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    Clinical Trial Results:
    A controlled, parallel group, open-label, multicenter extension study to investigate efficacy and safety of oral BAY 85-3934 and darbepoetin alfa comparator in the long term treatment of anemia in pre-dialysis subjects with chronic kidney disease in Europe and Asia Pacific

    Summary
    EudraCT number
    		 2013-001190-24
    Trial protocol
    		 GB   DE   IT   HU   ES   BG   PL  
    Global end of trial date
    12 Dec 2016

    Results information
    Results version number
    		 v1(current)
    This version publication date
    07 Dec 2017
    First version publication date
    07 Dec 2017
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    BAY85-3934/15653
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Bayer AG
    Sponsor organisation address
    Kaiser-Wilhelm-Allee, D-51368 Leverkusen, Germany,
    Public contact
    Therapeutic Area Head, Bayer AG, 0049 30300139003, clinical-trials-contact@bayer.com
    Scientific contact
    Therapeutic Area Head, Bayer AG, 0049 30300139003, clinical-trials-contact@bayer.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
    12 Dec 2016
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    12 Dec 2016
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The primary objectives of this study were to: • evaluate efficacy of treatment with BAY85-3934 (molidustat) compared with darbepoetin alfa as measured by change from baseline to post-baseline time points in haemoglobin (Hb) levels. • evaluate safety and tolerability of treatment with BAY85-3934 compared with darbepoetin by events of special interest, adjudicated serious adverse events (SAEs), and SAEs.
    Protection of trial subjects
    The conduct of this clinical study met all local legal and regulatory requirements. The study was conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki and the International Council for Harmonization guideline E6: Good Clinical Practice. Before entering the study, the informed consent form was read by and explained to all subjects. Participating subjects signed informed consent form and could withdraw from the study at any time without any disadvantage and without having to provide a reason for this decision. Only investigators qualified by training and experience were selected as appropriate experts to investigate the study drug.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    24 Jun 2014
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Israel: 2
    Country: Number of subjects enrolled
    Japan: 37
    Country: Number of subjects enrolled
    Korea, Republic of: 16
    Country: Number of subjects enrolled
    Romania: 19
    Country: Number of subjects enrolled
    Poland: 6
    Country: Number of subjects enrolled
    Spain: 4
    Country: Number of subjects enrolled
    United Kingdom: 3
    Country: Number of subjects enrolled
    Bulgaria: 11
    Country: Number of subjects enrolled
    France: 3
    Country: Number of subjects enrolled
    Germany: 4
    Country: Number of subjects enrolled
    Hungary: 34
    Country: Number of subjects enrolled
    Italy: 25
    Worldwide total number of subjects
    164
    EEA total number of subjects
    109
    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)
    44
    From 65 to 84 years
    120
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Study was conducted at 50 active study centers in 12 countries: Bulgaria, France, Germany, Hungary, Israel, Italy, Japan, Poland, Republic of Korea, Romania, Spain, and United Kingdom (UK), between 24 June 2014 (first subject first visit) and 12 December 2016 (last subject last visit).

    Pre-assignment
    Screening details
    		 Overall, 166 subjects were included in this extension study from parent studies 15141 (2013-001193-14); 15261 (2013-001192-21), of whom 2 were excluded (no reliable treatment data); 4 were not treated. 144 subjects entered main phase (97 subjects entered directly; 47 subjects rolled over from HbS phase). Finally, 128 subjects completed follow-up.

    Period 1
    Period 1 title
    Overall Trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 BAY85-3934
    Arm description
    		 Subjects received initial doses of BAY85-3934 tablet as per parent study once daily (OD) and then all the doses were titrated to 15, 25, 50, 75, 100, and 150 milligram per day (mg/day) up to a maximum of 36 months. Treatment included two phases: the hemoglobin (Hb) stabilization phase (HbS) (up to 16 weeks) for subjects who were outside of target Hb range at start of the extension study and the main phase (up to 36 months). In the HbS phase, subjects received initial doses of BAY85-3934 OD dose assigned by interactive voice or web response system (IXRS) and then titrated at each scheduled visit to maintain Hb in the target range of 10.0 to 12.0 gram per deciliter (g/dL). In the main phase, subjects received titrated dose of BAY85-3934 OD assigned by IXRS.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Molidustat
    Investigational medicinal product code
    BAY85-3934
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    In the HbS phase, subjects received initial doses of BAY85-3934 OD dose assigned by IXRS and then titrated at each scheduled visit to maintain Hb in the target range of 10.0 to 12.0 g/dL. In the main phase, subjects received titrated dose of BAY85-3934 OD assigned by IXRS.

    Arm title
    		 Darbepoetin
    Arm description
    		 Subjects received initial doses of darbepoetin intravenously (IV) or subcutaneously (SC) and all the doses were titrated at the scheduled dose up to a maximum of 36 months. Treatment included two phases: HbS (up to 16 weeks) and main phase (up to 36 months). In the HbS phase, subjects who were on placebo in the parent study or were out of Hb target range at start of the extension study received initial doses of darbepoetin IV or SC according to local label and then titrated at each scheduled visit to maintain Hb in the target range of 10.0 to 12.0 g/dL. In the main phase, subjects received titrated dose of darbepoetin IV or SC according to the local label and titrated at each scheduled visit for every 4 weeks.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Darbepoetin
    Investigational medicinal product code
    Other name
    Aranesp
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use, Subcutaneous use
    Dosage and administration details
    In the HbS phase, subjects who were on placebo in the parent study or were out of Hb target range at start of the extension study received initial doses of darbepoetin IV or SC according to local label and then titrated at each scheduled visit to maintain Hb in the target range of 10.0 to 12.0 g/dL. In the main phase, subjects received titrated dose of darbepoetin IV or SC according to the local label and titrated at each scheduled visit for every 4 weeks.

