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    Clinical Trial Results:
    A PHASE 3, MULTICENTER, RANDOMIZED, DOUBLE-BLIND STUDY TO COMPARE THE EFFICACY AND SAFETY OF ORAL AZACITIDINE PLUS BEST SUPPORTIVE CARE VERSUS PLACEBO PLUS BEST SUPPORTIVE CARE IN SUBJECTS WITH RED BLOOD CELL TRANSFUSION-DEPENDENT ANEMIA AND THROMBOCYTOPENIA DUE TO IPSS LOWER-RISK MYELODYSPLASTIC SYNDROMES

    Summary
    EudraCT number
    2012-002471-34
    Trial protocol
    BE   NO   SE   ES   CZ   PT   LT   IT   NL   GB   DE   FI   DK   FR   GR  
    Global end of trial date
    21 Dec 2023

    Results information
    Results version number
    v1(current)
    This version publication date
    01 Jan 2025
    First version publication date
    01 Jan 2025
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    AZA-MDS-003
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    -
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Bristol-Myers Squibb
    Sponsor organisation address
    Chaussee de la Hulpe 185, Brussels, Belgium, 1170
    Public contact
    EU Study Start-Up Unit, Bristol-Myers Squibb International Corporation, Clinical.Trials@bms.com
    Scientific contact
    Bristol-Myers Squibb Study Director, Bristol-Myers Squibb, Clinical.Trials@bms.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
    02 Feb 2024
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    21 Dec 2023
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of the study is to evaluate RBC transfusion independence in the 2 treatment arms (oral azacitidine plus best supportive care versus placebo plus best supportive care) in subjects with RBC transfusion-dependent anemia and thrombocytopenia due to IPSS lower-risk MDS.
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and in compliance with all International Conference on Harmonization Good Clinical Practice Guidelines. All the local regulatory requirements pertinent to safety of trial participants were followed.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    26 Apr 2013
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Australia: 18
    Country: Number of subjects enrolled
    Belgium: 5
    Country: Number of subjects enrolled
    Canada: 11
    Country: Number of subjects enrolled
    Czechia: 10
    Country: Number of subjects enrolled
    Finland: 2
    Country: Number of subjects enrolled
    France: 8
    Country: Number of subjects enrolled
    Germany: 27
    Country: Number of subjects enrolled
    Greece: 3
    Country: Number of subjects enrolled
    Israel: 4
    Country: Number of subjects enrolled
    Italy: 46
    Country: Number of subjects enrolled
    Korea, Republic of: 1
    Country: Number of subjects enrolled
    Mexico: 3
    Country: Number of subjects enrolled
    Netherlands: 2
    Country: Number of subjects enrolled
    Poland: 7
    Country: Number of subjects enrolled
    Portugal: 11
    Country: Number of subjects enrolled
    Spain: 24
    Country: Number of subjects enrolled
    Sweden: 3
    Country: Number of subjects enrolled
    Türkiye: 1
    Country: Number of subjects enrolled
    United Kingdom: 18
    Country: Number of subjects enrolled
    United States: 12
    Worldwide total number of subjects
    216
    EEA total number of subjects
    148
    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)
    30
    From 65 to 84 years
    172
    85 years and over
    14

    Subject disposition

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    Recruitment
    Recruitment details
    Participants were randomized at 101 sites globally. The sites were located in: Europe (76), North America (13), Asia/Pacific (10), and Latin America (2). Results are reported as of the data cut-off date of 25 January 2019.

    Pre-assignment
    Screening details
    Participants were stratified by: average baseline (BL) Red Blood Cell (RBC) transfusion requirement (≤ 4 units versus > 4 units of RBC per 28 days), BL platelet transfusion status (dependent or independent), country of enrollment and Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) (0 to 1 versus 2).

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Oral Azacitidine Plus Best Supportive Care
    Arm description
    Participants received 300 mg oral azacitidine tablets daily (QD) on days 1 to 21 of each 28-day treatment cycle and best supportive care (BSC) which included and was not limited to packed RBC (packed red blood cell [pRBC] and whole blood), platelet transfusions (single donor or pooled donor), antibiotic, antiviral and/or antifungal therapy, nutritional support, and granulocyte colony stimulating factors (G-CSF) for participants who experienced neutropenic fever/infections.
    Arm type
    Experimental

    Investigational medicinal product name
    Azacitidine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received 300 mg oral azacitidine tablets daily (QD) on days 1 to 21 of each 28-day treatment cycle

    Arm title
    Placebo Plus Best Supportive Care
    Arm description
    Participants received identically matching placebo tablets QD on days 1 to 21 of each 28-day treatment cycle and BSC which included but was not limited to, pRBC and whole blood, platelet transfusions (single donor or pooled donor), antibiotic, antiviral and/or antifungal therapy, nutritional support, and G-CSF for participants who experienced neutropenic fever/infections.
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received placebo tablets daily (QD) on days 1 to 21 of each 28-day treatment cycle

    Number of subjects in period 1
    Oral Azacitidine Plus Best Supportive Care Placebo Plus Best Supportive Care
    Started
    107
    109
    Completed
    0
    0
    Not completed
    107
    109
         Adverse event, serious fatal
    79
    86
         Consent withdrawn by subject
    13
    12
         Adverse event, non-fatal
    3
    -
         Other reasons
    11
    8
         Lost to follow-up
    -
    3
         Lack of efficacy
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Oral Azacitidine Plus Best Supportive Care
    Reporting group description
    Participants received 300 mg oral azacitidine tablets daily (QD) on days 1 to 21 of each 28-day treatment cycle and best supportive care (BSC) which included and was not limited to packed RBC (packed red blood cell [pRBC] and whole blood), platelet transfusions (single donor or pooled donor), antibiotic, antiviral and/or antifungal therapy, nutritional support, and granulocyte colony stimulating factors (G-CSF) for participants who experienced neutropenic fever/infections.

    Reporting group title
    Placebo Plus Best Supportive Care
    Reporting group description
    Participants received identically matching placebo tablets QD on days 1 to 21 of each 28-day treatment cycle and BSC which included but was not limited to, pRBC and whole blood, platelet transfusions (single donor or pooled donor), antibiotic, antiviral and/or antifungal therapy, nutritional support, and G-CSF for participants who experienced neutropenic fever/infections.

    Reporting group values
    Oral Azacitidine Plus Best Supportive Care Placebo Plus Best Supportive Care Total
    Number of subjects
    107 109 216
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    16 14 30
        From 65-84 years
    85 87 172
        85 years and over
    6 8 14
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    73.0 ( 9.23 ) 73.1 ( 8.36 ) -
    Sex: Female, Male
    Units: participants
        Female
    28 30 58
        Male
    79 79 158
    Race/Ethnicity, Customized
    Units: Subjects
        White
    96 99 195
        Black or African American
    1 0 1
        Asian
    2 3 5
        Native Hawaiian or Other Pacific Islanders
    0 0 0
        American Indian or Alaska Native
    0 0 0
        Japanese
    0 0 0
        Other
    8 7 15
    Race/Ethnicity, Customized
    Units: Subjects
        Hispanic or Latino
    4 9 13
        Not Hispanic or Latino
    91 93 184
        Not Reported
    12 7 19
    Myelodysplastic Syndrome (MDS) World Health Organization (WHO) 2008 Classification
    The WHO classification recognizes eight subtypes of MDS that are distinguished by the percentage of myeloblasts, presence or absence of ringed sideroblasts (i.e., erythroid precursors with iron deposits surrounding the nucleus), presence of a monocytosis or a deletion 5q.
    Units: Subjects
        RA = Refractory Anemia
    4 3 7
        RN = Refractory Neutropenia
    0 0 0
        RT = Refractory Thrombocytopenia
    1 0 1
        RARS = RA with Ringed Sideroblasts
    3 2 5
        RCMD = R Cytopenia w/ Multilineage Dysplasia
    80 73 153
        RAEB-1 RA with Excess Blasts - 1
    17 29 46
        RAEB-2 RA with Excess Blasts - 2
    0 0 0
        MDS-U (MDS-unclassified)
    2 2 4
        del (5q) MDS Associated with Isolated del 5q
    0 0 0
    International Prognostic Scoring System (IPSS)
    The international prognostic scoring system (IPSS) is a standard for risk assessment in primary myelodysplastic syndromes (MDS) that categorizes prognoses taking into account cytogenetics, cytopenias, blasts and blood counts. The IPSS prognostic subgroups consist of low-, intermediate-1-, intermediate-2-, and high-risk groups. The scale is 0-3.5 at 0.5 increments. Scores of 0=Low; 0.5-1.0=Int-1; 1.5-2.0=Int-2; 2.5-3.5=High risk which corresponds to poorer prognosis.
    Units: Subjects
        Low
    0 0 0
        Intermediate 1 (0..5-1.0)
    106 109 215
        Intermediate 2 (1.5-2.0)
    1 0 1
        High
    0 0 0
    Platelet Transfusion Status
    Participants with thrombocytopenia were defined by 2 platelet counts that were ≤ 75 × 10^9/cells/L with a platelet measurement ≥ 21 days apart. For those who were platelet transfusion-dependent at baseline and did not achieve platelet transfusion independence (TI) ≥ 56 days (8 weeks) during study treatment were considered as non-responders. For participants who were not platelet transfusion-dependent at baseline, development of platelet transfusion dependence, ie, ≥ 2 platelet transfusions in any 56-day (8 week) period during study treatment and were considered worse outcome.
    Units: Subjects
        Dependent
    30 35 65
        Independent
    77 74 151
    Eastern Cooperative Oncology Group (ECOG) Performance Status
    ECOG performance status is used to describe a patient’s level of functioning in terms of their ability to care for themselves, daily activity, and physical ability (walking, working, etc.). The scale ranges from 0 to 5: 0 = Fully active, no restrictions; 1 = Restricted activity but ambulatory, able to carry out work of a light nature; 2 = Ambulatory and capable of all self-care but unable to carry out work activities; 3 = Capable to only limited self-care, confined to bed or chair more than 50% of waking hours; 4 = Completely disabled, no self-care, confined to bed or chair; 5 = Dead.
    Units: Subjects
        Grade 0-1
    91 94 185
        Grade 2
    16 15 31
        Grade 3
    0 0 0
        Grade 4
    0 0 0
        Grade 5
    0 0 0
    Average Red Blood Cell Transfusion Requirement (units per 28 days)
    The average red blood cell (RBC) transfusion units per 28 days is derived using transfusion records before randomization date to randomization date - 84 days (if enrolled under original protocol or protocol amendment 1), or to randomization date - 56 days (if enrolled under protocol 2). "99999"=N/A
    Units: units per 28 days
        median (full range (min-max))
    3.33 (1.3 to 10.0) 3.33 (1.3 to 9.5) -
    Platelet Count
    "99999"=N/A
    Units: 10^9 cells/L
        arithmetic mean (standard deviation)
    27.0 ( 15.97 ) 27.9 ( 18.11 ) -
    Hemoglobin
    "99999"=N/A
    Units: g/dL
        arithmetic mean (standard deviation)
    8.22 ( 0.988 ) 8.04 ( 0.960 ) -

    End points

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    End points reporting groups
    Reporting group title
    Oral Azacitidine Plus Best Supportive Care
    Reporting group description
    Participants received 300 mg oral azacitidine tablets daily (QD) on days 1 to 21 of each 28-day treatment cycle and best supportive care (BSC) which included and was not limited to packed RBC (packed red blood cell [pRBC] and whole blood), platelet transfusions (single donor or pooled donor), antibiotic, antiviral and/or antifungal therapy, nutritional support, and granulocyte colony stimulating factors (G-CSF) for participants who experienced neutropenic fever/infections.

    Reporting group title
    Placebo Plus Best Supportive Care
    Reporting group description
    Participants received identically matching placebo tablets QD on days 1 to 21 of each 28-day treatment cycle and BSC which included but was not limited to, pRBC and whole blood, platelet transfusions (single donor or pooled donor), antibiotic, antiviral and/or antifungal therapy, nutritional support, and G-CSF for participants who experienced neutropenic fever/infections.

