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    Clinical Trial Results:
    A Randomized, Double-Blind, Placebo-Controlled, Multicenter Study Evaluating Epoetin Alfa Versus Placebo in Anemic Patients With IPSS Low- or Intermediate-1-Risk Myelodysplastic Syndromes

    Summary
    EudraCT number
    2010-022884-36
    Trial protocol
    GR   IT   BG  
    Global end of trial date
    07 Jan 2016

    Results information
    Results version number
    v2(current)
    This version publication date
    02 Apr 2017
    First version publication date
    01 Jan 2017
    Other versions
    v1
    Version creation reason
    • New data added to full data set
    New data added

    Trial information

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    Trial identification
    Sponsor protocol code
    EPOANE3021
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01381809
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Janssen-Cilag International NV
    Sponsor organisation address
    Turnhoutseweg 30, Beerse, Belgium, 2340
    Public contact
    Clinical Registry Group, Janssen-Cilag International NV, ClinicalTrialsEU@its.jnj.com
    Scientific contact
    Clinical Registry Group, Janssen-Cilag International NV, ClinicalTrialsEU@its.jnj.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
    16 Dec 2016
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    07 Jan 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main objective of the study was to demonstrate that epoetin alfa treatment is better at improving anemia outcome (as evaluated by erythroid response – International Working Group [IWG] 2006 criteria; ie, an increase in hemoglobin by at least 1.5 gram per deciliter (g/dL) or a relevant reduction of red blood cell (RBC) units transfused by an absolute number of at least 4 units every 8 weeks; responses must last at least 8 weeks) in subjects with International Prognostic Scoring System (IPSS) low- or intermediate-1-risk myelodysplastic syndromes (MDS) compared with placebo through Week 24.
    Protection of trial subjects
    This study was conducted in accordance with the ethical principles that have their origin in the declaration of Helsinki and that are consistent with good clinical practices and applicable regulatory requirements. Safety evaluations were based upon thrombotic vascular events; relapse after hematologic improvement and disease progression, loss of response to study agent, clinical laboratory tests, physical examinations, vital signs. Adverse events (AEs) were assessed throughout the study.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    29 Sep 2011
    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
    Bulgaria: 15
    Country: Number of subjects enrolled
    Germany: 41
    Country: Number of subjects enrolled
    France: 20
    Country: Number of subjects enrolled
    Greece: 19
    Country: Number of subjects enrolled
    Italy: 30
    Country: Number of subjects enrolled
    Russian Federation: 5
    Worldwide total number of subjects
    130
    EEA total number of subjects
    125
    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)
    14
    From 65 to 84 years
    104
    85 years and over
    12

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    A total of 186 subjects were screened and 130 subjects were randomly assigned to a treatment group (85 subjects to Epoetin Alfa and 45 subjects to Placebo) and 93 subjects have completed the study. Out of them, 26 subjects enrolled in the open label extension phase, of these 10 subjects enrolled after week 24 and 16 subjects enrolled after week 48.

    Period 1
    Period 1 title
    Period 1 (Double Blind)
    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
    Epoetin Alfa
    Arm description
    Subjects received a starting dose of 450 International Unit per kilogram (IU/kg) of Epoetin Alfa (maximum total dose of 40,000 IU) administered subcutaneously once every week during treatment phase [up to week 24 when no erythroid response in subjects (non-responders)] and up to week 48 for subjects who have entered in study extension phase.
    Arm type
    Experimental

    Investigational medicinal product name
    Epoetin Alfa
    Investigational medicinal product code
    EPO
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subjects received a starting dose of 450 (IU/kg) of Epoetin Alfa (maximum total dose of 40,000 IU) administered subcutaneously up to Week 48.

    Arm title
    Placebo
    Arm description
    Subjects received a starting dose of a matching volume of placebo were administered subcutaneously once every week during treatment phase [up to week 24 when no erythroid response in subjects (non-responders)] and up to Week 48 for subjects who have entered in study extension phase.
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subjects received a starting dose of a matching volume of placebo were administered subcutaneously once every week up to Week 48.

    Number of subjects in period 1
    Epoetin Alfa Placebo
    Started
    85
    45
    Completed
    60
    33
    Not completed
    25
    12
         Protocol deviation
    1
    -
         Physician decision
    -
    1
         Lack of efficacy
    1
    1
         Relapse after hemat imprmnt or disease progression
    2
    -
         Non responder
    3
    1
         Adverse event, serious fatal
    3
    -
         Adverse event, non-fatal
    2
    -
         Consent withdrawn by subject
    6
    3
         Adverse event, serious non-fatal
    7
    6
    Period 2
    Period 2 title
    Period 2 (Open Label)
    Is this the baseline period?
    No
    Allocation method
    Not applicable
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Enrolled After Week 24
    Arm description
    During the open-label extension phase, 10 subjects were enrolled after week 24 to evaluate the efficacy and safety with starting treatment of Epoetin Alfa. The dose escalation can be done [if no erythroid response was achieved, and the subject’s hemoglobin level was below 11 gram per deciliter (g/dL,) or subject’s hemoglobin level was equal to or greater than 11 g/dL,] to 1050 IU/kg and 787.5 IU/kg] but can not exceed more than 80,000 IU dose at any time during the study period.
    Arm type
    Experimental

    Investigational medicinal product name
    Epoetin Alfa
    Investigational medicinal product code
    EPO
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subjects received starting treatment of Epoetin Alfa 450 (IU/kg) with maximum dose of 40,000 IU once weekly. The dose escalation can be done [if no erythroid response was achieved, and the subject’s hemoglobin level was below 11 gram per deciliter (g/dL,) or subject’s hemoglobin level was equal to or greater than 11 g/dL,] to 1050 IU/kg and 787.5 IU/kg] but can not exceed more than 80,000 IU dose at any time during the study period.