    Number of subjects in period 1 [1]
    		BAY85-3934 Darbepoetin
    Started
    103
    41
    Entered HbS phase
    49
    18
    Entered main phase from HbS phase
    31
    16
    Entered main phase directly
    72
    25
    Completed follow-up
    97
    31
    Completed
    0
    0
    Not completed
    103
    41
         Physician decision
    1
    -
         Logistical difficulties
    1
    -
         Lost to follow-up
    1
    -
         Protocol driven decision point
    12
    7
         Protocol violation
    1
    1
         Death
    4
    -
         Other
    1
    -
         Adverse event
    18
    3
         Study terminated by sponsor
    62
    25
         Withdrawal by subject
    2
    5
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: Not all the enrolled subjects were treated with study drugs. As baseline only included treated subjects, the worldwide number enrolled in the trial differs with the number of subjects reported in the baseline period.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    BAY85-3934
    Reporting group description
    		 Subjects received initial doses of BAY85-3934 tablet as per parent study once daily (OD) and then all the doses were titrated to 15, 25, 50, 75, 100, and 150 milligram per day (mg/day) up to a maximum of 36 months. Treatment included two phases: the hemoglobin (Hb) stabilization phase (HbS) (up to 16 weeks) for subjects who were outside of target Hb range at start of the extension study and the main phase (up to 36 months). In the HbS phase, subjects received initial doses of BAY85-3934 OD dose assigned by interactive voice or web response system (IXRS) and then titrated at each scheduled visit to maintain Hb in the target range of 10.0 to 12.0 gram per deciliter (g/dL). In the main phase, subjects received titrated dose of BAY85-3934 OD assigned by IXRS.

    Reporting group title
    Darbepoetin
    Reporting group description
    		 Subjects received initial doses of darbepoetin intravenously (IV) or subcutaneously (SC) and all the doses were titrated at the scheduled dose up to a maximum of 36 months. Treatment included two phases: HbS (up to 16 weeks) and main phase (up to 36 months). In the HbS phase, subjects who were on placebo in the parent study or were out of Hb target range at start of the extension study received initial doses of darbepoetin IV or SC according to local label and then titrated at each scheduled visit to maintain Hb in the target range of 10.0 to 12.0 g/dL. In the main phase, subjects received titrated dose of darbepoetin IV or SC according to the local label and titrated at each scheduled visit for every 4 weeks.

    Reporting group values
    		 BAY85-3934 Darbepoetin Total
    Number of subjects
    		 103 41 144
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 69.6 ± 10.36 67.9 ± 11.72 -
    Gender categorical
    Units: Subjects
        Female
    		 55 20 75
        Male
    		 48 21 69

    End points

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    End points reporting groups
    Reporting group title
    BAY85-3934
    Reporting group description
    		 Subjects received initial doses of BAY85-3934 tablet as per parent study once daily (OD) and then all the doses were titrated to 15, 25, 50, 75, 100, and 150 milligram per day (mg/day) up to a maximum of 36 months. Treatment included two phases: the hemoglobin (Hb) stabilization phase (HbS) (up to 16 weeks) for subjects who were outside of target Hb range at start of the extension study and the main phase (up to 36 months). In the HbS phase, subjects received initial doses of BAY85-3934 OD dose assigned by interactive voice or web response system (IXRS) and then titrated at each scheduled visit to maintain Hb in the target range of 10.0 to 12.0 gram per deciliter (g/dL). In the main phase, subjects received titrated dose of BAY85-3934 OD assigned by IXRS.

    Reporting group title
    Darbepoetin
    Reporting group description
    		 Subjects received initial doses of darbepoetin intravenously (IV) or subcutaneously (SC) and all the doses were titrated at the scheduled dose up to a maximum of 36 months. Treatment included two phases: HbS (up to 16 weeks) and main phase (up to 36 months). In the HbS phase, subjects who were on placebo in the parent study or were out of Hb target range at start of the extension study received initial doses of darbepoetin IV or SC according to local label and then titrated at each scheduled visit to maintain Hb in the target range of 10.0 to 12.0 g/dL. In the main phase, subjects received titrated dose of darbepoetin IV or SC according to the local label and titrated at each scheduled visit for every 4 weeks.

    Subject analysis set title
    Modified intent-to-treat (mITT)
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    mITT (N=144) included all subjects who received at least 1 dose of study treatment during the main phase and had at least 1 post-baseline Hb value in the main phase.

    Subject analysis set title
    Safety analysis set (SAF)
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    SAF (N=144) included all subjects who received at least 1 dose of study treatment during the main phase.

    Primary: Change in Local Laboratory Hemoglobin Level from Baseline to Each Post-Baseline Visit During Main Phase

