to 0.92)
    0.90 (0.86 to 0.94)
        Week 60 (N=189, 182)
    0.86 (0.82 to 0.91)
    0.90 (0.86 to 0.94)
        Week 68 (N=177, 174)
    0.84 (0.79 to 0.89)
    0.87 (0.83 to 0.91)
        Week 76 (N=167, 166)
    0.84 (0.78 to 0.90)
    0.83 (0.78 to 0.88)
        Week 84 (N=155, 157)
    0.83 (0.77 to 0.89)
    0.83 (0.78 to 0.88)
        Week 92 (N=152, 151)
    0.85 (0.79 to 0.90)
    0.84 (0.79 to 0.90)
        Week 100 (N=145, 141)
    0.86 (0.81 to 0.92)
    0.84 (0.78 to 0.89)
        Week 104 (N=142, 140)
    0.84 (0.79 to 0.91)
    0.84 (0.79 to 0.90)
        Week 106 (N=154, 139)
    0.86 (0.79 to 0.92)
    0.84 (0.78 to 0.90)
        EOS (N=159, 146)
    0.85 (0.79 to 0.92)
    0.86 (0.81 to 0.91)
    No statistical analyses for this end point

    Secondary: Rate of Progression of Chronic Kidney Disease Measured by eGFR Slope Over Time

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    End point title
    Rate of Progression of Chronic Kidney Disease Measured by eGFR Slope Over Time
    End point description
    Annualized eGFR slope over time was estimated by a random slopes and intercepts model using all available eGFR values (one baseline and all post-treatment values up to EOT period or start of dialysis adjusted on baseline Hb, region, CV history at baseline and the interaction terms (baseline eGFR by timepoint and baseline Hb by timepoint). All assessments collected after initiation of dialysis (acute or chronic) were excluded from the analysis. Baseline assessment was the assessment from day 1 visit. If this value was missing, the value from screening visit was used. The analysis population was the FAS.
    End point type
    Secondary
    End point timeframe
    Baseline up to EOS (Up to week 108)
    End point values
    Darbepoetin alfa Roxadustat
    Number of subjects analysed
    292
    322
    Units: change/ year in ml/min per 1.73 m^2
        least squares mean (confidence interval 95%)
    -2.89 (-3.51 to -2.27)
    -2.95 (-3.56 to -2.34)
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Roxadustat v Darbepoetin alfa
    Number of subjects included in analysis
    614
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.902
    Method
    Mixed models analysis
    Parameter type
    LSM Difference
    Point estimate
    -0.05
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.93
         upper limit
    0.82

    Secondary: Change from Baseline to Each Scheduled Measurement in Urine Albumin/Creatinine Ratio (UACR)

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    End point title
    Change from Baseline to Each Scheduled Measurement in Urine Albumin/Creatinine Ratio (UACR)
    End point description
    Baseline assessment was assessment from day 1 visit. If baseline value was missing, the value from screening visit was used. In case of missing data, no imputation rules were applied. The analysis population was the FAS. Here, N signifies participants with available data at specified time points.
    End point type
    Secondary
    End point timeframe
    Baseline and weeks 12, 24, 36, 52, 64, 76, 88 and 104
    End point values
    Darbepoetin alfa Roxadustat
    Number of subjects analysed
    292
    322
    Units: Geometric mean ratio
    geometric mean (confidence interval 95%)
        Week 12 (N=230, 214)
    1.23 (1.1 to 1.38)
    1.19 (1.07 to 1.34)
        Week 24 (N=225, 200)
    1.22 (1.08 to 1.39)
    1.18 (1.06 to 1.33)
        Week 36 (N=187, 181)
    1.18 (1.03 to 1.36)
    1.22 (1.07 to 1.4)
        Week 52 (N=164, 147)
    1.1 (0.92 to 1.32)
    1.28 (1.1 to 1.49)
        Week 64 (N=149, 141)
    1.11 (0.9 to 1.38)
    1.23 (1.03 to 1.46)
        Week 76 (N=135, 133)
    1.18 (0.94 to 1.48)
    1.39 (1.14 to 1.7)
        Week 88 (N=122, 119)
    1.1 (0.86 to 1.39)
    1.21 (0.97 to 1.5)
        Week 104 (N=109, 101)
    1.18 (0.92 to 1.51)
    1.46 (1.17 to 1.82)
    No statistical analyses for this end point