    Arm title
    Enrolled After Week 48
    Arm description
    During the open-label extension phase, 16 subjects were enrolled after Week 48 to evaluate the efficacy and safety with continuing on the same dose of Epoetin Alfa as was used during the double-blind treatment.
    Arm type
    Experimental

    Investigational medicinal product name
    Epoetin Alfa
    Investigational medicinal product code
    EPO
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subjects received starting treatment of Epoetin Alfa 450 (IU/kg) with maximum dose of 40,000 IU once weekly. The dose escalation can be done [if no erythroid response was achieved, and the subject’s hemoglobin level was below 11 gram per deciliter (g/dL,) or subject’s hemoglobin level was equal to or greater than 11 g/dL,] to 1050 IU/kg and 787.5 IU/kg] but can not exceed more than 80,000 IU dose at any time during the study period.

    Number of subjects in period 2 [1]
    Enrolled After Week 24 Enrolled After Week 48
    Started
    10
    16
    Completed
    10
    16
    Notes
    [1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: The open label extension phase was optional, and only applicable for 3 countries. Hence the number of subjects are not consistent.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Epoetin Alfa
    Reporting group description
    Subjects received a starting dose of 450 International Unit per kilogram (IU/kg) of Epoetin Alfa (maximum total dose of 40,000 IU) administered subcutaneously once every week during treatment phase [up to week 24 when no erythroid response in subjects (non-responders)] and up to week 48 for subjects who have entered in study extension phase.

    Reporting group title
    Placebo
    Reporting group description
    Subjects received a starting dose of a matching volume of placebo were administered subcutaneously once every week during treatment phase [up to week 24 when no erythroid response in subjects (non-responders)] and up to Week 48 for subjects who have entered in study extension phase.

    Reporting group values
    Epoetin Alfa Placebo Total
    Number of subjects
    85 45 130
    Title for AgeCategorical
    Units: subjects
        infants and toddlers(28 days-23 months)
    0 0 0
        Children (2-11 years)
    0 0 0
        Adolescents (12-17 years)
    0 0 0
        Adults (18-64 years)
    10 4 14
        From 65 to 84 years
    67 37 104
        85 years and over
    8 4 12
    Title for AgeContinuous
    Units: years
        arithmetic mean (standard deviation)
    74.3 ± 8.62 74.1 ± 9.25 -
    Title for Gender
    Units: subjects
        Female
    39 20 59
        Male
    46 25 71
    Subject analysis sets

    Subject analysis set title
    Enrolled after Week 24
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    The safety analysis set includes all randomized subjects who were enrolled after week 24 and received at least 1 dose of study agent (Epoetin Alfa) during the open label extension phase.

    Subject analysis set title
    Enrolled after Week 48
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    The safety analysis set includes all randomized subjects who were enrolled after week 48 and received at least 1 dose of study agent (Epoetin Alfa) during the open label extension phase.

    Subject analysis sets values
    Enrolled after Week 24 Enrolled after Week 48
    Number of subjects
    10
    16
    Title for AgeCategorical
    Units: subjects
        infants and toddlers(28 days-23 months)
    0
    0
        Children (2-11 years)
    0
    0
        Adolescents (12-17 years)
    0
    0
        Adults (18-64 years)
    1
    2
        From 65 to 84 years
    7
    11
        85 years and over
    2
    3
    Title for AgeContinuous
    Units: years
        arithmetic mean (standard deviation)
    76.5 ± 8.71
    77.2 ± 8.04
    Title for Gender
    Units: subjects
        Female
    4
    7
        Male
    6
    9

    End points

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    End points reporting groups
    Reporting group title
    Epoetin Alfa
    Reporting group description
    Subjects received a starting dose of 450 International Unit per kilogram (IU/kg) of Epoetin Alfa (maximum total dose of 40,000 IU) administered subcutaneously once every week during treatment phase [up to week 24 when no erythroid response in subjects (non-responders)] and up to week 48 for subjects who have entered in study extension phase.

    Reporting group title
    Placebo
    Reporting group description
    Subjects received a starting dose of a matching volume of placebo were administered subcutaneously once every week during treatment phase [up to week 24 when no erythroid response in subjects (non-responders)] and up to Week 48 for subjects who have entered in study extension phase.
    Reporting group title
    Enrolled After Week 24
    Reporting group description
    During the open-label extension phase, 10 subjects were enrolled after week 24 to evaluate the efficacy and safety with starting treatment of Epoetin Alfa. The dose escalation can be done [if no erythroid response was achieved, and the subject’s hemoglobin level was below 11 gram per deciliter (g/dL,) or subject’s hemoglobin level was equal to or greater than 11 g/dL,] to 1050 IU/kg and 787.5 IU/kg] but can not exceed more than 80,000 IU dose at any time during the study period.