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    End point title
    		 Change in Local Laboratory Hemoglobin Level from Baseline to Each Post-Baseline Visit During Main Phase
    End point description
    Change in local laboratory Hb level from baseline to each post-baseline visit during the main phase was reported. Here 'n' signifies those subjects who were evaluable for this measure at given time points for each group respectively, and '99999' here indicates that data was not calculated as the evaluable subjects were less than 3, as 2 or less collected values were not sufficient to calculate a reliable estimation. EOT refers to end of treatment. Treatment duration for main phase was defined as date of last study drug (EOT day) – date of first study drug + 1. For subjects entering main phase directly, treatment duration = date of last non-zero dose - date of first dose at main phase + 1; for subjects entering main phase from HbS phase, treatment duration = date of last non-zero dose - main phase Day 1 + 1.
    End point type
    Primary
    End point timeframe
    Baseline, Weeks 12, 24, 36, 48, 60, 72, 96, 108 and EOT
    End point values
    		 BAY85-3934 Darbepoetin
    Number of subjects analysed
    103 [1]
    41 [2]
    Units: gram per deciliter (g/dL)
    arithmetic mean (standard deviation)
        Baseline (n=103, 41)
    11.28 ± 0.552
    11.08 ± 0.505
        Change at Week 12 (n=100, 40)
    -0.01 ± 0.962
    -0.02 ± 0.868
        Change at Week 24 (n=93, 37)
    -0.18 ± 0.875
    -0.15 ± 0.961
        Change at Week 36 (n=84, 31)
    -0.34 ± 0.965
    -0.11 ± 0.931
        Change at Week 48 (n=77, 28)
    -0.21 ± 0.923
    -0.06 ± 0.941
        Change at Week 60 (n=59, 21)
    -0.39 ± 1.321
    0.05 ± 0.915
        Change at Week 72 (n=32, 15)
    -0.13 ± 0.842
    -0.25 ± 1.039
        Change at Week 96 (n=12, 5)
    -0.57 ± 1.168
    -0.27 ± 0.337
        Change at Week 108 (n=1, 2)
    0.83 ± 99999
    -0.41 ± 0.018
        Change at EOT (n=93, 39)
    -0.33 ± 1.214
    -0.14 ± 1.215
    Notes
    [1] - mITT
    [2] - mITT
    Statistical analysis title
    		 Statistical Analysis for Week 12
    Statistical analysis description
    Results were reported including least square mean (LS-mean) difference and 95% confidence intervals (CIs) which was based on constrained longitudinal data analysis (cLDA) model. Erroneously, database auto calculates the total number of subjects for the selected arms. Number of subjects evaluated in this analysis was 140.
    Comparison groups
    BAY85-3934 v Darbepoetin
    Number of subjects included in analysis
    144
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 LS mean difference
    Point estimate
    0.13
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.18
         upper limit
    		 0.45
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.161
    Statistical analysis title
    		 Statistical Analysis for Week 24
    Statistical analysis description
    Results were reported including LS-mean difference and 95% CI. LS mean difference was based on cLDA model. Erroneously, database auto calculates the total number of subjects for the selected arms. Number of subjects evaluated in this analysis was 130.
    Comparison groups
    Darbepoetin v BAY85-3934
    Number of subjects included in analysis
    144
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 LS mean difference
    Point estimate
    0.11
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.22
         upper limit
    		 0.43
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.166
    Statistical analysis title
    		 Statistical Analysis for Week 36
    Statistical analysis description
    Results were reported including LS-mean difference and 95% CI. LS mean difference was based on cLDA model. Erroneously, database auto calculates the total number of subjects for the selected arms. Number of subjects evaluated in this analysis was 115.
    Comparison groups
    BAY85-3934 v Darbepoetin
    Number of subjects included in analysis
    144
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 LS mean difference
    Point estimate
    -0.06
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.4
         upper limit
    		 0.29
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.177
    Statistical analysis title
    		 Statistical Analysis for Week 48
    Statistical analysis description
    Results were reported including LS-mean difference and 95% CI. LS mean difference was based on cLDA model. Erroneously, database auto calculates the total number of subjects for the selected arms. Number of subjects evaluated in this analysis was 105.
    Comparison groups
    BAY85-3934 v Darbepoetin
    Number of subjects included in analysis
    144
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 LS mean difference
    Point estimate
    0.06
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.3
         upper limit
    		 0.43
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.185
    Statistical analysis title
    		 Statistical Analysis for Week 60
    Statistical analysis description
    Results were reported including LS-mean difference and 95% CI. LS mean difference was based on cLDA model. Erroneously, database auto calculates the total number of subjects for the selected arms. Number of subjects evaluated in this analysis was 80.
    Comparison groups
    BAY85-3934 v Darbepoetin
    Number of subjects included in analysis
    144
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 LS mean difference
    Point estimate
    -0.21
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.62
         upper limit
    		 0.2
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.209
    Statistical analysis title
    		 Statistical Analysis for Week 72
    Statistical analysis description
    Results were reported including LS-mean difference and 95% CI. LS mean difference was based on cLDA model. Erroneously, database auto calculates the total number of subjects for the selected arms. Number of subjects evaluated in this analysis was 47.
    Comparison groups
    BAY85-3934 v Darbepoetin
    Number of subjects included in analysis
    144
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 LS mean difference
    Point estimate
    0.24
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.25
         upper limit
    		 0.74
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.252
    Statistical analysis title
    		 Statistical Analysis for Week 96
    Statistical analysis description
    Results were reported including LS-mean difference and 95% CI. LS mean difference was based on cLDA model. Erroneously, database auto calculates the total number of subjects for the selected arms. Number of subjects evaluated in this analysis was 17.
    Comparison groups
    BAY85-3934 v Darbepoetin
    Number of subjects included in analysis
    144
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 LS mean difference
    Point estimate
    0.07
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.74
         upper limit
    		 0.89
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.415
    Statistical analysis title
    		 Statistical Analysis for Week 108
    Statistical analysis description
    Results were reported including LS-mean difference and 95% CI. LS mean difference was based on cLDA model. Erroneously, database auto calculates the total number of subjects for the selected arms. Number of subjects evaluated in this analysis was 3.
    Comparison groups
    BAY85-3934 v Darbepoetin
    Number of subjects included in analysis
    144
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 LS mean difference
    Point estimate
    2.11
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.26
         upper limit
    		 3.95
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.939
    Statistical analysis title
    		 Statistical Analysis for EOT
    Statistical analysis description
    Results were reported including LS-mean difference and 95% CI. LS mean difference was based on cLDA model. Erroneously, database auto calculates the total number of subjects for the selected arms. Number of subjects evaluated in this analysis was 132.
    Comparison groups
    BAY85-3934 v Darbepoetin
    Number of subjects included in analysis
    144
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 LS mean difference
    Point estimate
    -0.07
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.39
         upper limit
    		 0.25
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.163

    Primary: Number of Subjects With Treatment Emergent Serious Adverse Events During Main Phase

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    End point title
    		 Number of Subjects With Treatment Emergent Serious Adverse Events During Main Phase [3]
    End point description
    An adverse event (AE) was any untoward medical occurrence in a subject who received study drug without regard to possibility of causal relationship. A serious adverse event (SAE) was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; life threatening experience (immediate risk of dying); inpatient hospitalization or prolongation of existing hospitalization; persistent or significant disability/incapacity; congenital anomaly; any other medically important serious event as judged by the investigator. Treatment duration for main phase was defined as date of last study drug (EOT day) – date of first study drug + 1. For subjects entering main phase directly, treatment duration = date of last non-zero dose - date of first dose at main phase + 1; for subjects entering main phase from HbS phase, treatment duration = date of last non-zero dose - main phase Day 1 + 1.
    End point type
    Primary
    End point timeframe
    From start of study drug administration up to 3 days after the end of treatment
    Notes
    [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Descriptive statistics were done, no inferential statistical analyses were performed.
    End point values
    		 BAY85-3934 Darbepoetin
    Number of subjects analysed
    103 [4]
    41 [5]
    Units: subjects
    51
    22
    Notes
    [4] - SAF
    [5] - SAF
    No statistical analyses for this end point