    Secondary: Time to Doubling of Serum Creatinine or Chronic Dialysis or Renal Transplant Compared to Baseline

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    End point title
    Time to Doubling of Serum Creatinine or Chronic Dialysis or Renal Transplant Compared to Baseline
    End point description
    For participants who had doubled their serum creatinine or had chronic dialysis or renal transplant more than once, only their first occurrence during safety emergent period was used. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments. Data reported was analyzed by Kaplan-Meier estimate for cumulative proportion and the 95% confidence interval was calculated with Greenwood's formula. Percentage of participants were reported in this outcome measure. The analysis population was the FAS. Here, N signifies participants with available data at specified time points.
    End point type
    Secondary
    End point timeframe
    Year 0.5, 1, 1.5 and 2
    End point values
    Darbepoetin alfa Roxadustat
    Number of subjects analysed
    292
    322
    Units: Percentage of participants
    number (confidence interval 95%)
        Year 0.5 (N=255, 247)
    8.6 (5.3 to 11.9)
    12.9 (9.1 to 16.6)
        Year 1 (N=196, 186)
    27.2 (21.9 to 32.6)
    27.4 (22.3 to 32.6)
        Year 1.5 (N=155, 148)
    38.8 (32.9 to 44.7)
    38.2 (32.5 to 44)
        Year 2 (N=122, 113)
    45.4 (39.2 to 51.5)
    46.5 (40.5 to 52.5)
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Hazard Ratio was calculated using stratified Cox Proportional Hazards regression stratifying on CV history and region and adjusting on Hb and eGFR at baseline as continuous covariates. Superiority was declared if the upper bound of the 95% CI was below 1.0.
    Comparison groups
    Roxadustat v Darbepoetin alfa
    Number of subjects included in analysis
    614
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.96
    Method
    Regression, Cox
    Parameter type
    Hazard ratio (HR)
    Point estimate
    1.01
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.79
         upper limit
    1.29

    Secondary: Number of Participants With End Stage Renal Disease (ESRD)

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    End point title
    Number of Participants With End Stage Renal Disease (ESRD)
    End point description
    Occurrence of end stage renal disease during the study (i.e from day 1 up to the end of study) was defined as at least one of the following: underwent >30 days dialysis therapy, received kidney transplant, planned kidney transplant, physician recommended renal replacement therapy and participant refused therapy, began dialysis and died < 30 days later. The analysis population was the FAS.
    End point type
    Secondary
    End point timeframe
    Baseline up to EOS (Up to week 108)
    End point values
    Darbepoetin alfa Roxadustat
    Number of subjects analysed
    292
    322
    Units: Participants
    107
    110
    No statistical analyses for this end point

    Secondary: Time to Chronic Kidney Disease Progression (Composite of Doubling Serum Creatinine, Chronic Dialysis or Renal Transplant, and Death)

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    End point title
    Time to Chronic Kidney Disease Progression (Composite of Doubling Serum Creatinine, Chronic Dialysis or Renal Transplant, and Death)
    End point description
    Chronic kidney disease progression was defined as date of occurrence of chronic dialysis or date of renal transplant or doubled serum creatinine or date of death, whichever came first. For participants who had chronic dialysis or renal transplant or died, only their first occurrence during the safety emergent period was used. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments. Data reported was analyzed by Kaplan-Meier estimate for cumulative proportion and the 95% confidence interval was calculated with Greenwood's formula. Percentage of participants were reported in this outcome measure. The analysis population was the FAS. Here, N signifies participants with available data at specified time points.
    End point type
    Secondary
    End point timeframe
    Year 0.5, 1, 1.5 and 2
    End point values
    Darbepoetin alfa Roxadustat
    Number of subjects analysed
    292
    322
    Units: Percentage of participants
    number (confidence interval 95%)
        Year 0.5 (N=255, 247)
    10.2 (6.7 to 13.8)
    14 (10.1 to 17.9)
        Year 1 (N=196, 186)
    29.5 (24.1 to 34.9)
    30.9 (25.6 to 36.2)
        Year 1.5 (N=155, 148)
    42.6 (36.6 to 48.5)
    42.1 (36.4 to 47.8)
        Year 2 (N=122, 113)
    51 (44.9 to 57)
    49.9 (44 to 55.8)
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Hazard Ratio was calculated using stratified Cox Proportional Hazards regression stratifying on CV history and region and adjusting on Hb and eGFR at baseline as continuous covariates. Superiority was declared if the upper bound of the 95% CI was below 1.0.
    Comparison groups
    Roxadustat v Darbepoetin alfa
    Number of subjects included in analysis
    614
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.939
    Method
    Regression, Cox
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.99
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.79
         upper limit
    1.25