    Reporting group title
    Enrolled After Week 48
    Reporting group description
    During the open-label extension phase, 16 subjects were enrolled after Week 48 to evaluate the efficacy and safety with continuing on the same dose of Epoetin Alfa as was used during the double-blind treatment.

    Subject analysis set title
    Enrolled after Week 24
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    The safety analysis set includes all randomized subjects who were enrolled after week 24 and received at least 1 dose of study agent (Epoetin Alfa) during the open label extension phase.

    Subject analysis set title
    Enrolled after Week 48
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    The safety analysis set includes all randomized subjects who were enrolled after week 48 and received at least 1 dose of study agent (Epoetin Alfa) during the open label extension phase.

    Primary: Percentage of Subjects with Erythroid Response at Any Time in the First 24 Weeks During Double Blind Phase

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    End point title
    Percentage of Subjects with Erythroid Response at Any Time in the First 24 Weeks During Double Blind Phase
    End point description
    Erythroid response was evaluated to demonstrate that epoetin alfa treatment is better at improving anemia outcome (as evaluated by erythroid response – International Working Group [IWG] 2006 criteria; ie, an increase in hemoglobin by at least 1.5 gram per deciliter (g/dL) or a relevant reduction of Red blood cells (RBC) units transfused by an absolute number of at least 4 units every 8 weeks; responses must last at least 8 weeks) in subjects with International Prognostic Scoring System (IPSS) low- or intermediate-1-risk myelodysplastic syndromes (MDS) compared with placebo through Week 24. The modified intent-to-treat (mITT) analysis set includes all randomized subjects who received at least 1 dose of study agent and had at least 1 postbaseline efficacy assessment.
    End point type
    Primary
    End point timeframe
    Up to Week 24
    End point values
    Epoetin Alfa Placebo
    Number of subjects analysed
    85
    45
    Units: Percentage of Subjects
        number (not applicable)
    31.8
    4.4
    Statistical analysis title
    Statistical analysis 1
    Comparison groups
    Epoetin Alfa v Placebo
    Number of subjects included in analysis
    130
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001
    Method
    Fisher exact
    Confidence interval

    Primary: Percentage of Subjects with Erythroid Response or Relapse at Any Time During Open Label Extension Phase

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    End point title
    Percentage of Subjects with Erythroid Response or Relapse at Any Time During Open Label Extension Phase [1]
    End point description
    Erythroid response was defined as an increase in hemoglobin by at least 1.5 g/dL (compared to baseline) or a reduction in RBC units transfused by at least 4 units per 8 weeks , compared to the 8 weeks prior to start of treatment. Erythroid response according to IWG 2006 criteria is defined as an erythroid response for a period of at least 8 weeks for the subjects entering the OLE phase after Week 24 (ie, non-responders who received placebo in double-blind treatment phase). Relapse after erythroid response according to IWG 2006 criteria is defined as at least 1 of the following: reduction in hemoglobin by greater than or equal to (>=)1.5 g/dL or transfusion dependence, or at least 50 percent decrement from maximum response levels in granulocytes or platelets. The safety analysis set includes all randomized subjects who were enrolled after week 24, week 48 and received at least 1 dose of study agent.
    End point type
    Primary
    End point timeframe
    Up to Week 52
    Notes
    [1] - 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 statistical analysis has been reported for this endpoint.
    End point values
    Enrolled after Week 24 Enrolled after Week 48
    Number of subjects analysed
    10 [2]
    16 [3]
    Units: Percentage of subjects
    number (not applicable)
        Erythroid Response according to RRC
    50
    999
        Relapsec according to RRC
    888
    81.3
    Notes
    [2] - 888 indicates- Parameter Relapse was not applicable for subjects enrolled after week 24.
    [3] - 999 indicates- Parameter erythroid response was not applicable for subjects enrolled after week 48.
    No statistical analyses for this end point

    Secondary: Duration of Erythroid Response During Double Blind Phase

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    End point title
    Duration of Erythroid Response During Double Blind Phase
    End point description
    Duration of response (days) was defined by the assessment of the Response Review Committee (RRC) for subjects who responded at any time during the first 24 weeks of the study. The duration of response was defined as the number of days from the date of the week at which the response started until the date of the week the response ended +1 day. The mITT analysis set includes all randomized subjects who received at least 1 dose of study agent and had at least 1 postbaseline efficacy assessment.
    End point type
    Secondary
    End point timeframe
    Up to Week 24
    End point values
    Epoetin Alfa Placebo
    Number of subjects analysed
    85
    45
    Units: Days
        median (full range (min-max))
    197 (54 to 323)
    99 (50 to 148)
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Erythroid Responders at Week 48 During Double Blind Phase

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    End point title
    Percentage of Subjects With Erythroid Responders at Week 48 During Double Blind Phase
    End point description
    The percentage of responders at Week 48 was calculated using the RRC assessment of erythroid response: the number of subjects who responded at Week 48 divided by the total number of subjects in the given analysis data set for each treatment group. Responders at Week 48 were defined as subjects who were responders at Week 24, continued the study treatment, and maintained their response status through Week 48. The mITT analysis set includes all randomized subjects who received at least 1 dose of study agent and had at least 1 postbaseline efficacy assessment.
    End point type
    Secondary
    End point timeframe
    Week 48
    End point values
    Epoetin Alfa Placebo
    Number of subjects analysed
    85
    45
    Units: Percentage of Subjects
        number (not applicable)
    9.4
    0
    No statistical analyses for this end point