    Primary: Percentage of Participants who Achieved Red Blood Cell (RBC) Transfusion Independence for ≥ 56 Days

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    End point title
    Percentage of Participants who Achieved Red Blood Cell (RBC) Transfusion Independence for ≥ 56 Days
    End point description
    RBC transfusion (tfx) independence was defined as the absence of any RBC transfusion during any consecutive “rolling” 56 days within the treatment period. Participants who did not receive any RBC transfusion during a consecutive rolling 56 days (i.e., day 1 to day 56, day 2 to day 57) were considered as a 56-day RBC transfusion independent responder.
    End point type
    Primary
    End point timeframe
    Each participant was assessed for at least 56 days or more; from the date of randomization of study drug up to the data cut-off date of 25 January 2019, approximately 5 months.
    End point values
    Oral Azacitidine Plus Best Supportive Care Placebo Plus Best Supportive Care
    Number of subjects analysed
    107
    109
    Units: Percentage of Participants
        number (confidence interval 95%)
    30.8 (22.1 to 39.6)
    11.9 (5.8 to 18.0)
    Statistical analysis title
    RBC Transfusion Independence for ≥ 56 Days
    Comparison groups
    Placebo Plus Best Supportive Care v Oral Azacitidine Plus Best Supportive Care
    Number of subjects included in analysis
    216
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.0005 [1]
    Method
    Stratified Mantel-Haenszel Chi-squared
    Parameter type
    Rate Difference
    Point estimate
    18.9
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    8.3
         upper limit
    29.6
    Notes
    [1] - 2 sided

    Secondary: Duration of RBC Transfusion Independence Among Participants who Achieved RBC Transfusion Independence for at Least 56 Days

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    End point title
    Duration of RBC Transfusion Independence Among Participants who Achieved RBC Transfusion Independence for at Least 56 Days
    End point description
    Duration of RBC transfusion independence was analyzed only for participants who achieved RBC transfusion independence of ≥ 56 days on treatment. Duration of RBC transfusion independence was defined as the time from the date transfusion independence is first observed (day 1 of a ≥ 56 days period without a transfusion) until the date the participants had a subsequently documented RBC transfusion. In the event a participant had more than one ≥56 days rolling periods which met the RBC independence criteria, the duration with the longest rolling period was used in the analysis. Participants who maintained RBC TI through the end of the treatment period were censored at the date of treatment discontinuation, death, or 1 day before the start of the subsequent MDS treatment (if any), whichever occurred first, or the particiapnts latest available assessment date in the database if the treatment was still on-going. "99999"=N/A
    End point type
    Secondary
    End point timeframe
    From the date of randomization of study drug up to
    End point values
    Oral Azacitidine Plus Best Supportive Care Placebo Plus Best Supportive Care
    Number of subjects analysed
    33
    13
    Units: months
        median (confidence interval 95%)
    11.1 (8.2 to 26.0)
    12.0 (2.3 to 99999)
    Statistical analysis title
    Duration of RBC Transfusion Independence
    Comparison groups
    Placebo Plus Best Supportive Care v Oral Azacitidine Plus Best Supportive Care
    Number of subjects included in analysis
    46
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.0005
    Method
    Two-sided Unstratified Log Rank Test
    Parameter type
    Odds ratio (OR)
    Point estimate
    3.34
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.64
         upper limit
    6.79

    Secondary: Time to RBC Transfusion Independence for at Least 56 Days Among Participants who Achieved RBC Transfusion Independence for at Least 56 Days

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    End point title
    Time to RBC Transfusion Independence for at Least 56 Days Among Participants who Achieved RBC Transfusion Independence for at Least 56 Days
    End point description
    Time to RBC transfusion independence of ≥ 56 days was defined as the time between randomization and the date onset of transfusion independence was first observed (ie, Day 1 of 56 without any RBC transfusions).
    End point type
    Secondary
    End point timeframe
    From the date of randomization of study drug up to the data cut-off date of 25 January 2019; median duration of treatment to oral azacitidine was 5.29 months and 5.36 months for placebo
    End point values
    Oral Azacitidine Plus Best Supportive Care Placebo Plus Best Supportive Care
    Number of subjects analysed
    33
    13
    Units: Months
        median (full range (min-max))
    2.37 (0.0 to 10.9)
    2.04 (0.0 to 14.3)
    No statistical analyses for this end point

    Secondary: Duration of RBC Transfusion Reduction for Participants who Achieved RBC Transfusion Reduction of at Least 4 units of RBCs for at Least 8 Weeks

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    End point title
    Duration of RBC Transfusion Reduction for Participants who Achieved RBC Transfusion Reduction of at Least 4 units of RBCs for at Least 8 Weeks
    End point description
    A participant was considered as a RBC transfusion reduction responder if the participant had at least 4 units reduction in transfusion units over any consecutive 56 days period compared to the baseline transfusion units in 56 days.
    End point type
    Secondary
    End point timeframe
    From the date of randomization of study drug up to the treatment period; up to the data cut-off date of 25 January 2019; median duration of treatment to oral azacitidine was 5.29 months and 5.36 months for placebo
    End point values
    Oral Azacitidine Plus Best Supportive Care Placebo Plus Best Supportive Care
    Number of subjects analysed
    45
    34
    Units: months
        median (confidence interval 95%)
    10.0 (7.1 to 13.3)
    2.3 (2.0 to 5.0)
    No statistical analyses for this end point

    Secondary: Percentage of Participants who Achieved Red Blood Cell Transfusion Independence for ≥ 84 days

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    End point title
    Percentage of Participants who Achieved Red Blood Cell Transfusion Independence for ≥ 84 days
    End point description
    RBC transfusion independence was defined as the absence of any RBC transfusion during any consecutive “rolling” 84 days within the treatment period. Participants who did not receive any RBC transfusion during a consecutive rolling 84 days (i.e., day 1 to day 84, day 2 to day 85) were considered as a 84-day RBC transfusion independent responder.
    End point type
    Secondary
    End point timeframe
    From the date of randomization of study drug up to the treatment period; up to the data cut-off date of 25 January 2019; median duration of treatment to oral azacitidine was 5.29 months and 5.36 months for placebo
    End point values
    Oral Azacitidine Plus Best Supportive Care Placebo Plus Best Supportive Care
    Number of subjects analysed
    107
    109
    Units: Percentage of Participants
        number (confidence interval 95%)
    28.0 (19.5 to 36.5)
    6.4 (1.8 to 11.0)
    Statistical analysis title
    RBC Transfusion Independence for ≥ 84 days
    Comparison groups
    Placebo Plus Best Supportive Care v Oral Azacitidine Plus Best Supportive Care
    Number of subjects included in analysis
    216
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    < 0.0001 [2]
    Method
    Stratified Mantel-Haenszel; Chi-squared
    Parameter type
    Rate Difference
    Point estimate
    21.6
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    11.9
         upper limit
    31.3
    Notes
    [2] - 2 sided

    Secondary: Duration of RBC Transfusion Independence Among Participants who Achieved RBC Transfusion Independence for at Least 84 Days

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    End point title
    Duration of RBC Transfusion Independence Among Participants who Achieved RBC Transfusion Independence for at Least 84 Days
    End point description
    Duration of RBC transfusion independence was analyzed only for participants who achieved RBC transfusion independence of ≥ 84 days on treatment. Duration of RBC transfusion independence was defined as the time from the date transfusion independence is first observed (day 1 of a ≥ 84 days period without a transfusion) until the date the participants had a subsequently documented RBC transfusion. In case a participant had more than one ≥84 days rolling periods which met the RBC independence criteria, the duration with the longest rolling period was used in the analysis. "99999"=N/A
    End point type
    Secondary
    End point timeframe
    From the date of randomization of study drug up to the treatment period; up to the data cut-off date of 25 January 2019; median duration of treatment to oral azacitidine was 5.29 months and 5.36 months for placebo
    End point values
    Oral Azacitidine Plus Best Supportive Care Placebo Plus Best Supportive Care
    Number of subjects analysed
    30
    7
    Units: months
        median (confidence interval 95%)
    11.1 (8.2 to 26.0)
    99999 (5.0 to 99999)
    Statistical analysis title
    Duration of RBC Transfusion Independence
    Comparison groups
    Placebo Plus Best Supportive Care v Oral Azacitidine Plus Best Supportive Care
    Number of subjects included in analysis
    37
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.4347
    Method
    Two-Sided Unstratified Log Rank Test
    Confidence interval

    Secondary: Time to RBC Transfusion Independence for at Least 84 Days Among Participants who Achieved RBC Transfusion Independence for at Least 84 Days

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    End point title
    Time to RBC Transfusion Independence for at Least 84 Days Among Participants who Achieved RBC Transfusion Independence for at Least 84 Days
    End point description
    Time to RBC transfusion independence of ≥ 84 days was defined as the time between randomization and the date onset of transfusion independence was first observed (i.e., Day 1 of 84 without any RBC transfusions).
    End point type
    Secondary
    End point timeframe
    From the date of randomization of study drug up to the treatment period; up to the data cut-off date of 25 January 2019; median duration of treatment to oral azacitidine was 5.29 months and 5.36 months for placebo
    End point values
    Oral Azacitidine Plus Best Supportive Care Placebo Plus Best Supportive Care
    Number of subjects analysed
    30
    7
    Units: Months
        median (full range (min-max))
    2.64 (0.0 to 9.9)
    4.01 (0.5 to 14.3)
    No statistical analyses for this end point

    Secondary: Percentage of Participants with an Erythroid Hematological Improvement (HI-E) Response According to 2006 IWG Criteria

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    End point title
    Percentage of Participants with an Erythroid Hematological Improvement (HI-E) Response According to 2006 IWG Criteria
    End point description
    Erythroid HI-E improvement was defined as a hemoglobin increase of ≥ 1.5 g/dL; or a reduction in units of RBC transfusions by an absolute number of at least 4 RBC transfusions/8 weeks compared with the pretreatment transfusion number in the previous 8 weeks. Only RBC transfusions given for a hemoglobin of ≤ 9.0 g/dL on treatment were counted in the RBC transfusion response evaluation.
    End point type
    Secondary
    End point timeframe
    From the date of randomization of study drug up to the treatment period; up to the data cut-off date of 25 January 2019; median duration of treatment to oral azacitidine was 5.29 months and 5.36 months for placebo
    End point values
    Oral Azacitidine Plus Best Supportive Care Placebo Plus Best Supportive Care
    Number of subjects analysed
    107
    109
    Units: Percentage of Participants
    number (confidence interval 95%)
        HI-E Response
    43.0 (33.6 to 52.4)
    32.1 (23.3 to 40.9)
        ≥ 1.5 g/dL Hemoglobin Increase
    23.4 (15.3 to 31.4)
    5.5 (1.2 to 9.8)
        RBC Transfusion Reduction
    42.1 (32.7 to 51.4)
    31.2 (22.5 to 39.9)
    Statistical analysis title
    Erythroid Hematological Improvement (HI-E)
    Comparison groups
    Placebo Plus Best Supportive Care v Oral Azacitidine Plus Best Supportive Care
    Number of subjects included in analysis
    216
    Analysis specification
    Pre-specified
    Analysis type
    [3]
    P-value
    = 0.1467
    Method
    Stratified Mantel-Haenszel. Chi-squared
    Parameter type
    Rate Difference
    Point estimate
    10.9
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2
         upper limit
    23.7
    Notes
    [3] - HI-E
    Statistical analysis title
    Erythroid Hematological Improvement (HI-E)
    Comparison groups
    Placebo Plus Best Supportive Care v Oral Azacitidine Plus Best Supportive Care
    Number of subjects included in analysis
    216
    Analysis specification
    Pre-specified
    Analysis type
    [4]
    P-value
    = 0.1431
    Method
    Stratified Mantel-Haenszel. Chi-squared
    Parameter type
    Rate Difference
    Point estimate
    10.9
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.9
         upper limit
    23.6
    Notes
    [4] - RBC Transfusion Reduction
    Statistical analysis title
    Erythroid Hematological Improvement (HI-E)
    Comparison groups
    Placebo Plus Best Supportive Care v Oral Azacitidine Plus Best Supportive Care
    Number of subjects included in analysis
    216
    Analysis specification
    Pre-specified
    Analysis type
    [5]
    P-value
    = 0.0002
    Method
    Stratified Mantel-Haenszel. Chi-squared
    Parameter type
    Rate Diffrence
    Point estimate
    17.9
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    8.8
         upper limit
    26.9
    Notes
    [5] - ≥ 1.5 g/dL Hemoglobin Increase

    Secondary: Percentage of Participants with a Hematological Improvement Response in Platelets (HI-P) According to 2006 IWG Criteria

