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    Clinical Trial Results:
    A Phase 3, Randomized, Double-Blind, Placebo Controlled Study of the Efficacy and Safety of Roxadustat for the Treatment of Anemia in Chronic Kidney Disease Patients not on Dialysis

    Summary
    EudraCT number
    2012-005180-27
    Trial protocol
    GB   BE   HU   IT   ES   BG   PL   EE   GR  
    Global end of trial date
    01 Nov 2017

    Results information
    Results version number
    v2(current)
    This version publication date
    25 Oct 2020
    First version publication date
    16 Nov 2018
    Other versions
    v1
    Version creation reason

    Trial information

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    Trial identification
    Sponsor protocol code
    1517-CL-0608
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01887600
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Astellas Pharma Europe B.V. (APEB)
    Sponsor organisation address
    Sylviusweg 62, Leiden, Netherlands, 2333 BE
    Public contact
    Clinical Trial Disclosure, Astellas Pharma Europe B.V. (APEB), 31 (0) 71 5455 050, astellas.resultsdisclosure@astellas.com
    Scientific contact
    Clinical Trial Disclosure, Astellas Pharma Europe B.V. (APEB), 31 (0) 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
    01 Nov 2017
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    01 Nov 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study was to evaluate the efficacy of roxadustat in the treatment of anemia in non-dialysis chronic kidney disease (CKD) 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
    03 Sep 2013
    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
    Belarus: 12
    Country: Number of subjects enrolled
    Belgium: 9
    Country: Number of subjects enrolled
    Bulgaria: 35
    Country: Number of subjects enrolled
    Colombia: 3
    Country: Number of subjects enrolled
    Dominican Republic: 12
    Country: Number of subjects enrolled
    Estonia: 1
    Country: Number of subjects enrolled
    Georgia: 17
    Country: Number of subjects enrolled
    Greece: 6
    Country: Number of subjects enrolled
    Guatemala: 27
    Country: Number of subjects enrolled
    Hungary: 12
    Country: Number of subjects enrolled
    Italy: 6
    Country: Number of subjects enrolled
    Panama: 12
    Country: Number of subjects enrolled
    Peru: 3
    Country: Number of subjects enrolled
    Poland: 48
    Country: Number of subjects enrolled
    Romania: 46
    Country: Number of subjects enrolled
    Russian Federation: 98
    Country: Number of subjects enrolled
    South Africa: 16
    Country: Number of subjects enrolled
    Spain: 17
    Country: Number of subjects enrolled
    Turkey: 19
    Country: Number of subjects enrolled
    United Kingdom: 12
    Country: Number of subjects enrolled
    Ukraine: 98
    Country: Number of subjects enrolled
    Serbia: 85
    Worldwide total number of subjects
    594
    EEA total number of subjects
    192
    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)
    335
    From 65 to 84 years
    249
    85 years and over
    10

    Subject disposition

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    Recruitment
    Recruitment details
    Study population consisted of anemic participants with stages 3, 4 or 5 chronic kidney disease (CKD) (eGFR < 60 mL/min/1.73 m^2) who are not on dialysis. Participants were recruited from 125 study centers located in 22 countries.

    Pre-assignment
    Screening details
    A total of 594 participants with CKD were randomized to receive one of the 2 treatment arms in a 2:1 ratio receiving roxadustat or placebo. Anemia was defined as a mean Hb ≤ 10.0 g/dL upon repeated measurements during the screening period. Participants needed a ferritin ≥30 ng/mL (≥ 67.4 pm ol/L) and transferrin saturation (TSAT) ≥ 5%.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Roxadustat
    Arm description
    Participants received roxadustat according to the tiered weight-based approach, with starting doses of 70 mg given thrice weekly (TIW) to participants weighing up to 70 kg and 100 mg given TIW to participants weighing more than 70 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 (BL) 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 at least 52 weeks up to a maximum of 104 weeks.
    Arm type
    Experimental

    Investigational medicinal product name
    roxadustat
    Investigational medicinal product code
    ASP1517
    Other name
    FG-4592
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Roxadustat was administered initially according to the tiered weight-based dosing, where participants with weight from ≥ 45 to ≤ 70 kg received 70 mg and participants with > 70 to ≤ 160 kg received 100 mg of roxadustat. Dose-titration based upon regular measurement of Hb levels was performed until participants achieved central Hb value of ≥ 11.0 g/dL and Hb increase from baseline (BL) 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.

    Arm title
    Placebo
    Arm description
    Participants received matching placebo according to the tiered weight-based approach, with starting doses of 70 mg given thrice weekly (TIW) to participants weighing up to 70 kg and 100 mg given TIW to participants weighing more than 70 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 (BL) 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 matching placebo for at least 52 weeks up to a maximum of 104 weeks.
    Arm type
    Placebo

    Investigational medicinal product name
    placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo was administered initially according to the tiered weight-based dosing, where participants with weight from ≥ 45 to ≤ 70 kg received 70 mg and participants with > 70 to ≤ 160 kg received 100 mg of roxadustat. Dose-titration based upon regular measurement of Hb levels was performed until participants achieved central Hb value of ≥ 11.0 g/dL and Hb increase from baseline (BL) 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.

    Number of subjects in period 1
    Roxadustat Placebo
    Started
    391
    203
    Treatment Received
    391
    203
    Completed
    245
    89
    Not completed
    146
    114
         Progressive disease
    1
    -
         Protocol deviation
    3
    -
         Death
    39
    16
         Miscellaneous
    6
    2
         Physician decision
    7
    8
         Non-compliance with study drug
    3
    -
         Lack of efficacy
    3
    26
         Consent withdrawn by subject
    58
    52
         Adverse Event
    21
    9
         Lost to follow-up
    5
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Roxadustat
    Reporting group description
    Participants received roxadustat according to the tiered weight-based approach, with starting doses of 70 mg given thrice weekly (TIW) to participants weighing up to 70 kg and 100 mg given TIW to participants weighing more than 70 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 (BL) 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 at least 52 weeks up to a maximum of 104 weeks.

    Reporting group title
    Placebo
    Reporting group description
    Participants received matching placebo according to the tiered weight-based approach, with starting doses of 70 mg given thrice weekly (TIW) to participants weighing up to 70 kg and 100 mg given TIW to participants weighing more than 70 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 (BL) 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 matching placebo for at least 52 weeks up to a maximum of 104 weeks.

    Reporting group values
    Roxadustat Placebo Total
    Number of subjects
    391 203
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    60.6 ± 13.5 61.7 ± 13.8 -
    Gender categorical
    Units:
        Male
    169 99 268
        Female
    222 104 326
    Race
    Units: Subjects
        White
    335 182 517
        Black or African American
    10 3 13
        Asian
    9 0 9
        Other
    37 18 55
    History of Diabetes
    Units: Subjects
        Yes
    146 89 235
        No
    245 114 359
    Iron Repletion at Baseline
    Units: Subjects
        TSAT >= 20% and Ferritin >= 100 ng/mL
    204 109 313
        TSAT < 20% or Ferritin < 100 ng/mL
    187 94 281
    Baseline Hemoglobin (Baseline Hb) Value
    Baseline Hb was defined as the mean of four latest central laboratory Hb values prior or on the same date as first study drug intake (pre-dose).
    Units: g/dL
        arithmetic mean (standard deviation)
    9.08 ± 0.76 9.10 ± 0.72 -
    Baseline Estimated Glomerular Filtration Rate (eGFR)
    Units: ml/min/1.73 m^2
        arithmetic mean (standard deviation)
    16.5 ± 10.2 17.2 ± 11.7 -
    Time From Chronic Kidney Disease (CKD) Diagnosis
    Units: Years
        arithmetic mean (standard deviation)
    5.65 ± 7.02 4.91 ± 5.99 -

    End points

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    End points reporting groups
    Reporting group title
    Roxadustat
    Reporting group description
    Participants received roxadustat according to the tiered weight-based approach, with starting doses of 70 mg given thrice weekly (TIW) to participants weighing up to 70 kg and 100 mg given TIW to participants weighing more than 70 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 (BL) 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 at least 52 weeks up to a maximum of 104 weeks.

    Reporting group title
    Placebo
    Reporting group description
    Participants received matching placebo according to the tiered weight-based approach, with starting doses of 70 mg given thrice weekly (TIW) to participants weighing up to 70 kg and 100 mg given TIW to participants weighing more than 70 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 (BL) 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 matching placebo for at least 52 weeks up to a maximum of 104 weeks.

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

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    End point title
    Percentage of Participants With a Hemoglobin (Hb) Response to Treatment at Two Consecutive Visits During the First 24 Weeks of Treatment Without Rescue Therapy Prior to Hb Response
    End point description
    Hemoglobin (Hb) response was measured as Yes or No. Response Yes (responders) was defined as: Hb ≥11.0 g/dL and Hb increase from baseline by ≥ 1.0 g/dL, for participants with baseline Hb > 8.0 g/dL; or Hb increase from baseline by ≥ 2.0 g/dL, for participants with baseline Hb ≤ 8.0 g/dL at two consecutive visits with available data separated at least 5 days during the first 24 weeks of treatment without having received rescue therapy (red blood cell (RBC) transfusion, erythropoiesis-stimulating agent (ESA), or intravenous (IV) iron prior to Hb response. This was the primary efficacy endpoint for EU (EMA). The analysis population was the full analysis set (FAS), which consisted of all randomized participants who received at least one dose of study drug and had at least one post-dose Hb assessment.
    End point type
    Primary
    End point timeframe
    Baseline to week 24
    End point values
    Roxadustat Placebo
    Number of subjects analysed
    389
    203
    Units: Percentage of Participants
    number (confidence interval 95%)
        Responders
    79.2 (74.8 to 83.1)
    9.9 (6.1 to 14.8)
    Statistical analysis title
    Hemoglobin (Hb) Response to Treatment (Yes/No)
    Statistical analysis description
    The Cochran-Mantel-Haenszel (CMH) test was adjusted by region, history of of cardiovascular, cerebrovascular or thromboembolic (CV) disease, baseline Hb and baseline estimated glomerular filtration rate (eGFR). Superiority of roxadustat versus placebo was to be declared if the lower bound of the two-sided 95% confidence interval of the CMH odds ratio was higher than 1.
    Comparison groups
    Roxadustat v Placebo
    Number of subjects included in analysis
    592
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Odds ratio (OR)
    Point estimate
    34.74
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    20.48
         upper limit
    58.93

    Primary: Hb Change From Baseline (BL) to the Average Hb in Weeks 28-52 Regardless of Rescue Therapy

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    End point title
    Hb Change From Baseline (BL) to the Average Hb in Weeks 28-52 Regardless of Rescue Therapy
    End point description
    The change from baseline to the average Hb values across weeks 28 to 52 without having received rescue therapy. The Hb values from visit windows at weeks 28, 32, 36, 40, 44, 48 and 52 were used for the calculation of the average of weeks 28 to 52. This was the primary efficacy endpoint for US (FDA). The analysis population was All Randomized, and it consisted of all randomized participants with available data at all time points.
    End point type
    Primary
    End point timeframe
    Baseline and weeks 28 to 52
    End point values
    Roxadustat Placebo
    Number of subjects analysed
    312
    146
    Units: g/dL
        least squares mean (confidence interval 95%)
    1.992 (1.82 to 2.16)
    0.300 (0.09 to 0.51)
    Statistical analysis title
    Change From BL to the Average Hb in Weeks 28-52
    Statistical analysis description
    The Analysis of Covariance (ANCOVA) with Multiple Imputations (MI) model, adjusting for covariates was used for the analysis. The model included treatment as fixed factor, region and history of CV disease as class factors and baseline Hb, baseline eGFR as continuous covariates. Superiority of roxadustat versus placebo was considered successful if the lower bound of the two-sided 95% confidence interval of the difference between treatment arms (roxadustat minus placebo) was higher than 0.
    Comparison groups
    Roxadustat v Placebo
    Number of subjects included in analysis
    458
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001
    Method
    ANCOVA
    Parameter type
    Least squares mean difference
    Point estimate
    1.692
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.52
         upper limit
    1.86

    Secondary: Hb Change From BL to the Average Hb in Weeks 28-36 Without Having Received Rescue Therapy Within 6 Weeks Prior to and During 8-Week Evaluation Period

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    End point title
    Hb Change From BL to the Average Hb in Weeks 28-36 Without Having Received Rescue Therapy Within 6 Weeks Prior to and During 8-Week Evaluation Period
    End point description
    The Hb values from visit windows at weeks 28, 32 and 36 were used for the calculation of the average of weeks 28 to 36. The analysis population was the FAS, which consisted of all randomized participants who received at least one dose of study drug and had at least one post-dose Hb assessment.
    End point type
    Secondary
    End point timeframe
    Baseline and weeks 28 to 36
    End point values
    Roxadustat Placebo
    Number of subjects analysed
    311
    139
    Units: g/dL
        least squares mean (confidence interval 95%)
    2.069 (1.94 to 2.20)
    0.470 (0.30 to 0.64)
    Statistical analysis title
    Change from BL to the Average Hb in weeks 28-36
    Statistical analysis description
    A Mixed Model of Repeated Measures (MMRM) has been applied using the visits up to week 36. The results were based on the estimated difference between the two treatment arms overall mean effects throughout the evaluation period (weeks 28 to 36). The model included treatment arm, region, CV History, visits and visit by treatment as categorical variables and baseline Hb, baseline eGFR and baseline Hb by visit as continuous variables.
    Comparison groups
    Roxadustat v Placebo
    Number of subjects included in analysis
    450
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001 [1]
    Method
    Mixed models analysis
    Parameter type
    Least squares mean difference
    Point estimate
    1.599
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.41
         upper limit
    1.78
    Notes
    [1] - LSM Difference p-value is for test of differences. Tested using a fixed sequence testing procedure to maintain the overall two-sided type I error rate at 0.05.

    Secondary: Change From BL in Low-Density Lipoprotein (LDL) Cholesterol (Regardless of Fasting Status) to the Average LDL Cholesterol of Weeks 12 to 28

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    End point title
    Change From BL in Low-Density Lipoprotein (LDL) Cholesterol (Regardless of Fasting Status) to the Average LDL Cholesterol of Weeks 12 to 28
    End point description
    Analysis was completed on all values collected on day 1 and weeks 12, 20 and 28. The analysis population was the FAS, which consisted of all randomized participants who received at least one dose of study drug and had at least one post-dose Hb assessment.
    End point type
    Secondary
    End point timeframe
    Baseline and weeks 12 to 28
    End point values
    Roxadustat Placebo
    Number of subjects analysed
    342
    185
    Units: mmol/l
        least squares mean (confidence interval 95%)
    -0.650 (-0.76 to -0.54)
    0.051 (-0.08 to 0.18)
    Statistical analysis title
    LDL Change From BL
    Statistical analysis description
    A Mixed Model of Repeated Measures has been applied using the visits up to week 28. The results were based on the estimated difference between the two treatment arms and overall mean effects throughout the evaluation period (weeks 12 to 28). The model included treatment arm, region, CV history, visits and visit by treatment as categorical variables and baseline Hb, baseline eGFR and baseline LDL as continuous variables.
    Comparison groups
    Roxadustat v Placebo
    Number of subjects included in analysis
    527
    Analysis specification
    Pre-specified
    Analysis type
    superiority [2]
    P-value
    < 0.001 [3]
    Method
    Mixed models analysis
    Parameter type
    Least squares mean difference
    Point estimate
    -0.701
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.83
         upper limit
    -0.57
    Notes
    [2] - Superiority of roxadustat versus placebo was considered successful if the upper bound of the two-sided 95% confidence interval of the difference between treatment arms (roxadustat minus placebo) is below 0.
    [3] - LSM Difference p-value is for test of differences. Tested using a fixed sequence testing procedure to maintain the overall two-sided type I error rate at 0.05.

    Secondary: Time to First Use of Rescue Therapy (Composite of Red Blood Cell (RBC) Transfusions, Erythropoiesis-stimulating Agent (ESA) Use, and Intravenous (IV) Iron)

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    End point title
    Time to First Use of Rescue Therapy (Composite of Red Blood Cell (RBC) Transfusions, Erythropoiesis-stimulating Agent (ESA) Use, and Intravenous (IV) Iron)
    End point description
    The time to first use of rescue therapy was calculated (in years) as: (First event date – Analysis date of first dose intake + 1) / 365.25. The First event date was defined as Date of first dose of rescue medication during the efficacy emergent period and Analysis date of first dose intake was defined as date of first study drug dose intake collected on day 1. The Efficacy Emergent Period was defined as the evaluation period from the analysis date of first dose intake up to 7 days after the analysis date of last dose or the end of treatment (EOT) visit, whichever occurred first. Data reported was analysed by Kaplan-Meier estimate for cumulative proportion. Medication onset date was the date of the first use of rescue medication. The analysis population was the FAS, which consisted of all randomized participants who received at least one dose of study drug and had at least one post-dose Hb assessment.
    End point type
    Secondary
    End point timeframe
    Baseline to week 104 (End of Treatment)
    End point values
    Roxadustat Placebo
    Number of subjects analysed
    389
    203
    Units: Percentage
    number (confidence interval 95%)
        Year 0.5
    6.1 (3.6 to 8.7)
    33.3 (26.5 to 40.1)
        Year 1
    13.0 (9.3 to 16.7)
    50.1 (42.4 to 57.7)
        Year 1.5
    22.0 (16.6 to 27.3)
    52.5 (44.5 to 60.5)
        Year 2
    26.3 (20.2 to 32.4)
    57.8 (48.7 to 66.9)
    Statistical analysis title
    Time to First Use of Rescue Therapy
    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 is declared if the upper bound of the 95% CI is below 1.0.
    Comparison groups
    Roxadustat v Placebo
    Number of subjects included in analysis
    592
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001 [4]
    Method
    Regression, Cox
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.238
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.17
         upper limit
    0.33
    Notes
    [4] - Tested using a fixed sequence testing procedure to maintain the overall two-sided type I error rate at 0.05.