    Secondary: Time to First Red Blood Cell (RBC) transfusion During Double Blind Phase

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    End point title
    Time to First Red Blood Cell (RBC) transfusion During Double Blind Phase
    End point description
    The analysis population is subjects with at least one RBC transfusions either in the 8 weeks prior to baseline and/or after randomization. The mITT analysis set includes all randomized subjects who received at least 1 dose of study agent and had at least 1 postbaseline efficacy assessment.
    End point type
    Secondary
    End point timeframe
    Up to Week 52
    End point values
    Epoetin Alfa Placebo
    Number of subjects analysed
    57
    31
    Units: Days
        arithmetic mean (standard error)
    121.9 ± 15.93
    62.3 ± 11.17
    Statistical analysis title
    Statistical analysis 1
    Comparison groups
    Epoetin Alfa v Placebo
    Number of subjects included in analysis
    88
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.046
    Method
    Log-rank test
    Parameter type
    Hazard ratio (HR)
    Point estimate
    1.653
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.999
         upper limit
    2.736

    Secondary: Transfusion-Free Intervals During Double Blind Phase

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    End point title
    Transfusion-Free Intervals During Double Blind Phase
    End point description
    Transfusion-free interval is defined as the time (days) from the last visit date minus baseline date plus 1 minus the number of days with transfusions (day on which 1 or more RBC or whole blood units were transfused). The mITT analysis set includes all randomized subjects who received at least 1 dose of study agent and had at least 1 postbaseline efficacy assessment.
    End point type
    Secondary
    End point timeframe
    Up to Week 48
    End point values
    Epoetin Alfa Placebo
    Number of subjects analysed
    85
    45
    Units: Days
        median (full range (min-max))
    191 (41 to 378)
    192 (41 to 302)
    No statistical analyses for this end point

    Secondary: Percentage of Subjects with RBC Units Transfused During Double Blind Phase

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    End point title
    Percentage of Subjects with RBC Units Transfused During Double Blind Phase
    End point description
    The mITT analysis set includes all randomized subjects who received at least 1 dose of study agent and had at least 1 postbaseline efficacy assessment.
    End point type
    Secondary
    End point timeframe
    8 Weeks Prior to Baseline Visit to Week 24
    End point values
    Epoetin Alfa Placebo
    Number of subjects analysed
    85
    45
    Units: Percentage of Subjects
    number (not applicable)
        In 8 Weeks Prior to Baseline Visit
    51.8
    48.9
        Between Baseline and Week 8
    36.5
    44.4
        Between Week 8 and Week 16
    28
    51.2
        Between Week 16 and Week 24
    24.7
    54.1
        Between Baseline and Week 24
    42.4
    57.8
    No statistical analyses for this end point

    Secondary: Percentage of Subjects with Erythroid Response at Week 24 Based on RRC and CRF Evaluations During Double Blind Phase

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    End point title
    Percentage of Subjects with Erythroid Response at Week 24 Based on RRC and CRF Evaluations During Double Blind Phase
    End point description
    Erythroid response was evaluated to demonstrate that epoetin alfa treatment is better at improving anemia outcome (as evaluated by erythroid response – International Working Group [IWG] 2006 criteria; ie, an increase in hemoglobin by at least 1.5 gram per deciliter (g/dL) or a relevant reduction of Red blood cells (RBC) units transfused by an absolute number of at least 4 units every 8 weeks; responses must last at least 8 weeks) in subjects with International Prognostic Scoring System (IPSS) low- or intermediate-1-risk myelodysplastic syndromes (MDS) compared with placebo through Week 24. Erythroid Response reported for this endpoint was assessed by Response Review Committee (RRC) and case report form (CRF). The modified intent-to-treat (mITT) analysis set includes all randomized subjects who received at least 1 dose of study agent and had at least 1 postbaseline efficacy assessment.
    End point type
    Secondary
    End point timeframe
    Week 24
    End point values
    Epoetin Alfa Placebo
    Number of subjects analysed
    85
    45
    Units: Percentage of Subjects
    number (not applicable)
        RRC
    27.1
    2.2
        CRF
    36.5
    4.4
    Statistical analysis title
    Statistical analysis 1
    Comparison groups
    Epoetin Alfa v Placebo
    Number of subjects included in analysis
    130
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001
    Method
    Fisher exact test
    Confidence interval
    Statistical analysis title
    Statistical analysis 2
    Comparison groups
    Epoetin Alfa v Placebo
    Number of subjects included in analysis
    130
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001
    Method
    Fisher exact test
    Confidence interval

    Secondary: Change From Baseline in Quality of Life as Measured by Functional Assessment of Cancer Therapy-Anemia/Fatigue (FACT-An) Questionnaire During Double Blind Phase