    Secondary: Overall Rate of Responders in Local Hemoglobin During Main Phase

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    End point title
    		 Overall Rate of Responders in Local Hemoglobin During Main Phase
    End point description
    A responder was defined as a subject who had a mean of the Hb levels during the main phase in the target range (10.0 to 12.0 g/dL, inclusive), greater than or equal to (>=) 50 percent (%) of the Hb levels in the target range during the main phase, and no red blood cell (RBC) containing transfusion during main phase. Treatment duration for main phase was defined as date of last study drug (EOT day) – date of first study drug + 1. For subjects entering main phase directly, treatment duration = date of last non-zero dose - date of first dose at main phase + 1; for subjects entering main phase from HbS phase, treatment duration = date of last non-zero dose - main phase Day 1 + 1.
    End point type
    Secondary
    End point timeframe
    Baseline up to 36 months
    End point values
    		 BAY85-3934 Darbepoetin
    Number of subjects analysed
    103 [6]
    41 [7]
    Units: percentage of responders
        number (not applicable)
    89.3
    73.2
    Notes
    [6] - mITT with number of subjects evaluable for this specific end point.
    [7] - mITT with number of subjects evaluable for this specific end point.
    Statistical analysis title
    		 Statistical analysis 1
    Statistical analysis description
    Analysis was based on Miettinen and Nurminen method (an unconditional, asymptotic method). If the total observed subjects were less than 5 who met or did not meet specific criterion in any one of compared groups, unconditional confidence limits for the proportion difference were presented in 95% CI of difference.
    Comparison groups
    BAY85-3934 v Darbepoetin
    Number of subjects included in analysis
    144
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Percentage difference from darbepoetin
    Point estimate
    16.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 2.8
         upper limit
    		 32.2

    Secondary: Time Within Hemoglobin Target Range During Main Phase

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    End point title
    		 Time Within Hemoglobin Target Range During Main Phase
    End point description
    Hb target range was defined as 10.0 to 12.0 g/dL, inclusive. Treatment duration for main phase was defined as date of last study drug (EOT day) – date of first study drug + 1. For subjects entering main phase directly, treatment duration = date of last non-zero dose - date of first dose at main phase + 1; for subjects entering main phase from HbS phase, treatment duration = date of last non-zero dose - main phase Day 1 + 1.
    End point type
    Secondary
    End point timeframe
    up to 36 months
    End point values
    		 BAY85-3934 Darbepoetin
    Number of subjects analysed
    103 [8]
    41 [9]
    Units: days
        median (full range (min-max))
    335 (9 to 696)
    325.3 (22.9 to 813.5)
    Notes
    [8] - mITT with number of subjects evaluable for this specific end point.
    [9] - mITT with number of subjects evaluable for this specific end point.
    No statistical analyses for this end point

    Secondary: Duration of Exposure During Main Phase

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    End point title
    		 Duration of Exposure During Main Phase
    End point description
    Treatment duration for main phase was defined as date of last study drug (EOT day) – date of first study drug + 1. For subjects entering main phase directly, treatment duration = date of last non-zero dose - date of first dose at main phase + 1; for subjects entering main phase from HbS phase, treatment duration = date of last non-zero dose - main phase Day 1 + 1.
    End point type
    Secondary
    End point timeframe
    From baseline up to 36 months
    End point values
    		 BAY85-3934 Darbepoetin
    Number of subjects analysed
    103 [10]
    41 [11]
    Units: days
        arithmetic mean (standard deviation)
    399.8 ± 185.92
    414.6 ± 205.63
    Notes
    [10] - SAF with number of subjects evaluable for this specific end point.
    [11] - SAF with number of subjects evaluable for this specific end point.
    No statistical analyses for this end point

    Secondary: Number of Subjects Requiring Titration of Dose (Down-Titration, Up-Titration) During Main Phase

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    End point title
    		 Number of Subjects Requiring Titration of Dose (Down-Titration, Up-Titration) During Main Phase
    End point description
    Individual dose-titration for BAY 85-3934 was based on the subject’s Hb response and tolerability of previous dose, IXRS assigned the titrated dose for each subject and as per local label for darbepoetin. Treatment duration for main phase was defined as date of last study drug (EOT day) – date of first study drug + 1. For subjects entering main phase directly, treatment duration = date of last non-zero dose - date of first dose at main phase + 1; for subjects entering main phase from HbS phase, treatment duration = date of last non-zero dose - main phase Day 1 + 1. In the below table, > is greater than.
    End point type
    Secondary
    End point timeframe
    From baseline up to 36 months
    End point values
    		 BAY85-3934 Darbepoetin
    Number of subjects analysed
    103 [12]
    41 [13]
    Units: subjects
        Number of dose down-titration: 1
    23
    5
        Number of dose down-titration: 2 to 3
    28
    11
        Number of dose down-titration: >3 to 5
    9
    2
        Number of dose down-titration: >5
    1
    2
        Number of dose up-titration: 1
    18
    6
        Number of dose up-titration: 2 to 3
    30
    8
        Number of dose up-titration: >3 to 5
    12
    4
        Number of dose up-titration: >5
    3
    6
    Notes
    [12] - SAF with number of subjects evaluable for this specific end point.
    [13] - SAF with number of subjects evaluable for this specific end point.
    No statistical analyses for this end point