    Secondary: Change From BL in Short Form (SF)-36 Vitality (VT) Sub-score to the Average VT Sub-score of Weeks 12 to 28

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    End point title
    Change From BL in Short Form (SF)-36 Vitality (VT) Sub-score to the Average VT Sub-score of Weeks 12 to 28
    End point description
    Change from BL in SF-36 VT sub-score to the average value in weeks 12-28 was calculated using the physical component scores (PCS) of SF-36. The multi-purpose, short-form health survey has 36 questions with an 8-scale profile of functional health and well-being scores as well as psychometrically-based physical and mental health summary measures. The survey measures eight dimensions or scales: (1) physical functioning (PF) (10 items); (2) role limitations due to physical health problems (RP) (3 items); (3) bodily pain (BP) (2 items); (4) social functioning (SF) (2 items); (5) general health perceptions (GH) (5 items); (6) role limitations due to emotional problems (RE) (3 items); (7) vitality, energy or fatigue (VT) (4 items); and (8) mental health (MH) (5 items). The SF-36 scores ranged from 0-100 with higher scores indicating better health status.The analysis population was the FAS.
    End point type
    Secondary
    End point timeframe
    Baseline and weeks 12 to 28
    End point values
    Roxadustat Placebo
    Number of subjects analysed
    340
    185
    Units: Units on a Scale
        least squares mean (confidence interval 95%)
    2.788 (1.56 to 4.01)
    1.661 (0.23 to 3.10)
    Statistical analysis title
    Change from BL in Vitality SF-36
    Statistical analysis description
    A Mixed Model of Repeated Measures has been applied using the visits up to week 28. The results were based on the estimated difference between the two treatment arms and overall mean effects throughout the evaluation period (weeks 12 to 28). The model included treatment arm, region, CV history, visits and visit by treatment as categorical variables and baseline SF-36 VT, baseline Hb and baseline eGFR as continuous variables.
    Comparison groups
    Roxadustat v Placebo
    Number of subjects included in analysis
    525
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.093 [5]
    Method
    Mixed models analysis
    Parameter type
    Least squares mean difference
    Point estimate
    1.127
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.19
         upper limit
    2.44
    Notes
    [5] - LSM Difference p-value is for test of differences. Tested using a fixed sequence testing procedure to maintain the overall two-sided type I error rate at 0.05.

    Secondary: Change From BL in SF-36 Physical Functioning (PF) Sub-score to the Average PF Sub-score of Weeks 12 to 28

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    End point title
    Change From BL in SF-36 Physical Functioning (PF) Sub-score to the Average PF Sub-score of Weeks 12 to 28
    End point description
    Change from baseline in SF-36 PF normalized sub-score compared to the average PF sub-score of weeks 12 to 28. The multi-purpose, short-form health survey has 36 questions with an 8-scale profile of functional health and well-being scores as well as psychometrically-based physical and mental health summary measures. Change from baseline in PF subscore of SF-36 to the average of weeks 12–28 was compared by treatment arm for all participants (primary analysis) and in the subsets of participants with baseline PF subscore below 35 and equal or above 35. The SF-36 scores ranged from 0-100 with higher scores indicating better health status. All available SF-36 PF values were used i.e., both scheduled and unscheduled for the calculation of the average PF sub-score of weeks 12 to 28. The analysis population was the FAS, which consisted of all randomized participants who received at least one dose of study drug and had at least one post-dose Hb assessment.
    End point type
    Secondary
    End point timeframe
    Baseline and weeks 12 to 28
    End point values
    Roxadustat Placebo
    Number of subjects analysed
    340
    185
    Units: Units on a Scale
        least squares mean (confidence interval 95%)
    1.344 (0.15 to 2.54)
    0.632 (-0.76 to 2.03)
    Statistical analysis title
    Change from BL in Physical Functioning SF-36
    Statistical analysis description
    A Mixed Model of Repeated Measures has been applied using the visits up to week 28. The results were based on the estimated difference between the two treatment arms and overall mean effects throughout the evaluation period (weeks 12 to 28). The model included treatment arm, region, CV history, visits and visit by treatment as categorical variables and baseline SF-36 PF, baseline Hb and baseline eGFR as continuous variables.
    Comparison groups
    Roxadustat v Placebo
    Number of subjects included in analysis
    525
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.27 [6]
    Method
    Mixed models analysis
    Parameter type
    Least squares mean difference
    Point estimate
    0.713
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.56
         upper limit
    1.98
    Notes
    [6] - LSM Difference p-value is for test of differences. Tested using a fixed sequence testing procedure to maintain the overall two-sided type I error rate at 0.05.

    Secondary: Change From BL in Mean Arterial Pressure (MAP) to the Average MAP of Weeks 20 to 28

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    End point title
    Change From BL in Mean Arterial Pressure (MAP) to the Average MAP of Weeks 20 to 28
    End point description
    The MAP was derived for each visit from the average systolic (SBP) and diastolic blood pressure (DBP) calculated for each visit using the three readings and the following equation: MAP = (2/3) * DBP + (1/3) * SBP. Baseline assessment was the assessment on day 1 (average of the three readings). If the baseline assessment was missing, then the latest available value prior to first drug administration was used. The analysis population was the per protocol set (PPS), which consisted of all FAS participants who did not meet any reasons for exclusion from the PPS and had all available data at all time points.
    End point type
    Secondary
    End point timeframe
    Baseline and weeks 20 to 28
    End point values
    Roxadustat Placebo
    Number of subjects analysed
    310
    146
    Units: mmHg
        least squares mean (confidence interval 95%)
    -0.814 (-1.83 to 0.20)
    -1.656 (-2.91 to -0.41)
    Statistical analysis title
    Change From BL MAP to Average MAP
    Statistical analysis description
    A Mixed Model of Repeated Measures was applied using the visits up to week 28. The results were based on the estimated difference between the two treatment arms with overall mean effects throughout the evaluation period (weeks 20 to 28). 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 Placebo
    Number of subjects included in analysis
    456
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority [7]
    P-value
    = 0.182 [8]
    Method
    Mixed models analysis
    Parameter type
    Least squares mean difference
    Point estimate
    0.842
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.4
         upper limit
    2.08
    Notes
    [7] - Non-inferiority can be concluded if the upper bound of the two-sided 95% CI of the difference between roxadustat and placebo (roxadustat minus placebo) is below 2 mmHg.
    [8] - LSM Difference p-value is for test of differences.

    Secondary: Time to First Occurrence of Hypertension

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    End point title
    Time to First Occurrence of Hypertension
    End point description
    Occurrence of hypertension was defined as SBP increase from BL ≥20 mmHg and SBP >170 mmHg or DBP increase from BL ≥15 mmHg and DBP ≥110 mmHg. Time to first occurrence of hypertension was defined as first date where SBP criterion or DBP criterion is met, whichever occurred first. Data was analysed using Kaplan-Meier estimate for cumulative proportion. The analysis population was the PPS, which consisted of all FAS participants who did not meet any reasons for exclusion from the PPS and had all available data at all time points.
    End point type
    Secondary
    End point timeframe
    Baseline to week 108
    End point values
    Roxadustat Placebo
    Number of subjects analysed
    359
    183
    Units: Percentage
    number (confidence interval 95%)
        Year 0.5
    11.4 (7.9 to 14.8)
    10.1 (5.5 to 14.7)
        Year 1
    14.8 (10.9 to 18.8)
    12.5 (7.3 to 17.7)
        Year 1.5
    17.5 (13.0 to 21.9)
    12.5 (7.3 to 17.7)
        Year 2
    18.5 (13.7 to 23.3)
    12.5 (7.3 to 17.7)
    Statistical analysis title
    Time to First Occurrence of Hypertension
    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 Placebo
    Number of subjects included in analysis
    542
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority [9]
    P-value
    = 0.334
    Method
    Regression, Cox
    Parameter type
    Hazard ratio (HR)
    Point estimate
    1.29
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.77
         upper limit
    2.16
    Notes
    [9] - Non-inferiority is declared if the upper bound of the 95% CI is below 1.3 (hazard ratio).

    Secondary: Rate of Progression of CKD Measured by Annualized Estimated Glomerular Filtration Rate (eGFR) Slope Over Time

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    End point title
    Rate of Progression of CKD Measured by Annualized Estimated Glomerular Filtration Rate (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 chronic dialysis (acute or chronic) are 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, which consisted of all randomized participants who received at least one dose of study drug and had at least one post-dose Hb assessment.
    End point type
    Secondary
    End point timeframe
    Baseline up to week 108
    End point values
    Roxadustat Placebo
    Number of subjects analysed
    389
    203
    Units: ml/min per 1.73 m^2
        least squares mean (confidence interval 95%)
    -2.65 (-3.29 to -2.02)
    -3.24 (-4.21 to -2.28)
    Statistical analysis title
    Annualized eGFR Slope
    Statistical analysis description
    Annualized eGFR slope over time was estimated by a random slopes and intercepts model using all available eGFR values adjusted on baseline Hb, region, CV history at Baseline and the interaction terms.
    Comparison groups
    Roxadustat v Placebo
    Number of subjects included in analysis
    592
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.316
    Method
    Mixed models analysis
    Parameter type
    Least squares mean difference
    Point estimate
    0.59
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.57
         upper limit
    1.75

    Secondary: Average Level of Hb Over Weeks 28 to 36 Without Use of Rescue Therapy Within 6 Weeks Prior to and During the Evaluation Period

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    End point title
    Average Level of Hb Over Weeks 28 to 36 Without Use of Rescue Therapy Within 6 Weeks Prior to and During the Evaluation Period
    End point description
    All scheduled and unscheduled hemoglobin values from weeks 28 to 36 were taken into account for calculating the average values. The analysis population was the FAS, which consisted of all randomized participants who received at least one dose of study drug and had at least one post-dose Hb assessment.
    End point type
    Secondary
    End point timeframe
    Baseline and weeks 28 to 36
    End point values
    Roxadustat Placebo
    Number of subjects analysed
    311
    139
    Units: g/dl
        least squares mean (confidence interval 95%)
    11.106 (10.97 to 11.24)
    9.468 (9.29 to 9.65)
    Statistical analysis title
    Average Level of Hb Over Weeks 28 to 36
    Statistical analysis description
    A Mixed Model of Repeated Measures was applied using the visits over weeks 28 to 36. The results were based on the estimated difference between the two treatment arms by visit based on this MMRM model. The model included treatment arm, region, CV History, visits and visit by treatment as categorical variables and baseline Hb and baseline eGFR as continuous variables.
    Comparison groups
    Roxadustat v Placebo
    Number of subjects included in analysis
    450
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001 [10]
    Method
    Mixed models analysis
    Parameter type
    Least squares mean difference
    Point estimate
    1.638
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.44
         upper limit
    1.84
    Notes
    [10] - LSM Difference p-value is for test of differences

    Secondary: Average Level of Hb Over Weeks 44 to 52 Without Use of Rescue Therapy Within 6 Weeks Prior to and During the Evaluation Period

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    End point title
    Average Level of Hb Over Weeks 44 to 52 Without Use of Rescue Therapy Within 6 Weeks Prior to and During the Evaluation Period
    End point description
    All scheduled and unscheduled hemoglobin values from weeks 44 to 52 were taken into account for calculating the average values. The analysis population was the FAS, which consisted of all randomized participants who received at least one dose of study drug and had at least one post-dose Hb assessment.
    End point type
    Secondary
    End point timeframe
    Baseline and weeks 44 to 52
    End point values
    Roxadustat Placebo
    Number of subjects analysed
    287
    118
    Units: g/dl
        least squares mean (confidence interval 95%)
    10.984 (10.85 to 11.12)
    9.381 (9.19 to 9.58)
    Statistical analysis title
    Average Level of Hb Over Weeks 44 to 52
    Statistical analysis description
    A Mixed Model of Repeated Measures was applied using the visits over weeks 44 to 52. The results were based on the estimated difference between the two treatment arms by visit. The model included treatment arm, region, CV history, visits and visit by treatment as categorical variables and baseline Hb and baseline eGFR as continuous variables.
    Comparison groups
    Roxadustat v Placebo
    Number of subjects included in analysis
    405
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001 [11]
    Method
    Mixed models analysis
    Parameter type
    Least squares mean difference
    Point estimate
    1.604
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.39
         upper limit
    1.82
    Notes
    [11] - LSM difference p-value is for test of differences.

    Secondary: Average Level of Hb Over Weeks 96 to 104 Without Use of Rescue Therapy Within 6 Weeks Prior to and During the Evaluation Period

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    End point title
    Average Level of Hb Over Weeks 96 to 104 Without Use of Rescue Therapy Within 6 Weeks Prior to and During the Evaluation Period
    End point description
    All scheduled and unscheduled hemoglobin values from weeks 96 to 104 were taken into account for calculating the average values. The analysis population was the FAS, which consisted of all randomized participants who received at least one dose of study drug and had at least one post-dose Hb assessment.
    End point type
    Secondary
    End point timeframe
    Baseline and weeks 96 to 104
    End point values
    Roxadustat Placebo
    Number of subjects analysed
    120
    32
    Units: g/dl
        least squares mean (confidence interval 95%)
    10.816 (10.63 to 11.00)
    9.324 (9.01 to 9.64)
    Statistical analysis title
    Average Level of Hb Over Weeks 96 to 104
    Statistical analysis description
    A Mixed Model of Repeated Measures was applied using the visits over weeks 96 to 104. The results were based on the estimated difference between the two treatment arms by visit. The model included treatment arm, region, CV history, visits and visit by treatment as categorical variables and baseline Hb and baseline eGFR as continuous variables.
    Comparison groups
    Roxadustat v Placebo
    Number of subjects included in analysis
    152
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001 [12]
    Method
    Mixed models analysis
    Parameter type
    Least squares mean difference
    Point estimate
    1.492
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.14
         upper limit
    1.85
    Notes
    [12] - LSM Difference p-value is for test of differences

    Secondary: Time to Achieve the First Hb Response Without Rescue Therapy, as Defined by Primary Endpoint

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    End point title
    Time to Achieve the First Hb Response Without Rescue Therapy, as Defined by Primary Endpoint
    End point description
    For a participant without rescue therapy before Hb response (defined in 1 primary outcome), the time to achieve Hb response was calculated (in weeks) as: (First event date – Analysis date of first dose intake + 1) / 7 where First event date was defined as First date of both values that met the criteria for response. Participants who discontinued or received rescue therapy prior to the first Hb response or before the second consecutive Hb value defined as a response were classified as non- responders and were censored at week 24 or end of efficacy emergent period, whichever came first. Data analysis was completed using Kaplan-Meier estimate for cumulative proportion. The analysis population was the FAS, which consisted of all randomized participants who received at least one dose of study drug and had at least one post-dose Hb assessment.
    End point type
    Secondary
    End point timeframe
    Baseline to week 24
    End point values
    Roxadustat Placebo
    Number of subjects analysed
    389
    203
    Units: Percentage
    number (confidence interval 95%)
        Week 4
    26.0 (21.6 to 30.4)
    3.5 (0.9 to 6.0)
        Week 8
    59.8 (54.7 to 64.9)
    6.2 (2.8 to 9.7)
        Week 16
    83.4 (79.3 to 87.5)
    9.4 (5.1 to 13.7)
        Week 24
    89.1 (85.5 to 92.6)
    11.6 (6.8 to 16.5)
    Statistical analysis title
    Time to Achieve the First Hb Response
    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 Placebo
    Number of subjects included in analysis
    592
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001
    Method
    Regression, Cox
    Parameter type
    Hazard ratio (HR)
    Point estimate
    19.001
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    11.98
         upper limit
    30.15