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    End point title
    Change From Baseline in Quality of Life as Measured by Functional Assessment of Cancer Therapy-Anemia/Fatigue (FACT-An) Questionnaire During Double Blind Phase
    End point description
    The FACT-An questionaire is used to assess heath-related quality of life (HRQol). It measures the impact of anemia-related symptoms on patient functioning. The overall score range for the FACT-An is 0-188. Higher scores indicate better HRQoL. Patients with higher hemoglobin levels and better performance status reported significantly higher scores on these instruments (including the newly created subscales) than did those with lower hemoglobin levels and poorer performance status. The mITT analysis set includes all randomized subjects who received at least 1 dose of study agent and had at least 1 postbaseline efficacy assessment. Here the data value 998, -999 and 999 indicates no data evaluated at specific timepoint for this endpoint. Here, n indicates the number of subjects evaluated at specific timepoint for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24, Week 48 and up to Early Termination
    End point values
    Epoetin Alfa Placebo
    Number of subjects analysed
    85
    45
    Units: Units on a Scale
    arithmetic mean (standard deviation)
        FACT-An: Baseline (n= 74, 38)
    125.861 ± 31.2489
    131.837 ± 27.7914
        FACT-An: Change baseline to Week 24 (n= 66, 34)
    -0.626 ± 24.5955
    0.018 ± 18.091
        FACT-An: Change baseline to Week 48 (n= 29, 0)
    7.319 ± 18.2709
    999 ± 999
        FACT-An: Change baseline to Early Term (n= 15, 34)
    -12.006 ± 29.137
    -0.264 ± 25.0688
    Statistical analysis title
    Statistical Analysis at Week 24
    Comparison groups
    Placebo v Epoetin Alfa
    Number of subjects included in analysis
    130
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.884
    Method
    Wilcoxon 2-sample test
    Confidence interval
    Statistical analysis title
    Statistical Analysis at Early Termination
    Comparison groups
    Epoetin Alfa v Placebo
    Number of subjects included in analysis
    130
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.513
    Method
    Wilcoxon 2-sample test
    Confidence interval

    Secondary: Change From Baseline in Quality of Life as Measured by EuroQol 5-dimension (EQ-5D) Questionnaire During Double Blind Phase

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    End point title
    Change From Baseline in Quality of Life as Measured by EuroQol 5-dimension (EQ-5D) Questionnaire During Double Blind Phase
    End point description
    The EQ-5D is a patient-completed, multidimensional measure of health related quality of life. The instrument is applicable to a wide range of health conditions and treatments and results in a single index score. Each dimension comprises three levels (no problems, some/moderate problems, extreme problems). A unique EQ-5D health state is defined by combining one level from each of the five dimensions. EQ-5D index values range from -0.59 to 1.00. Higher EQ-5D Index scores represent better health status. The mITT analysis set includes all randomized subjects who received at least 1 dose of study agent and had at least 1 postbaseline efficacy assessment. Here, n indicates the number of subjects evaluated at specific timepoint for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24, Week 48 and Early Termination
    End point values
    Epoetin Alfa Placebo
    Number of subjects analysed
    85
    45
    Units: Units on a Scale
    arithmetic mean (standard deviation)
        Index Score: Baseline (n= 75, 38)
    0.709 ± 0.2678
    0.752 ± 0.2638
        Index Score:Change baseline to Week 24 (n= 66, 34)
    0.022 ± 0.3146
    0.042 ± 0.2779
        Index Score:Change baseline to Week 48 (n= 29, 0)
    0.032 ± 0.1658
    999 ± 999
        IndexScore:Change baseline to Early Term.(n= 15,5)
    0.011 ± 0.264
    0.01 ± 0.3402
    Statistical analysis title
    Statistical analysis -Index Score
    Comparison groups
    Epoetin Alfa v Placebo
    Number of subjects included in analysis
    130
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.66
    Method
    Wilcoxon 2-sample test
    Confidence interval

    Secondary: Duration of Erythroid Response During Open-Label Extension Phase

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    End point title
    Duration of Erythroid Response During Open-Label Extension Phase
    End point description
    Duration of response (days) for subjects who enrolled after Week 24 was defined by the assessment of the RRC for subjects who responded at any time during the OLE phase. The duration of response (days) was defined as the number of days in the OLE phase from date of response starting week until date of response ending week (ie, date of ending week response – date of starting week response + 1). The safety analysis set includes all randomized subjects who were enrolled after week 24, week 48 and received at least 1 dose of study agent.
    End point type
    Secondary
    End point timeframe
    Up to Week 52
    End point values
    Enrolled after Week 24
    Number of subjects analysed
    10
    Units: Days
        median (full range (min-max))
    105 (71 to 122)
    No statistical analyses for this end point

    Secondary: Time to Erythroid Response Relapse for Subjects Enrolled After Week 48 During Open-Label Extension Phase

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    End point title
    Time to Erythroid Response Relapse for Subjects Enrolled After Week 48 During Open-Label Extension Phase
    End point description
    Time to response after erythroid response determined by the RRC defined as the number of days from (date of ending week response - date of starting week response + 1). The safety analysis set includes all randomized subjects who were enrolled after week 24, week 48 and received at least 1 dose of study agent.
    End point type
    Secondary
    End point timeframe
    Up to Week 52
    End point values
    Enrolled after Week 48
    Number of subjects analysed
    13 [4]
    Units: Days
        median (full range (min-max))
    182 (141 to 409)
    Notes
    [4] - 13 subjects were observed with no relapse, time for Erythroid Response Relapse is assessed in them.
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Red Blood Cell Transfusions During Open-Label Extension Phase