    Secondary: Time to Chronic Dialysis or Renal Transplant or Death

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    End point title
    Time to Chronic Dialysis or Renal Transplant or Death
    End point description
    For participants who had chronic dialysis or renal transplant or died, only their first occurrence during the safety emergent period was used. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments. Data reported was analyzed by Kaplan-Meier estimate for cumulative proportion and the 95% confidence interval was calculated with Greenwood's formula. Percentage of participants were reported in this outcome measure. The analysis population was the FAS. Here, N signifies participants with available data at specified time points.
    End point type
    Secondary
    End point timeframe
    Year 0.5, 1, 1.5 and 2
    End point values
    Darbepoetin alfa Roxadustat
    Number of subjects analysed
    292
    322
    Units: Percentage of participants
    number (confidence interval 95%)
        Year 0.5 (N=259, 250)
    9.2 (5.8 to 12.6)
    12.7 (9 to 16.4)
        Year 1 (N=207, 195)
    26.2 (21 to 31.4)
    27.1 (22 to 32.2)
        Year 1.5 (N=169, 161)
    37.7 (31.9 to 43.5)
    37.1 (31.6 to 42.7)
        Year 2 (N=139, 126)
    45.6 (39.6 to 51.7)
    42.9 (37.1 to 48.7)
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Hazard Ratio was calculated using stratified Cox Proportional Hazards regression stratifying on CV history and Region and adjusting on Hb and eGFR at baseline as continuous covariates. Superiority was declared if the upper bound of the 95% CI was below 1.0.
    Comparison groups
    Roxadustat v Darbepoetin alfa
    Number of subjects included in analysis
    614
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.948
    Method
    Regression, Cox
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.99
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.77
         upper limit
    1.27

    Secondary: Time to at Least 40% Decrease in eGFR From Baseline, Chronic Dialysis or Renal Transplant

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    End point title
    Time to at Least 40% Decrease in eGFR From Baseline, Chronic Dialysis or Renal Transplant
    End point description
    For participants who had at least 40% decrease in eGFR from baseline, chronic dialysis or renal transplant during the safety emergent period, only their first occurrence was used. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments. Data reported was analyzed by Kaplan-Meier estimate for cumulative proportion and the 95% confidence interval was calculated with Greenwood's formula. The analysis population was the FAS. Percentage of participants were reported in this outcome measure. Here, N signifies participants with available data at specified time points.
    End point type
    Secondary
    End point timeframe
    Year 0.5, 1, 1.5 and 2
    End point values
    Darbepoetin alfa Roxadustat
    Number of subjects analysed
    292
    322
    Units: Percentage of participants
    number (confidence interval 95%)
        Year 0.5 (N=248, 235)
    13 (9 to 16.9)
    15.4 (11.3 to 19.5)
        Year 1 (N=178, 166)
    35.5 (29.8 to 41.3)
    34.5 (29 to 40)
        Year 1.5 (N=133, 122)
    50.2 (44.1 to 56.3)
    47.2 (41.3 to 53.1)
        Year 2 (N=104, 85)
    59.3 (53.2 to 65.3)
    55.7 (49.7 to 61.7)
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Hazard Ratio was calculated using stratified Cox Proportional Hazards regression stratifying on CV history and Region and adjusting on Hb and eGFR at baseline as continuous covariates. Superiority was declared if the upper bound of the 95% CI was below 1.0.
    Comparison groups
    Roxadustat v Darbepoetin alfa
    Number of subjects included in analysis
    614
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.568
    Method
    Regression, Cox
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.94
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.75
         upper limit
    1.17