    Secondary: Hb Change From BL to Each Post-Dosing Time Point

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    End point title
    Hb Change From BL to Each Post-Dosing Time Point
    End point description
    All scheduled and unscheduled hemoglobin values that belong to each visit window were taken into account using one value per analysis window. Baseline Hb was defined as the mean of four latest central laboratory Hb values prior or on the same date as first study drug intake (pre-dose). N is the number of participants with available data at each time point. The analysis population was the FAS, which consisted of all randomized participants who received at least one dose of study drug and had at least one post-dose Hb assessment.
    End point type
    Secondary
    End point timeframe
    Baseline (day 1) 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, 68,72,76,80,84,88,92,96,100,104
    End point values
    Roxadustat Placebo
    Number of subjects analysed
    389
    203
    Units: Number
    least squares mean (confidence interval 95%)
        Hb Change From BL to Week 1 [N=372,193]
    0.390 (0.29 to 0.49)
    -0.006 (-0.12 to 0.11)
        Hb Change From BL to Week 2 [N=363,195]
    0.977 (0.87 to 1.08)
    0.039 (-0.09 to 0.17)
        Hb Change From BL to Week 4 [N=360,189]
    1.591 (1.47 to 1.71)
    0.119 (-0.04 to 0.27)
        Hb Change From BL to Week 6 [N=347,186]
    1.927 (1.79 to 2.06)
    0.100 (-0.07 to 0.27)
        Hb Change From BL to Week 8 [N=346,188]
    2.236 (2.10 to 2.37)
    0.178 (0.01 to 0.35)
        Hb Change From BL to Week 10 [N=335,184]
    2.129 (1.99 to 2.26)
    0.180 (0.01 to 0.35)
        Hb Change From BL to Week 12 [N=337,179]
    2.412 (2.28 to 2.55)
    0.322 (0.15 to 0.49)
        Hb Change From BL to Week 14 [N=332,174]
    2.214 (2.08 to 2.35)
    0.163 (0.00 to 0.33)
        Hb Change From BL to Week 16 [N=321,173]
    2.365 (2.23 to 2.50)
    0.378 (0.20 to 0.56)
        Hb Change From BL to Week 18 [N=317,161]
    2.087 (1.95 to 2.23)
    0.246 (0.06 to 0.43)
        Hb Change From BL to Week 20 [N=310,151]
    2.191 (2.04 to 2.34)
    0.367 (0.18 to 0.56)
        Hb Change From BL to Week 22 [N=312,149]
    1.873 (1.73 to 2.02)
    0.222 (0.03 to 0.41)
        Hb Change From BL to Week 24 [N=307,142]
    1.802 (1.66 to 1.95)
    0.355 (0.16 to 0.55)
        Hb Change From BL to Week 28 [N=301,145]
    1.996 (1.85 to 2.14)
    0.435 (0.24 to 0.63)
        Hb Change From BL to Week 32 [N=300,137]
    1.911 (1.77 to 2.05)
    0.324 (0.13 to 0.52)
        Hb Change From BL to Week 36 [N=290,131]
    2.100 (1.95 to 2.25)
    0.410 (0.21 to 0.61)
        Hb Change From BL to Week 40 [N=290,125]
    1.887 (1.74 to 2.03)
    0.241 (0.04 to 0.45)
        Hb Change From BL to Week 44 [N=275,122]
    1.977 (1.82 to 2.13)
    0.278 (0.06 to 0.49)
        Hb Change From BL to Week 48 [N=282,114]
    1.695 (1.54 to 1.85)
    0.249 (0.03 to 0.46)
        Hb Change From BL to Week 52 [N=267,111]
    1.939 (1.78 to 2.10)
    0.298 (0.07 to 0.52)
        Hb Change From BL to Week 56 [N=217,74]
    1.725 (1.56 to 1.88)
    0.085 (-0.16 to 0.33)
        Hb Change From BL to Week 60 [N=198,68]
    1.988 (1.81 to 2.16)
    0.354 (0.09 to 0.62)
        Hb Change From BL to Week 64 [N=174,55]
    1.637 (1.45 to 1.82)
    0.233 (-0.06 to 0.52)
        Hb Change From BL to Week 68 [N=173,49]
    1.913 (1.74 to 2.09)
    0.414 (0.13 to 0.70)
        Hb Change From BL to Week 72 [N=158,50]
    1.765 (1.58 to 1.95)
    0.328 (0.03 to 0.63)
        Hb Change From BL to Week 76 [N=156,47]
    1.859 (1.67 to 2.05)
    0.674 (0.36 to 0.99)
        Hb Change From BL to Week 80 [N=145,43]
    1.752 (1.57 to 1.93)
    0.308 (0.01 to 0.61)
        Hb Change From BL to Week 84 [N=143,37]
    1.854 (1.66 to 2.05)
    0.480 (0.14 to 0.82)
        Hb Change From BL to Week 88 [N=132,31]
    1.570 (1.38 to 1.76)
    0.399 (0.06 to 0.74)
        Hb Change From BL to Week 92 [N=125,32]
    1.800 (1.60 to 2.00)
    0.418 (0.06 to 0.78)
        Hb Change From BL to Week 96 [N=122,32]
    1.701 (1.49 to 1.91)
    0.139 (-0.23 to 0.51)
        Hb Change From BL to Week 100 [N=119,30]
    1.763 (1.57 to 1.96)
    0.315 (-0.03 to 0.66)
        Hb Change From BL to Week 104 [N=102,26]
    1.857 (1.64 to 2.08)
    0.511 (0.11 to 0.91)
    Statistical analysis title
    Hb Change From BL to Week 1
    Statistical analysis description
    A Mixed Model of Repeated Measures was applied using the visits up to Week 104. The results were based on the estimated difference between the two treatment arms by visit. The model included treatment arm, region, CV history, visits and visit by treatment as categorical variables and baseline Hb and baseline eGFR as continuous variables.
    Comparison groups
    Roxadustat v Placebo
    Number of subjects included in analysis
    592
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001 [13]
    Method
    Mixed models analysis
    Parameter type
    Least squares mean difference
    Point estimate
    0.396
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.29
         upper limit
    0.5
    Notes
    [13] - LSM Difference p-value is for test of differences.
    Statistical analysis title
    Hb Change From BL to Week 2
    Statistical analysis description
    A Mixed Model of Repeated Measures was applied using the visits up to Week 104. The results were based on the estimated difference between the two treatment arms by visit. The model included treatment arm, region, CV history, visits and visit by treatment as categorical variables and baseline Hb and baseline eGFR as continuous variables.
    Comparison groups
    Roxadustat v Placebo
    Number of subjects included in analysis
    592
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001 [14]
    Method
    Mixed models analysis
    Parameter type
    Least squares mean difference
    Point estimate
    0.938
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.81
         upper limit
    1.07
    Notes
    [14] - LSM Difference p-value is for test of differences.
    Statistical analysis title
    Hb Change From BL to Week 4
    Statistical analysis description
    A Mixed Model of Repeated Measures was applied using the visits up to Week 104. The results were based on the estimated difference between the two treatment arms by visit. The model included treatment arm, region, CV history, visits and visit by treatment as categorical variables and baseline Hb and baseline eGFR as continuous variables.
    Comparison groups
    Roxadustat v Placebo
    Number of subjects included in analysis
    592
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001 [15]
    Method
    Mixed models analysis
    Parameter type
    Least squares mean difference
    Point estimate
    1.471
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.3
         upper limit
    1.64
    Notes
    [15] - LSM Difference p-value is for test of differences.
    Statistical analysis title
    Hb Change From BL to Week 6
    Statistical analysis description
    A Mixed Model of Repeated Measures was applied using the visits up to Week 104. The results were based on the estimated difference between the two treatment arms by visit. The model included treatment arm, region, CV history, visits and visit by treatment as categorical variables and baseline Hb and baseline eGFR as continuous variables.
    Comparison groups
    Roxadustat v Placebo
    Number of subjects included in analysis
    592
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001 [16]
    Method
    Mixed models analysis
    Parameter type
    Least squares mean difference
    Point estimate
    1.827
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.64
         upper limit
    2.02
    Notes
    [16] - LSM Difference p-value is for test of differences.
    Statistical analysis title
    Hb Change From BL to Week 8
    Statistical analysis description
    A Mixed Model of Repeated Measures was applied using the visits up to Week 104. The results were based on the estimated difference between the two treatment arms by visit. The model included treatment arm, region, CV history, visits and visit by treatment as categorical variables and baseline Hb and baseline eGFR as continuous variables.
    Comparison groups
    Roxadustat v Placebo
    Number of subjects included in analysis
    592
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001 [17]
    Method
    Mixed models analysis
    Parameter type
    Least squares mean difference
    Point estimate
    2.058
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.87
         upper limit
    2.25
    Notes
    [17] - LSM Difference p-value is for test of differences.
    Statistical analysis title
    Hb Change From BL to Week 10
    Statistical analysis description
    A Mixed Model of Repeated Measures was applied using the visits up to Week 104. The results were based on the estimated difference between the two treatment arms by visit. The model included treatment arm, region, CV history, visits and visit by treatment as categorical variables and baseline Hb and baseline eGFR as continuous variables.
    Comparison groups
    Roxadustat v Placebo
    Number of subjects included in analysis
    592
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001 [18]
    Method
    Mixed models analysis
    Parameter type
    Least squares mean difference
    Point estimate
    1.949
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.75
         upper limit
    2.14
    Notes
    [18] - LSM Difference p-value is for test of differences.
    Statistical analysis title
    Hb Change From BL to Week 12
    Statistical analysis description
    A Mixed Model of Repeated Measures was applied using the visits up to Week 104. The results were based on the estimated difference between the two treatment arms by visit. The model included treatment arm, region, CV history, visits and visit by treatment as categorical variables and baseline Hb and baseline eGFR as continuous variables.
    Comparison groups
    Roxadustat v Placebo
    Number of subjects included in analysis
    592
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001 [19]
    Method
    Mixed models analysis
    Parameter type
    Least squares mean difference
    Point estimate
    2.09
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.9
         upper limit
    2.28
    Notes
    [19] - LSM Difference p-value is for test of differences.
    Statistical analysis title
    Hb Change From BL to Week 14
    Statistical analysis description
    A Mixed Model of Repeated Measures was applied using the visits up to Week 104. The results were based on the estimated difference between the two treatment arms by visit. The model included treatment arm, region, CV history, visits and visit by treatment as categorical variables and baseline Hb and baseline eGFR as continuous variables.
    Comparison groups
    Roxadustat v Placebo
    Number of subjects included in analysis
    592
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001 [20]
    Method
    Mixed models analysis
    Parameter type
    Least squares mean difference
    Point estimate
    2.051
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.86
         upper limit
    2.24
    Notes
    [20] - LSM Difference p-value is for test of differences.
    Statistical analysis title
    Hb Change From BL to Week 16
    Statistical analysis description
    A Mixed Model of Repeated Measures was applied. The results were based on the estimated difference between the two treatment arms by visit. The model included treatment arm, region, CV history, visits and visit by treatment as categorical variables and baseline Hb and baseline eGFR as continuous variables.
    Comparison groups
    Roxadustat v Placebo
    Number of subjects included in analysis
    592
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001 [21]
    Method
    Mixed models analysis
    Parameter type
    Least squares mean difference
    Point estimate
    1.987
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.79
         upper limit
    2.19
    Notes
    [21] - LSM Difference p-value is for test of differences.
    Statistical analysis title
    Hb Change From BL to Week 18
    Statistical analysis description
    A Mixed Model of Repeated Measures was applied. The results were based on the estimated difference between the two treatment arms by visit. The model included treatment arm, region, CV history, visits and visit by treatment as categorical variables and baseline Hb and baseline eGFR as continuous variables.
    Comparison groups
    Roxadustat v Placebo
    Number of subjects included in analysis
    592
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001 [22]
    Method
    Mixed models analysis
    Parameter type
    Least squares mean difference
    Point estimate
    1.841
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.64
         upper limit
    2.05
    Notes
    [22] - LSM Difference p-value is for test of differences.
    Statistical analysis title
    Hb Change From BL to Week 20
    Statistical analysis description
    A Mixed Model of Repeated Measures was applied. The results were based on the estimated difference between the two treatment arms by visit. The model included treatment arm, region, CV history, visits and visit by treatment as categorical variables and baseline Hb and baseline eGFR as continuous variables.
    Comparison groups
    Roxadustat v Placebo
    Number of subjects included in analysis
    592
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001 [23]
    Method
    Mixed models analysis
    Parameter type
    Least squares mean difference
    Point estimate
    1.824
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.61
         upper limit
    2.04
    Notes
    [23] - LSM Difference p-value is for test of differences.
    Statistical analysis title
    Hb Change From BL to Week 22
    Statistical analysis description
    A Mixed Model of Repeated Measures was applied. The results were based on the estimated difference between the two treatment arms by visit. The model included treatment arm, region, CV history, visits and visit by treatment as categorical variables and baseline Hb and baseline eGFR as continuous variables.
    Comparison groups
    Roxadustat v Placebo
    Number of subjects included in analysis
    592
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001 [24]
    Method
    Mixed models analysis
    Parameter type
    Least squares mean difference
    Point estimate
    1.651
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.43
         upper limit
    1.87
    Notes
    [24] - LSM Difference p-value is for test of differences.
    Statistical analysis title
    Hb Change From BL to Week 24
    Statistical analysis description
    A Mixed Model of Repeated Measures was applied. The results were based on the estimated difference between the two treatment arms by visit. The model included treatment arm, region, CV history, visits and visit by treatment as categorical variables and baseline Hb and baseline eGFR as continuous variables.
    Comparison groups
    Roxadustat v Placebo
    Number of subjects included in analysis
    592
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001 [25]
    Method
    Mixed models analysis
    Parameter type
    Least squares mean difference
    Point estimate
    1.447
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.23
         upper limit
    1.67
    Notes
    [25] - LSM Difference p-value is for test of differences.
    Statistical analysis title
    Hb Change From BL to Week 28
    Statistical analysis description
    A Mixed Model of Repeated Measures was applied. The results were based on the estimated difference between the two treatment arms by visit. The model included treatment arm, region, CV history, visits and visit by treatment as categorical variables and baseline Hb and baseline eGFR as continuous variables.
    Comparison groups
    Roxadustat v Placebo
    Number of subjects included in analysis
    592
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001 [26]
    Method
    Mixed models analysis
    Parameter type
    Least squares mean difference
    Point estimate
    1.561
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.34
         upper limit
    1.78
    Notes
    [26] - LSM Difference p-value is for test of differences.
    Statistical analysis title
    Hb Change From BL to Week 32
    Statistical analysis description
    A Mixed Model of Repeated Measures was applied. The results were based on the estimated difference between the two treatment arms by visit. The model included treatment arm, region, CV history, visits and visit by treatment as categorical variables and baseline Hb and baseline eGFR as continuous variables.
    Comparison groups
    Roxadustat v Placebo
    Number of subjects included in analysis
    592
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001 [27]
    Method
    Mixed models analysis
    Parameter type
    Least squares mean difference
    Point estimate
    1.587
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.37
         upper limit
    1.81
    Notes
    [27] - LSM Difference p-value is for test of differences.
    Statistical analysis title
    Hb Change From BL to Week 36
    Statistical analysis description
    A Mixed Model of Repeated Measures was applied. The results were based on the estimated difference between the two treatment arms by visitl. The model included treatment arm, region, CV history, visits and visit by treatment as categorical variables and baseline Hb and baseline eGFR as continuous variables.
    Comparison groups
    Roxadustat v Placebo
    Number of subjects included in analysis
    592
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001 [28]
    Method
    Mixed models analysis
    Parameter type
    Least squares mean difference
    Point estimate
    1.69
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.46
         upper limit
    1.92
    Notes
    [28] - LSM Difference p-value is for test of differences.
    Statistical analysis title
    Hb Change From BL to Week 40
    Statistical analysis description
    A Mixed Model of Repeated Measures was applied. The results were based on the estimated difference between the two treatment arms by visit. The model included treatment arm, region, CV history, visits and visit by treatment as categorical variables and baseline Hb and baseline eGFR as continuous variables.
    Comparison groups
    Roxadustat v Placebo
    Number of subjects included in analysis
    592
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001 [29]
    Method
    Mixed models analysis
    Parameter type
    Least squares mean difference
    Point estimate
    1.645
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.41
         upper limit
    1.88
    Notes
    [29] - LSM Difference p-value is for test of differences.
    Statistical analysis title
    Hb Change From BL to Week 44
    Statistical analysis description
    A Mixed Model of Repeated Measures was applied. The results were based on the estimated difference between the two treatment arms by visit. The model included treatment arm, region, CV history, visits and visit by treatment as categorical variables and baseline Hb and baseline eGFR as continuous variables.
    Comparison groups
    Roxadustat v Placebo
    Number of subjects included in analysis
    592
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001 [30]
    Method
    Mixed models analysis
    Parameter type
    Least squares mean difference
    Point estimate
    1.699
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.45
         upper limit
    1.94
    Notes
    [30] - LSM Difference p-value is for test of differences.
    Statistical analysis title
    Hb Change From BL to Week 48
    Statistical analysis description
    A Mixed Model of Repeated Measures was applied. The results were based on the estimated difference between the two treatment arms by visit. The model included treatment arm, region, CV history, visits and visit by treatment as categorical variables and baseline Hb and baseline eGFR as continuous variables.
    Comparison groups
    Roxadustat v Placebo
    Number of subjects included in analysis
    592
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001 [31]
    Method
    Mixed models analysis
    Parameter type
    Least squares mean difference
    Point estimate
    1.446
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.2
         upper limit
    1.69
    Notes
    [31] - LSM Difference p-value is for test of differences.
    Statistical analysis title
    Hb Change From BL to Week 52
    Statistical analysis description
    A Mixed Model of Repeated Measures was applied. The results were based on the estimated difference between the two treatment arms by visit. The model included treatment arm, region, CV history, visits and visit by treatment as categorical variables and baseline Hb and baseline eGFR as continuous variables.
    Comparison groups
    Roxadustat v Placebo
    Number of subjects included in analysis
    592
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001 [32]
    Method
    Mixed models analysis
    Parameter type
    Least squares mean difference
    Point estimate
    1.641
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.39
         upper limit
    1.89
    Notes
    [32] - LSM Difference p-value is for test of differences.
    Statistical analysis title
    Hb Change From BL to Week 56
    Statistical analysis description
    A Mixed Model of Repeated Measures was applied. The results were based on the estimated difference between the two treatment arms by visit. The model included treatment arm, region, CV history, visits and visit by treatment as categorical variables and baseline Hb and baseline eGFR as continuous variables.
    Comparison groups
    Roxadustat v Placebo
    Number of subjects included in analysis
    592
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001 [33]
    Method
    Mixed models analysis
    Parameter type
    Least squares mean difference
    Point estimate
    1.64
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.37
         upper limit
    1.91
    Notes
    [33] - LSM Difference p-value is for test of differences.
    Statistical analysis title
    Hb Change From BL to Week 60
    Statistical analysis description
    A Mixed Model of Repeated Measures was applied. The results were based on the estimated difference between the two treatment arms by visit. The model included treatment arm, region, CV history, visits and visit by treatment as categorical variables and baseline Hb and baseline eGFR as continuous variables.
    Comparison groups
    Roxadustat v Placebo
    Number of subjects included in analysis
    592
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001 [34]
    Method
    Mixed models analysis
    Parameter type
    Least squares mean difference
    Point estimate
    1.634
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.33
         upper limit
    1.94
    Notes
    [34] - LSM Difference p-value is for test of differences.
    Statistical analysis title
    Hb Change From BL to Week 64
    Statistical analysis description
    A Mixed Model of Repeated Measures was applied. The results were based on the estimated difference between the two treatment arms by visit. The model included treatment arm, region, CV history, visits and visit by treatment as categorical variables and baseline Hb and baseline eGFR as continuous variables.
    Comparison groups
    Roxadustat v Placebo
    Number of subjects included in analysis
    592
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001 [35]
    Method
    Mixed models analysis
    Parameter type
    Least squares mean difference
    Point estimate
    1.404
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.08
         upper limit
    1.73
    Notes
    [35] - LSM Difference p-value is for test of differences.
    Statistical analysis title
    Hb Change From BL to Week 68
    Statistical analysis description
    A Mixed Model of Repeated Measures was applied. The results were based on the estimated difference between the two treatment arms by visit. The model included treatment arm, region, CV history, visits and visit by treatment as categorical variables and baseline Hb and baseline eGFR as continuous variables.
    Comparison groups
    Roxadustat v Placebo
    Number of subjects included in analysis
    592
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001 [36]
    Method
    Mixed models analysis
    Parameter type
    Least squares mean difference
    Point estimate
    1.499
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.18
         upper limit
    1.82
    Notes
    [36] - LSM Difference p-value is for test of differences.
    Statistical analysis title
    Hb Change From BL to Week 72
    Statistical analysis description
    A Mixed Model of Repeated Measures was applied. The results were based on the estimated difference between the two treatment arms by visit. The model included treatment arm, region, CV history, visits and visit by treatment as categorical variables and baseline Hb and baseline eGFR as continuous variables.
    Comparison groups
    Roxadustat v Placebo
    Number of subjects included in analysis
    592
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001 [37]
    Method
    Mixed models analysis
    Parameter type
    Least squares mean difference
    Point estimate
    1.438
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.1
         upper limit
    1.78
    Notes
    [37] - LSM Difference p-value is for test of differences.
    Statistical analysis title
    Hb Change From BL to Week 76
    Statistical analysis description
    A Mixed Model of Repeated Measures was applied. The results were based on the estimated difference between the two treatment arms by visit. The model included treatment arm, region, CV history, visits and visit by treatment as categorical variables and baseline Hb and baseline eGFR as continuous variables.
    Comparison groups
    Roxadustat v Placebo
    Number of subjects included in analysis
    592
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001 [38]
    Method
    Mixed models analysis
    Parameter type
    Least squares mean difference
    Point estimate
    1.185
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.83
         upper limit
    1.54
    Notes
    [38] - LSM Difference p-value is for test of differences.
    Statistical analysis title
    Hb Change From BL to Week 80
    Statistical analysis description
    A Mixed Model of Repeated Measures was applied. The results were based on the estimated difference between the two treatment arms by visit. The model included treatment arm, region, CV history, visits and visit by treatment as categorical variables and baseline Hb and baseline eGFR as continuous variables.
    Comparison groups
    Roxadustat v Placebo
    Number of subjects included in analysis
    592
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001 [39]
    Method
    Mixed models analysis
    Parameter type
    Least squares mean difference
    Point estimate
    1.443
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.11
         upper limit
    1.78
    Notes
    [39] - LSM Difference p-value is for test of differences.
    Statistical analysis title
    Hb Change From BL to Week 84
    Statistical analysis description
    A Mixed Model of Repeated Measures was applied. The results were based on the estimated difference between the two treatment arms by visit. The model included treatment arm, region, CV history, visits and visit by treatment as categorical variables and baseline Hb and baseline eGFR as continuous variables.
    Comparison groups
    Roxadustat v Placebo
    Number of subjects included in analysis
    592
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001 [40]
    Method
    Mixed models analysis
    Parameter type
    Least squares mean difference
    Point estimate
    1.374
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.99
         upper limit
    1.75
    Notes
    [40] - LSM Difference p-value is for test of differences.
    Statistical analysis title
    Hb Change From BL to Week 88
    Statistical analysis description
    A Mixed Model of Repeated Measures was applied. The results were based on the estimated difference between the two treatment arms by visit. The model included treatment arm, region, CV history, visits and visit by treatment as categorical variables and baseline Hb and baseline eGFR as continuous variables.
    Comparison groups
    Roxadustat v Placebo
    Number of subjects included in analysis
    592
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001 [41]
    Method
    Mixed models analysis
    Parameter type
    Least squares mean difference
    Point estimate
    1.171
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.79
         upper limit
    1.55
    Notes
    [41] - LSM Difference p-value is for test of differences.
    Statistical analysis title
    Hb Change From BL to Week 92
    Statistical analysis description
    A Mixed Model of Repeated Measures was applied. The results were based on the estimated difference between the two treatment arms by visit. The model included treatment arm, region, CV history, visits and visit by treatment as categorical variables and baseline Hb and baseline eGFR as continuous variables.
    Comparison groups
    Roxadustat v Placebo
    Number of subjects included in analysis
    592
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001 [42]
    Method
    Mixed models analysis
    Parameter type
    Least squares mean difference
    Point estimate
    1.382
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.98
         upper limit
    1.78
    Notes
    [42] - LSM Difference p-value is for test of differences.
    Statistical analysis title
    Hb Change From BL to Week 96
    Statistical analysis description
    A Mixed Model of Repeated Measures was applied. The results were based on the estimated difference between the two treatment arms by visit. The model included treatment arm, region, CV history, visits and visit by treatment as categorical variables and baseline Hb and baseline eGFR as continuous variables.
    Comparison groups
    Roxadustat v Placebo
    Number of subjects included in analysis
    592
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001 [43]
    Method
    Mixed models analysis
    Parameter type
    Least squares mean difference
    Point estimate
    1.563
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.15
         upper limit
    1.97
    Notes
    [43] - LSM Difference p-value is for test of differences.
    Statistical analysis title
    Hb Change From BL to Week 100
    Statistical analysis description
    A Mixed Model of Repeated Measures was applied. The results were based on the estimated difference between the two treatment arms by visit. The model included treatment arm, region, CV history, visits and visit by treatment as categorical variables and baseline Hb and baseline eGFR as continuous variables.
    Comparison groups
    Roxadustat v Placebo
    Number of subjects included in analysis
    592
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001 [44]
    Method
    Mixed models analysis
    Parameter type
    Least squares mean difference
    Point estimate
    1.448
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.06
         upper limit
    1.83
    Notes
    [44] - LSM Difference p-value is for test of differences.
    Statistical analysis title
    Hb Change From BL to Week 104
    Statistical analysis description
    A Mixed Model of Repeated Measures was applied. The results were based on the estimated difference between the two treatment arms by visit. The model included treatment arm, region, CV history, visits and visit by treatment as categorical variables and baseline Hb and baseline eGFR as continuous variables.
    Comparison groups
    Roxadustat v Placebo
    Number of subjects included in analysis
    592
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001 [45]
    Method
    Mixed models analysis
    Parameter type
    Least squares mean difference
    Point estimate
    1.347
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.9
         upper limit
    1.79
    Notes
    [45] - LSM Difference p-value is for test of differences.