    Secondary: Change from Baseline in Reticulocyte Count During Main Phase

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    End point title
    		 Change from Baseline in Reticulocyte Count During Main Phase
    End point description
    Reticulocyte count (absolute reticulocyte counts and reticulocytes / erythrocyte %) was summarized for each post-baseline assessment until EOT during the main phase of study. Here 'n' signifies those subjects who were evaluable for this measure at given time points for each group respectively. In below table, '99999' here indicates that data was not calculated as the evaluable subjects were less than 3, as 2 or less collected values were not sufficient to calculate a reliable estimation. Treatment duration for main phase was defined as date of last study drug (EOT day) – date of first study drug + 1. For subjects entering main phase directly, treatment duration = date of last non-zero dose - date of first dose at main phase + 1; for subjects entering main phase from HbS phase, treatment duration = date of last non-zero dose - main phase Day 1 + 1.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 12, 24, 36, 48, 60, 72, 84, 96, 108 and EOT
    End point values
    		 BAY85-3934 Darbepoetin
    Number of subjects analysed
    103 [14]
    41 [15]
    Units: giga per liter (giga/L)
    arithmetic mean (standard deviation)
        Baseline (n=76, 34)
    71.7 ± 32.53
    69.4 ± 25.93
        Change at Week 12 (n=67, 30)
    0.6 ± 23.39
    -5.2 ± 19.91
        Change at Week 24 (n=61, 29)
    0.8 ± 24.45
    -9.1 ± 16.81
        Change at Week 36 (n=56, 25)
    -3 ± 21.88
    -4.7 ± 22.63
        Change at Week 48 (n=48, 24)
    -0.4 ± 24.82
    -3 ± 22.91
        Change at Week 60 (n=33, 14)
    -5.2 ± 26.54
    -8.5 ± 13.66
        Change at Week 72 (n=13, 11)
    5.4 ± 16.57
    -5.7 ± 19.86
        Change at Week 84 (n=9, 6)
    2.8 ± 28.27
    2 ± 16.28
        Change at Week 96 (n=6, 5)
    3.5 ± 28.93
    -10 ± 11.14
        Change at Week 108 (n=1, 1)
    -4 ± 99999
    -4 ± 99999
        Change at EOT (n=66, 31)
    -11.6 ± 26.17
    4 ± 24.77
    Notes
    [14] - mITT with number of subjects evaluable for this specific end point.
    [15] - mITT with number of subjects evaluable for this specific end point.
    No statistical analyses for this end point

    Secondary: Change from Baseline in Red Blood Cell Count During Main Phase

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    End point title
    		 Change from Baseline in Red Blood Cell Count During Main Phase
    End point description
    Red blood cell count was summarized for each post-baseline assessment until EOT during the main phase of study. Here 'n' signifies those subjects who were evaluable for this measure at given time points for each group respectively. In below table, '99999' here indicates that data was not calculated as the evaluable subjects were less than 3, as 2 or less collected values were not sufficient to calculate a reliable estimation. Treatment duration for main phase was defined as date of last study drug (EOT day) – date of first study drug + 1. For subjects entering main phase directly, treatment duration = date of last non-zero dose - date of first dose at main phase + 1; for subjects entering main phase from HbS phase, treatment duration = date of last non-zero dose - main phase Day 1 + 1.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 12, 24, 36, 48, 60, 72, 84, 96, 108 and EOT
    End point values
    		 BAY85-3934 Darbepoetin
    Number of subjects analysed
    103 [16]
    41 [17]
    Units: millions per microliters (M/mcL)
    arithmetic mean (standard deviation)
        Baseline (n=98, 39)
    3.73 ± 0.381
    3.71 ± 0.446
        Change at Week 12 (n=88, 33)
    -0.04 ± 0.349
    -0.02 ± 0.34
        Change at Week 24 (n=80, 33)
    -0.12 ± 0.36
    -0.05 ± 0.333
        Change at Week 36 (n=71, 30)
    -0.12 ± 0.359
    -0.05 ± 0.395
        Change at Week 48 (n=62, 27)
    -0.12 ± 0.332
    -0.07 ± 0.296
        Change at Week 60 (n=42, 16)
    -0.2 ± 0.446
    -0.03 ± 0.328
        Change at Week 72 (n=19, 13)
    -0.01 ± 0.373
    -0.02 ± 0.28
        Change at Week 84 (n=13, 7)
    -0.05 ± 0.45
    0.1 ± 0.379
        Change at Week 96 (n=6, 5)
    -0.12 ± 0.36
    -0.08 ± 0.164
        Change at Week 108 (n=0, 1)
    99999 ± 99999
    -4 ± 99999
        Change at EOT (n=81, 33)
    -0.25 ± 0.399
    -0.15 ± 0.442
    Notes
    [16] - mITT with number of subjects evaluable for this specific end point.
    [17] - mITT with number of subjects evaluable for this specific end point.
    No statistical analyses for this end point

    Secondary: Change from Baseline in Hematocrit During Main Phase

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    End point title
    		 Change from Baseline in Hematocrit During Main Phase
    End point description
    Hematocrit values were summarized for each post-baseline assessment until EOT during the main phase of study. Here 'n' signifies those subjects who were evaluable for this measure at given time points for each group respectively. In below table, '99999' here indicates that data was not calculated as the evaluable subjects were less than 3, as 2 or less collected values were not sufficient to calculate a reliable estimation. Treatment duration for main phase was defined as date of last study drug (EOT day) – date of first study drug + 1. For subjects entering main phase directly, treatment duration = date of last non-zero dose - date of first dose at main phase + 1; for subjects entering main phase from HbS phase, treatment duration = date of last non-zero dose - main phase Day 1 + 1.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 12, 24, 36, 48, 60, 72, 84, 96, 108 and EOT
    End point values
    		 BAY85-3934 Darbepoetin
    Number of subjects analysed
    103 [18]
    41 [19]
    Units: percentage
    arithmetic mean (standard deviation)
        Baseline (n=98, 39)
    35.1 ± 2.51
    34.1 ± 2.31
        Change at Week 12 (n=87, 33)
    -0.2 ± 3.17
    -0.4 ± 2.64
        Change at Week 24 (n=80, 33)
    -1 ± 3.55
    -0.4 ± 3.44
        Change at Week 36 (n=71, 30)
    -1 ± 3.4
    -0.5 ± 3.94
        Change at Week 48 (n=61, 26)
    -0.8 ± 3.39
    -0.6 ± 2.7
        Change at Week 60 (n=42, 16)
    -1.5 ± 4.31
    -0.3 ± 3.55
        Change at Week 72 (n=19, 13)
    0.5 ± 2.86
    -0.1 ± 2.84
        Change at Week 84 (n=13, 7)
    -0.1 ± 4.57
    0.4 ± 3.87
        Change at Week 96 (n=6, 5)
    -0.8 ± 2.99
    -0.4 ± 2.3
        Change at Week 108 (n=0, 1)
    99999 ± 99999
    -3 ± 99999
        Change at EOT (n=81, 33)
    -2.8 ± 3.93
    -1 ± 4.24
    Notes
    [18] - mITT with number of subjects evaluable for this specific end point.
    [19] - mITT with number of subjects evaluable for this specific end point.
    No statistical analyses for this end point

    Secondary: Change from Baseline in Central Laboratory Hemoglobin During Main Phase