    Secondary: Number of Participants With Treatment Emergent Adverse Events (TEAEs)

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    End point title
    Number of Participants With Treatment Emergent Adverse Events (TEAEs)
    End point description
    An AE was defined as any untoward medical occurrence in a participant who was given the study drug or who had undergone study procedures and did not necessarily have a causal relationship with this treatment. All AEs collected during the safety emergent period were counted as TEAE. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments. Based on national cancer institute common terminology criteria (NCI-CTCAE), AEs were graded as grade 1=mild, grade 2=moderate, grade 3 =severe or medically significant, grade 4 =life threatening, grade 5 =death related to AE. All reported deaths after the first study drug administration and up to 28 days after the analysis date of last dose were based on last dosing frequency. The Safety Analysis Set included all randomized participants who received at least one dose of study drug.
    End point type
    Secondary
    End point timeframe
    Baseline up to EOS (Up to week 108)
    End point values
    Darbepoetin alfa Roxadustat
    Number of subjects analysed
    293
    323
    Units: Participants
        TEAE
    271
    296
        Drug-Related TEAE
    66
    78
        Serious TEAE
    181
    209
        Drug-Related Serious TEAE
    9
    18
        TEAE Leading to Death
    34
    34
        Drug-Related TEAE Leading to Death
    0
    2
        TEAE Leading to Withdrawal of Treatment
    11
    25
        Drug-Related TEAE Leading to Withdraw of Treatment
    1
    7
        NCI CTCAE Grades 3 or Higher
    164
    181
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From first dose of study drug up to end of study (up to week 108)
    Adverse event reporting additional description
    Total number of deaths (all causes) includes deaths reported after the time frame above. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the end of treatment taking into account the different dosing frequencies of the study treatments.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    20.0
    Reporting groups
    Reporting group title
    Darbepoetin alfa
    Reporting group description
    Participants received initial dose of darbepoetin alfa based upon the weight (either 0.45 μg/kg of body weight, as a single subcutaneous or IV injection once weekly or 0.75 μg/kg of body weight, as a single subcutaneous injection once every 2 weeks) as per EU SmPC along with IV iron supplementation according to the standard of care. Dose-adjustment was performed based upon regular measurement of Hb levels until participants achieved central Hb value of ≥11.0 g/dL and Hb increase from baseline of ≥ 1.0 g/dL at two consecutive study visits, separated by at least 5 days. Once target Hb level was reached participants entered maintenance period during which darbepoetin alfa dosage was adjusted every 4 weeks to maintain participants Hb level within the target range of 10.0 g/dL and 12.0 g/dL. Participants received darbepoetin alfa for up to a maximum of 104 weeks.

    Reporting group title
    Roxadustat
    Reporting group description
    Participants received roxadustat orally according to the tiered weight-based approach, with starting dose of 70 mg given TIW to participants weighing between 45 kg up to 70 kg and 100 mg given TIW to participants weighing more than 70 kg up to 160 kg. Dose-titration was performed based upon regular measurement of Hb levels until participants achieved central Hb value of ≥ 11.0 g/dL and Hb increase from baseline of ≥ 1.0 g/dL at two consecutive study visits, separated by at least 5 days. Once target Hb level was reached participants entered maintenance period during which roxadustat dosage was adjusted every 4 weeks to maintain participants Hb level within the target range of 10.0 g/dL and 12.0 g/dL. Participants received roxadustat for up to a maximum of 104 weeks.