    Secondary: Hb Change From BL to the Average Hb Value of Weeks 28-36 Regardless of the Use of Rescue Therapy

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    End point title
    Hb Change From BL to the Average Hb Value of Weeks 28-36 Regardless of the Use of Rescue Therapy
    End point description
    The Hb values from visit windows from weeks 28 to 36 were used for the calculation of the average regardless of rescue therapy. Baseline Hb was defined as the mean of four latest central laboratory Hb values prior or on the same date as first study drug intake (pre-dosing). The analysis population was the FAS, which consisted of all randomized participants who received at least one dose of study drug and had at least one post-dose Hb assessment.
    End point type
    Secondary
    End point timeframe
    Baseline and week 28 to 36
    End point values
    Roxadustat Placebo
    Number of subjects analysed
    312
    146
    Units: g/dl
        least squares mean (confidence interval 95%)
    2.013 (1.88 to 2.15)
    0.399 (0.22 to 0.58)
    Statistical analysis title
    Change From Baseline to Average Hb Weeks 28-36
    Statistical analysis description
    A Mixed Model of Repeated Measures was applied using the visits up to week 36. The results were based on the estimated difference between the two treatment arms overall mean effect during week 28 to 36 period based on this MMRM model. The model included treatment arm, region, CV history, visits and visit by treatment as categorical variables and baseline Hb and baseline eGFR as continuous variables.
    Comparison groups
    Roxadustat v Placebo
    Number of subjects included in analysis
    458
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001 [46]
    Method
    Mixed models analysis
    Parameter type
    Least squares mean difference
    Point estimate
    1.614
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.42
         upper limit
    1.81
    Notes
    [46] - LSM difference p-value is for test of differences.

    Secondary: Hb Change From BL to the Average Hb Value of Weeks 44-52 Regardless of the Use of Rescue Therapy

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    End point title
    Hb Change From BL to the Average Hb Value of Weeks 44-52 Regardless of the Use of Rescue Therapy
    End point description
    The Hb values from visit windows from weeks 44 to 52 were used for the calculation of the average regardless of rescue therapy. Baseline Hb was defined as the mean of four latest central laboratory Hb values prior or on the same date as first study drug intake (pre-dosing). The analysis population was the FAS, which consisted of all randomized participants who received at least one dose of study drug and had at least one post-dose Hb assessment.
    End point type
    Secondary
    End point timeframe
    Baseline and week 44 to 52
    End point values
    Roxadustat Placebo
    Number of subjects analysed
    291
    123
    Units: g/dl
        least squares mean (confidence interval 95%)
    1.886 (1.75 to 2.03)
    0.292 (0.10 to 0.48)
    Statistical analysis title
    Change From Baseline to Average Hb Weeks 44-52
    Statistical analysis description
    A Mixed Model of Repeated Measures was applied using the visits up to week 52. The results were based on the estimated difference between the two treatment arms overall mean effect during week 44 to 52 period based on this MMRM model. The model included treatment arm, region, CV history, visits and visit by treatment as categorical variables and baseline Hb and baseline eGFR as continuous variables.
    Comparison groups
    Roxadustat v Placebo
    Number of subjects included in analysis
    414
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001
    Method
    Mixed models analysis
    Parameter type
    Least squares mean difference
    Point estimate
    1.594
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.38
         upper limit
    1.81

    Secondary: Hb Change From BL to the Average Hb Value of Weeks 96-104 Regardless of the Use of Rescue Therapy

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    End point title
    Hb Change From BL to the Average Hb Value of Weeks 96-104 Regardless of the Use of Rescue Therapy
    End point description
    The Hb values from visit windows from weeks 96 to 104 were used for the calculation of the average regardless of rescue therapy. Baseline Hb was defined as the mean of four latest central laboratory Hb values prior or on the same date as first study drug intake (pre-dosing). The analysis population was the FAS, which consisted of all randomized participants who received at least one dose of study drug and had at least one post-dose Hb assessment.
    End point type
    Secondary
    End point timeframe
    Baseline and week 96 to 104
    End point values
    Roxadustat Placebo
    Number of subjects analysed
    124
    32
    Units: g/dl
        least squares mean (confidence interval 95%)
    1.779 (1.60 to 1.96)
    0.327 (0.01 to 0.64)
    Statistical analysis title
    Change From Baseline to Average Hb Weeks 96-104
    Statistical analysis description
    A Mixed Model of Repeated Measures was applied using the visits up to week 104. The results were based on the estimated difference between the two treatment arms overall mean effect during week 96 to 104 period based on this MMRM model. The model included treatment arm, region, CV history, visits and visit by treatment as categorical variables and baseline Hb and baseline eGFR as continuous variables.
    Comparison groups
    Roxadustat v Placebo
    Number of subjects included in analysis
    156
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001 [47]
    Method
    Mixed models analysis
    Parameter type
    Least squares mean difference
    Point estimate
    1.452
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.1
         upper limit
    1.8
    Notes
    [47] - LSM difference p-value is for test of differences.

    Secondary: Percentage of Hb Values Within 10.0-12.0 g/dL in Weeks 28-36 Without Use of Rescue Therapy

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    End point title
    Percentage of Hb Values Within 10.0-12.0 g/dL in Weeks 28-36 Without Use of Rescue Therapy
    End point description
    The percentage of Hb values measured during weeks 28-36 within 10.0 -12.0 g/dL, without having received rescue therapy within 6 weeks prior to and during the 8-week evaluation period is reported. The analysis population was the FAS, which consisted of all randomized participants who received at least one dose of study drug and had at least one post-dose Hb assessment.
    End point type
    Secondary
    End point timeframe
    Baseline and week 28 to 36
    End point values
    Roxadustat Placebo
    Number of subjects analysed
    311
    139
    Units: Percentage
        arithmetic mean (standard deviation)
    64.18 ± 32.90
    34.20 ± 39.47
    No statistical analyses for this end point

    Secondary: Percentage of Hb Values Within 10.0-12.0 g/dL in Weeks 44-52 Without Use of Rescue Therapy

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    End point title
    Percentage of Hb Values Within 10.0-12.0 g/dL in Weeks 44-52 Without Use of Rescue Therapy
    End point description
    The percentage of Hb values measured during weeks 44-52 with values within 10.0 - 12.0 g/dL, without having received rescue therapy within 6 weeks prior to and during the 8-week evaluation period is reported. The analysis population was the FAS, which consisted of all randomized participants who received at least one dose of study drug and had at least one post-dose Hb assessment.
    End point type
    Secondary
    End point timeframe
    Baseline and week 44 to 52
    End point values
    Roxadustat Placebo
    Number of subjects analysed
    287
    118
    Units: Percentage
        arithmetic mean (standard deviation)
    69.39 ± 32.47
    35.45 ± 41.75
    No statistical analyses for this end point

    Secondary: Percentage of Hb Values Within 10.0-12.0 g/dL in Weeks 96-104 Without Use of Rescue Therapy

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    End point title
    Percentage of Hb Values Within 10.0-12.0 g/dL in Weeks 96-104 Without Use of Rescue Therapy
    End point description
    The percentage of Hb values measured during weeks 96-104 within 10.0 -12.0 g/dL, without having received rescue therapy within 6 weeks prior to and during the 8-week evaluation period is reported. The analysis population was the FAS, which consisted of all randomized participants who received at least one dose of study drug and had at least one post-dose Hb assessment.
    End point type
    Secondary
    End point timeframe
    Baseline and week 96 to 104
    End point values
    Roxadustat Placebo
    Number of subjects analysed
    120
    32
    Units: Percentage
        arithmetic mean (standard deviation)
    64.65 ± 37.16
    40.63 ± 44.39
    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 was defined in years as the First event date during the Efficacy Emergent Period – (Analysis date of first dose intake +1)/365.25. The first event date was defined as the Date of first admission. The Efficacy Emergent Period was defined as the evaluation period from the analysis date of first dose intake up to 7 days after the analysis date of last dose or EOT visit, whichever occured first. Analysis date of first dose intake was defined as the date of first study drug intake collected on day 1 visit. For participants who experienced more than one hospitalization, only their first event following study treatment was used. Data analysis was completed using Kaplan-Meier estimate for cumulative proportion. Data for Year 2 roxadustat could not be calculated and is denoted as "99999" as applicable. The analysis population was the FAS.
    End point type
    Secondary
    End point timeframe
    Baseline up to week 104
    End point values
    Roxadustat Placebo
    Number of subjects analysed
    389
    203
    Units: Percentage
    number (confidence interval 95%)
        Year 0.5
    32.2 (27.3 to 37.0)
    39.8 (32.7 to 46.9)
        Year 1
    49.9 (44.6 to 55.2)
    49.3 (41.8 to 56.8)
        Year 1.5
    62.1 (56.3 to 67.9)
    64.0 (54.5 to 73.4)
        Year 2
    99999 (99999 to 99999)
    67.8 (57.9 to 77.7)
    Statistical analysis title
    Time to First Hospitalization
    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 Placebo
    Number of subjects included in analysis
    592
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.643
    Method
    Regression, Cox
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.945
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.74
         upper limit
    1.2