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    End point title
    		 Change from Baseline in Central Laboratory Hemoglobin During Main Phase
    End point description
    Hb was analysed using the blood samples drawn during the main phase of the study. Here 'n' signifies those subjects who were evaluable for this measure at given time points for each group respectively. In below table, "99999" denotes that data was not calculated as no subjects were evaluated for the specified arm / standard deviation cannot be calculated as there was only one subject in the specified arm. Treatment duration for main phase was defined as date of last study drug (EOT day) – date of first study drug + 1. For subjects entering main phase directly, treatment duration = date of last non-zero dose - date of first dose at main phase + 1; for subjects entering main phase from HbS phase, treatment duration = date of last non-zero dose - main phase Day 1 + 1.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 12, 24, 36, 48, 60, 72, 84, 96, 108 and EOT
    End point values
    		 BAY85-3934 Darbepoetin
    Number of subjects analysed
    102 [20]
    40 [21]
    Units: gram per deciliter (g/dL)
    arithmetic mean (standard deviation)
        Baseline (n=102,40)
    11.54 ± 0.719
    10.99 ± 0.746
        Change at Week 12 (n=94,34)
    -0.11 ± 1.015
    0.17 ± 1.059
        Change at Week 24 (n=87,36)
    -0.42 ± 1.016
    0.03 ± 1.059
        Change at Week 36 (n=77,30)
    -0.52 ± 0.938
    0.13 ± 1.084
        Change at Week 48 (n=67,27)
    -0.43 ± 1.110
    0.09 ± 1.104
        Change at Week 60 (n=47,18)
    -0.74 ± 1.341
    0.18 ± 1.084
        Change at Week 72 (n=24,13)
    -0.39 ± 0.723
    -0.01 ± 0.941
        Change at Week 84 (n=19,7)
    -0.35 ± 1.200
    0.34 ± 1.041
        Change at Week 96 (n=7,5)
    -0.81 ± 0.938
    -0.26 ± 0.500
        Change at Week 108 (n=0,1)
    99999 ± 99999
    -0.58 ± 99999
        Change at Week EOT (n=36,14)
    -0.7 ± 1.489
    -0.7 ± 1.288
    Notes
    [20] - mITT with number of subjects evaluable for this specific end point.
    [21] - mITT with number of subjects evaluable for this specific end point.
    No statistical analyses for this end point

    Secondary: Number of Subjects Meeting Specific Local Hemoglobin Criteria During Main Phase

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    End point title
    		 Number of Subjects Meeting Specific Local Hemoglobin Criteria During Main Phase
    End point description
    The following were the specific hemoglobin criteria: > 50 % of the Hb levels below the lower limit of 10.0 g/dL, mean of the Hb levels below the lower limit of 10.0 g/dL, > 50% of the Hb levels above the upper limit of 12.0 g/dL, mean of the Hb levels above the upper limit of 12.0 g/dL. Treatment duration for main phase was defined as date of last study drug (EOT day) – date of first study drug + 1. For subjects entering main phase directly, treatment duration = date of last non-zero dose - date of first dose at main phase + 1; for subjects entering main phase from HbS phase, treatment duration = date of last non-zero dose - main phase Day 1 + 1.
    End point type
    Secondary
    End point timeframe
    From baseline up to 36 months
    End point values
    		 BAY85-3934 Darbepoetin
    Number of subjects analysed
    103 [22]
    41 [23]
    Units: subjects
        > 50% of Hb levels below lower limit of 10 g/dL
    2
    2
        Mean of Hb levels below lower limit of 10 g/dL
    3
    3
        > 50% of Hb levels above upper limit of 12 g/dL
    3
    2
        Mean of Hb levels above upper limit of 12 g/dL
    2
    2
    Notes
    [22] - mITT with number of subjects evaluable for this specific end point.
    [23] - mITT with number of subjects evaluable for this specific end point.
    Statistical analysis title
    		 BAY85-3934 (> 50% of Hb levels below 10 g/dL)
    Statistical analysis description
    Analysis was based on Miettinen and Nurminen method (an unconditional, asymptotic method). If the total observed subjects were less than 5 who met or did not meet specific criterion in any one of compared groups, unconditional confidence limits for the proportion difference were presented in 95% CI of difference.
    Comparison groups
    BAY85-3934 v Darbepoetin
    Number of subjects included in analysis
    144
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Difference from darbepoetin
    Point estimate
    -2.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -20.8
         upper limit
    		 15.1
    Statistical analysis title
    		 BAY85-3934 (Mean of Hb levels below 10 g/dL)
    Statistical analysis description
    Analysis was based on Miettinen and Nurminen method (an unconditional, asymptotic method). If the total observed subjects were less than 5 who met or did not meet specific criterion in any one of compared groups, unconditional confidence limits for the proportion difference were presented in 95% CI of difference.
    Comparison groups
    BAY85-3934 v Darbepoetin
    Number of subjects included in analysis
    144
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Difference from darbepoetin
    Point estimate
    -4.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -22.2
         upper limit
    		 13.6
    Statistical analysis title
    		 BAY85-3934 (> 50% of Hb levels above 12 g/dL)
    Statistical analysis description
    Analysis was based on Miettinen and Nurminen method (an unconditional, asymptotic method). If the total observed subjects were less than 5 who met or did not meet specific criterion in any one of compared groups, unconditional confidence limits for the proportion difference were presented in 95% CI of difference.
    Comparison groups
    BAY85-3934 v Darbepoetin
    Number of subjects included in analysis
    144
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Difference from darbepoetin
    Point estimate
    -2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -19.8
         upper limit
    		 16
    Statistical analysis title
    		 BAY85-3934 (Mean of Hb levels above 12 g/dL)
    Statistical analysis description
    Analysis was based on Miettinen and Nurminen method (an unconditional, asymptotic method). If the total observed subjects were less than 5 who met or did not meet specific criterion in any one of compared groups, unconditional confidence limits for the proportion difference were presented in 95% CI of difference.
    Comparison groups
    BAY85-3934 v Darbepoetin
    Number of subjects included in analysis
    144
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Difference from darbepoetin
    Point estimate
    -2.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -20.8
         upper limit
    		 15.1

    Secondary: Number of Subjects with Hemoglobin Levels >13 g/dL or Excessive Increase During Main Phase