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    End point title
    Percentage of Subjects With Red Blood Cell Transfusions During Open-Label Extension Phase
    End point description
    The safety analysis set includes all randomized subjects who were enrolled after Week 24, Week 48 and received at least 1 dose of study agent.
    End point type
    Secondary
    End point timeframe
    Up to Week 52
    End point values
    Enrolled after Week 24 Enrolled after Week 48
    Number of subjects analysed
    10
    16
    Units: Percentage of subjects
        number (not applicable)
    60
    12.5
    No statistical analyses for this end point

    Secondary: Number of Subjects With Adverse Events up to Week 52

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    End point title
    Number of Subjects With Adverse Events up to Week 52
    End point description
    An AE is any untoward medical occurrence in a subject who received study drug without regard to possibility of causal relationship. The safety analysis set consists of all subjects who are randomly assigned to a treatment group and received at least 1 dose of study agent.
    End point type
    Secondary
    End point timeframe
    Up to Week 52
    End point values
    Epoetin Alfa Placebo
    Number of subjects analysed
    85
    45
    Units: Number of Subjects
    73
    41
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to Week 52
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    14.0
    Reporting groups
    Reporting group title
    Epoetin Alfa
    Reporting group description
    Subjects received a Starting dose of 450 International Unit per kilogram (IU/kg) of Epoetin Alfa (maximum total dose of 40,000 IU) administered subcutaneously once every week during treatment phase [up to week 24 when no Erythroid response in subjects (non-responders) and] and up to Week 48 for subjects who have entered in study extension phase.

    Reporting group title
    Placebo
    Reporting group description
    Subjects received a Starting dose of a matching volume of placebo were administered subcutaneously once every week during treatment phase [up to week 24 when no Erythroid response in subjects (nonresponders) and] and up to Week 48 for subjects who have entered in study extension phase.

    Reporting group title
    Enrolled after Week 24
    Reporting group description
    During the open-label extension phase, 10 subjects were enrolled after week 24 to evaluate the efficacy and safety with continuing on the same dose of epoetin alfa as was used during the double-blind treatment. The dose escalation can be done [if no erythroid response was achieved, and the subject’s hemoglobin level was below 11 gram per deciliter (g/dL,) or subject’s hemoglobin level was equal to or greater than 11 g/dL,] to 1050 IU/kg and 787.5 IU/kg] but can not exceed more than 80,000 IU dose at any time during the study period.

    Reporting group title
    Enrolled after Week 48
    Reporting group description
    During the open-label extension phase, 16 subjects were enrolled after Week 48 to evaluate the efficacy and safety with continuing on the same dose of Epoetin Alfa as was used during the double-blind treatment.