    Secondary: Number of Days of Hospitalization Per Patient Exposure Year (PEY)

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    End point title
    Number of Days of Hospitalization Per Patient Exposure Year (PEY)
    End point description
    The sum of the durations of all hospitalizations in days was adjusted for the duration of exposure. Derived only for participants with at least one hospitalization. The number of days of hospitalization per PEY was calculated as the sum of the durations of all hospitalizations in days [Minimum (Date of discharge, End of Efficacy Emergent Period) - Date of admission + 1] / [Duration of Efficacy Emergent Period in days / 365.25]. The analysis population was the FAS, which consisted of participants with hospitalizations. Participants can have more than one hospitalization.
    End point type
    Secondary
    End point timeframe
    Baseline up to week 104
    End point values
    Roxadustat Placebo
    Number of subjects analysed
    214
    101
    Units: Number of days per year
        arithmetic mean (standard deviation)
    26.479 ± 35.182
    31.928 ± 36.441
    No statistical analyses for this end point

    Secondary: Time to First Use of Rescue Therapy (Composite of Red Blood Cell (RBC) Transfusions, Erythropoiesis Stimulating Agent (ESA) Use, and Intravenous (IV) Iron) in the First 24 Weeks of Treatment

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    End point title
    Time to First Use of Rescue Therapy (Composite of Red Blood Cell (RBC) Transfusions, Erythropoiesis Stimulating Agent (ESA) Use, and Intravenous (IV) Iron) in the First 24 Weeks of Treatment
    End point description
    Time to first use of rescue therapy in years. Data analysis was completed using Kaplan-Meier estimate for cumulative proportion. The analysis population was the FAS, which consisted of all randomized participants who received at least one dose of study drug and had at least one post-dose Hb assessment.
    End point type
    Secondary
    End point timeframe
    Baseline up to week 24
    End point values
    Roxadustat Placebo
    Number of subjects analysed
    389
    203
    Units: Percentage
    number (confidence interval 95%)
        Week 6
    0.8 (0.0 to 1.7)
    6.0 (2.7 to 9.3)
        Week 12
    2.5 (0.9 to 4.1)
    15.8 (10.7 to 20.9)
        Week 18
    3.3 (1.5 to 5.2)
    25.3 (19.2 to 31.5)
        Week 24
    5.5 (3.1 to 7.9)
    32.1 (25.4 to 38.7)
    Statistical analysis title
    Time to Start Rescue Therapy Within First 24 Weeks
    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 Placebo
    Number of subjects included in analysis
    592
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001
    Method
    Regression, Cox
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.139
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.08
         upper limit
    0.23

    Secondary: Time to First Use of RBC Transfusions

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    End point title
    Time to First Use of RBC Transfusions
    End point description
    Time to First Use of RBC Transfusions during efficacy emergent period. For participants who have experienced more than one RBC transfusion, only their first event following study treatment was used. The efficacy emergent period was defined as the evaluation period from the analysis date of first dose intake up to 7 days after the analysis date of last dose or EOT visit, whichever occurred first. Data analysis was completed using Kaplan-Meier estimate for cumulative proportion. The analysis population was the FAS, which consisted of all randomized participants who received at least one dose of study drug and had at least one post-dose Hb assessment.
    End point type
    Secondary
    End point timeframe
    Baseline to week 104
    End point values
    Roxadustat Placebo
    Number of subjects analysed
    389
    203
    Units: Percentage
    number (confidence interval 95%)
        Year 0.5
    2.9 (1.1 to 4.7)
    15.2 (10.1 to 20.4)
        Year 1
    5.6 (3.0 to 8.1)
    20.2 (14.2 to 26.2)
        Year 1.5
    12.1 (7.7 to 16.5)
    21.8 (15.1 to 28.5)
        Year 2
    15.0 (9.9 to 20.1)
    27.0 (17.7 to 36.4)
    Statistical analysis title
    Time To First Use of RBS Transfusions
    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 Placebo
    Number of subjects included in analysis
    592
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001
    Method
    Regression, Cox
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.343
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.21
         upper limit
    0.55

    Secondary: Mean Monthly Number of RBC Packs

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    End point title
    Mean Monthly Number of RBC Packs
    End point description
    During efficacy emergent period, the mean monthly number of RBC packs was calculated as the sum of units transfused between the first dose and up to the last dose in the period divided by duration of efficacy emergent period (in days) divided by 28 days. The efficacy emergent period was defined as the evaluation period from the analysis date of first dose intake up to 7 days after the analysis date of last dose or EOT visit, whichever occured first. In case of missing number of packs, values were estimated based on 1 unit for packed cells = 250 mL or 1 unit for whole blood = 500 mL. Participants without RBC transfusion were included with a value of zero. No estimation if values were missing. The analysis population was the FAS, which consisted of all randomized participants who received at least one dose of study drug and had at least one post-dose Hb assessment.
    End point type
    Secondary
    End point timeframe
    Baseline to week 104
    End point values
    Roxadustat Placebo
    Number of subjects analysed
    389
    203
    Units: RBC Packs per 28 days
        arithmetic mean (standard deviation)
    0.041 ± 0.397
    0.089 ± 0.243
    Statistical analysis title
    Mean Monthly Number of RBC Packs
    Statistical analysis description
    The Analysis of Covariance (ANCOVA) model was applied including treatment as fixed factor, region and history of CV disease as class factors and baseline Hb, baseline eGFR as continuous covariates.
    Comparison groups
    Roxadustat v Placebo
    Number of subjects included in analysis
    592
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.128
    Method
    ANCOVA
    Parameter type
    Least squares mean difference
    Point estimate
    -0.045
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.1
         upper limit
    0.01

    Secondary: Mean Monthly Volume of Blood transfused

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    End point title
    Mean Monthly Volume of Blood transfused
    End point description
    During efficacy emergent period, the mean monthly volume of blood transfused was calculated as the sum of blood volume transfused between the first dose and up to the la st dose in the period divide d by duration of efficacy emergent period (in days) divide d by 28 days. The efficacy emergent period was define d a s the evaluation period from the analysis date of first dose intake up to 7 days after the analysis date of last dose or EOT visit, which ever occurred first. The mean monthly volume transfused was calculated as the sum of the volume transfused between the first dose and up to the last dose in the period divided by duration (in days) and multiplied by 28 days. Participants without RBC transfusion were included with a value of zero. The analysis population was the FAS, which consisted of all randomized participants who received at least one dose of study drug and had at least one post-dose Hb assessment.
    End point type
    Secondary
    End point timeframe
    Baseline to week 104
    End point values
    Roxadustat Placebo
    Number of subjects analysed
    389
    203
    Units: Milliliters (ml) per 28 days
        arithmetic mean (standard deviation)
    11.331 ± 106.624
    22.596 ± 60.666
    Statistical analysis title
    Mean Monthly Volume of Blood Transfused
    Statistical analysis description
    The Analysis of Covariance (ANCOVA) model was applied included treatment arm, region, CV history as categorical variables and baseline Hb and baseline eGFR as continuous variables.
    Comparison groups
    Roxadustat v Placebo
    Number of subjects included in analysis
    592
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.183
    Method
    ANCOVA
    Parameter type
    Least squares mean difference
    Point estimate
    -10.429
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -25.81
         upper limit
    4.95

    Secondary: Time to First Use of ESA Rescue Therapy

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    End point title
    Time to First Use of ESA Rescue Therapy
    End point description
    Time to First Use of ESA Rescue Therapy during efficacy emergent period. For participants with use of ESA, the time to first use of ESA was calculated as (First event date – Analysis date of first dose intake + 1) / 365.25. The efficacy emergent period was defined as the evaluation period from the analysis date of first dose intake up to 7 days after the analysis date of last dose or EOT visit, whichever occurred first. Data analysis was completed using Kaplan-Meier estimate for cumulative proportion. Participants without ESA rescue were censored at the end of treatment. The analysis population was the FAS, which consisted of all randomized participants who received at least one dose of study drug and had at least one post-dose Hb assessment.
    End point type
    Secondary
    End point timeframe
    Baseline to week 104
    End point values
    Roxadustat Placebo
    Number of subjects analysed
    389
    203
    Units: Percentage
    number (confidence interval 95%)
        Year 0.5
    1.8 (0.4 to 3.2)
    20.4 (14.5 to 26.3)
        Year 1
    4.8 (2.4 to 7.2)
    36.4 (28.9 to 43.9)
        Year 1.5
    6.0 (3.1 to 8.9)
    42.3 (33.9 to 50.8)
        Year 2
    6.7 (3.5 to 9.9)
    42.3 (33.9 to 50.8)
    Statistical analysis title
    Time to First Use of ESA Rescue Therapy
    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 Placebo
    Number of subjects included in analysis
    592
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001
    Method
    Regression, Cox
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.101
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.06
         upper limit
    0.17

    Secondary: Time to First Use of IV Iron

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    End point title
    Time to First Use of IV Iron
    End point description
    Time to first use of IV iron during efficacy emergent period in years. For participants with use of IV iron, the time to first use of IV iron was calculated as (First event date – Analysis date of first dose intake + 1) / 365.25. The efficacy emergent period was defined as the evaluation period from the analysis date of first dose intake up to 7 days after the analysis date of last dose or EOT visit, whichever occurred first. Data analysis was completed using Kaplan-Meier estimate for cumulative proportion. The analysis population was the FAS, which consisted of all randomized participants who received at least one dose of study drug and had at least one post-dose Hb assessment.
    End point type
    Secondary
    End point timeframe
    Baseline to week 104
    End point values
    Roxadustat Placebo
    Number of subjects analysed
    389
    203
    Units: Percentage
    number (confidence interval 95%)
        Year 0.5
    2.3 (0.7 to 3.9)
    6.2 (2.7 to 9.8)
        Year 1
    5.3 (2.8 to 7.8)
    9.4 (4.8 to 14.0)
        Year 1.5
    7.5 (4.3 to 10.7)
    10.7 (5.5 to 15.9)
        Year 2
    10.6 (6.3 to 14.8)
    19.1 (8.8 to 29.5)
    Statistical analysis title
    Time to First Use of IV Iron Supplementation
    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 Placebo
    Number of subjects included in analysis
    592
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.045
    Method
    Regression, Cox
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.538
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.29
         upper limit
    0.99

    Secondary: Change From BL to Each Post-Dosing Visit in Total Cholesterol

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    End point title
    Change From BL to Each Post-Dosing Visit in Total Cholesterol
    End point description
    Change from baseline to each planned assessment for total cholesterol is reported. Baseline was defined as the value on day 1. If the value was missing, the latest value prior to first study drug administration was used. N is the number of participants with available data at each time point. The analysis population was the FAS, which consisted of all randomized participants who received at least one dose of study drug and had at least one post-dose Hb assessment.
    End point type
    Secondary
    End point timeframe
    Baseline and weeks 4,8,12,20,28,36,44,52,68,84,104
    End point values
    Roxadustat Placebo
    Number of subjects analysed
    389
    203
    Units: mmol/L
    arithmetic mean (standard deviation)
        Week 4 [N=368,194]
    -1.151 ± 1.058
    0.108 ± 0.842
        Week 8 [N=348,191]
    -1.066 ± 1.086
    0.048 ± 0.932
        Week 12 [N=342,185]
    -0.836 ± 1.173
    0.088 ± 1.116
        Week 20 [N=323,167]
    -0.747 ± 1.227
    0.193 ± 1.129
        Week 28 [N=310,149]
    -0.816 ± 1.284
    0.201 ± 1.271
        Week 36 [N=295,133]
    -0.803 ± 1.300
    0.183 ± 1.174
        Week 44 [N=285,126]
    -0.854 ± 1.238
    0.077 ± 1.346
        Week 52 [N=278,120]
    -0.815 ± 1.314
    0.104 ± 1.304
        Week 68 [N=197,67]
    -0.971 ± 1.382
    0.188 ± 1.222
        Week 84 [N=154,43]
    -1.055 ± 1.554
    0.102 ± 1.284
        Week 104 [N=123,32]
    -0.944 ± 1.584
    0.218 ± 1.067
    No statistical analyses for this end point

    Secondary: Change From BL to Each Post-Dosing Visit in Low Density Lipoprotein (LDL)/High-Density Lipoprotein (HDL) Ratio

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    End point title
    Change From BL to Each Post-Dosing Visit in Low Density Lipoprotein (LDL)/High-Density Lipoprotein (HDL) Ratio
    End point description
    Change from baseline to each planned assessment for LDL/HDL ratio is reported. Baseline was defined as the value on Day 1. If this value was missing, the latest value prior to first study drug administration was used. N is the number of participants with available data at each time point. The analysis population was the FAS, which consisted of all randomized participants who received at least one dose of study drug and had at least one post-dose Hb assessment.
    End point type
    Secondary
    End point timeframe
    Baseline and weeks 4,8,12,20,28,36,44,52,68,84,104
    End point values
    Roxadustat Placebo
    Number of subjects analysed
    389
    203
    Units: Ratio
    arithmetic mean (standard deviation)
        Week 4 [N=367,193]
    -0.331 ± 0.777
    0.076 ± 0.635
        Week 8 [N=347,190]
    -0.374 ± 0.952
    0.068 ± 0.685
        Week 12 [N=341,185]
    -0.268 ± 0.905
    0.081 ± 0.915
        Week 20 [N=322,166]
    -0.250 ± 1.024
    0.155 ± 0.788
        Week 28 [N=309,149]
    -0.313 ± 1.057
    0.156 ± 0.861
        Week 36 [N=293,133]
    -0.349 ± 1.040
    0.157 ± 1.053
        Week 44 [N=283,126]
    -0.368 ± 1.099
    0.099 ± 1.198
        Week 52 [N=277,120]
    -0.429 ± 1.125
    0.019 ± 1.076
        Week 68 [N=196,67]
    -0.466 ± 1.219
    0.052 ± 0.955
        Week 84 [N=154,43]
    -0.509 ± 1.307
    0.114 ± 1.113
        Week 104 [N=122,32]
    -0.414 ± 1.306
    0.105 ± 0.873
    No statistical analyses for this end point

    Secondary: Change From BL to Each Post-Dosing Visit in Non-HDL Cholesterol

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    End point title
    Change From BL to Each Post-Dosing Visit in Non-HDL Cholesterol
    End point description
    Change from baseline to each planned assessment for non-HDL is reported. Baseline was defined as the value on day 1. If this value was missing, the latest value prior to first study drug administration was used. N is the number of participants with available data at each time point. The analysis population was the FAS, which consisted of all randomized participants who received at least one dose of study drug and had at least one post-dose Hb assessment.
    End point type
    Secondary
    End point timeframe
    Baseline and weeks 4,8,12,20,28,36,44,52,68,84,104
    End point values
    Roxadustat Placebo
    Number of subjects analysed
    389
    203
    Units: mmol/L
    arithmetic mean (standard deviation)
        Week 4 [N=367,193]
    -0.969 ± 0.989
    0.118 ± 0.789
        Week 8 [N=347,190]
    -0.909 ± 1.064
    0.070 ± 0.864
        Week 12 [N=341,185]
    -0.709 ± 1.107
    0.078 ± 1.050
        Week 20 [N=322,166]
    -0.638 ± 1.175
    0.186 ± 1.072
        Week 28 [N=309,149]
    -0.710 ± 1.227
    0.206 ± 1.227
        Week 36 [N=293,133]
    -0.711 ± 1.239
    0.202 ± 1.133
        Week 44 [N=283,125]
    -0.751 ± 1.190
    0.106 ± 1.342
        Week 52 [N=277,120]
    -0.751 ± 1.276
    0.104 ± 1.299
        Week 68 [N=196,67]
    -0.882 ± 1.325
    0.174 ± 1.187
        Week 84 [N=154,43]
    -0.939 ± 1.518
    0.089 ± 1.343
        Week 104 [N=123,32]
    -0.839 ± 1.554
    0.174 ± 1.014
    No statistical analyses for this end point