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    End point title
    		 Number of Subjects with Hemoglobin Levels >13 g/dL or Excessive Increase During Main Phase
    End point description
    Excessive increase in Hb values was defined as an increase of >1 g/dL in 2 weeks or >2 g/dL in 4 weeks. Treatment duration for main phase was defined as date of last study drug (EOT day) – date of first study drug + 1. For subjects entering main phase directly, treatment duration = date of last non-zero dose - date of first dose at main phase + 1; for subjects entering main phase from HbS phase, treatment duration = date of last non-zero dose - main phase Day 1 + 1.
    End point type
    Secondary
    End point timeframe
    From baseline up to 36 months
    End point values
    		 BAY85-3934 Darbepoetin
    Number of subjects analysed
    103 [24]
    41 [25]
    Units: subjects
        Hb > 13 g/dL at any time
    10
    5
        Excessive increase of Hb with >2 g/dL over 4 weeks
    5
    0
    Notes
    [24] - mITT with number of subjects evaluable for this specific end point.
    [25] - mITT with number of subjects evaluable for this specific end point.
    Statistical analysis title
    		 BAY85-3934 (Hb >13 g/dL at any time)
    Statistical analysis description
    Analysis was based on Miettinen and Nurminen method (an unconditional, asymptotic method). If the total observed subjects were less than 5 who met or did not meet specific criterion in any one of compared groups, unconditional confidence limits for the proportion difference were presented in 95% CI of difference.
    Comparison groups
    BAY85-3934 v Darbepoetin
    Number of subjects included in analysis
    144
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Difference from darbepoetin
    Point estimate
    -2.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -16.7
         upper limit
    		 7.7
    Statistical analysis title
    		 BAY85-3934 (Excessive increase of Hb over 4 weeks)
    Statistical analysis description
    Analysis was based on Miettinen and Nurminen method (an unconditional, asymptotic method). If the total observed subjects were less than 5 who met or did not meet specific criterion in any one of compared groups, unconditional confidence limits for the proportion difference were presented in 95% CI of difference.
    Comparison groups
    BAY85-3934 v Darbepoetin
    Number of subjects included in analysis
    144
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Difference from darbepoetin
    Point estimate
    4.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -13.2
         upper limit
    		 22.7

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From start of study drug administration up to 3 days after the end of treatment
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19.1
    Reporting groups
    Reporting group title
    BAY85-3934
    Reporting group description
    		 Subjects received initial doses of BAY85-3934 tablet as per parent study OD and then all the doses were titrated to 15, 25, 50, 75, 100, and 150 milligram per day (mg/day) up to a maximum of 36 months. Treatment included two phases: the HbS (up to 16 weeks) for subjects who were outside of target Hb range at start of the extension study and the main phase (up to 36 months). In the HbS phase, subjects received initial doses of BAY85-3934 OD dose assigned by IXRS and then titrated at each scheduled visit to maintain Hb in the target range of 10.0 to 12.0 g/dL. In the main phase, subjects received titrated dose of BAY85-3934 OD assigned by IXRS.

    Reporting group title
    Darbepoetin
    Reporting group description
    		 Subjects received initial doses of darbepoetin IV or SC and all the doses were titrated at the scheduled dose up to a maximum of 36 months. Treatment included two phases: HbS (up to 16 weeks) and main phase (up to 36 months). In the HbS phase, subjects who were on placebo in the parent study or were out of Hb target range at start of the extension study received initial doses of darbepoetin IV or SC according to local label and then titrated at each scheduled visit to maintain Hb in the target range of 10.0 to 12.0 g/dL. In the main phase, subjects received titrated dose of darbepoetin IV or SC according to the local label and titrated at each scheduled visit for every 4 weeks.