    Serious adverse events
    Epoetin Alfa Placebo Enrolled after Week 24 Enrolled after Week 48
    Total subjects affected by serious adverse events
         subjects affected / exposed
    35 / 85 (41.18%)
    10 / 45 (22.22%)
    3 / 10 (30.00%)
    2 / 16 (12.50%)
         number of deaths (all causes)
    7
    1
    0
    0
         number of deaths resulting from adverse events
    Vascular disorders
    Aortic Dissection
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 85 (0.00%)
    1 / 45 (2.22%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Embolism
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 85 (1.18%)
    0 / 45 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Temporal Arteritis
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 85 (1.18%)
    0 / 45 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Surgical and medical procedures
    Knee Arthroplasty
    alternative assessment type: Systematic
         subjects affected / exposed
    2 / 85 (2.35%)
    0 / 45 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Acute Myeloid Leukaemia
    alternative assessment type: Systematic
         subjects affected / exposed
    2 / 85 (2.35%)
    2 / 45 (4.44%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    Leukaemia
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 85 (1.18%)
    0 / 45 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myelodysplastic Syndrome
    alternative assessment type: Systematic
         subjects affected / exposed
    5 / 85 (5.88%)
    0 / 45 (0.00%)
    0 / 10 (0.00%)
    1 / 16 (6.25%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Prostate Cancer
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 85 (1.18%)
    0 / 45 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Refractory Anaemia with An Excess of Blasts
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 85 (1.18%)
    1 / 45 (2.22%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Social circumstances
    Elderly
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 85 (1.18%)
    0 / 45 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Chest Pain
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 85 (1.18%)
    0 / 45 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Disease Progression
    alternative assessment type: Systematic
         subjects affected / exposed
    4 / 85 (4.71%)
    1 / 45 (2.22%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Impaired Healing
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 85 (1.18%)
    0 / 45 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
    alternative assessment type: Systematic
         subjects affected / exposed
    2 / 85 (2.35%)
    1 / 45 (2.22%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sudden Death
    alternative assessment type: Systematic
         subjects affected / exposed
    2 / 85 (2.35%)
    0 / 45 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Femur Fracture
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 85 (1.18%)
    0 / 45 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hip Fracture
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 85 (1.18%)
    0 / 45 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 85 (1.18%)
    0 / 45 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Laceration
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 85 (1.18%)
    0 / 45 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Traumatic Brain Injury
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 85 (1.18%)
    0 / 45 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Anti-Erythropoietin Antibody Positive
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 85 (1.18%)
    0 / 45 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemoglobin Decreased
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 85 (0.00%)
    1 / 45 (2.22%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Arrhythmia
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 85 (0.00%)
    1 / 45 (2.22%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac Failure
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 85 (1.18%)
    0 / 45 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac Failure Congestive
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 85 (1.18%)
    0 / 45 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Acute myocardial infarction
         subjects affected / exposed
    0 / 85 (0.00%)
    0 / 45 (0.00%)
    1 / 10 (10.00%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Thrombocytopenia
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 85 (1.18%)
    0 / 45 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Anaemia haemolytic autoimmune
         subjects affected / exposed
    0 / 85 (0.00%)
    0 / 45 (0.00%)
    1 / 10 (10.00%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 85 (1.18%)
    0 / 45 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lung Disorder
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 85 (1.18%)
    0 / 45 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pleural Effusion
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 85 (1.18%)
    0 / 45 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Age-Related Macular Degeneration
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 85 (0.00%)
    1 / 45 (2.22%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vertigo positional
         subjects affected / exposed
    0 / 85 (0.00%)
    0 / 45 (0.00%)
    1 / 10 (10.00%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal Pain
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 85 (1.18%)
    0 / 45 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastritis
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 85 (1.18%)
    0 / 45 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ileitis
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 85 (1.18%)
    0 / 45 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nausea
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 85 (1.18%)
    0 / 45 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Oesophagitis
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 85 (1.18%)
    0 / 45 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis Acute
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 85 (0.00%)
    1 / 45 (2.22%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sigmoiditis
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 85 (0.00%)
    1 / 45 (2.22%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vomiting
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 85 (1.18%)
    0 / 45 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    0 / 85 (0.00%)
    0 / 45 (0.00%)
    0 / 10 (0.00%)
    1 / 16 (6.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 85 (0.00%)
    0 / 45 (0.00%)
    1 / 10 (10.00%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal Failure
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 85 (1.18%)
    0 / 45 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Haematuria
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 85 (1.18%)
    0 / 45 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Neuropathic Ulcer
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 85 (1.18%)
    0 / 45 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Intervertebral Disc Compression
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 85 (1.18%)
    0 / 45 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Cachexia
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 85 (1.18%)
    0 / 45 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Hyperglycaemia
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 85 (1.18%)
    0 / 45 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Diabetic Gangrene
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 85 (1.18%)
    0 / 45 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
    alternative assessment type: Systematic
         subjects affected / exposed
    2 / 85 (2.35%)
    2 / 45 (4.44%)
    1 / 10 (10.00%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Soft Tissue Infection
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 85 (1.18%)
    0 / 45 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tooth Abscess
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 85 (1.18%)
    0 / 45 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urosepsis
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 85 (1.18%)
    0 / 45 (0.00%)
    1 / 10 (10.00%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abscess
         subjects affected / exposed
    0 / 85 (0.00%)
    0 / 45 (0.00%)
    0 / 10 (0.00%)
    1 / 16 (6.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Aspergillosis
         subjects affected / exposed
    0 / 85 (0.00%)
    0 / 45 (0.00%)
    1 / 10 (10.00%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchopneumonia
         subjects affected / exposed
    0 / 85 (0.00%)
    0 / 45 (0.00%)
    1 / 10 (10.00%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Localised infection
         subjects affected / exposed
    0 / 85 (0.00%)
    0 / 45 (0.00%)
    1 / 10 (10.00%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 85 (0.00%)
    0 / 45 (0.00%)
    1 / 10 (10.00%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Epoetin Alfa Placebo Enrolled after Week 24 Enrolled after Week 48
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    51 / 85 (60.00%)
    25 / 45 (55.56%)
    1 / 10 (10.00%)
    0 / 16 (0.00%)
    Vascular disorders
    Hypertension
    alternative assessment type: Systematic
         subjects affected / exposed
    3 / 85 (3.53%)
    3 / 45 (6.67%)
    1 / 10 (10.00%)
    0 / 16 (0.00%)
         occurrences all number
    3
    3
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
    alternative assessment type: Systematic
         subjects affected / exposed
    4 / 85 (4.71%)
    3 / 45 (6.67%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    4
    3
    0
    0
    Dyspnoea
    alternative assessment type: Systematic
         subjects affected / exposed
    10 / 85 (11.76%)
    1 / 45 (2.22%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    15
    1
    0
    0
    Blood and lymphatic system disorders
    Anaemia
    alternative assessment type: Systematic
         subjects affected / exposed
    6 / 85 (7.06%)
    5 / 45 (11.11%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    7
    25
    0
    0
    General disorders and administration site conditions
    Asthenia
    alternative assessment type: Systematic
         subjects affected / exposed
    12 / 85 (14.12%)
    5 / 45 (11.11%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    25
    7
    0
    0
    Fatigue
    alternative assessment type: Systematic
         subjects affected / exposed
    10 / 85 (11.76%)
    3 / 45 (6.67%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    13
    3
    0
    0
    Oedema Peripheral
    alternative assessment type: Systematic
         subjects affected / exposed
    4 / 85 (4.71%)
    5 / 45 (11.11%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    4
    5
    0
    0
    Pyrexia
    alternative assessment type: Systematic
         subjects affected / exposed
    7 / 85 (8.24%)
    4 / 45 (8.89%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    10
    4
    0
    0
    Ear and labyrinth disorders
    Vertigo
    alternative assessment type: Systematic
         subjects affected / exposed
    4 / 85 (4.71%)
    3 / 45 (6.67%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    5
    3
    0
    0
    Gastrointestinal disorders
    Abdominal Pain
    alternative assessment type: Systematic
         subjects affected / exposed
    5 / 85 (5.88%)
    2 / 45 (4.44%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    6
    2
    0
    0
    Constipation
    alternative assessment type: Systematic
         subjects affected / exposed
    8 / 85 (9.41%)
    0 / 45 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    9
    0
    0
    0
    Diarrhoea
    alternative assessment type: Systematic
         subjects affected / exposed
    9 / 85 (10.59%)
    3 / 45 (6.67%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    13
    3
    0
    0
    Nausea
    alternative assessment type: Systematic
         subjects affected / exposed
    6 / 85 (7.06%)
    0 / 45 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    7
    0
    0
    0
    Vomiting
    alternative assessment type: Systematic
         subjects affected / exposed
    5 / 85 (5.88%)
    1 / 45 (2.22%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    5
    1
    0
    0
    Skin and subcutaneous tissue disorders
    Pruritus
    alternative assessment type: Systematic
         subjects affected / exposed
    5 / 85 (5.88%)
    1 / 45 (2.22%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    6
    1
    0
    0
    Musculoskeletal and connective tissue disorders
    Back Pain
    alternative assessment type: Systematic
         subjects affected / exposed
    3 / 85 (3.53%)
    3 / 45 (6.67%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    3
    3
    0
    0
    Bone Pain
    alternative assessment type: Systematic
         subjects affected / exposed
    6 / 85 (7.06%)
    0 / 45 (0.00%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    6
    0
    0
    0
    Infections and infestations
    Nasopharyngitis
    alternative assessment type: Systematic
         subjects affected / exposed
    7 / 85 (8.24%)
    2 / 45 (4.44%)
    0 / 10 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    12
    2
    0
    0