    Secondary: Change From BL to Each Post-Dosing Visit in Apolipoproteins A1

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    End point title
    Change From BL to Each Post-Dosing Visit in Apolipoproteins A1
    End point description
    Change from baseline to each planned assessment for apolipoproteins A1 is reported. N is the number of participants with available data at each time point. The analysis population was the FAS, which consisted of all randomized participants who received at least one dose of study drug and had at least one post-dose Hb assessment.
    End point type
    Secondary
    End point timeframe
    Baseline and weeks 4,8,12,20,28,36,44,52,68,84,104
    End point values
    Roxadustat Placebo
    Number of subjects analysed
    389
    203
    Units: g/L
    arithmetic mean (standard deviation)
        Apolipoprotein A1 Week 4 [N=183,102]
    -0.168 ± 0.232
    0.013 ± 0.190
        Apolipoprotein A1 Week 8 [N=174,102]
    -0.148 ± 0.229
    0.008 ± 0.227
        Apolipoprotein A1 Week 12 [N=170,97]
    -0.072 ± 0.723
    0.004 ± 0.203
        Apolipoprotein A1 Week 20 [N=158,90]
    -0.114 ± 0.245
    0.036 ± 0.222
        Apolipoprotein A1 Week 28 [N=134,67]
    -0.104 ± 0.265
    0.006 ± 0.233
        Apolipoprotein A1 Week 36 [N=149,77]
    -0.101 ± 0.252
    0.002 ± 0.223
        Apolipoprotein A1 Week 44 [N=140,72]
    -0.135 ± 0.259
    -0.013 ± 0.268
        Apolipoprotein A1 Week 52 [N=139,71]
    -0.090 ± 0.260
    -0.028 ± 0.248
        Apolipoprotein A1 Week 68 [N=63,28]
    -0.157 ± 0.310
    0.018 ± 0.204
        Apolipoprotein A1 Week 84 [N=30,12]
    -0.132 ± 0.282
    0.060 ± 0.196
        Apolipoprotein A1 Week 104 [N=12,4]
    -0.098 ± 0.227
    0.070 ± 0.136
    No statistical analyses for this end point

    Secondary: Change From BL to Each Post-Dosing Visit in Apolipoproteins B

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    End point title
    Change From BL to Each Post-Dosing Visit in Apolipoproteins B
    End point description
    Change from baseline to each planned assessment for apolipoproteins B is reported. N is the number of participants with available data at each time point. The analysis population was the FAS, which consisted of all randomized participants who received at least one dose of study drug and had at least one post-dose Hb assessment.
    End point type
    Secondary
    End point timeframe
    Baseline and weeks 4,8,12,20,28,36,44,52,68,84,104
    End point values
    Roxadustat Placebo
    Number of subjects analysed
    389
    203
    Units: mg/dL
    arithmetic mean (standard deviation)
        Apolipoproteins B Week 4 [N=183,102]
    -19.891 ± 20.669
    2.059 ± 22.220
        Apolipoproteins B Week 8 [N=174,102]
    -19.483 ± 21.009
    2.059 ± 20.297
        Apolipoproteins B Week 12 [N=170,97]
    -14.935 ± 24.613
    0.278 ± 21.707
        Apolipoproteins B Week 20 [N=158,90]
    -12.709 ± 24.424
    5.711 ± 25.883
        Apolipoproteins B Week 28 [N=133,67]
    -13.782 ± 28.634
    9.746 ± 26.864
        Apolipoproteins B Week 36 [N=149,77]
    -14.866 ± 25.469
    6.623 ± 25.895
        Apolipoproteins B Week 44 [N=140,72]
    -15.593 ± 26.594
    3.222 ± 30.771
        Apolipoproteins B Week 52 [N=139,71]
    -14.122 ± 27.503
    4.676 ± 31.440
        Apolipoproteins B Week 68 [N=63,28]
    -18.746 ± 28.633
    2.786 ± 28.900
        Apolipoproteins B Week 84 [N=30,12]
    -20.133 ± 28.134
    12.500 ± 32.152
        Apolipoproteins B Week 104 [N=12,4]
    -10.917 ± 22.885
    14.750 ± 20.271
    No statistical analyses for this end point

    Secondary: Change From BL to Each Post-Dosing Visit in Ratio Apolipoprotein ApoB/ApoA1

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    End point title
    Change From BL to Each Post-Dosing Visit in Ratio Apolipoprotein ApoB/ApoA1
    End point description
    Change from baseline to each planned assessment for ratio ApoB/ApoA1 is reported. Baseline was defined as the value on day 1. If this value was missing, the latest value prior to first study drug administration was used. N is the number of participants with available data at each time point. The analysis population was the FAS, which consisted of all randomized participants who received at least one dose of study drug and had at least one post-dose Hb assessment.
    End point type
    Secondary
    End point timeframe
    Baseline and weeks 4,8,12,20,28,36,44,52,68,84,104
    End point values
    Roxadustat Placebo
    Number of subjects analysed
    389
    203
    Units: Ratio
    arithmetic mean (standard deviation)
        Week 4 [N=183,101]
    -0.073 ± 0.165
    0.010 ± 0.169
        Week 8 [N=172,101]
    -0.084 ± 0.202
    0.000 ± 0.184
        Week 12 [N=169,96]
    -0.059 ± 0.164
    -0.006 ± 0.201
        Week 20 [N=158,89]
    -0.043 ± 0.189
    0.009 ± 0.198
        Week 28 [N=133,66]
    -0.066 ± 0.222
    0.063 ± 0.205
        Week 36 [N=149,76]
    -0.070 ± 0.200
    0.045 ± 0.213
        Week 44 [N=140,71]
    -0.053 ± 0.220
    0.031 ± 0.265
        Week 52 [N=137,70]
    -0.065 ± 0.207
    0.047 ± 0.266
        Week 68 [N=63,28]
    -0.086 ± 0.212
    0.001 ± 0.184
        Week 84 [N=29,12]
    -0.066 ± 0.210
    0.058 ± 0.295
        Week 104 [N=12,4]
    -0.024 ± 0.126
    0.085 ± 0.132
    No statistical analyses for this end point

    Secondary: Percentage of Participants With Mean LDL Cholesterol <100 mg/dL Calculated Over Weeks 12 to 28

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    End point title
    Percentage of Participants With Mean LDL Cholesterol <100 mg/dL Calculated Over Weeks 12 to 28
    End point description
    Mean LDL cholesterol <100 mg/dL over weeks 12 to 28 was defined as a binary variable (Yes/No), where Yes was defined as mean LDL cholesterol <100 mg/dL over weeks 12 to 28. Participants without any LDL value within this duration were excluded. The analysis population was the FAS, which consisted of all randomized participants who received at least one dose of study drug and had at least one post-dose Hb assessment.
    End point type
    Secondary
    End point timeframe
    Weeks 12-28
    End point values
    Roxadustat Placebo
    Number of subjects analysed
    389
    203
    Units: Percentage of Participants
    number (not applicable)
        Yes (Regardless of fasting status)
    62.9
    41.1
        No (Regardless of fasting status)
    37.1
    58.9
    No statistical analyses for this end point

    Secondary: Percentage of Participants Who Have Achieved Antihypertensive Treatment Goal in CKD Participants Over Weeks 12-28

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    End point title
    Percentage of Participants Who Have Achieved Antihypertensive Treatment Goal in CKD Participants Over Weeks 12-28
    End point description
    Occurrence of achieved antihypertensive treatment goal was defined as the average SBP < 130 mmHg and the average DBP < 80 mmHg over the period of weeks 12-28. Participants without any blood pressure measurement were excluded. The analysis population was the FAS, which consisted of all randomized participants who received at least one dose of study drug and had at least one post-dose Hb assessment.
    End point type
    Secondary
    End point timeframe
    Weeks 12-28
    End point values
    Roxadustat Placebo
    Number of subjects analysed
    389
    203
    Units: Percentage of Participants
    number (not applicable)
        Yes
    25.6
    28.0
        No
    74.4
    72.0
    No statistical analyses for this end point

    Secondary: Change From BL to the Average Value of Weeks 12-28 in Quality of Life (QoL) SF-36 Physical Component Score (PCS)

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    End point title
    Change From BL to the Average Value of Weeks 12-28 in Quality of Life (QoL) SF-36 Physical Component Score (PCS)
    End point description
    The 36-Item short-form health survey (SF-36) is a multi-purpose survey with 36 questions. It provides an 8-scale profile of functional health and well-being scores as well as psychometrically-based physical and mental health summary measures. For each scale scores range from 0-100. The physical component score was calculated based on the results of the SF-36 scores. Higher scores indicate better health status. The analysis population was the FAS, which consisted of all randomized participants who received at least one dose of study drug and had at least one post-dose Hb assessment.
    End point type
    Secondary
    End point timeframe
    Baseline and weeks 12-28
    End point values
    Roxadustat Placebo
    Number of subjects analysed
    340
    185
    Units: Units on a Scale
        least squares mean (confidence interval 95%)
    1.842 (0.88 to 2.80)
    1.468 (0.34 to 2.59)
    Statistical analysis title
    Change from Baseline to Weeks 12-28 SF-36 PCS
    Statistical analysis description
    The Mixed Model of Repeated Measures included treatment, visit (week 8, week 12 and week 28), visit by treatment interaction, region and history of CV disease as fixed class factors and baseline SF-36 PCS, baseline Hb, baseline eGFR as continuous covariates.
    Comparison groups
    Roxadustat v Placebo
    Number of subjects included in analysis
    525
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.475
    Method
    Mixed models analysis
    Parameter type
    Least squares mean difference
    Point estimate
    0.374
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.65
         upper limit
    1.4

    Secondary: Change From BL to the Average Value of Weeks 12-28 in Anemia Subscale (Ans) of Functional Assessment of Cancer Therapy (FACT-An) Score

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    End point title
    Change From BL to the Average Value of Weeks 12-28 in Anemia Subscale (Ans) of Functional Assessment of Cancer Therapy (FACT-An) Score
    End point description
    The functional assessment of cancer therapy general (FACT-G) Version 4 contains 27 items that cover four dimensions of well-being: physical (PWB)—7 items, functional (FWB)—7 items, social/family (SWB)—7 items each, and emotional (EWB)—6 items. A subscale of 13 fatigue specific items (the Fatigue Subscale) plus seven additional items related to anemia were developed for use in conjunction with the FACT-G. The 13 fatigue items plus the seven additional items related to anemia comprise the Anemia Subscale (AnS). Administration of the FACT-G plus the AnS is referred to as the FACT-An. Respondents are asked to provide responses, (i.e., ‘Not at all’, ‘A little bit’, ‘Somewhat’, ‘Quite a bit’ and ‘Very much’), to a list of statements which are either positively or negatively phrased. For all FACT-An scales, a higher score indicates better QoL. The analysis population was the FAS.
    End point type
    Secondary
    End point timeframe
    Baseline and weeks 12-28
    End point values
    Roxadustat Placebo
    Number of subjects analysed
    339
    185
    Units: Units on a Scale
        least squares mean (confidence interval 95%)
    4.470 (2.86 to 6.08)
    2.766 (0.91 to 4.62)
    Statistical analysis title
    FACT-An Ans Change from Baseline to Weeks 12-28
    Statistical analysis description
    A Mixed Model of Repeated Measures was applied using the visits up to week 28. The model includes treatment, visit (week 8, week 12 and week 28), visit by treatment interaction, region and history of CV disease as fixed class factors and baseline FACT-An Ans, baseline Hb, baseline eGFR as continuous covariates. Baseline FACT-An Ans is defined as the FACT-An Ans value on day 1.
    Comparison groups
    Roxadustat v Placebo
    Number of subjects included in analysis
    524
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.047 [48]
    Method
    Mixed models analysis
    Parameter type
    Least squares mean difference
    Point estimate
    1.704
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.02
         upper limit
    3.38
    Notes
    [48] - LSM difference p-value is for test of differences

    Secondary: Change From BL to the Average Value of Weeks 12-28 in Total FACT-An Score

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    End point title
    Change From BL to the Average Value of Weeks 12-28 in Total FACT-An Score
    End point description
    FACT-An Total Score consist of 27 items that cover four dimensions of well-being: physical (PWB) – 7 items, functional (FWB) – 7 items, social/family (SWB) – 7 items, and emotional (EWB) – 6 items and Anemia Subscale (AnS). Respondents were asked to provide responses, (Not at all, A little bit, Somewhat, Quite a bit and Very much), to a list of statements which were either positively or negatively phrased. Each individual item was scored from 0 (Not at all) to 4 (Very much), and then the total score was obtained by summation of the resulted scores. A final higher score indicates better QoL. The analysis population was the FAS, which consisted of all randomized participants who received at least one dose of study drug and had at least one post-dose Hb assessment.
    End point type
    Secondary
    End point timeframe
    Baseline and weeks 12-28
    End point values
    Roxadustat Placebo
    Number of subjects analysed
    338
    185
    Units: Units on a Scale
        least squares mean (confidence interval 95%)
    5.777 (2.60 to 8.95)
    3.691 (0.01 to 7.37)
    Statistical analysis title
    Total FACT-An Score Change from BL to Average
    Statistical analysis description
    A Mixed Model of Repeated Measures was applied using the visits up to week 28. The results were based on the estimated difference between the two treatment arms overall mean effect during week 12 to 28 period based on this MMRM model.The model includes treatment, visit (week8, week12 and week28), visit by treatment interaction, region and history of CV disease as fixed class factors and baseline FACT-An Total Score, baseline Hb, baseline eGFR as continuous covariates.
    Comparison groups
    Roxadustat v Placebo
    Number of subjects included in analysis
    523
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.225
    Method
    Mixed models analysis
    Parameter type
    Least squares mean difference
    Point estimate
    2.086
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.29
         upper limit
    5.46

    Secondary: Change From BL to the Average Value of Weeks 12-28 The Euroqol Questionnaire – 5 Dimensions 5 Levels (EQ-5D 5L) Visual Analogue Scale (VAS) Score

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    End point title
    Change From BL to the Average Value of Weeks 12-28 The Euroqol Questionnaire – 5 Dimensions 5 Levels (EQ-5D 5L) Visual Analogue Scale (VAS) Score
    End point description
    The Euroqol Questionnaire – 5 Dimensions 5 Levels (EQ-5D 5L) is a self-reported questionnaire. The EQ-5D is used as a measure of respondents' Health Related Quality of Life (HRQoL). The EQ- 5D consists of the EQ-5D descriptive system and the EQ visual analogue scale (VAS). The EQ-5D descriptive system comprises of 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 answers are labeled ‘Best imaginable health state’ and ‘Worst imaginable health state’ with higher scores for higher HRQoL. The analysis population was the FAS, which consisted of all randomized participants who received at least one dose of study drug and had at least one post-dose Hb assessment.
    End point type
    Secondary
    End point timeframe
    Baseline and weeks 12-28
    End point values
    Roxadustat Placebo
    Number of subjects analysed
    340
    184
    Units: Units on a Scale
    arithmetic mean (standard deviation)
        Average in week 12-28
    5.390 ± 17.278
    0.990 ± 15.859
    No statistical analyses for this end point

    Secondary: Change From BL to the Average Value of Weeks 12-28 in Work Productivity and Activity Impairment:Anemic Symptoms (WPAI:ANS)

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    End point title
    Change From BL to the Average Value of Weeks 12-28 in Work Productivity and Activity Impairment:Anemic Symptoms (WPAI:ANS)
    End point description
    Work productivity and activity impairment:anemic symptoms (WPAI:ANS) questionnaire version 2 was used to measure work and activity impairment during the last seven days due to anemia. It is self-assessed questionnaire which consists of 2 domains and 6 questions covering work and daily activities. Questions include asking if participant is working, how many hours the person missed work due to anemic symptoms, how many hours participant actually worked and how the anemic symptoms impacted their productivity and ability to do daily activities. WPAI:ANS was scored from 0-10 with 0 identifying low impact and 10 highest impact on the work activities. Work time missed due to anaemic symptoms was calculated as 100 x Q2/(Q2+Q4). Overall work impairment due to anaemic symptoms was calculated as 100 x Q2/(Q2+Q4)+[(1-Q2/(Q2+Q4))x(Q5/10)]. N is the number of participants with available data at each time point. The analysis population was the FAS.
    End point type
    Secondary
    End point timeframe
    Baseline and weeks 12 and 28
    End point values
    Roxadustat Placebo
    Number of subjects analysed
    389
    203
    Units: Units on a Scale
    arithmetic mean (standard deviation)
        Work time missed due to ANS [N=49,27]
    -4.688 ± 23.927
    -0.431 ± 30.738
        Impairment at work due to ANS [N=51,27]
    -4.359 ± 25.964
    7.963 ± 28.998
    No statistical analyses for this end point

    Secondary: Percentage of Participants in Each Category in Patients’ Global Impression of Change (PGIC)

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    End point title
    Percentage of Participants in Each Category in Patients’ Global Impression of Change (PGIC)
    End point description
    The Patients' Global Impression of Change (PGIC) is a participant rated instrument that measures change in participants overall status on a 7-point scale ranging from 1 (very much improved) t0 7 (very much worse).' The analysis population was the FAS, which consisted of all randomized participants who received at least one dose of study drug and had at least one post-dose Hb assessment.
    End point type
    Secondary
    End point timeframe
    Weeks 12 and 28
    End point values
    Roxadustat Placebo
    Number of subjects analysed
    389
    203
    Units: Percentage of Participants
    number (not applicable)
        Week 12 [Very much improved + Much improved]
    41.2
    18.9
        Week 28 [Very much improved + Much improved]
    46.4
    28.6
    No statistical analyses for this end point