    Serious adverse events
    Darbepoetin alfa Roxadustat
    Total subjects affected by serious adverse events
         subjects affected / exposed
    181 / 293 (61.77%)
    209 / 323 (64.71%)
         number of deaths (all causes)
    37
    40
         number of deaths resulting from adverse events
    34
    34
    Vascular disorders
    Aortic aneurysm
         subjects affected / exposed
    1 / 293 (0.34%)
    0 / 323 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Aortic intramural haematoma
         subjects affected / exposed
    1 / 293 (0.34%)
    0 / 323 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood pressure fluctuation
         subjects affected / exposed
    0 / 293 (0.00%)
    1 / 323 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Circulatory collapse
         subjects affected / exposed
    0 / 293 (0.00%)
    1 / 323 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Deep vein thrombosis
         subjects affected / exposed
    1 / 293 (0.34%)
    4 / 323 (1.24%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Embolism arterial
         subjects affected / exposed
    1 / 293 (0.34%)
    0 / 323 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Extremity necrosis
         subjects affected / exposed
    1 / 293 (0.34%)
    1 / 323 (0.31%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhage
         subjects affected / exposed
    1 / 293 (0.34%)
    0 / 323 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    5 / 293 (1.71%)
    8 / 323 (2.48%)
         occurrences causally related to treatment / all
    3 / 6
    1 / 11
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertensive crisis
         subjects affected / exposed
    5 / 293 (1.71%)
    5 / 323 (1.55%)
         occurrences causally related to treatment / all
    2 / 6
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertensive emergency
         subjects affected / exposed
    1 / 293 (0.34%)
    1 / 323 (0.31%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    2 / 293 (0.68%)
    4 / 323 (1.24%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Hypovolaemic shock
         subjects affected / exposed
    1 / 293 (0.34%)
    0 / 323 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Iliac artery occlusion
         subjects affected / exposed
    0 / 293 (0.00%)
    1 / 323 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Orthostatic hypotension
         subjects affected / exposed
    0 / 293 (0.00%)
    1 / 323 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral arterial occlusive disease
         subjects affected / exposed
    4 / 293 (1.37%)
    3 / 323 (0.93%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral artery occlusion
         subjects affected / exposed
    0 / 293 (0.00%)
    1 / 323 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral artery stenosis
         subjects affected / exposed
    1 / 293 (0.34%)
    1 / 323 (0.31%)
         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 / 293 (0.68%)
    4 / 323 (1.24%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Phlebitis
         subjects affected / exposed
    0 / 293 (0.00%)
    1 / 323 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Shock haemorrhagic
         subjects affected / exposed
    1 / 293 (0.34%)
    0 / 323 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombosis
         subjects affected / exposed
    0 / 293 (0.00%)
    1 / 323 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Venous thrombosis
         subjects affected / exposed
    1 / 293 (0.34%)
    1 / 323 (0.31%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Venous thrombosis limb
         subjects affected / exposed
    0 / 293 (0.00%)
    1 / 323 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Acute myeloid leukaemia
         subjects affected / exposed
    1 / 293 (0.34%)
    0 / 323 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Adenocarcinoma gastric
         subjects affected / exposed
    1 / 293 (0.34%)
    0 / 323 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Adenocarcinoma of colon
         subjects affected / exposed
    1 / 293 (0.34%)
    1 / 323 (0.31%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Basal cell carcinoma
         subjects affected / exposed
    0 / 293 (0.00%)
    4 / 323 (1.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Benign neoplasm of thyroid gland
         subjects affected / exposed
    0 / 293 (0.00%)
    1 / 323 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Benign renal neoplasm
         subjects affected / exposed
    0 / 293 (0.00%)
    1 / 323 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bladder cancer
         subjects affected / exposed
    1 / 293 (0.34%)
    0 / 323 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Breast cancer stage I
         subjects affected / exposed
    0 / 293 (0.00%)
    1 / 323 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Carcinoma in situ of skin
         subjects affected / exposed
    0 / 293 (0.00%)
    1 / 323 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic myelomonocytic leukaemia
         subjects affected / exposed
    1 / 293 (0.34%)
    1 / 323 (0.31%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatocellular carcinoma
         subjects affected / exposed
    1 / 293 (0.34%)
    0 / 323 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Malignant melanoma
         subjects affected / exposed
    0 / 293 (0.00%)
    1 / 323 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Meningioma