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    02 Mar 2012
    The second amendment (INT-2) was considered substantial and included specification that for all non-responders at Week 24, the treatment code would be broken after the Week 28 assessments. For responders at Week 48, the treatment code would be broken after Week 48, following assessment of response. It was also clarified that blinded study treatment would be administered to all subjects at Week 24, and that blood samples for erythropoietin antibody testing in Week 24 non-responders would be obtained after Week 24 response assessments. Additionally, study inclusion criterion 4 was modified: a maximum hemoglobin concentration of 10.5 gram per deciliter (g/dL) at baseline was deemed acceptable for subjects undergoing Red blood cells (RBC) transfusion between screening and baseline. For inclusion criterion 6, a transfusion requirement of less than or equal to (≤) 4 RBC units over the 8 weeks before randomization was defined.
    24 Jan 2013
    The third amendment (INT-3; 24 January 2013) was considered substantial and included a number of changes to the inclusion/exclusion criteria to reduce the burden on subjects and to provide clarifications. Inclusion criteria 2 and 3 were modified to include diagnosis of myelodysplastic syndromes (MDS) and documentation of International Prognostic Scoring System (IPSS) during the screening phase as well as within the 12 weeks previously, but in case of signs of possible disease progression, a bone marrow aspirate/biopsy for diagnosis of primary MDS and an IPSS score were to be obtained during the screening period. In addition, the possibilities for retesting or rescreening were extended for potential subjects who were suitable for the study but temporarily ineligible due to either factors at screening that could be corrected or that were potentially due to fluctuations in laboratory tests. Inclusion criterion 5 was amended to clarify that erythropoietin could be retested. Additional changes allowed the resupply of vitamin B12 and/or folate to potential subjects who had confirmed MDS diagnosis but had B12/folate deficiency at screening. Such subjects could be eligible for study if adequate retested B12/folate levels were demonstrable before randomization. Inclusion criterion 4 was modified further such that the maximum allowable hemoglobin concentration of 10.5 g/dL was also applied to potential subjects who had received RBC transfusions within 2 weeks before screening. Changes to exclusion criteria included clarifications regarding: prior use of approved or experimental agents for the treatment of MDS ; history of uncontrolled hypertension; androgen or corticosteroid use; 2-week period before screening for prior treatment for neutropenia; and history of heart disease before screening. A new criterion was added to exclude patients who were receiving iron chelation therapy for greater than or equal (≥) 6 months at screening for iron overload caused by blood transfusion.
    19 Feb 2013
    The local Country-specific protocol amendments that were considered were implemented in Germany (12th Feb 2013), Bulgaria (19th Feb 2014), and Greece (15th Feb 2013). The amendments provided an optional open-label treatment phase and were implemented in Germany, Bulgaria, and Greece. Non-responders at Week 24 who received placebo in the double-blind phase and responders at Week 48 who received epoetin alfa in the treatment extension phase could receive open-label epoetin alfa for up to 6 months after the end of the main double-blind study phase (Germany and Greece) or until up to 1 year after the last subject had enrolled in the open-label treatment phase (Bulgaria). The key aspects and results of the open-label treatment phase will be reported separately. Additionally, a local protocol amendment indicated that measurement of iron-binding capacity was optional in Germany, consistent with local clinical practice.

    Interruptions (globally)

    Were there any global interruptions to the trial? No

    Limitations and caveats

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