    Secondary: Change From BL to Each Study Visit in Serum Hepcidin

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    End point title
    Change From BL to Each Study Visit in Serum Hepcidin
    End point description
    In case of missing data, no imputation rules were applied. N is the number of participants with available data at each time point. The analysis population was the FAS, which consisted of all randomized participants who received at least one dose of study drug and had at least one post-dose Hb assessment.
    End point type
    Secondary
    End point timeframe
    Baseline and weeks 4,12,20,36,52,104
    End point values
    Roxadustat Placebo
    Number of subjects analysed
    389
    203
    Units: ug/L
    arithmetic mean (standard deviation)
        Week 4 [N=345,182]
    -19.835 ± 29.765
    1.748 ± 35.368
        Week 12 [N=323,171]
    -17.369 ± 31.572
    0.971 ± 33.952
        Week 20 [N=303,148]
    -10.684 ± 35.858
    -1.879 ± 30.661
        Week 36 [N=218,98]
    -12.981 ± 32.351
    0.803 ± 39.816
        Week 52 [N=268,114]
    -12.274 ± 37.445
    2.025 ± 40.678
        Week 104 [N=108,28]
    -10.051 ± 33.671
    -7.436 ± 22.923
    No statistical analyses for this end point

    Secondary: Change From BL to Each Study Visit in Serum Ferritin

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    End point title
    Change From BL to Each Study Visit in Serum Ferritin
    End point description
    In case of missing data, no imputation rules were applied. N is the number of participants with available data at each time point. The analysis population was the FAS, which consisted of all randomized participants who received at least one dose of study drug and had at least one post-dose Hb assessment.
    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
    End point values
    Roxadustat Placebo
    Number of subjects analysed
    389
    203
    Units: pmol/L
    arithmetic mean (standard deviation)
        Week 4 [N=360,192]
    -221.827 ± 248.902
    11.564 ± 335.096
        Week 8 [N=346,191]
    -247.955 ± 295.920
    -8.004 ± 252.615
        Week 12 [N=337,179]
    -265.818 ± 318.445
    -31.548 ± 257.410
        Week 20 [N=318,154]
    -198.349 ± 284.015
    -32.561 ± 320.382
        Week 28 [N=308,146]
    -184.501 ± 341.114
    -5.123 ± 470.691
        Week 36 [N=295,132]
    -142.876 ± 608.677
    36.005 ± 538.357
        Week 44 [N=287,124]
    -137.151 ± 352.715
    57.373 ± 594.125
        Week 52 [N=276,118]
    -164.009 ± 564.396
    93.245 ± 640.998
        Week 60 [N=200,70]
    -133.499 ± 467.931
    -18.833 ± 441.131
        Week 68 [N=177,50]
    -159.906 ± 453.802
    39.794 ± 581.616
        Week 76 [N=160,47]
    -149.226 ± 408.126
    25.291 ± 627.834
        Week 84 [N=149,38]
    -103.284 ± 530.021
    93.647 ± 753.265
        Week 92 [N=132,32]
    -106.070 ± 464.192
    1.011 ± 474.434
        Week 100 [N=127,30]
    -119.647 ± 452.209
    30.829 ± 514.823
        Week 104 [N=112,30]
    -107.814 ± 458.702
    4.524 ± 475.524
    No statistical analyses for this end point

    Secondary: Change From BL to Each Study Visit in Serum Transferrin Saturation (TSAT)

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    End point title
    Change From BL to Each Study Visit in Serum Transferrin Saturation (TSAT)
    End point description
    In case of missing data, no imputation rules were applied. N is the number of participants with available data at each time point. The analysis population was the FAS, which consisted of all randomized participants who received at least one dose of study drug and had at least one post-dose Hb assessment.
    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
    End point values
    Roxadustat Placebo
    Number of subjects analysed
    389
    203
    Units: Percentage
    arithmetic mean (standard deviation)
        Week 4 [N=357,190]
    -7.4 ± 11.7
    0.7 ± 11.4
        Week 8 [N=344,191]
    -5.7 ± 11.7
    -0.4 ± 13.0
        Week 12 [N=334,181]
    -4.6 ± 13.5
    -0.7 ± 11.5
        Week 20 [N=317,152]
    -1.1 ± 13.4
    -0.3 ± 11.5
        Week 28 [N=306,145]
    -1.8 ± 13.8
    0.8 ± 13.2
        Week 36 [N=292,127]
    -1.6 ± 13.6
    1.1 ± 14.6
        Week 44 [N=281,123]
    -0.2 ± 14.0
    1.0 ± 16.0
        Week 52 [N=275,115]
    -0.7 ± 13.6
    0.0 ± 16.3
        Week 60 [N=198,68]
    -0.6 ± 14.1
    -2.7 ± 13.9
        Week 68 [N=177,49]
    -2.2 ± 13.1
    -3.3 ± 12.3
        Week 76 [N=158,44]
    -2.6 ± 13.8
    -1.7 ± 13.9
        Week 84 [N=148,35]
    -3.4 ± 13.3
    -3.6 ± 13.8
        Week 92 [N=131,31]
    -1.9 ± 13.2
    -1.8 ± 12.8
        Week 100 [N=125,29]
    0.0 ± 13.4
    0.7 ± 12.0
        Week 104 [N=112,29]
    -0.4 ± 12.6
    0.0 ± 12.3
    No statistical analyses for this end point

    Secondary: Change From BL to Each Study Visit in Serum HbA1c Level

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    End point title
    Change From BL to Each Study Visit in Serum HbA1c Level
    End point description
    In case of missing data, no imputation rules were applied. N is the number of participants with available data at each time point. The analysis population was the FAS, which consisted of all randomized participants who received at least one dose of study drug and had at least one post-dose Hb assessment.
    End point type
    Secondary
    End point timeframe
    Baseline and weeks 12,28,36,44,60,84,104
    End point values
    Roxadustat Placebo
    Number of subjects analysed
    389
    203
    Units: Fraction of 1
    arithmetic mean (standard deviation)
        Week 12 [N=338,182]
    0.0007 ± 0.0064
    -0.0001 ± 0.0061
        Week 28 [N=304,145]
    0.0006 ± 0.0086
    0.0008 ± 0.0091
        Week 36 [N=225,108]
    0.0011 ± 0.0098
    0.0007 ± 0.0075
        Week 44 [N=282,125]
    0.0018 ± 0.0081
    -0.0002 ± 0.0074
        Week 60 [N=200,70]
    0.0009 ± 0.0073
    0.0012 ± 0.0080
        Week 84 [N=147,38]
    0.0028 ± 0.0085
    0.0022 ± 0.0111
        Week 104 [N=111,29]
    0.0014 ± 0.0073
    0.0004 ± 0.0059
    No statistical analyses for this end point

    Secondary: Change From BL to Each Study Visit in Fasting Blood Glucose

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    End point title
    Change From BL to Each Study Visit in Fasting Blood Glucose
    End point description
    In case of missing data, no imputation rules were applied. N is the number of participants with available data at each time point. The analysis population was the FAS, which consisted of all randomized participants who received at least one dose of study drug and had at least one post-dose Hb assessment.
    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
    End point values
    Roxadustat Placebo
    Number of subjects analysed
    389
    203
    Units: mmol/L
    arithmetic mean (standard deviation)
        Week 4 [N=241,134]
    0.107 ± 2.573
    -0.076 ± 2.730
        Week 8 [N=233,128]
    -0.103 ± 3.179
    -0.162 ± 3.118
        Week 12 [N=223,118]
    -0.100 ± 3.504
    -0.153 ± 4.629
        Week 20 [N=211,99]
    -0.302 ± 4.052
    0.523 ± 2.981
        Week 28 [N=199,95]
    0.160 ± 3.489
    0.045 ± 3.281
        Week 36 [N=185,83]
    0.015 ± 2.991
    -0.117 ± 2.812
        Week 44 [N=167,76]
    0.073 ± 2.683
    0.801 ± 3.416
        Week 52 [N=168,79]
    0.048 ± 4.348
    -0.086 ± 4.883
        Week 60 [N=116,47]
    0.130 ± 2.907
    1.190 ± 3.946
        Week 68 [N=91,33]
    0.185 ± 2.831
    0.698 ± 3.386
        Week 76 [N=81,28]
    -0.015 ± 2.031
    -0.671 ± 5.148
        Week 84 [N=75,20]
    0.495 ± 3.117
    0.435 ± 2.037
        Week 92 [N=65,19]
    0.612 ± 2.494
    -0.861 ± 3.298
        Week 100 [N=58,19]
    0.405 ± 2.932
    -0.699 ± 2.161
        Week 104 [N=59,20]
    0.125 ± 2.633
    0.237 ± 3.938
    No statistical analyses for this end point

    Secondary: Change From BL to Each Study Visit in Albumin/Creatinine Ratio in Urine

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    End point title
    Change From BL to Each Study Visit in Albumin/Creatinine Ratio in Urine
    End point description
    Baseline assessment was the assessment from day 1 visit. If baseline value was missing, value from screening visit was used. In case of missing data, no imputation rules were applied. To compute the geometric mean of albumin/creatinine ratio in urine and associated 95% CI, the mean of log-transformed albumin/creatinine ratio in urine values (ratio) and associated 95% CI are back-transformed to the raw scale. All assessments collected after initiation of dialysis (acute or chronic) were excluded from the analysis. N is the number of participants with available data at each time point. The analysis population was the FAS, which consisted of all randomized participants who received at least one dose of study drug and had at least one post-dose Hb assessment.
    End point type
    Secondary
    End point timeframe
    Baseline and weeks 12,24,36,52,64,76,88,104
    End point values
    Roxadustat Placebo
    Number of subjects analysed
    389
    203
    Units: Ratio
    geometric mean (confidence interval 95%)
        Week 12 [N=122,75]
    1.08 (0.96 to 1.20)
    1.06 (0.84 to 1.34)
        Week 24 [N=103,53]
    1.19 (1.04 to 1.36)
    1.16 (0.89 to 1.53)
        Week 36 [N=90,49]
    1.21 (1.04 to 1.41)
    1.04 (0.77 to 1.40)
        Week 52 [N=74,38]
    1.28 (1.02 to 1.59)
    1.04 (0.72 to 1.51)
        Week 64 [N=22,11]
    1.25 (0.84 to 1.87)
    0.96 (0.53 to 1.71)
        Week 76 [N=14,10]
    1.12 (0.51 to 2.44)
    0.82 (0.41 to 1.65)
        Week 88 [N=11,2]
    1.10 (0.38 to 3.17)
    0.51 (0.27 to 0.97)
        Week 104 [N=4,2]
    1.92 (0.75 to 4.89)
    0.38 (0.08 to 1.88)
    No statistical analyses for this end point

    Secondary: Change From BL to Each Study Visit in Serum Creatinine (Cr) Ratio

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    End point title
    Change From BL to Each Study Visit in Serum Creatinine (Cr) Ratio
    End point description
    Baseline assessment was the 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. To compute the geometric mean of serum Cr (ratio) and associated 95% CI, the mean of log-transformed serum Cr (ratio) values and associated 95% CI are back-transformed to the raw scale. All assessments collected after initiation of dialysis (acute or chronic) were excluded from the analysis. N is the number of participants with available data at each time point. The analysis population was the FAS, which consisted of all randomized participants who received at least one dose of study drug and had at least one post-dose Hb assessment.
    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
    End point values
    Roxadustat Placebo
    Number of subjects analysed
    389
    203
    Units: Ratio
    geometric mean (confidence interval 95%)
        Week 4 [N=355,188]
    1.01 (1.00 to 1.03)
    1.05 (1.03 to 1.07)
        Week 8 [N=338,184]
    1.03 (1.01 to 1.05)
    1.07 (1.04 to 1.09)
        Week 12 [N=323,169]
    1.04 (1.02 to 1.06)
    1.07 (1.04 to 1.11)
        Week 20 [N=289,135]
    1.08 (1.06 to 1.12)
    1.09 (1.05 to 1.13)
        Week 28 [N=267,124]
    1.12 (1.08 to 1.16)
    1.13 (1.08 to 1.17)
        Week 36 [N=238,108]
    1.12 (1.08 to 1.16)
    1.12 (1.07 to 1.18)
        Week 44 [N=216,99]
    1.12 (1.07 to 1.16)
    1.16 (1.10 to 1.22)
        Week 52 [N=201,90]
    1.12 (1.07 to 1.16)
    1.15 (1.09 to 1.22)
        Week 60 [N=135,52]
    1.09 (1.05 to 1.14)
    1.15 (1.07 to 1.23)
        Week 68 [N=117,36]
    1.11 (1.06 to 1.17)
    1.24 (1.13 to 1.37)
        Week 76 [N=102,33]
    1.13 (1.07 to 1.20)
    1.23 (1.12 to 1.36)
        Week 84 [N=94,26]
    1.13 (1.07 to 1.20)
    1.19 (1.05 to 1.35)
        Week 92 [N=83,24]
    1.19 (1.12 to 1.27)
    1.22 (1.05 to 1.41)
        Week 100 [N=75,22]
    1.16 (1.08 to 1.24)
    1.26 (1.06 to 1.50)
        Week 104 [N=66,23]
    1.16 (1.05 to 1.27)
    1.28 (1.09 to 1.51)
    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
    The endpoint was defined as time to doubling serum creatinine or chronic dialysis or renal transplant what ever came first. Time to event was defined as (First event date – Analysis date of first dose intake + 1) / 365.25. First event date was defined as date of dialysis or date of renal transplant (whichever occurred first) and analysis date of first dose intake was defined as date of first study drug dose intake collected on day 1 visit. Data analysis was completed using Kaplan-Meier estimate for cumulative proportion. The analysis population was the FAS, which consisted of all randomized participants who received at least one dose of study drug and had at least one post-dose Hb assessment.
    End point type
    Secondary
    End point timeframe
    Baseline and up to week 108
    End point values
    Roxadustat Placebo
    Number of subjects analysed
    389
    203
    Units: Percentage
    number (confidence interval 95%)
        Years 0.5
    17.4 (13.4 to 21.4)
    17.8 (12.3 to 23.4)
        Years 1
    36.8 (31.6 to 42.1)
    35.4 (27.9 to 42.9)
        Years 1.5
    47.3 (41.4 to 53.1)
    48.2 (38.6 to 57.8)
        Years 2
    55.0 (48.5 to 61.4)
    54.7 (43.8 to 65.6)
    Statistical analysis title
    Time to Doubling of Serum Creatinine
    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 Placebo
    Number of subjects included in analysis
    592
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.973
    Method
    Regression, Cox
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.995
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.75
         upper limit
    1.32

    Secondary: Time to Chronic Kidney Disease (CKD) 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 (CKD) Progression (Composite of Doubling Serum Creatinine, Chronic Dialysis or Renal Transplant, and Death)
    End point description
    CKD 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. The time to CKD progression was calculated (in years) as (First event date – Analysis date of first dose intake + 1) / 365.25. First event date was defined as first occurrence of serum creatinine being doubled compared with baseline, first occurrence of chronic dialysis or renal transplant, occurrence of participants who died (whichever occurred first). Analysis date of first dose intake was defined as date of first study drug dose intake collected on day 1 visit. Data analysis was completed using Kaplan-Meier estimate for cumulative proportion. The analysis population was the FAS, which consisted of all randomized participants who received at least one dose of study drug and had at least one post-dose Hb assessment.
    End point type
    Secondary
    End point timeframe
    Baseline and up to week 108
    End point values
    Roxadustat Placebo
    Number of subjects analysed
    389
    203
    Units: Percentage
    number (confidence interval 95%)
        Years 0.5
    20.5 (16.3 to 24.7)
    20.0 (14.2 to 25.8)
        Years 1
    40.3 (35.1 to 45.5)
    38.3 (30.7 to 45.8)
        Years 1.5
    50.2 (44.5 to 55.9)
    50.5 (41.1 to 59.9)
        Years 2
    58.9 (52.7 to 65.1)
    61.1 (50.5 to 71.7)
    Statistical analysis title
    Time to CKD Progression
    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 Placebo
    Number of subjects included in analysis
    592
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.972
    Method
    Regression, Cox
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.995
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.76
         upper limit
    1.3

    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
    All eGFR values collected during the safety emergent period are considered, excluding those collected on or after initiation of dialysis (acute or chronic). The First event date was defined as First occurrence of 40% decrease in eGFR from baseline, first occurrence of chronic dialysis or renal transplant (whichever occurred first and Analysis date of first dose intake was defined as date of first study drug dose intake collected on day 1 visit. The safety emergent period was defined as the evaluation period from the analysis date of first drug intake up to 28 days after the analysis date of last dose or end of study (EOS), whichever occurred first. Data analysis was completed using Kaplan-Meier estimate for cumulative proportion. The analysis population was the FAS, which consisted of all randomized participants who received at least one dose of study drug and had at least one post-dose Hb assessment.
    End point type
    Secondary
    End point timeframe
    Baseline and up to week 108
    End point values
    Roxadustat Placebo
    Number of subjects analysed
    389
    203
    Units: Percentage
    number (confidence interval 95%)
        Years 0.5
    20.7 (16.5 to 25.0)
    22.3 (16.2 to 28.4)
        Years 1
    44.4 (39.0 to 49.8)
    44.0 (36.2 to 51.7)
        Years 1.5
    54.6 (48.9 to 60.4)
    62.8 (53.2 to 72.5)
        Years 2
    64.5 (64.5 to 70.7)
    67.0 (56.8 to 77.1)
    Statistical analysis title
    Time to at Least 40% Decrease in eGFR from BL
    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 Placebo
    Number of subjects included in analysis
    592
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.439
    Method
    Regression, Cox
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.905
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.7
         upper limit
    1.16

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From first dose of study drug up to 28 days after the last dose of study drug (up to 108 weeks)
    Adverse event reporting additional description
    Total number of deaths (all causes) includes deaths reported after the time frame above.The mortality rate during the safety emergent period was 7.4 per 100-yr in roxadustat and 7.6 in placebo.Rate for Acute myocardial infraction was 1.2 per 100-yr in roxadustat and 1.0 in placebo,Pulmonary embolism was 0.6 per 100-yr in roxadustat and 0.5 placebo.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    20.0
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Participants received matching placebo according to the tiered weight-based approach, with starting doses of 70 mg given thrice weekly (TIW) to participants weighing up to 70 kg and 100 mg given TIW to participants weighing more than 70 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 (BL) 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 matching placebo for at least 52 weeks up to a maximum of 104 weeks.