    Serious adverse events
    		 BAY85-3934 Darbepoetin
    Total subjects affected by serious adverse events
         subjects affected / exposed
    56 / 118 (47.46%)
    22 / 42 (52.38%)
         number of deaths (all causes)
    5
    1
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Basal cell carcinoma
         subjects affected / exposed
    1 / 118 (0.85%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colorectal cancer
         subjects affected / exposed
    1 / 118 (0.85%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal adenocarcinoma
         subjects affected / exposed
    1 / 118 (0.85%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung neoplasm malignant
         subjects affected / exposed
    0 / 118 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastatic gastric cancer
         subjects affected / exposed
    0 / 118 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Vascular disorders
    Hypertension
         subjects affected / exposed
    2 / 118 (1.69%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Orthostatic hypotension
         subjects affected / exposed
    1 / 118 (0.85%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    1 / 118 (0.85%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oedema
         subjects affected / exposed
    1 / 118 (0.85%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oedema peripheral
         subjects affected / exposed
    1 / 118 (0.85%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Anaphylactic shock
         subjects affected / exposed
    0 / 118 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory failure
         subjects affected / exposed
    1 / 118 (0.85%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pleural effusion
         subjects affected / exposed
    1 / 118 (0.85%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleurisy
         subjects affected / exposed
    0 / 118 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    1 / 118 (0.85%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sleep apnoea syndrome
         subjects affected / exposed
    1 / 118 (0.85%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Haemoglobin decreased
         subjects affected / exposed
    1 / 118 (0.85%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Arteriovenous fistula site complication
         subjects affected / exposed
    0 / 118 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Brain contusion
         subjects affected / exposed
    0 / 118 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Joint injury
         subjects affected / exposed
    1 / 118 (0.85%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal column injury
         subjects affected / exposed
    0 / 118 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subdural haemorrhage
         subjects affected / exposed
    1 / 118 (0.85%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    0 / 118 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Angina pectoris
         subjects affected / exposed
    2 / 118 (1.69%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Angina unstable
         subjects affected / exposed
    0 / 118 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    2 / 118 (1.69%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bradyarrhythmia
         subjects affected / exposed
    1 / 118 (0.85%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    4 / 118 (3.39%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Cardiac failure acute
         subjects affected / exposed
    0 / 118 (0.00%)
    2 / 42 (4.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure chronic
         subjects affected / exposed
    1 / 118 (0.85%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    1 / 118 (0.85%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    1 / 118 (0.85%)
    0 / 42 (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
    Carotid artery occlusion
         subjects affected / exposed
    1 / 118 (0.85%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    1 / 118 (0.85%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Parkinson's disease
         subjects affected / exposed
    0 / 118 (0.00%)
    1 / 42 (2.38%)
         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
    2 / 118 (1.69%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    2 / 118 (1.69%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nephrogenic anaemia
         subjects affected / exposed
    1 / 118 (0.85%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Cataract
         subjects affected / exposed
    0 / 118 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    1 / 118 (0.85%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enteritis
         subjects affected / exposed
    0 / 118 (0.00%)
    1 / 42 (2.38%)
         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 / 118 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Melaena
         subjects affected / exposed
    1 / 118 (0.85%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal haemorrhage
         subjects affected / exposed
    1 / 118 (0.85%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Bile duct stone
         subjects affected / exposed
    1 / 118 (0.85%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    1 / 118 (0.85%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    1 / 118 (0.85%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic kidney disease
         subjects affected / exposed
    16 / 118 (13.56%)
    6 / 42 (14.29%)
         occurrences causally related to treatment / all
    0 / 18
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    End stage renal disease
         subjects affected / exposed
    4 / 118 (3.39%)
    3 / 42 (7.14%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hydronephrosis
         subjects affected / exposed
    0 / 118 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nephropathy
         subjects affected / exposed
    0 / 118 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    2 / 118 (1.69%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal impairment
         subjects affected / exposed
    2 / 118 (1.69%)
    2 / 42 (4.76%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    Hypothyroidism
         subjects affected / exposed
    1 / 118 (0.85%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Rhabdomyolysis
         subjects affected / exposed
    0 / 118 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    1 / 118 (0.85%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Catheter site infection
         subjects affected / exposed
    1 / 118 (0.85%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device related sepsis
         subjects affected / exposed
    1 / 118 (0.85%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetic gangrene
         subjects affected / exposed
    1 / 118 (0.85%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    0 / 118 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gangrene
         subjects affected / exposed
    1 / 118 (0.85%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    1 / 118 (0.85%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infective exacerbation of chronic obstructive airways disease
         subjects affected / exposed
    0 / 118 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    6 / 118 (5.08%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    1 / 118 (0.85%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis acute
         subjects affected / exposed
    2 / 118 (1.69%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis chronic
         subjects affected / exposed
    0 / 118 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sinusitis
         subjects affected / exposed
    1 / 118 (0.85%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Diabetes mellitus inadequate control
         subjects affected / exposed
    1 / 118 (0.85%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fluid overload
         subjects affected / exposed
    1 / 118 (0.85%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    1 / 118 (0.85%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperkalaemia
         subjects affected / exposed
    1 / 118 (0.85%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    0 / 118 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    1 / 118 (0.85%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 BAY85-3934 Darbepoetin
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    94 / 118 (79.66%)
    34 / 42 (80.95%)
    Injury, poisoning and procedural complications
    Laceration
         subjects affected / exposed
    0 / 118 (0.00%)
    3 / 42 (7.14%)
         occurrences all number
    0
    3
    Vascular disorders
    Hypertension
         subjects affected / exposed
    23 / 118 (19.49%)
    14 / 42 (33.33%)
         occurrences all number
    36
    21
    Hypotension
         subjects affected / exposed
    8 / 118 (6.78%)
    0 / 42 (0.00%)
         occurrences all number
    10
    0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    0 / 118 (0.00%)
    4 / 42 (9.52%)
         occurrences all number
    0
    4
    General disorders and administration site conditions
    Oedema
         subjects affected / exposed
    7 / 118 (5.93%)
    0 / 42 (0.00%)
         occurrences all number
    10
    0
    Oedema peripheral
         subjects affected / exposed
    6 / 118 (5.08%)
    4 / 42 (9.52%)
         occurrences all number
    7
    4
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    10 / 118 (8.47%)
    0 / 42 (0.00%)
         occurrences all number
    12
    0
    Diarrhoea
         subjects affected / exposed
    11 / 118 (9.32%)
    4 / 42 (9.52%)
         occurrences all number
    13
    4
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    0 / 118 (0.00%)
    3 / 42 (7.14%)
         occurrences all number
    0
    3
    Renal and urinary disorders
    Chronic kidney disease
         subjects affected / exposed
    14 / 118 (11.86%)
    4 / 42 (9.52%)
         occurrences all number
    17
    5
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    7 / 118 (5.93%)
    0 / 42 (0.00%)
         occurrences all number
    7
    0
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    7 / 118 (5.93%)
    0 / 42 (0.00%)
         occurrences all number
    7
    0
    Nasopharyngitis
         subjects affected / exposed
    15 / 118 (12.71%)
    7 / 42 (16.67%)
         occurrences all number
    23
    9
    Urinary tract infection
         subjects affected / exposed
    0 / 118 (0.00%)
    3 / 42 (7.14%)
         occurrences all number
    0
    3
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    6 / 118 (5.08%)
    0 / 42 (0.00%)
         occurrences all number
    7
    0

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    30 Oct 2014
    Following modifications were made in this amendment: •To improve study feasibility and safety monitoring, Day 8 of HbS phase was removed and the subjects from Study 15141 who had an Hb stopping event after Day 15 in that study were added to the safety monitoring at Day 15 of HbS phase •Heart failure was added to the list of adjudicated AEs as it was the most frequently observed event amongst all components of the composite safety endpoint in this population •To improve study feasibility, ECG assessments were reduced from triplicate to single measurements and clarified to reflect the use of ECG as a safety measure. In addition information on ECG central review was removed which had been included in error since it was not applicable to the study •Following statement was included in the protocol: prescribed continuous dosing of acetaminophen / paracetamol was not allowed •Atrial fibrillation as an exclusion criterion was removed as it was considered common in the study population •Clarification on time separation of intake of BAY85-3934 and breast cancer resistant protein substrates
    24 Nov 2015
    Discrepancy was identified between the BAY85-3934 dose titrations (dose increase, dose decrease, and dose suspension) and those utilized in the IXRS system, the IXRS system was programmed to allow dose suspension in case of high Hb (Hb > 11.7 g/dL).

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

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    Analyses on changes of the following measures from baseline in parent study were not performed: reticulocyte count, red blood cell count, haematocrit and central laboratory hemoglobin.
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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