         subjects affected / exposed
    0 / 293 (0.00%)
    2 / 323 (0.62%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastases to bone
         subjects affected / exposed
    1 / 293 (0.34%)
    0 / 323 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastases to lung
         subjects affected / exposed
    1 / 293 (0.34%)
    0 / 323 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastasis
         subjects affected / exposed
    0 / 293 (0.00%)
    1 / 323 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Oesophageal adenocarcinoma
         subjects affected / exposed
    0 / 293 (0.00%)
    1 / 323 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Parathyroid tumour benign
         subjects affected / exposed
    1 / 293 (0.34%)
    1 / 323 (0.31%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Prostate cancer
         subjects affected / exposed
    2 / 293 (0.68%)
    2 / 323 (0.62%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small cell lung cancer metastatic
         subjects affected / exposed
    1 / 293 (0.34%)
    0 / 323 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Squamous cell carcinoma of skin
         subjects affected / exposed
    0 / 293 (0.00%)
    1 / 323 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transitional cell carcinoma
         subjects affected / exposed
    1 / 293 (0.34%)
    0 / 323 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Uterine neoplasm
         subjects affected / exposed
    0 / 293 (0.00%)
    1 / 323 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Anti-neutrophil cytoplasmic antibody positive vasculitis
         subjects affected / exposed
    0 / 293 (0.00%)
    1 / 323 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Drug hypersensitivity
         subjects affected / exposed
    0 / 293 (0.00%)
    1 / 323 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypersensitivity
         subjects affected / exposed
    0 / 293 (0.00%)
    1 / 323 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal transplant failure
         subjects affected / exposed
    1 / 293 (0.34%)
    0 / 323 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sarcoidosis
         subjects affected / exposed
    0 / 293 (0.00%)
    1 / 323 (0.31%)
         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
    Asthenia
         subjects affected / exposed
    2 / 293 (0.68%)
    1 / 323 (0.31%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac death
         subjects affected / exposed
    0 / 293 (0.00%)
    2 / 323 (0.62%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Catheter site haemorrhage
         subjects affected / exposed
    1 / 293 (0.34%)
    0 / 323 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Catheter site pain
         subjects affected / exposed
    1 / 293 (0.34%)
    0 / 323 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chest pain
         subjects affected / exposed
    1 / 293 (0.34%)
    2 / 323 (0.62%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Complication associated with device
         subjects affected / exposed
    1 / 293 (0.34%)
    0 / 323 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    4 / 293 (1.37%)
    5 / 323 (1.55%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 5
         deaths causally related to treatment / all
    0 / 4
    0 / 5
    General physical health deterioration
         subjects affected / exposed
    4 / 293 (1.37%)
    1 / 323 (0.31%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Generalised oedema
         subjects affected / exposed
    1 / 293 (0.34%)
    2 / 323 (0.62%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Inflammation
         subjects affected / exposed
    1 / 293 (0.34%)
    0 / 323 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malaise
         subjects affected / exposed
    1 / 293 (0.34%)
    0 / 323 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multiple organ dysfunction syndrome
         subjects affected / exposed
    1 / 293 (0.34%)
    0 / 323 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 293 (0.00%)
    1 / 323 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oedema peripheral
         subjects affected / exposed
    0 / 293 (0.00%)
    2 / 323 (0.62%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    0 / 293 (0.00%)
    1 / 323 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sudden death
         subjects affected / exposed
    1 / 293 (0.34%)
    1 / 323 (0.31%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Psychiatric disorders
    Alcoholism
         subjects affected / exposed
    0 / 293 (0.00%)
    1 / 323 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Confusional state
         subjects affected / exposed
    1 / 293 (0.34%)
    0 / 323 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Delirium
         subjects affected / exposed
    2 / 293 (0.68%)
    3 / 323 (0.93%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Depression
         subjects affected / exposed
    0 / 293 (0.00%)
    1 / 323 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frustration tolerance decreased
         subjects affected / exposed
    1 / 293 (0.34%)
    0 / 323 (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
    Menometrorrhagia
         subjects affected / exposed
    0 / 293 (0.00%)
    1 / 323 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ovarian cyst
         subjects affected / exposed
    0 / 293 (0.00%)
    1 / 323 (0.31%)