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    End point title
    Percentage of Participants with a Hematological Improvement Response in Platelets (HI-P) According to 2006 IWG Criteria
    End point description
    HI-P response was defined according to IWG 2006 criteria (Cheson, 2006) and as: 1. Absolute increase of ≥ 30 X 10^9/L for participants^ starting with > 20 X 10^9/L platelets; 2. Increase from < 20 X 10^9/L to > 20 X 10^9/L and by at least 100%. HI-P must have lasted at least 8 weeks.
    End point type
    Secondary
    End point timeframe
    From the date of randomization of study drug up to the treatment period; up to the data cut-off date of 25 January 2019; median duration of treatment to oral azacitidine was 5.29 months and 5.36 months for placebo
    End point values
    Oral Azacitidine Plus Best Supportive Care Placebo Plus Best Supportive Care
    Number of subjects analysed
    107
    109
    Units: Percentage of Participants
        number (confidence interval 95%)
    24.3 (16.2 to 32.4)
    7.3 (2.4 to 12.2)
    Statistical analysis title
    HI-P
    Comparison groups
    Placebo Plus Best Supportive Care v Oral Azacitidine Plus Best Supportive Care
    Number of subjects included in analysis
    216
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.0007
    Method
    Stratified Mantel-Haenszel. Chi-squared
    Parameter type
    Rate Difference
    Point estimate
    17
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    7.5
         upper limit
    26.4

    Secondary: Percentage of Participants who Achieved Platelet Transfusion Independence with a Duration of ≥ 8 weeks (56 days)

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    End point title
    Percentage of Participants who Achieved Platelet Transfusion Independence with a Duration of ≥ 8 weeks (56 days)
    End point description
    Platelet transfusion independence was defined as the absence of any platelet transfusion during any consecutive “rolling” 56 days during the treatment period, (ie, Day 1 to 56, Day 2 to 57, Days 3 to 58, etc.). Participants were considered platelet transfusion dependent at baseline if they had received ≥ 2 platelet transfusions during the 56 days immediately preceding randomization and had no consecutive 28-day period during which no platelet transfusions were administered.
    End point type
    Secondary
    End point timeframe
    From the date of randomization of study drug up to the treatment period; up to the data cut-off date of 25 January 2019; median duration of treatment to oral azacitidine was 5.29 months and 5.36 months for placebo
    End point values
    Oral Azacitidine Plus Best Supportive Care Placebo Plus Best Supportive Care
    Number of subjects analysed
    30
    35
    Units: Percentage Participants
        number (not applicable)
    16.7
    14.3
    No statistical analyses for this end point

    Secondary: Time to Platelet Transfusion Independence

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    End point title
    Time to Platelet Transfusion Independence
    End point description
    Time to platelet transfusion independence was defined as the time between randomization and the first documented date of onset of transfusion independence (ie, Day 1 of 56 without any platelet transfusions). "99999"=N/A
    End point type
    Secondary
    End point timeframe
    From the date of randomization of study drug up to the treatment period; up to the data cut-off date of 25 January 2019; median duration of treatment to oral azacitidine was 5.29 months and 5.36 months for placebo
    End point values
    Oral Azacitidine Plus Best Supportive Care Placebo Plus Best Supportive Care
    Number of subjects analysed
    5
    5
    Units: Months
        median (full range (min-max))
    9.6 (9.6 to 10.9)
    99999 (99999 to 99999)
    No statistical analyses for this end point

    Secondary: Overall Survival (OS)

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    End point title
    Overall Survival (OS)
    End point description
    Overall survival was defined as the time from randomization to death from any cause and was calculated using randomization date and date of death, or date of last follow-up for censored participants. All subjects were followed until drop out (withdrawal of consent from further data collection or lost to follow-up), death, or study closure. Participants who dropped out or were alive at study closure (or at the time of the interim analysis) had their OS times censored at the time of last contact, as appropriate.
    End point type
    Secondary
    End point timeframe
    From randomization up to death from any cause; up to a maximum of approximately 10 years on study; median duration of treatment to oral azacitidine was 5.29 months and 5.36 months for placebo
    End point values
    Oral Azacitidine Plus Best Supportive Care Placebo Plus Best Supportive Care
    Number of subjects analysed
    107
    109
    Units: Months
        median (confidence interval 95%)
    17.3 (12.9 to 20.8)
    16.7 (12.8 to 24.0)
    Statistical analysis title
    OS
    Comparison groups
    Placebo Plus Best Supportive Care v Oral Azacitidine Plus Best Supportive Care
    Number of subjects included in analysis
    216
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.6257
    Method
    Logrank
    Parameter type
    Cox proportional hazard
    Point estimate
    1.08
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.79
         upper limit
    1.49

    Secondary: Percentage of Participants with a Hematologic Response According to the 2006 IWG Criteria for MDS

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    End point title
    Percentage of Participants with a Hematologic Response According to the 2006 IWG Criteria for MDS
    End point description
    Hematologic response was defined as: • A complete response (CR): <5% myeloblasts, and normal maturation of all cell lines; Peripheral blood (PB) shows: hemoglobin >10 g/dL, neutrophils ≥1.0x10^9/L, platelets ≥100x10^9/dL, blasts (0%) • Partial Response (PR): same as CR bone marrow (BM) shows blasts decreased by ≥ 50% over pre-treatment but still > 5%; Cellularity and morphology not relevant • Marrow CR: BM: ≤ 5% myeloblasts and decrease by ≥ 50% over pre-treatment PB • Stable disease (SD): failure to achieve at least PR, but no evidence of progression for > 8 wks • Failure: death during treatment or disease progression • Disease Progression for those with: - Less than 5% blasts: ≥ 50% increase in blasts to > 5% blasts - 5%-10% blasts:≥ 50% increase to > 10% blasts - 10%-20% blasts:≥ 50% increase to > 20% blasts - 20%-30% blasts ≥ 50% increase to > 30% blasts Any of the following: - ≥ 50% decrease from maximum remission/response in granulocytes or platelets
    End point type
    Secondary
    End point timeframe
    Response was assessed every 3 cycles; up to the data cut-off date of 25 Jan 2019; median duration of exposure to oral azacitidine was 86.0 days and 119.0 days for placebo
    End point values
    Oral Azacitidine Plus Best Supportive Care Placebo Plus Best Supportive Care
    Number of subjects analysed
    107
    109
    Units: Percentage of Participants
    number (not applicable)
        Complete Response (CR)
    7.7
    0
        Partial Response
    0
    0
        Marrow CR
    23.1
    4.2
        Stable Disease (SD)
    2.8
    30.3
        Disease Progression
    62.6
    46.8
        Failure due to Death
    0.9
    0.9
    No statistical analyses for this end point

    Secondary: Percentage of Participants who Progressed to Acute Myeloid Leukemia (AML)

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    End point title
    Percentage of Participants who Progressed to Acute Myeloid Leukemia (AML)
    End point description
    Participants with a documented diagnosis of AML arising from previous MDS documented diagnosis.
    End point type
    Secondary
    End point timeframe
    From randomization of study drug to the end up to final data cut-off date of 25 January 2019; maximum follow-up time was 67.9 months for azacitidine and 64.8 months for placebo group
    End point values
    Oral Azacitidine Plus Best Supportive Care Placebo Plus Best Supportive Care
    Number of subjects analysed
    107
    109
    Units: Percentage of Participants
        number (not applicable)
    7.5
    16.5
    No statistical analyses for this end point

    Secondary: Time to Progression to Acute Myeloid Leukemia (AML) Among Participants who Progressed to AML

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    End point title
    Time to Progression to Acute Myeloid Leukemia (AML) Among Participants who Progressed to AML
    End point description
    Time to AML progression was defined as the time from the date of randomization until the date the subject has documented progression to AML. For participants who had progression to AML documented in MLL central lab report, the earliest sample collection date with the diagnosis of “s-AML arising from previous MDS” was used as the date to AML progression. "99999"=N/A
    End point type
    Secondary
    End point timeframe
    From randomization of study drug to progression of AML; up to a maximum of approximately 10 years on study; median duration of treatment to oral azacitidine was 5.29 months and 5.36 months for placebo
    End point values
    Oral Azacitidine Plus Best Supportive Care Placebo Plus Best Supportive Care
    Number of subjects analysed
    8
    18
    Units: Months
        median (full range (min-max))
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    No statistical analyses for this end point

    Secondary: Percentage of Participants with Significant Bleeding Events

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    End point title
    Percentage of Participants with Significant Bleeding Events
    End point description
    Clinically significant bleeding event was defined as: any intracranial or retroperitoneal bleed; bleeding requiring transfusions of > 2 units of blood/blood products; bleeding associated with a decrease in hemoglobin of > 2 g/dL; or bleeding from any site requiring transfusions of > 2 units of blood.
    End point type
    Secondary
    End point timeframe
    From date of randomization until 28 days after the last dose of IP; up to data cut off date of 25 January 2019; median duration of treatment to oral azacitidine was 5.29 months and 5.36 months for placebo
    End point values
    Oral Azacitidine Plus Best Supportive Care Placebo Plus Best Supportive Care
    Number of subjects analysed
    107
    109
    Units: Percentage of Participants
        number (not applicable)
    8.4
    9.2
    No statistical analyses for this end point

    Secondary: Number of Participants with Treatment Emergent Adverse Events (TEAE)

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    End point title
    Number of Participants with Treatment Emergent Adverse Events (TEAE)
    End point description
    A TEAE was defined as an adverse event that begins or worsens in intensity of frequency on or after the first dose of study drug through 28 days after last dose of study drug. A serious adverse event (SAE) is any: • Death; • Life-threatening event; • Any inpatient hospitalization or prolongation of existing hospitalization; • Persistent or significant disability or incapacity; • Congenital anomaly or birth defect; • Any other important medical event The investigator determined the relationship of an AE to study drug based on the timing of the AE relative to drug administration and whether or not other drugs, therapeutic interventions, or underlying conditions could provide a sufficient explanation for the event. The severity of an AE was evaluated by the investigator according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) (Version 4.0) where Grade 1 = Mild, Grade 2 = Moderate, Grade 3 = Severe, Grade 4 = Life-threatening and Grade 5 = Death.
    End point type
    Secondary
    End point timeframe
    From first dose of IP up to 28 days after the last dose of IP; up to a maximum of approximately 10 years on study; median duration of treatment to oral azacitaidine was 5.29 months and 5.36 months for placebo
    End point values
    Oral Azacitidine Plus Best Supportive Care Placebo Plus Best Supportive Care
    Number of subjects analysed
    107
    109
    Units: Participants
        ≥ 1 TEAE
    107
    108
        ≥ 1 TEAE Related to Study Drug
    102
    54
        ≥ 1 Serious TEAE
    83
    69
        ≥ 1 Serious TEAE Related to Study Drug
    38
    8
        ≥ 1 Grade (GR) 3-4 TEAE
    98
    81
        ≥ 1 Grade 3-4 TEAE Related to Study Drug
    73
    20
        ≥ 1 Grade (GR) 3-4 Serious TEAE
    79
    56
        ≥ 1 GR 3-4 Serious TEAE Related to Study Drug
    38
    5
        ≥ 1 TEAE Leading to Death
    25
    14
        ≥ 1 TEAE Related to Study Drug Leading to Death
    9
    2
        ≥ 1 TEAE Leading to Dose Reduction
    31
    4
        ≥ 1 TEAE Leading to Dose Interruption
    68
    40
        ≥ 1 TEAE Leading to Dose Interruption/Reduction
    29
    2
        ≥ 1 TEAE Leading to Treatment Discontinuation
    34
    31
    No statistical analyses for this end point

    Secondary: Mean Change From Baseline in the Physical Well-Being Component of the Functional Assessment of Cancer Therapy-Anemia (FACT-An) Endpoints at Cycle 6

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    End point title
    Mean Change From Baseline in the Physical Well-Being Component of the Functional Assessment of Cancer Therapy-Anemia (FACT-An) Endpoints at Cycle 6
    End point description
    The FACT-An questionnaire is a 47-item, cancer specific questionnaire consisting of a core 27 items measuring 4 general domains physical well being (PWG), social/family (SWB), emotional well being (EWB) and Functional Well-Being (FWB) and an additional 20-item anemia questionnaire that measures fatigue associated items and 7 non-fatigue items. The scales are formatted on 1 to 4 pages for self-administration using a 5-point Likert rating scale (0 = Not at all; 1 = A little bit; 2 = Somewhat; 3 = Quite a Bit and 4 = Very much). Also, general health related quality of life (HRQoL), the FACT-An measures the impact of fatigue and other anemia-related symptoms on patient functioning and is used to assess the effect of treatments in various therapeutic areas, including MDS. The instrument and the fatigue and non-fatigue subscales are scored by summing points from all questions, then converting this sum to a 100 point scale; 0 indicates the poorest QOL and 100 denotes the highest QOL.
    End point type
    Secondary
    End point timeframe
    Baseline to Cycle 6 Day 1
    End point values
    Oral Azacitidine Plus Best Supportive Care Placebo Plus Best Supportive Care
    Number of subjects analysed
    42
    49
    Units: Units on a Scale
        arithmetic mean (standard deviation)
    0.2 ( 4.12 )
    -0.8 ( 3.91 )
    Statistical analysis title
    FACT-An
    Comparison groups
    Placebo Plus Best Supportive Care v Oral Azacitidine Plus Best Supportive Care
    Number of subjects included in analysis
    91
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.214
    Method
    t-test, 2-sided
    Confidence interval