    Reporting group title
    Roxadustat
    Reporting group description
    Participants received roxadustat according to the tiered weight-based approach, with starting doses of 70 mg given thrice weekly (TIW) to participants weighing up to 70 kg and 100 mg given TIW to participants weighing more than 70 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 (BL) 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 at least 52 weeks up to a maximum of 104 weeks.

    Serious adverse events
    Placebo Roxadustat
    Total subjects affected by serious adverse events
         subjects affected / exposed
    115 / 203 (56.65%)
    241 / 391 (61.64%)
         number of deaths (all causes)
    20
    45
         number of deaths resulting from adverse events
    19
    40
    Injury, poisoning and procedural complications
    Arterial injury
         subjects affected / exposed
    0 / 203 (0.00%)
    1 / 391 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arteriovenous fistula site complication
         subjects affected / exposed
    0 / 203 (0.00%)
    1 / 391 (0.26%)
         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
    0 / 203 (0.00%)
    14 / 391 (3.58%)
         occurrences causally related to treatment / all
    0 / 0
    5 / 17
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Concussion
         subjects affected / exposed
    1 / 203 (0.49%)
    0 / 391 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Craniocerebral injury
         subjects affected / exposed
    0 / 203 (0.00%)
    3 / 391 (0.77%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Facial bones fracture
         subjects affected / exposed
    0 / 203 (0.00%)
    1 / 391 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    1 / 203 (0.49%)
    1 / 391 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fat embolism
         subjects affected / exposed
    1 / 203 (0.49%)
    0 / 391 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    1 / 203 (0.49%)
    0 / 391 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    0 / 203 (0.00%)
    4 / 391 (1.02%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Humerus fracture
         subjects affected / exposed
    1 / 203 (0.49%)
    0 / 391 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post procedural haemorrhage
         subjects affected / exposed
    0 / 203 (0.00%)
    1 / 391 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Postoperative wound complication
         subjects affected / exposed
    0 / 203 (0.00%)
    2 / 391 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pubis fracture
         subjects affected / exposed
    0 / 203 (0.00%)
    1 / 391 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subarachnoid haemorrhage
         subjects affected / exposed
    0 / 203 (0.00%)
    1 / 391 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Blood bilirubin increased
         subjects affected / exposed
    0 / 203 (0.00%)
    1 / 391 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood creatinine increased
         subjects affected / exposed
    0 / 203 (0.00%)
    1 / 391 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Blood urea increased
         subjects affected / exposed
    0 / 203 (0.00%)
    1 / 391 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Glomerular filtration rate decreased
         subjects affected / exposed
    11 / 203 (5.42%)
    21 / 391 (5.37%)
         occurrences causally related to treatment / all
    1 / 15
    0 / 23
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute coronary syndrome
         subjects affected / exposed
    0 / 203 (0.00%)
    1 / 391 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute left ventricular failure
         subjects affected / exposed
    1 / 203 (0.49%)
    1 / 391 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Acute myocardial infarction
         subjects affected / exposed
    2 / 203 (0.99%)
    6 / 391 (1.53%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Angina pectoris
         subjects affected / exposed
    1 / 203 (0.49%)
    0 / 391 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Angina unstable
         subjects affected / exposed
    1 / 203 (0.49%)
    0 / 391 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arteriosclerosis coronary artery
         subjects affected / exposed
    1 / 203 (0.49%)
    0 / 391 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    3 / 203 (1.48%)
    3 / 391 (0.77%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial flutter
         subjects affected / exposed
    0 / 203 (0.00%)
    1 / 391 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrioventricular block complete
         subjects affected / exposed
    1 / 203 (0.49%)
    0 / 391 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    1 / 203 (0.49%)
    3 / 391 (0.77%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 3
    Cardiac failure
         subjects affected / exposed
    1 / 203 (0.49%)
    3 / 391 (0.77%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure acute
         subjects affected / exposed
    0 / 203 (0.00%)
    1 / 391 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cardiac failure chronic
         subjects affected / exposed
    3 / 203 (1.48%)
    3 / 391 (0.77%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    1 / 203 (0.49%)
    1 / 391 (0.26%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardio-respiratory arrest
         subjects affected / exposed
    0 / 203 (0.00%)
    1 / 391 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cardiogenic shock
         subjects affected / exposed
    1 / 203 (0.49%)
    0 / 391 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cardiopulmonary failure
         subjects affected / exposed
    0 / 203 (0.00%)
    1 / 391 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Coronary artery disease
         subjects affected / exposed
    2 / 203 (0.99%)
    1 / 391 (0.26%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Left ventricular failure
         subjects affected / exposed
    1 / 203 (0.49%)
    0 / 391 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    3 / 203 (1.48%)
    8 / 391 (2.05%)
         occurrences causally related to treatment / all
    0 / 3
    5 / 8
         deaths causally related to treatment / all
    0 / 2
    1 / 1
    Myocardial ischaemia
         subjects affected / exposed
    0 / 203 (0.00%)
    2 / 391 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ventricular tachycardia
         subjects affected / exposed
    0 / 203 (0.00%)
    1 / 391 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Congenital cystic kidney disease
         subjects affected / exposed
    1 / 203 (0.49%)
    0 / 391 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    7 / 203 (3.45%)
    8 / 391 (2.05%)
         occurrences causally related to treatment / all
    0 / 9
    0 / 10
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhagic anaemia
         subjects affected / exposed
    1 / 203 (0.49%)
    1 / 391 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Heparin-induced thrombocytopenia
         subjects affected / exposed
    1 / 203 (0.49%)
    0 / 391 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lymphadenopathy mediastinal
         subjects affected / exposed
    0 / 203 (0.00%)
    1 / 391 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nephrogenic anaemia
         subjects affected / exposed
    1 / 203 (0.49%)
    1 / 391 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    1 / 203 (0.49%)
    0 / 391 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    1 / 203 (0.49%)
    0 / 391 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebral haemorrhage
         subjects affected / exposed
    1 / 203 (0.49%)
    0 / 391 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    0 / 203 (0.00%)
    5 / 391 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 5
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Dementia
         subjects affected / exposed
    1 / 203 (0.49%)
    0 / 391 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetic neuropathy
         subjects affected / exposed
    2 / 203 (0.99%)
    0 / 391 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    0 / 203 (0.00%)
    1 / 391 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epilepsy
         subjects affected / exposed
    0 / 203 (0.00%)
    1 / 391 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhagic stroke
         subjects affected / exposed
    1 / 203 (0.49%)
    2 / 391 (0.51%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 2
    Headache
         subjects affected / exposed
    1 / 203 (0.49%)
    1 / 391 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertensive encephalopathy
         subjects affected / exposed
    0 / 203 (0.00%)
    1 / 391 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoglycaemic coma
         subjects affected / exposed
    1 / 203 (0.49%)
    0 / 391 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    1 / 203 (0.49%)
    4 / 391 (1.02%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Loss of consciousness
         subjects affected / exposed
    0 / 203 (0.00%)
    1 / 391 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myasthenic syndrome
         subjects affected / exposed
    0 / 203 (0.00%)
    1 / 391 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Partial seizures
         subjects affected / exposed
    0 / 203 (0.00%)
    1 / 391 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sciatica
         subjects affected / exposed
    1 / 203 (0.49%)
    0 / 391 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 203 (0.00%)
    1 / 391 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    1 / 203 (0.49%)
    3 / 391 (0.77%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular encephalopathy
         subjects affected / exposed
    0 / 203 (0.00%)
    2 / 391 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Macular hole
         subjects affected / exposed
    0 / 203 (0.00%)
    1 / 391 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Retinal detachment
         subjects affected / exposed
    1 / 203 (0.49%)
    0 / 391 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ulcerative keratitis
         subjects affected / exposed
    1 / 203 (0.49%)
    0 / 391 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    1 / 203 (0.49%)
    0 / 391 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    0 / 203 (0.00%)
    1 / 391 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetic gastroparesis
         subjects affected / exposed
    0 / 203 (0.00%)
    1 / 391 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    1 / 203 (0.49%)
    3 / 391 (0.77%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Duodenal ulcer
         subjects affected / exposed
    0 / 203 (0.00%)
    2 / 391 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterocolitis
         subjects affected / exposed
    0 / 203 (0.00%)
    1 / 391 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Gastric ulcer
         subjects affected / exposed
    0 / 203 (0.00%)
    1 / 391 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric ulcer perforation
         subjects affected / exposed
    0 / 203 (0.00%)
    1 / 391 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Gastritis
         subjects affected / exposed
    0 / 203 (0.00%)
    2 / 391 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastritis erosive
         subjects affected / exposed
    1 / 203 (0.49%)
    0 / 391 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 203 (0.00%)
    2 / 391 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhagic erosive gastritis
         subjects affected / exposed
    1 / 203 (0.49%)
    0 / 391 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhoids
         subjects affected / exposed
    0 / 203 (0.00%)
    1 / 391 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Inguinal hernia
         subjects affected / exposed
    0 / 203 (0.00%)
    1 / 391 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal perforation
         subjects affected / exposed
    0 / 203 (0.00%)
    1 / 391 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Large intestinal ulcer
         subjects affected / exposed
    0 / 203 (0.00%)
    1 / 391 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    0 / 203 (0.00%)
    3 / 391 (0.77%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophagitis
         subjects affected / exposed
    0 / 203 (0.00%)
    3 / 391 (0.77%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis chronic
         subjects affected / exposed
    0 / 203 (0.00%)
    1 / 391 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal haemorrhage
         subjects affected / exposed
    0 / 203 (0.00%)
    1 / 391 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    0 / 203 (0.00%)
    1 / 391 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 203 (0.00%)
    1 / 391 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 203 (0.49%)
    3 / 391 (0.77%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    2 / 203 (0.99%)
    1 / 391 (0.26%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute prerenal failure
         subjects affected / exposed
    1 / 203 (0.49%)
    1 / 391 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Azotaemia
         subjects affected / exposed
    8 / 203 (3.94%)
    10 / 391 (2.56%)
         occurrences causally related to treatment / all
    0 / 10
    0 / 11
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Calculus bladder
         subjects affected / exposed
    0 / 203 (0.00%)
    1 / 391 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    End stage renal disease
         subjects affected / exposed
    62 / 203 (30.54%)
    135 / 391 (34.53%)
         occurrences causally related to treatment / all
    0 / 63
    1 / 135
         deaths causally related to treatment / all
    0 / 4
    0 / 8
    Haematuria
         subjects affected / exposed
    0 / 203 (0.00%)
    2 / 391 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nephrolithiasis
         subjects affected / exposed
    0 / 203 (0.00%)
    1 / 391 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oliguria
         subjects affected / exposed
    0 / 203 (0.00%)
    1 / 391 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Renal colic
         subjects affected / exposed
    0 / 203 (0.00%)
    1 / 391 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urethral stenosis
         subjects affected / exposed
    0 / 203 (0.00%)
    1 / 391 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary retention
         subjects affected / exposed
    0 / 203 (0.00%)
    2 / 391 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Product issues
    Device dislocation
         subjects affected / exposed
    0 / 203 (0.00%)
    1 / 391 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device malfunction
         subjects affected / exposed
    0 / 203 (0.00%)
    1 / 391 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Dermatitis
         subjects affected / exposed
    1 / 203 (0.49%)
    0 / 391 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetic foot
         subjects affected / exposed
    0 / 203 (0.00%)
    2 / 391 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eczema nummular
         subjects affected / exposed
    0 / 203 (0.00%)
    1 / 391 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Panniculitis
         subjects affected / exposed
    1 / 203 (0.49%)
    0 / 391 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pruritus
         subjects affected / exposed
    0 / 203 (0.00%)
    2 / 391 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rash
         subjects affected / exposed
    0 / 203 (0.00%)
    1 / 391 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin ulcer
         subjects affected / exposed
    0 / 203 (0.00%)
    2 / 391 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Toxic skin eruption
         subjects affected / exposed
    0 / 203 (0.00%)
    1 / 391 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Gouty arthritis
         subjects affected / exposed
    0 / 203 (0.00%)
    2 / 391 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Joint contracture
         subjects affected / exposed
    0 / 203 (0.00%)
    1 / 391 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rhabdomyolysis
         subjects affected / exposed
    1 / 203 (0.49%)
    1 / 391 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal osteoarthritis
         subjects affected / exposed
    0 / 203 (0.00%)
    1 / 391 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    Goitre
         subjects affected / exposed
    0 / 203 (0.00%)
    1 / 391 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperparathyroidism primary
         subjects affected / exposed
    0 / 203 (0.00%)
    1 / 391 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperparathyroidism secondary
         subjects affected / exposed
    0 / 203 (0.00%)
    1 / 391 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    1 / 203 (0.49%)
    1 / 391 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetes mellitus
         subjects affected / exposed
    1 / 203 (0.49%)
    1 / 391 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetes mellitus inadequate control
         subjects affected / exposed
    0 / 203 (0.00%)
    1 / 391 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetic metabolic decompensation
         subjects affected / exposed
    2 / 203 (0.99%)
    1 / 391 (0.26%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fluid overload
         subjects affected / exposed
    0 / 203 (0.00%)
    1 / 391 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gout
         subjects affected / exposed
    0 / 203 (0.00%)
    1 / 391 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypercalcaemia
         subjects affected / exposed
    0 / 203 (0.00%)
    1 / 391 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    0 / 203 (0.00%)
    2 / 391 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperkalaemia
         subjects affected / exposed
    2 / 203 (0.99%)
    4 / 391 (1.02%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypervolaemia
         subjects affected / exposed
    1 / 203 (0.49%)
    2 / 391 (0.51%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Hypoglycaemia
         subjects affected / exposed
    0 / 203 (0.00%)
    2 / 391 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    1 / 203 (0.49%)
    0 / 391 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Abscess limb
         subjects affected / exposed
    0 / 203 (0.00%)
    1 / 391 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anal abscess
         subjects affected / exposed
    1 / 203 (0.49%)
    0 / 391 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    0 / 203 (0.00%)
    2 / 391 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Appendicitis perforated
         subjects affected / exposed
    1 / 203 (0.49%)
    0 / 391 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    1 / 203 (0.49%)
    0 / 391 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis bacterial
         subjects affected / exposed
    0 / 203 (0.00%)
    1 / 391 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bursitis infective
         subjects affected / exposed
    0 / 203 (0.00%)
    1 / 391 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    0 / 203 (0.00%)
    3 / 391 (0.77%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clostridium difficile colitis
         subjects affected / exposed
    1 / 203 (0.49%)
    2 / 391 (0.51%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clostridium difficile infection
         subjects affected / exposed
    0 / 203 (0.00%)
    1 / 391 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    0 / 203 (0.00%)
    4 / 391 (1.02%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Diabetic foot infection
         subjects affected / exposed
    1 / 203 (0.49%)
    0 / 391 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterobacter bacteraemia
         subjects affected / exposed
    1 / 203 (0.49%)
    0 / 391 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epididymitis
         subjects affected / exposed
    0 / 203 (0.00%)
    1 / 391 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Erysipelas
         subjects affected / exposed
    0 / 203 (0.00%)
    3 / 391 (0.77%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Escherichia urinary tract infection
         subjects affected / exposed
    0 / 203 (0.00%)
    2 / 391 (0.51%)
         occurrences causally related to treatment / all
    0 / 0