         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
    Accidental overdose
         subjects affected / exposed
    1 / 293 (0.34%)
    0 / 323 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arterial bypass occlusion
         subjects affected / exposed
    0 / 293 (0.00%)
    1 / 323 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arteriovenous fistula site complication
         subjects affected / exposed
    1 / 293 (0.34%)
    3 / 323 (0.93%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arteriovenous fistula site haematoma
         subjects affected / exposed
    0 / 293 (0.00%)
    1 / 323 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arteriovenous fistula thrombosis
         subjects affected / exposed
    5 / 293 (1.71%)
    9 / 323 (2.79%)
         occurrences causally related to treatment / all
    2 / 5
    0 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Brain contusion
         subjects affected / exposed
    0 / 293 (0.00%)
    1 / 323 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chest injury
         subjects affected / exposed
    0 / 293 (0.00%)
    1 / 323 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Complications of transplanted kidney
         subjects affected / exposed
    0 / 293 (0.00%)
    1 / 323 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Facial bones fracture
         subjects affected / exposed
    0 / 293 (0.00%)
    1 / 323 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Fall
         subjects affected / exposed
    2 / 293 (0.68%)
    3 / 323 (0.93%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Femur fracture
         subjects affected / exposed
    0 / 293 (0.00%)
    3 / 323 (0.93%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Humerus fracture
         subjects affected / exposed
    1 / 293 (0.34%)
    0 / 323 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Limb injury
         subjects affected / exposed
    0 / 293 (0.00%)
    1 / 323 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lumbar vertebral fracture
         subjects affected / exposed
    0 / 293 (0.00%)
    1 / 323 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multiple injuries
         subjects affected / exposed
    1 / 293 (0.34%)
    1 / 323 (0.31%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peritoneal dialysis complication
         subjects affected / exposed
    2 / 293 (0.68%)
    0 / 323 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post procedural haemorrhage
         subjects affected / exposed
    1 / 293 (0.34%)
    1 / 323 (0.31%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Postoperative wound complication
         subjects affected / exposed
    0 / 293 (0.00%)
    1 / 323 (0.31%)
         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
    0 / 293 (0.00%)
    1 / 323 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Shunt malfunction
         subjects affected / exposed
    1 / 293 (0.34%)
    0 / 323 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Shunt occlusion
         subjects affected / exposed
    1 / 293 (0.34%)
    0 / 323 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin injury
         subjects affected / exposed
    0 / 293 (0.00%)
    1 / 323 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Splenic rupture
         subjects affected / exposed
    1 / 293 (0.34%)
    0 / 323 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subarachnoid haemorrhage
         subjects affected / exposed
    0 / 293 (0.00%)
    1 / 323 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subdural haematoma
         subjects affected / exposed
    2 / 293 (0.68%)
    0 / 323 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Synovial rupture
         subjects affected / exposed
    0 / 293 (0.00%)
    1 / 323 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tendon rupture
         subjects affected / exposed
    0 / 293 (0.00%)
    1 / 323 (0.31%)
         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 / 293 (0.34%)
    0 / 323 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Toxicity to various agents
         subjects affected / exposed
    0 / 293 (0.00%)
    1 / 323 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Traumatic intracranial haemorrhage
         subjects affected / exposed
    0 / 293 (0.00%)
    1 / 323 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary anastomotic leak
         subjects affected / exposed
    1 / 293 (0.34%)
    0 / 323 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular access malfunction
         subjects affected / exposed
    1 / 293 (0.34%)
    0 / 323 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular access site bruising
         subjects affected / exposed
    1 / 293 (0.34%)
    0 / 323 (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 swelling
         subjects affected / exposed
    1 / 293 (0.34%)
    0 / 323 (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 thrombosis
         subjects affected / exposed
    1 / 293 (0.34%)
    0 / 323 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular pseudoaneurysm
         subjects affected / exposed
    1 / 293 (0.34%)
    0 / 323 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Blood glucose increased
         subjects affected / exposed
    1 / 293 (0.34%)
    1 / 323 (0.31%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood potassium increased
         subjects affected / exposed
    2 / 293 (0.68%)
    2 / 323 (0.62%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2