    Secondary: Mean Change From Baseline in the Social Well-Being Component of the Functional Assessment of Cancer Therapy-Anemia Instrument at Cycle 6

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    End point title
    Mean Change From Baseline in the Social Well-Being Component of the Functional Assessment of Cancer Therapy-Anemia Instrument at Cycle 6
    End point description
    The FACT-An questionnaire is a 47-item, cancer specific questionnaire consisting of a core 27 items measuring 4 general domains physical well being (PWG), social/family (SWB), emotional well being (EWB) and Functional Well-Being (FWB) and an additional 20-item anemia questionnaire that measures fatigue associated items and 7 non-fatigue items. The scales are formatted on 1 to 4 pages for self-administration using a 5-point Likert rating scale (0 = Not at all; 1 = A little bit; 2 = Somewhat; 3 = Quite a Bit and 4 = Very much). Also, general health related quality of life (HRQoL), the FACT-An measures the impact of fatigue and other anemia-related symptoms on patient functioning and is used to assess the effect of treatments in various therapeutic areas, including MDS. The instrument and the fatigue and non-fatigue subscales are scored by summing points from all questions, then converting this sum to a 100 point scale; 0 indicates the poorest QOL and 100 denotes the highest QOL.
    End point type
    Secondary
    End point timeframe
    Baseline to Cycle 6 Day 1
    End point values
    Oral Azacitidine Plus Best Supportive Care Placebo Plus Best Supportive Care
    Number of subjects analysed
    42
    49
    Units: Units on a Scale
        arithmetic mean (standard deviation)
    -0.4 ( 3.96 )
    -1.1 ( 4.69 )
    Statistical analysis title
    Social Well-Being
    Comparison groups
    Placebo Plus Best Supportive Care v Oral Azacitidine Plus Best Supportive Care
    Number of subjects included in analysis
    91
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.446
    Method
    t-test, 2-sided
    Confidence interval

    Secondary: Mean Change From Baseline in the Emotional Well-Being Component of the Functional Assessment of Cancer Therapy-Anemia Instrument at Cycle 6

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    End point title
    Mean Change From Baseline in the Emotional Well-Being Component of the Functional Assessment of Cancer Therapy-Anemia Instrument at Cycle 6
    End point description
    The FACT-An questionnaire is a 47-item, cancer specific questionnaire consisting of a core 27 items measuring 4 general domains physical well being (PWG), social/family (SWB), emotional well being (EWB) and Functional Well-Being (FWB) and an additional 20-item anemia questionnaire that measures fatigue associated items and 7 non-fatigue items. The scales are formatted on 1 to 4 pages for self-administration using a 5-point Likert rating scale (0 = Not at all; 1 = A little bit; 2 = Somewhat; 3 = Quite a Bit and 4 = Very much). Also, general health related quality of life (HRQoL), the FACT-An measures the impact of fatigue and other anemia-related symptoms on patient functioning and is used to assess the effect of treatments in various therapeutic areas, including MDS. The instrument and the fatigue and non-fatigue subscales are scored by summing points from all questions, then converting this sum to a 100 point scale; 0 indicates the poorest QOL and 100 denotes the highest QOL.
    End point type
    Secondary
    End point timeframe
    Baseline to Cycle 6 Day 1
    End point values
    Oral Azacitidine Plus Best Supportive Care Placebo Plus Best Supportive Care
    Number of subjects analysed
    42
    49
    Units: Units on a Scale
        arithmetic mean (standard deviation)
    1.3 ( 4.33 )
    0.2 ( 4.35 )
    Statistical analysis title
    Emotional Well-Being
    Comparison groups
    Placebo Plus Best Supportive Care v Oral Azacitidine Plus Best Supportive Care
    Number of subjects included in analysis
    91
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.248
    Method
    t-test, 2-sided
    Confidence interval

    Secondary: Mean Change From Baseline in the Functional Well-Being Component of the FACT-An Instrument at Cycle 6

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    End point title
    Mean Change From Baseline in the Functional Well-Being Component of the FACT-An Instrument at Cycle 6
    End point description
    The FACT-An questionnaire is a 47-item, cancer specific questionnaire consisting of a core 27 items measuring 4 general domains physical well being (PWG), social/family (SWB), emotional well being (EWB) and Functional Well-Being (FWB) and an additional 20-item anemia questionnaire that measures fatigue associated items and 7 non-fatigue items. The scales are formatted on 1 to 4 pages for self-administration using a 5-point Likert rating scale (0 = Not at all; 1 = A little bit; 2 = Somewhat; 3 = Quite a Bit and 4 = Very much). Also, general health related quality of life (HRQoL), the FACT-An measures the impact of fatigue and other anemia-related symptoms on patient functioning and is used to assess the effect of treatments in various therapeutic areas, including MDS. The instrument and the fatigue and non-fatigue subscales are scored by summing points from all questions, then converting this sum to a 100 point scale; 0 indicates the poorest QOL and 100 denotes the highest QOL.
    End point type
    Secondary
    End point timeframe
    Baseline to Cycle 6 Day 1
    End point values
    Oral Azacitidine Plus Best Supportive Care Placebo Plus Best Supportive Care
    Number of subjects analysed
    42
    49
    Units: Units on a Scale
        arithmetic mean (standard deviation)
    0.5 ( 3.95 )
    -1.2 ( 4.45 )
    Statistical analysis title
    Functional Well-Being
    Comparison groups
    Placebo Plus Best Supportive Care v Oral Azacitidine Plus Best Supportive Care
    Number of subjects included in analysis
    91
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.058
    Method
    t-test, 2-sided
    Confidence interval

    Secondary: Mean Change From Baseline in the Anemia Subscale within FACT-An Instrument at Cycle 6

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    End point title
    Mean Change From Baseline in the Anemia Subscale within FACT-An Instrument at Cycle 6
    End point description
    The FACT-An questionnaire is a 47-item, cancer specific questionnaire consisting of a core 27 items measuring 4 general domains physical well being (PWG), social/family (SWB), emotional well being (EWB) and Functional Well-Being (FWB) and an additional 20-item anemia questionnaire that measures fatigue associated items and 7 non-fatigue items. The scales are formatted on 1 to 4 pages for self-administration using a 5-point Likert rating scale (0 = Not at all; 1 = A little bit; 2 = Somewhat; 3 = Quite a Bit and 4 = Very much). Also, general health related quality of life (HRQoL), the FACT-An measures the impact of fatigue and other anemia-related symptoms on patient functioning and is used to assess the effect of treatments in various therapeutic areas, including MDS. The instrument and the fatigue and non-fatigue subscales are scored by summing points from all questions, then converting this sum to a 100 point scale; 0 indicates the poorest QOL and 100 denotes the highest QOL.
    End point type
    Secondary
    End point timeframe
    Baseline to Cycle 6 Day 1
    End point values
    Oral Azacitidine Plus Best Supportive Care Placebo Plus Best Supportive Care
    Number of subjects analysed
    42
    49
    Units: Units on a Scale
        arithmetic mean (standard deviation)
    2.9 ( 11.81 )
    -0.6 ( 10.39 )
    Statistical analysis title
    Anemia
    Comparison groups
    Placebo Plus Best Supportive Care v Oral Azacitidine Plus Best Supportive Care
    Number of subjects included in analysis
    91
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.13
    Method
    t-test, 2-sided
    Confidence interval

    Secondary: Mean Change From Baseline in the Fatigue-Related Subscale within the FACT-An Instrument at Cycle 6

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    End point title
    Mean Change From Baseline in the Fatigue-Related Subscale within the FACT-An Instrument at Cycle 6
    End point description
    The FACT-An questionnaire is a 47-item, cancer specific questionnaire consisting of a core 27 items measuring 4 general domains physical well being (PWG), social/family (SWB), emotional well being (EWB) and Functional Well-Being (FWB) and an additional 20-item anemia questionnaire that measures fatigue associated items and 7 non-fatigue items. The scales are formatted on 1 to 4 pages for self-administration using a 5-point Likert rating scale (0 = Not at all; 1 = A little bit; 2 = Somewhat; 3 = Quite a Bit and 4 = Very much). Also, general health related quality of life (HRQoL), the FACT-An measures the impact of fatigue and other anemia-related symptoms on patient functioning and is used to assess the effect of treatments in various therapeutic areas, including MDS. The instrument and the fatigue and non-fatigue subscales are scored by summing points from all questions, then converting this sum to a 100 point scale; 0 indicates the poorest QOL and 100 denotes the highest QOL.
    End point type
    Secondary
    End point timeframe
    Baseline to Cycle 6 Day 1
    End point values
    Oral Azacitidine Plus Best Supportive Care Placebo Plus Best Supportive Care
    Number of subjects analysed
    42
    49
    Units: Units on a Scale
        arithmetic mean (standard deviation)
    2.1 ( 8.74 )
    -0.6 ( 7.84 )
    Statistical analysis title
    Fatigue
    Comparison groups
    Placebo Plus Best Supportive Care v Oral Azacitidine Plus Best Supportive Care
    Number of subjects included in analysis
    91
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.123
    Method
    t-test, 2-sided
    Confidence interval

    Secondary: Mean Change From Baseline in the Functional Assessment of Cancer Therapy-Anemia Trial Outcome Index (FACT-An TOI) Summary Scale within the FACT-An Instrument at Cycle 6

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    End point title
    Mean Change From Baseline in the Functional Assessment of Cancer Therapy-Anemia Trial Outcome Index (FACT-An TOI) Summary Scale within the FACT-An Instrument at Cycle 6
    End point description
    The FACT-G and FACT-An score are summed to form the FACT-An total score. The FACT-An Trial Outcome Index (TOI) consists of the summation of a "summary scale" and includes the Physical Well-being, (PWB; 7 items; score range, 0–28), the Functional Well-being (7 items; score range, 0–28) and the Anemia subscale consisting of 20 items on the same five-point scale, with 13 of them measuring fatigue related symptoms (FS) and seven measuring non-FS. The FACT-An TOI has been demonstrated to be a sensitive indicator of clinical outcomes in a number of diseases including MDS. The Fact-TOI score ranges from 0 to 136. Higher scores on all scales of the Fact-An and subscales on the FACT-TOI reflect better quality of life or fewer symptoms.
    End point type
    Secondary
    End point timeframe
    Baseline to Cycle 6 Day 1
    End point values
    Oral Azacitidine Plus Best Supportive Care Placebo Plus Best Supportive Care
    Number of subjects analysed
    42
    49
    Units: Units on a Scale
        arithmetic mean (standard deviation)
    3.7 ( 17.29 )
    -2.7 ( 15.45 )
    Statistical analysis title
    FACT-An TOI
    Comparison groups
    Placebo Plus Best Supportive Care v Oral Azacitidine Plus Best Supportive Care
    Number of subjects included in analysis
    91
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.069
    Method
    t-test, 2-sided
    Confidence interval

    Secondary: Mean Change From Baseline in the Functional Assessment of Cancer Therapy-Anemia-General (FACT-G) Summary Scale within the FACT-An Instrument at Cycle 6

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    End point title
    Mean Change From Baseline in the Functional Assessment of Cancer Therapy-Anemia-General (FACT-G) Summary Scale within the FACT-An Instrument at Cycle 6
    End point description
    The FACT-An is a 47-item, cancer-specific questionnaire consisting of a core 27-item general questionnaire (i.e., the Functional Assessment of Cancer Therapy-General [FACT-G]) The FACT-G measures the 4 domains on a 5-point scale ranging from 0 (not at all) to 4 (very much). The 4 domains are: • Physical Well-being (PWB; 7 items; score range, 0–28), • Social/Family Well-being (SWB; 7 items; score range, 0–28), • Emotional Well-being (EWB; 6 items; score range, 0–24), and • Functional Well-being (7 items; score range, 0–28). The FACT-G is a summation composed of a "summary scale" including the PWB, SWB, EWB and FWB. The FACT-G score range is from 0 to 108. For all summary scales including FACT-G, a higher score indicates better HRQoL or lower level of symptoms.
    End point type
    Secondary
    End point timeframe
    Baseline to Cycle 6 Day 1
    End point values
    Oral Azacitidine Plus Best Supportive Care Placebo Plus Best Supportive Care
    Number of subjects analysed
    42
    49
    Units: Units on a Scale
        arithmetic mean (standard deviation)
    1.6 ( 12.00 )
    -2.9 ( 12.11 )
    Statistical analysis title
    FACT-G
    Comparison groups
    Placebo Plus Best Supportive Care v Oral Azacitidine Plus Best Supportive Care
    Number of subjects included in analysis
    91
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.078
    Method
    t-test, 2-sided
    Confidence interval

    Secondary: Mean Change From Baseline in the Functional Assessment of Cancer Therapy-Anemia-Total Score at Cycle 6

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    End point title
    Mean Change From Baseline in the Functional Assessment of Cancer Therapy-Anemia-Total Score at Cycle 6
    End point description
    The FACT-G and the anemia subscale (AnS) are summed to form the FACT-An total score and the total score ranges from 0 to 188. The FACT-G measures the 4 domains on a 5-point scale ranging from 0 (not at all) to 4 (very much). The 4 domains are: • Physical Well-being (PWB; 7 items; score range, 0–28), • Social/Family Well-being (SWB; 7 items; score range, 0–28), • Emotional Well-being (EWB; 6 items; score range, 0–24), and • Functional Well-being (7 items; score range, 0–28). The AnS consists of 20 items on the same 5-point scale, with 13 of them measuring fatigue-related symptoms (FS) and 7 measuring non-FS. The AnS and FS scores can range from 0-80 and 0-52, respectively. For all domains and summary subscales, a higher score indicates better HRQoL or lower level of symptoms.
    End point type
    Secondary
    End point timeframe
    Baseline to Cycle 6 Day 1
    End point values
    Oral Azacitidine Plus Best Supportive Care Placebo Plus Best Supportive Care
    Number of subjects analysed
    42
    49
    Units: Units on a Scale
        arithmetic mean (standard deviation)
    4.5 ( 21.88 )
    -3.5 ( 20.62 )
    Statistical analysis title
    Anemia Total Score
    Comparison groups
    Placebo Plus Best Supportive Care v Oral Azacitidine Plus Best Supportive Care
    Number of subjects included in analysis
    91
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.073
    Method
    t-test, 2-sided
    Confidence interval

    Secondary: Percentage of Participants with a Clinically Meaningful Improvment (CMI) From Baseline on the Physical Well-Being Domain within the FACT-An Instrument at Cycle 6

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    End point title
    Percentage of Participants with a Clinically Meaningful Improvment (CMI) From Baseline on the Physical Well-Being Domain within the FACT-An Instrument at Cycle 6
    End point description
    A clinically meaningful improvement or deterioration was defined by domain specific thresholds of change from baseline. The FACT-An questionnaire is a 47-item, cancer specific questionnaire consisting of a core 27 items measuring 4 general domains physical well being, social/family, emotional well being and Functional Well-Being and an additional 20-item anemia questionnaire that measures fatigue and 7 non-fatigue items. The scales are formatted on 4 pages for self-administration using a 5-point Likert rating scale (0 = Not at all; 1 = A little bit; 2 = Somewhat; 3 = Quite a Bit and 4 = Very much). Also, general HRQoL measures the impact of fatigue and other anemia-related symptoms on patient functioning and is used to assess the effect of treatments in various areas, including MDS. The instrument and the fatigue and non-fatigue subscales are scored by summing points from all questions, then converting this sum to a 100 point scale; 0 = the poorest QOL and 100 = the highest QOL.
    End point type
    Secondary
    End point timeframe
    Cycle 6 Day 1
    End point values
    Oral Azacitidine Plus Best Supportive Care Placebo Plus Best Supportive Care
    Number of subjects analysed
    81
    95
    Units: Percentage of Participants
        number (not applicable)
    17.3
    13.7
    Statistical analysis title
    CMI
    Comparison groups
    Placebo Plus Best Supportive Care v Oral Azacitidine Plus Best Supportive Care
    Number of subjects included in analysis
    176
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.56
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Common Odds Raatio
    Point estimate
    0.77
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.54
         upper limit
    1.3

    Secondary: Percentage of Participants with a Clinically Meaningful Improvment (CMI) From Baseline on the Social Well-Being Domain within the FACT-An Instrument at Cycle 6

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    End point title
    Percentage of Participants with a Clinically Meaningful Improvment (CMI) From Baseline on the Social Well-Being Domain within the FACT-An Instrument at Cycle 6
    End point description
    A clinically meaningful improvement or deterioration was defined by domain specific thresholds of change from baseline. The FACT-An questionnaire is a 47-item, cancer specific questionnaire consisting of a core 27 items measuring 4 general domains physical well being, social/family, emotional well being and Functional Well-Being and an additional 20-item anemia questionnaire that measures fatigue and 7 non-fatigue items. The scales are formatted on 4 pages for self-administration using a 5-point Likert rating scale (0 = Not at all; 1 = A little bit; 2 = Somewhat; 3 = Quite a Bit and 4 = Very much). Also, general HRQoL measures the impact of fatigue and other anemia-related symptoms on patient functioning and is used to assess the effect of treatments in various areas, including MDS. The instrument and the fatigue and non-fatigue subscales are scored by summing points from all questions, then converting this sum to a 100 point scale; 0 = the poorest QOL and 100 = the highest QOL.
    End point type
    Secondary
    End point timeframe
    Cycle 6 Day 1
    End point values
    Oral Azacitidine Plus Best Supportive Care Placebo Plus Best Supportive Care
    Number of subjects analysed
    81
    95
    Units: Percentage of Participants
        number (not applicable)
    11.1
    14.7
    Statistical analysis title
    Social Well-Being
    Comparison groups
    Placebo Plus Best Supportive Care v Oral Azacitidine Plus Best Supportive Care
    Number of subjects included in analysis
    176
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.48
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Common Odds Raatio
    Point estimate
    0.72
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.29
         upper limit
    1.78

    Secondary: Percentage of Participants with a Clinically Meaningful Improvment (CMI) From Baseline on the Emotional Well-Being Domain within the FACT-An Instrument at Cycle 6

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    End point title
    Percentage of Participants with a Clinically Meaningful Improvment (CMI) From Baseline on the Emotional Well-Being Domain within the FACT-An Instrument at Cycle 6
    End point description
    A clinically meaningful improvement or deterioration was defined by domain specific thresholds of change from baseline. The FACT-An questionnaire is a 47-item, cancer specific questionnaire consisting of a core 27 items measuring 4 general domains physical well being, social/family, emotional well being and Functional Well-Being and an additional 20-item anemia questionnaire that measures fatigue and 7 non-fatigue items. The scales are formatted on 4 pages for self-administration using a 5-point Likert rating scale (0 = Not at all; 1 = A little bit; 2 = Somewhat; 3 = Quite a Bit and 4 = Very much). Also, general HRQoL measures the impact of fatigue and other anemia-related symptoms on patient functioning and is used to assess the effect of treatments in various areas, including MDS. The instrument and the fatigue and non-fatigue subscales are scored by summing points from all questions, then converting this sum to a 100 point scale; 0 = the poorest QOL and 100 = the highest QOL.
    End point type
    Secondary
    End point timeframe
    Cycle 6 Day 1
    End point values
    Oral Azacitidine Plus Best Supportive Care Placebo Plus Best Supportive Care
    Number of subjects analysed
    81
    95
    Units: Percentage of Participants
        number (not applicable)
    23.5
    15.8
    Statistical analysis title
    CMI
    Comparison groups
    Placebo Plus Best Supportive Care v Oral Azacitidine Plus Best Supportive Care
    Number of subjects included in analysis
    176
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.197
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Common Odds Ratio
    Point estimate
    1.67
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.76
         upper limit
    3.65

    Secondary: Percentage of Participants with a Clinically Meaningful Improvment (CMI) From Baseline on the Functional Well-Being Domain within the FACT-An Instrument at Cycle 6

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    End point title
    Percentage of Participants with a Clinically Meaningful Improvment (CMI) From Baseline on the Functional Well-Being Domain within the FACT-An Instrument at Cycle 6
    End point description
    A clinically meaningful improvement or deterioration was defined by domain specific thresholds of change from baseline. The FACT-An questionnaire is a 47-item, cancer specific questionnaire consisting of a core 27 items measuring 4 general domains physical well being, social/family, emotional well being and Functional Well-Being and an additional 20-item anemia questionnaire that measures fatigue and 7 non-fatigue items. The scales are formatted on 4 pages for self-administration using a 5-point Likert rating scale (0 = Not at all; 1 = A little bit; 2 = Somewhat; 3 = Quite a Bit and 4 = Very much). Also, general HRQoL measures the impact of fatigue and other anemia-related symptoms on patient functioning and is used to assess the effect of treatments in various areas, including MDS. The instrument and the fatigue and non-fatigue subscales are scored by summing points from all questions, then converting this sum to a 100 point scale; 0 = the poorest QOL and 100 = the highest QOL.
    End point type
    Secondary
    End point timeframe
    Cycle 6 Day 1
    End point values
    Oral Azacitidine Plus Best Supportive Care Placebo Plus Best Supportive Care
    Number of subjects analysed
    81
    95
    Units: Percentage of Participants
        number (not applicable)
    14.8
    8.4
    Statistical analysis title
    CMI
    Comparison groups
    Placebo Plus Best Supportive Care v Oral Azacitidine Plus Best Supportive Care
    Number of subjects included in analysis
    176
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.121
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Common Odds Ratio
    Point estimate
    2.14
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.82
         upper limit
    5.57

    Secondary: Percentage of Participants with a Clinically Meaningful Improvment (CMI) From Baseline on the Anemia Subscale Domain within the FACT-An Instrument at Cycle 6

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    End point title
    Percentage of Participants with a Clinically Meaningful Improvment (CMI) From Baseline on the Anemia Subscale Domain within the FACT-An Instrument at Cycle 6
    End point description
    A clinically meaningful improvement or deterioration was defined by domain specific thresholds of change from baseline. The FACT-An questionnaire is a 47-item, cancer specific questionnaire consisting of a core 27 items measuring 4 general domains physical well being, social/family, emotional well being and Functional Well-Being and an additional 20-item anemia questionnaire that measures fatigue and 7 non-fatigue items. The scales are formatted on 4 pages for self-administration using a 5-point Likert rating scale (0 = Not at all; 1 = A little bit; 2 = Somewhat; 3 = Quite a Bit and 4 = Very much). Also, general HRQoL measures the impact of fatigue and other anemia-related symptoms on patient functioning and is used to assess the effect of treatments in various areas, including MDS. The instrument and the fatigue and non-fatigue subscales are scored by summing points from all questions, then converting this sum to a 100 point scale; 0 = the poorest QOL and 100 = the highest QOL.
    End point type
    Secondary
    End point timeframe
    Cycle 6 Day 1
    End point values
    Oral Azacitidine Plus Best Supportive Care Placebo Plus Best Supportive Care
    Number of subjects analysed
    81
    95
    Units: Percentage of Participants
        number (not applicable)
    27.2
    15.8
    Statistical analysis title
    CMI
    Comparison groups
    Placebo Plus Best Supportive Care v Oral Azacitidine Plus Best Supportive Care
    Number of subjects included in analysis
    176
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.075
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Common Odds Ratio
    Point estimate
    2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.93
         upper limit
    4.3

    Secondary: Percentage of Participants with a Clinically Meaningful Improvment (CMI) From Baseline in the Fatigue Related Symptoms Subscale Domain within the FACT-An Instrument at Cycle 6

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    End point title
    Percentage of Participants with a Clinically Meaningful Improvment (CMI) From Baseline in the Fatigue Related Symptoms Subscale Domain within the FACT-An Instrument at Cycle 6
    End point description
    A clinically meaningful improvement or deterioration was defined by domain specific thresholds of change from baseline. The FACT-An questionnaire is a 47-item, cancer specific questionnaire consisting of a core 27 items measuring 4 general domains physical well being, social/family, emotional well being and Functional Well-Being and an additional 20-item anemia questionnaire that measures fatigue and 7 non-fatigue items. The scales are formatted on 4 pages for self-administration using a 5-point Likert rating scale (0 = Not at all; 1 = A little bit; 2 = Somewhat; 3 = Quite a Bit and 4 = Very much). Also, general HRQoL measures the impact of fatigue and other anemia-related symptoms on patient functioning and is used to assess the effect of treatments in various areas, including MDS. The instrument and the fatigue and non-fatigue subscales are scored by summing points from all questions, then converting this sum to a 100 point scale; 0 = the poorest QOL and 100 = the highest QOL.
    End point type
    Secondary
    End point timeframe
    Cycle 6 Day 1
    End point values
    Oral Azacitidine Plus Best Supportive Care Placebo Plus Best Supportive Care
    Number of subjects analysed
    81
    95
    Units: Percentage of Participants
        number (not applicable)
    27.2
    18.9
    Statistical analysis title
    CMI
    Comparison groups
    Placebo Plus Best Supportive Care v Oral Azacitidine Plus Best Supportive Care
    Number of subjects included in analysis
    176
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.222
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Common Odds Ratio
    Point estimate
    1.58
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.76
         upper limit
    3.29

    Secondary: Percentage of Participants with a Clinically Meaningful Improvment (CMI) From Baseline in the Functional Assessment of Cancer Therapy-Anemia Trial Outcome Index Subscale Domain within the FACT-An Instrument at Cycle 6

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    End point title
    Percentage of Participants with a Clinically Meaningful Improvment (CMI) From Baseline in the Functional Assessment of Cancer Therapy-Anemia Trial Outcome Index Subscale Domain within the FACT-An Instrument at Cycle 6
    End point description
    A clinically meaningful improvement or deterioration was defined by domain specific thresholds of change from baseline. The FACT-An questionnaire is a 47-item, cancer specific questionnaire consisting of a core 27 items measuring 4 general domains physical well being, social/family, emotional well being and Functional Well-Being and an additional 20-item anemia questionnaire that measures fatigue and 7 non-fatigue items. The scales are formatted on 4 pages for self-administration using a 5-point Likert rating scale (0 = Not at all; 1 = A little bit; 2 = Somewhat; 3 = Quite a Bit and 4 = Very much). Also, general HRQoL measures the impact of fatigue and other anemia-related symptoms on patient functioning and is used to assess the effect of treatments in various areas, including MDS. The instrument and the fatigue and non-fatigue subscales are scored by summing points from all questions, then converting this sum to a 100 point scale; 0 = the poorest QOL and 100 = the highest QOL.
    End point type
    Secondary
    End point timeframe
    Cycle 6 Day 1
    End point values
    Oral Azacitidine Plus Best Supportive Care Placebo Plus Best Supportive Care
    Number of subjects analysed
    81
    95
    Units: Percentage of Participants
        number (not applicable)
    19.8
    12.6
    Statistical analysis title
    CMI
    Comparison groups
    Placebo Plus Best Supportive Care v Oral Azacitidine Plus Best Supportive Care
    Number of subjects included in analysis
    176
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.249
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Common Odds Ratio
    Point estimate
    1.65
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.71
         upper limit
    3.83

    Secondary: Percentage of Participants with a Clinically Meaningful Improvment (CMI) From Baseline in the Functional Assessment of Cancer Therapy-Anemia-General Subscale Domain within the FACT-An Instrument at Cycle 6

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    End point title
    Percentage of Participants with a Clinically Meaningful Improvment (CMI) From Baseline in the Functional Assessment of Cancer Therapy-Anemia-General Subscale Domain within the FACT-An Instrument at Cycle 6
    End point description
    A clinically meaningful improvement or deterioration was defined by domain specific thresholds of change from baseline. The FACT-An questionnaire is a 47-item, cancer specific questionnaire consisting of a core 27 items measuring 4 general domains physical well being, social/family, emotional well being and Functional Well-Being and an additional 20-item anemia questionnaire that measures fatigue and 7 non-fatigue items. The scales are formatted on 4 pages for self-administration using a 5-point Likert rating scale (0 = Not at all; 1 = A little bit; 2 = Somewhat; 3 = Quite a Bit and 4 = Very much). Also, general HRQoL measures the impact of fatigue and other anemia-related symptoms on patient functioning and is used to assess the effect of treatments in various areas, including MDS. The instrument and the fatigue and non-fatigue subscales are scored by summing points from all questions, then converting this sum to a 100 point scale; 0 = the poorest QOL and 100 = the highest QOL.
    End point type
    Secondary
    End point timeframe
    Cycle 6 Day 1
    End point values
    Oral Azacitidine Plus Best Supportive Care Placebo Plus Best Supportive Care
    Number of subjects analysed
    81
    95
    Units: Percentage of Participants
        number (not applicable)
    23.5
    13.7
    Statistical analysis title
    CMI
    Comparison groups
    Placebo Plus Best Supportive Care v Oral Azacitidine Plus Best Supportive Care
    Number of subjects included in analysis
    176
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.082
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Common Odds Ratio
    Point estimate
    2.03
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.92
         upper limit
    4.48

    Secondary: Percentage of Participants with a Clinically Meaningful Improvement (CMI) From Baseline in the Functional Assessment of Cancer Therapy Anemia-Total Score Domain within the FACT-An Instrument at Cycle 6

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    End point title
    Percentage of Participants with a Clinically Meaningful Improvement (CMI) From Baseline in the Functional Assessment of Cancer Therapy Anemia-Total Score Domain within the FACT-An Instrument at Cycle 6
    End point description
    A clinically meaningful improvement or deterioration was defined by domain specific thresholds of change from baseline. The FACT-An questionnaire is a 47-item, cancer specific questionnaire consisting of a core 27 items measuring 4 general domains physical well being, social/family, emotional well being and Functional Well-Being and an additional 20-item anemia questionnaire that measures fatigue and 7 non-fatigue items. The scales are formatted on 4 pages for self-administration using a 5-point Likert rating scale (0 = Not at all; 1 = A little bit; 2 = Somewhat; 3 = Quite a Bit and 4 = Very much). Also, general HRQoL measures the impact of fatigue and other anemia-related symptoms on patient functioning and is used to assess the effect of treatments in various areas, including MDS. The instrument and the fatigue and non-fatigue subscales are scored by summing points from all questions, then converting this sum to a 100 point scale; 0 = the poorest QOL and 100 = the highest QOL.
    End point type
    Secondary
    End point timeframe
    Cycle 6 Day 1
    End point values
    Oral Azacitidine Plus Best Supportive Care Placebo Plus Best Supportive Care
    Number of subjects analysed
    81
    95
    Units: Percentage of Participants
        number (not applicable)
    19.8
    11.6
    Statistical analysis title
    CMI
    Comparison groups
    Placebo Plus Best Supportive Care v Oral Azacitidine Plus Best Supportive Care
    Number of subjects included in analysis
    176
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.153
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Common Odds Ratio
    Point estimate
    1.86
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.79
         upper limit
    4.34

    Secondary: Percentage of Participants with Change from Baseline in Responses to the Fact-Anemia Item GP-5 - Cycle 2 Day 1 (C2D1)

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    End point title
    Percentage of Participants with Change from Baseline in Responses to the Fact-Anemia Item GP-5 - Cycle 2 Day 1 (C2D1)
    End point description
    The distribution (frequency and percentage) of the observed responses (i.e., “Not at all (0),” “A little bit (1),” “Somewhat (2),” “Quite a bit (3),” “Very much (4),” and missing) to Item GP-5 (“I am bothered by side effects of treatment” in the past seven days) of the FACT-An at each scheduled visit were summarized for each treatment group. The denominator for the percentage calculation per treatment group was based on the number of the FACT-An evaluable population at baseline. The distribution of change in responses (improved [i.e., change score from 1 to 4], no change [0], worsened by one level [-1], worsened by ≥2 levels [-2 to -4], and missing) from baseline at each post-baseline scheduled visit were summarized by treatment group.
    End point type
    Secondary
    End point timeframe
    From Baseline to Cycle 2 Day 1 (C2D1)
    End point values
    Oral Azacitidine Plus Best Supportive Care Placebo Plus Best Supportive Care
    Number of subjects analysed
    81
    95
    Units: Percentage of Participants
    number (not applicable)
        Improved
    2.5
    10.5
        No Change
    30.9
    49.5
        Worsened by 1 Level
    25.9
    23.2
        Worsened by 2 Levels
    23.5
    6.3
        Missing
    17.3
    10.5
    Statistical analysis title
    Fact-Anemia Item GP-5
    Comparison groups
    Placebo Plus Best Supportive Care v Oral Azacitidine Plus Best Supportive Care
    Number of subjects included in analysis
    176
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    < 0.001
    Method
    Fisher exact
    Confidence interval

    Secondary: Percentage of Participants with Change from Baseline in Responses to the Fact-Anemia Item GP-5 - Cycle 3 Day 1 (C3D1)

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    End point title
    Percentage of Participants with Change from Baseline in Responses to the Fact-Anemia Item GP-5 - Cycle 3 Day 1 (C3D1)
    End point description
    The distribution (frequency and percentage) of the observed responses (i.e., “Not at all (0),” “A little bit (1),” “Somewhat (2),” “Quite a bit (3),” “Very much (4),” and missing) to Item GP-5 (“I am bothered by side effects of treatment” in the past seven days) of the FACT-An at each scheduled visit were summarized for each treatment group. The denominator for the percentage calculation per treatment group was based on the number of the FACT-An evaluable population at baseline. The distribution of change in responses (improved [i.e., change score from 1 to 4], no change [0], worsened by one level [-1], worsened by ≥2 levels [-2 to -4], and missing) from baseline at each post-baseline scheduled visit were summarized by treatment group.
    End point type
    Secondary
    End point timeframe
    From Baseline to Cycle 3 Day 1 (C3D1)
    End point values
    Oral Azacitidine Plus Best Supportive Care Placebo Plus Best Supportive Care
    Number of subjects analysed
    81
    95
    Units: Percentage of Participants
    number (not applicable)
        No Change
    24.7
    41.1
        Worsened by 1 Level
    16.0
    18.9
        Worsened by 2 Levels
    23.5
    13.7
        Missing
    28.4
    15.8
        Improved
    7.4
    10.5
    Statistical analysis title
    Responses to the Fact-Anemia Item GP-5
    Comparison groups
    Placebo Plus Best Supportive Care v Oral Azacitidine Plus Best Supportive Care
    Number of subjects included in analysis
    176
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.046
    Method
    Fisher exact
    Confidence interval

    Secondary: Percentage of Participants with Change from Baseline in Responses to the Fact-Anemia Item GP-5 - Cycle 4 Day 1 (C4D1)

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    End point title
    Percentage of Participants with Change from Baseline in Responses to the Fact-Anemia Item GP-5 - Cycle 4 Day 1 (C4D1)
    End point description
    The distribution (frequency and percentage) of the observed responses (i.e., “Not at all (0),” “A little bit (1),” “Somewhat (2),” “Quite a bit (3),” “Very much (4),” and missing) to Item GP-5 (“I am bothered by side effects of treatment” in the past seven days) of the FACT-An at each scheduled visit were summarized for each treatment group. The denominator for the percentage calculation per treatment group was based on the number of the FACT-An evaluable population at baseline. The distribution of change in responses (improved [i.e., change score from 1 to 4], no change [0], worsened by one level [-1], worsened by ≥2 levels [-2 to -4], and missing) from baseline at each post-baseline scheduled visit were summarized by treatment group.
    End point type
    Secondary
    End point timeframe
    From Baseline to Cycle 4 Day 1 (C4D1)
    End point values
    Oral Azacitidine Plus Best Supportive Care Placebo Plus Best Supportive Care
    Number of subjects analysed
    81
    95
    Units: Percentage of Participants
    number (not applicable)
        Improved
    2.5
    9.5
        No Change
    32.1
    37.9
        Worsened by 1 Level
    16.0
    14.7
        Worsened by 2 Levels
    14.8
    6.3
        Missing
    34.6
    31.6
    Statistical analysis title
    Fact-Anemia Item GP-5
    Comparison groups
    Placebo Plus Best Supportive Care v Oral Azacitidine Plus Best Supportive Care
    Number of subjects included in analysis
    176
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.134
    Method
    Fisher exact
    Confidence interval

    Secondary: Percentage of Participants with Change from Baseline in Responses to the Fact-Anemia Item GP-5 - Cycle 5 Day 1 (C5D1)

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    End point title
    Percentage of Participants with Change from Baseline in Responses to the Fact-Anemia Item GP-5 - Cycle 5 Day 1 (C5D1)
    End point description
    The distribution (frequency and percentage) of the observed responses (i.e., “Not at all (0),” “A little bit (1),” “Somewhat (2),” “Quite a bit (3),” “Very much (4),” and missing) to Item GP-5 (“I am bothered by side effects of treatment” in the past seven days) of the FACT-An at each scheduled visit were summarized for each treatment group. The denominator for the percentage calculation per treatment group was based on the number of the FACT-An evaluable population at baseline. The distribution of change in responses (improved [i.e., change score from 1 to 4], no change [0], worsened by one level [-1], worsened by ≥2 levels [-2 to -4], and missing) from baseline at each post-baseline scheduled visit were summarized by treatment group.
    End point type
    Secondary
    End point timeframe
    From Baseline to Cycle 5 Day 1 (C5D1)
    End point values
    Oral Azacitidine Plus Best Supportive Care Placebo Plus Best Supportive Care
    Number of subjects analysed
    81
    95
    Units: Percentage of Participants
    number (not applicable)
        Improved
    2.5
    7.4
        No Change
    25.9
    34.7
        Worsened by 1 Level
    13.6
    12.6
        Worsened by 2 Levels
    8.6
    5.3
        Missing
    49.4
    40.0
    Statistical analysis title
    Fact-Anemia Item GP-5
    Comparison groups
    Placebo Plus Best Supportive Care v Oral Azacitidine Plus Best Supportive Care
    Number of subjects included in analysis
    176
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.324
    Method
    Fisher exact
    Confidence interval

    Secondary: Percentage of Participants with Change from Baseline in Responses to the Fact-Anemia Item GP-5 - Cycle 6 Day 1 (C6 D1)

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    End point title
    Percentage of Participants with Change from Baseline in Responses to the Fact-Anemia Item GP-5 - Cycle 6 Day 1 (C6 D1)
    End point description
    The distribution (frequency and percentage) of the observed responses (i.e., “Not at all (0),” “A little bit (1),” “Somewhat (2),” “Quite a bit (3),” “Very much (4),” and missing) to Item GP-5 (“I am bothered by side effects of treatment” in the past seven days) of the FACT-An at each scheduled visit were summarized for each treatment group. The denominator for the percentage calculation per treatment group was based on the number of the FACT-An evaluable population at baseline. The distribution of change in responses (improved [i.e., change score from 1 to 4], no change [0], worsened by one level [-1], worsened by ≥2 levels [-2 to -4], and missing) from baseline at each post-baseline scheduled visit were summarized by treatment group.
    End point type
    Secondary
    End point timeframe
    From Baseline to Cycle 6 Day 1 (C6 D1)
    End point values
    Oral Azacitidine Plus Best Supportive Care Placebo Plus Best Supportive Care
    Number of subjects analysed
    81
    95
    Units: Percentage of Participants
    number (not applicable)
        Improved
    1.2
    4.2
        No Change
    25.9
    27.4
        Worsened by 1 Level
    9.9
    12.6
        Worsened by 2 Levels
    14.8
    7.4
        Missing
    48.1
    48.4
    Statistical analysis title
    Fact-Anemia Item GP-5
    Comparison groups
    Placebo Plus Best Supportive Care v Oral Azacitidine Plus Best Supportive Care
    Number of subjects included in analysis
    176
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.442
    Method
    Fisher exact
    Confidence interval

    Secondary: Percentage of Participants with Change from Baseline in Responses to the Fact-Anemia Item GP-5 - Cycle 7 Day 1 (C7D1)

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    End point title
    Percentage of Participants with Change from Baseline in Responses to the Fact-Anemia Item GP-5 - Cycle 7 Day 1 (C7D1)
    End point description
    The distribution (frequency and percentage) of the observed responses (i.e., “Not at all (0),” “A little bit (1),” “Somewhat (2),” “Quite a bit (3),” “Very much (4),” and missing) to Item GP-5 (“I am bothered by side effects of treatment” in the past seven days) of the FACT-An at each scheduled visit were summarized for each treatment group. The denominator for the percentage calculation per treatment group was based on the number of the FACT-An evaluable population at baseline. The distribution of change in responses (improved [i.e., change score from 1 to 4], no change [0], worsened by one level [-1], worsened by ≥2 levels [-2 to -4], and missing) from baseline at each post-baseline scheduled visit were summarized by treatment group.
    End point type
    Secondary
    End point timeframe
    From Baseline to Cycle 7 Day 1 (C7D1)
    End point values
    Oral Azacitidine Plus Best Supportive Care Placebo Plus Best Supportive Care
    Number of subjects analysed
    81
    95
    Units: Percentage of Participants
    number (not applicable)
        Improved
    1.2
    1.1
        No Change
    25.9
    21.1
        Worsened by 1 Level
    11.1
    3.2
        Worsened by 2 Levels
    7.4
    3.2
        Missing
    54.3
    71.6
    Statistical analysis title
    Fact-Anemia Item GP-5
    Comparison groups
    Placebo Plus Best Supportive Care v Oral Azacitidine Plus Best Supportive Care
    Number of subjects included in analysis
    176
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.063
    Method
    Fisher exact
    Confidence interval

    Secondary: Percentage of Participants with Change from Baseline in Responses to the Fact-Anemia Item GP-5 - End of Treatment

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    End point title
    Percentage of Participants with Change from Baseline in Responses to the Fact-Anemia Item GP-5 - End of Treatment
    End point description
    The distribution (frequency and percentage) of the observed responses (i.e., “Not at all (0),” “A little bit (1),” “Somewhat (2),” “Quite a bit (3),” “Very much (4),” and missing) to Item GP-5 (“I am bothered by side effects of treatment” in the past seven days) of the FACT-An at each scheduled visit were summarized for each treatment group. The denominator for the percentage calculation per treatment group was based on the number of the FACT-An evaluable population at baseline. The distribution of change in responses (improved [i.e., change score from 1 to 4], no change [0], worsened by one level [-1], worsened by ≥2 levels [-2 to -4], and missing) from baseline at each post-baseline scheduled visit were summarized by treatment group.
    End point type
    Secondary
    End point timeframe
    From Baseline to End of Treatment
    End point values
    Oral Azacitidine Plus Best Supportive Care Placebo Plus Best Supportive Care
    Number of subjects analysed
    81
    95
    Units: Percentage of Participants
    number (not applicable)
        Improved
    2.5
    6.3
        No Change
    14.8
    25.3
        Worsened by 1 Level
    9.9
    8.4
        Worsened by 2 Levels
    9.9
    12.6
        Missing
    63.0
    47.4
    Statistical analysis title
    Fact-Anemia Item GP-5
    Comparison groups
    Placebo Plus Best Supportive Care v Oral Azacitidine Plus Best Supportive Care
    Number of subjects included in analysis
    176
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.198
    Method
    Fisher exact
    Confidence interval

    Secondary: Percentage of Participants with Improved, Worsened, or No Change in the European Quality of Life–Five Dimension–Three Level (EQ-5D-3L) Mobility Dimension Responses at Cycle 6

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    End point title
    Percentage of Participants with Improved, Worsened, or No Change in the European Quality of Life–Five Dimension–Three Level (EQ-5D-3L) Mobility Dimension Responses at Cycle 6
    End point description
    The EQ-5D-3L is a generic, self-administered questionnaire that consists of 5 dimensions: mobility, self-care, pain, usual activities, and anxiety/depression. Each dimension has 3 levels of severity corresponding to no problems, some problems, and extreme problems. It also includes a Visual Analog Scale that recorded the respondent’s self-rated health on a vertical, 0–100 scale, where 100 = Best imaginable health state and 0 = Worst imaginable health state. Distribution of the observed responses (i.e., no problems, moderate problems, severe problems, and missing) of the 5 dimensions at each visit was summarized per arm. The denominator for the percentage calculation per group was based on the number of the EQ-5D-3L evaluable population at baseline. The distribution of change in responses (i.e., improved [by ≥1 level], no change, worsened [by ≥1 level], and missing) from baseline are reported.
    End point type
    Secondary
    End point timeframe
    From Baseline to Cycle 6 Day 1
    End point values
    Oral Azacitidine Plus Best Supportive Care Placebo Plus Best Supportive Care
    Number of subjects analysed
    81
    95
    Units: Percentage of Participants
    number (not applicable)
        Improved
    8.6
    8.4
        No Change
    35.8
    33.7
        Worsened
    7.4
    9.5
        Missing
    48.1
    48.4
    Statistical analysis title
    EQ-5D-3L
    Comparison groups
    Placebo Plus Best Supportive Care v Oral Azacitidine Plus Best Supportive Care
    Number of subjects included in analysis
    176
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.972
    Method
    Fisher exact
    Confidence interval

    Secondary: Percentage of Participants with Improved, Worsened, or No Change in the European Quality of Life–Five Dimension–Three Level of Self-Care Dimension Responses at Cycle 6

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    End point title
    Percentage of Participants with Improved, Worsened, or No Change in the European Quality of Life–Five Dimension–Three Level of Self-Care Dimension Responses at Cycle 6
    End point description
    The EQ-5D-3L is a generic, self-administered questionnaire that consists of 5 dimensions: mobility, self-care, pain, usual activities, and anxiety/depression. Each dimension has 3 levels of severity corresponding to no problems, some problems, and extreme problems. It also includes a Visual Analog Scale that recorded the respondent’s self-rated health on a vertical, 0–100 scale, where 100 = Best imaginable health state and 0 = Worst imaginable health state. Distribution of the observed responses (i.e., no problems, moderate problems, severe problems, and missing) of the 5 dimensions at each visit was summarized per arm. The denominator for the percentage calculation per group was based on the number of the EQ-5D-3L evaluable population at baseline. The distribution of change in responses (i.e., improved [by ≥1 level], no change, worsened [by ≥1 level], and missing) from baseline are reported.
    End point type
    Secondary
    End point timeframe
    From Baseline to Cycle 6 Day 1
    End point values
    Oral Azacitidine Plus Best Supportive Care Placebo Plus Best Supportive Care
    Number of subjects analysed
    81
    95
    Units: Percentage of Participants
    number (not applicable)
        Improved
    2.5
    4.2
        No Change
    42.0
    44.2
        Worsened
    7.4
    3.2
        Missing
    48.1
    48.4
    Statistical analysis title
    European Quality of Life
    Comparison groups
    Placebo Plus Best Supportive Care v Oral Azacitidine Plus Best Supportive Care
    Number of subjects included in analysis
    176
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.601
    Method
    Fisher exact
    Confidence interval

    Secondary: Percentage of Participants with Improved, Worsened, or No Change in the European Quality of Life–Five Dimension–Three Level Usual Activities Dimension Responses at Cycle 6

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    End point title
    Percentage of Participants with Improved, Worsened, or No Change in the European Quality of Life–Five Dimension–Three Level Usual Activities Dimension Responses at Cycle 6
    End point description
    TThe EQ-5D-3L is a generic, self-administered questionnaire that consists of 5 dimensions: mobility, self-care, pain, usual activities, and anxiety/depression. Each dimension has 3 levels of severity corresponding to no problems, some problems, and extreme problems. It also includes a Visual Analog Scale that recorded the respondent’s self-rated health on a vertical, 0–100 scale, where 100 = Best imaginable health state and 0 = Worst imaginable health state. Distribution of the observed responses (i.e., no problems, moderate problems, severe problems, and missing) of the 5 dimensions at each visit was summarized per arm. The denominator for the percentage calculation per group was based on the number of the EQ-5D-3L evaluable population at baseline. The distribution of change in responses (i.e., improved [by ≥1 level], no change, worsened [by ≥1 level], and missing) from baseline are reported.
    End point type
    Secondary
    End point timeframe
    From Baseline to Cycle 6 Day 1
    End point values
    Oral Azacitidine Plus Best Supportive Care Placebo Plus Best Supportive Care
    Number of subjects analysed
    81
    95
    Units: Percentage of Participants
    number (not applicable)
        Improved
    11.1
    3.2
        No Change
    28.4
    41.1
        Worsened
    12.3
    7.4
        Missing
    48.1
    48.4
    Statistical analysis title
    EQ-5D-3L
    Comparison groups
    Placebo Plus Best Supportive Care v Oral Azacitidine Plus Best Supportive Care
    Number of subjects included in analysis
    176
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.07
    Method
    Fisher exact
    Confidence interval

    Secondary: Percentage of Participants with Improved, Worsened, or No Change in the European Quality of Life–Five Dimension–Three Level in the Pain/Discomfort Dimension Responses at Cycle 6

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    End point title
    Percentage of Participants with Improved, Worsened, or No Change in the European Quality of Life–Five Dimension–Three Level in the Pain/Discomfort Dimension Responses at Cycle 6
    End point description
    The EQ-5D-3L is a generic, self-administered questionnaire that consists of 5 dimensions: mobility, self-care, pain, usual activities, and anxiety/depression. Each dimension has 3 levels of severity corresponding to no problems, some problems, and extreme problems. It also includes a Visual Analog Scale that recorded the respondent’s self-rated health on a vertical, 0–100 scale, where 100 = Best imaginable health state and 0 = Worst imaginable health state. Distribution of the observed responses (i.e., no problems, moderate problems, severe problems, and missing) of the 5 dimensions at each visit was summarized per arm. The denominator for the percentage calculation per group was based on the number of the EQ-5D-3L evaluable population at baseline. The distribution of change in responses (i.e., improved [by ≥1 level], no change, worsened [by ≥1 level], and missing) from baseline are reported.
    End point type
    Secondary
    End point timeframe
    From Baseline to Cycle 6 Day 1
    End point values
    Oral Azacitidine Plus Best Supportive Care Placebo Plus Best Supportive Care
    Number of subjects analysed
    81
    95
    Units: Percentage of Participants
    number (not applicable)
        Improved
    13.6
    8.4
        No Change
    33.3
    32.6
        Worsened
    4.9
    10.5
        Missing
    48.1
    48.4
    Statistical analysis title
    EQ-5D-3L
    Comparison groups
    Placebo Plus Best Supportive Care v Oral Azacitidine Plus Best Supportive Care
    Number of subjects included in analysis
    176
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.436
    Method
    Fisher exact
    Confidence interval

    Secondary: Percentage of Participants with Improved, Worsened, or No Change in the European Quality of Life–Five Dimension–Three Level in the Anxiety/Depression Dimension Responses at Cycle 6

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    End point title
    Percentage of Participants with Improved, Worsened, or No Change in the European Quality of Life–Five Dimension–Three Level in the Anxiety/Depression Dimension Responses at Cycle 6
    End point description
    The EQ-5D-3L is a generic, self-administered questionnaire that consists of 5 dimensions: mobility, self-care, pain, usual activities, and anxiety/depression. Each dimension has 3 levels of severity corresponding to no problems, some problems, and extreme problems. It also includes a Visual Analog Scale that recorded the respondent’s self-rated health on a vertical, 0–100 scale, where 100 = Best imaginable health state and 0 = Worst imaginable health state. Distribution of the observed responses (i.e., no problems, moderate problems, severe problems, and missing) of the 5 dimensions at each visit was summarized per arm. The denominator for the percentage calculation per group was based on the number of the EQ-5D-3L evaluable population at baseline. The distribution of change in responses (i.e., improved [by ≥1 level], no change, worsened [by ≥1 level], and missing) from baseline are reported.
    End point type
    Secondary
    End point timeframe
    From Baseline to Cycle 6 Day 1
    End point values
    Oral Azacitidine Plus Best Supportive Care Placebo Plus Best Supportive Care
    Number of subjects analysed
    81
    95
    Units: Percentage of Participants
    number (not applicable)
        Improved
    4.9
    7.4
        No Change
    35.8
    37.9
        Worsened
    11.1
    6.3
        Missing
    48.1
    48.4
    Statistical analysis title
    EQ-5D-3L
    Comparison groups
    Placebo Plus Best Supportive Care v Oral Azacitidine Plus Best Supportive Care
    Number of subjects included in analysis
    176
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.683
    Method
    Fisher exact
    Confidence interval

    Secondary: Healthcare Resource Utilization (HRU): Number of Participants Who Were Hospitalized During the Treatment Period

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    End point title
    Healthcare Resource Utilization (HRU): Number of Participants Who Were Hospitalized During the Treatment Period
    End point description
    The number of reasons for hospitalizations and hospital admissions during the treatment period were monitored and include those associated with: AEs, protocol-driven procedures, transfusions, non-protocol procedures, elective procedures or those associated with social, practical or technical reasons in the absence of AEs. HRU was defined as any consumption of healthcare resources directly or indirectly related to the treatment of the patient.
    End point type
    Secondary
    End point timeframe
    From date of randomization up to 28 days after the last dose of study drug; up to data cut off date of 25 January 2019; median duration of treatment to oral azacitaidine was 5.29 months and 5.36 months for placebo
    End point values
    Oral Azacitidine Plus Best Supportive Care Placebo Plus Best Supportive Care
    Number of subjects analysed
    107
    109
    Units: Participants
        Adverse Events
    79
    65
        Protocol Driven Procedures
    2
    7
        Non-Protocol Driven Procedures
    9
    19
        Transfusion
    32
    33
        Procedure Planned Prior to Signing Consent
    0
    4
        Elective Procedures
    4
    10
        Social, Technical or Practical Reason except AEs
    4
    6
    No statistical analyses for this end point

    Secondary: Healthcare Resource Utilization (HRU): Total Number of Days Hospitalized Due to any Reason During the Treatment Period

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    End point title
    Healthcare Resource Utilization (HRU): Total Number of Days Hospitalized Due to any Reason During the Treatment Period
    End point description
    The total number of days hospitalized due to any reason during the treatment period was monitored. HRU was defined as any consumption of healthcare resources directly or indirectly related to the treatment of the patient.
    End point type
    Secondary
    End point timeframe
    From date of randomization up to 28 days after the last dose of study drug; up to data cut off date of 25 January 2019; median duration of treatment to oral azacitaidine was 5.29 months and 5.36 months for placebo
    End point values
    Oral Azacitidine Plus Best Supportive Care Placebo Plus Best Supportive Care
    Number of subjects analysed
    107
    109
    Units: Days
    3513
    2688
    No statistical analyses for this end point

    Secondary: Healthcare Resource Utilization (HRU): Total Number of Days Hospitalized Per Total Patient-Years

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    End point title
    Healthcare Resource Utilization (HRU): Total Number of Days Hospitalized Per Total Patient-Years
    End point description
    The number of days hospitalized per total patient years. HRU was defined as any consumption of healthcare resources directly or indirectly related to the treatment of the patient.
    End point type
    Secondary
    End point timeframe
    From date of randomization up to 28 days after the last dose of study drug; up to data cut off date of 25 January 2019; median duration of treatment to oral azacitaidine was 5.29 months and 5.36 months for placebo
    End point values
    Oral Azacitidine Plus Best Supportive Care Placebo Plus Best Supportive Care
    Number of subjects analysed
    107
    109
    Units: Days Per Total Patient Years
        number (not applicable)
    41.44
    40.53
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Participants were assessed for all-cause mortality from their randomization to study completion, (up to approximately 10 years). SAEs and Other AEs were assessed from first dose to 28 days following last dose (up to approximately 6 months)
    Adverse event reporting additional description
    Median duration of treatment to oral azacitaidine was 5.29 months and 5.36 months for placebo
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    26.0
    Reporting groups
    Reporting group title
    CC-486
    Reporting group description
    Participants received 300 mg oral azacitidine tablets daily (QD) on days 1 to 21 of each 28-day treatment cycle and best supportive care (BSC) which included and was not limited to packed RBC (packed red blood cell [pRBC] and whole blood), platelet transfusions (single donor or pooled donor), antibiotic, antiviral and/or antifungal therapy, nutritional support, and granulocyte colony stimulating factors (G-CSF) for participants who experienced neutropenic fever/infections.

    Reporting group title
    Placebo
    Reporting group description
    Participants received identically matching placebo tablets QD on days 1 to 21 of each 28-day treatment cycle and BSC which included but was not limited to, pRBC and whole blood, platelet transfusions (single donor or pooled donor), antibiotic, antiviral and/or antifungal therapy, nutritional support, and G-CSF for participants who experienced neutropenic fever/infections.

    Serious adverse events
    CC-486 Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    83 / 107 (77.57%)
    69 / 109 (63.30%)
         number of deaths (all causes)
    83
    86
         number of deaths resulting from adverse events
    27
    14
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Bowen's disease
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bone neoplasm
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Basal cell carcinoma
         subjects affected / exposed
    1 / 107 (0.93%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Adenocarcinoma of colon
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute myeloid leukaemia
         subjects affected / exposed
    1 / 107 (0.93%)
    2 / 109 (1.83%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Carcinoma in situ of skin
         subjects affected / exposed
    0 / 107 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Central nervous system leukaemia
         subjects affected / exposed
    0 / 107 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Chronic myelomonocytic leukaemia
         subjects affected / exposed
    0 / 107 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transformation to acute myeloid leukaemia
         subjects affected / exposed
    0 / 107 (0.00%)
    6 / 109 (5.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Squamous cell carcinoma of skin
         subjects affected / exposed
    0 / 107 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal cord neoplasm
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small intestine carcinoma
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Myelodysplastic syndrome with excess blasts
         subjects affected / exposed
    0 / 107 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myelodysplastic syndrome
         subjects affected / exposed
    0 / 107 (0.00%)
    3 / 109 (2.75%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    1 / 2
    Metastases to liver
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mantle cell lymphoma recurrent
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malignant neoplasm of unknown primary site
         subjects affected / exposed
    0 / 107 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colon cancer
         subjects affected / exposed
    0 / 107 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colorectal adenoma
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diffuse large B-cell lymphoma
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lip squamous cell carcinoma
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Haematoma
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arteritis
         subjects affected / exposed
    0 / 107 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Polyarteritis nodosa
         subjects affected / exposed
    0 / 107 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Shock haemorrhagic
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Gait disturbance
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    3 / 107 (2.80%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Hypothermia
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multiple organ dysfunction syndrome
         subjects affected / exposed
    2 / 107 (1.87%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Pyrexia
         subjects affected / exposed
    8 / 107 (7.48%)
    4 / 109 (3.67%)
         occurrences causally related to treatment / all
    1 / 9
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sudden death
         subjects affected / exposed
    0 / 107 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Fatigue
         subjects affected / exposed
    0 / 107 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Haemophagocytic lymphohistiocytosis
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Prostatitis
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pulmonary embolism
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleuritic pain
         subjects affected / exposed
    0 / 107 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleurisy
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    1 / 107 (0.93%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Laryngeal oedema
         subjects affected / exposed
    0 / 107 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemoptysis
         subjects affected / exposed
    0 / 107 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epistaxis
         subjects affected / exposed
    2 / 107 (1.87%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute respiratory distress syndrome
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pulmonary oedema
         subjects affected / exposed
    0 / 107 (0.00%)
    2 / 109 (1.83%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Bipolar disorder
         subjects affected / exposed
    0 / 107 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Confusional state
         subjects affected / exposed
    1 / 107 (0.93%)
    2 / 109 (1.83%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Weight decreased
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    0 / 107 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood urea increased
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 109 (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 haemorrhage
         subjects affected / exposed
    0 / 107 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cystitis radiation
         subjects affected / exposed
    0 / 107 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    4 / 107 (3.74%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    1 / 5
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Febrile nonhaemolytic transfusion reaction
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper limb fracture
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transfusion reaction
         subjects affected / exposed
    0 / 107 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subdural haematoma
         subjects affected / exposed
    2 / 107 (1.87%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Periorbital haematoma
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Head injury
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subdural haemorrhage
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 109 (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 coronary syndrome
         subjects affected / exposed
    0 / 107 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute myocardial infarction
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    1 / 107 (0.93%)
    2 / 109 (1.83%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Angina unstable
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Angina pectoris
         subjects affected / exposed
    0 / 107 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrioventricular block complete
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrioventricular block first degree
         subjects affected / exposed
    0 / 107 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    0 / 107 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cardiac failure
         subjects affected / exposed
    2 / 107 (1.87%)
    2 / 109 (1.83%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    3 / 107 (2.80%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ventricular tachycardia
         subjects affected / exposed
    0 / 107 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiogenic shock
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Long QT syndrome
         subjects affected / exposed
    0 / 107 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    1 / 107 (0.93%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Tachyarrhythmia
         subjects affected / exposed
    2 / 107 (1.87%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardio-respiratory arrest
         subjects affected / exposed
    0 / 107 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Nervous system disorders
    Generalised tonic-clonic seizure
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epilepsy
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral ischaemia
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral haemorrhage
         subjects affected / exposed
    0 / 107 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Presyncope
         subjects affected / exposed
    0 / 107 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lethargy
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    IIIrd nerve paresis
         subjects affected / exposed
    0 / 107 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhage intracranial
         subjects affected / exposed
    2 / 107 (1.87%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    1 / 2
    0 / 0
    Guillain-Barre syndrome
         subjects affected / exposed
    0 / 107 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Central nervous system lesion
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Sciatica
         subjects affected / exposed
    0 / 107 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    1 / 107 (0.93%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Status epilepticus
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    7 / 107 (6.54%)
    5 / 109 (4.59%)
         occurrences causally related to treatment / all
    3 / 8
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Blood loss anaemia
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bone marrow failure
         subjects affected / exposed
    2 / 107 (1.87%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    5 / 107 (4.67%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    4 / 5
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemolytic anaemia
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    2 / 107 (1.87%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancytopenia
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    29 / 107 (27.10%)
    9 / 109 (8.26%)
         occurrences causally related to treatment / all
    28 / 45
    4 / 13
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    3 / 107 (2.80%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    0 / 107 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    3 / 107 (2.80%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenic colitis
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Haemorrhoidal haemorrhage
         subjects affected / exposed
    0 / 107 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal perforation
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Intra-abdominal haemorrhage
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Melaena
         subjects affected / exposed
    0 / 107 (0.00%)
    2 / 109 (1.83%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    2 / 107 (1.87%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 107 (0.93%)
    2 / 109 (1.83%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophageal achalasia
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophageal varices haemorrhage
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oral mucosal blistering
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal haemorrhage
         subjects affected / exposed
    1 / 107 (0.93%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 107 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Biliary colic
         subjects affected / exposed
    0 / 107 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis
         subjects affected / exposed
    2 / 107 (1.87%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperbilirubinaemia
         subjects affected / exposed
    2 / 107 (1.87%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cutaneous vasculitis
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Urinary tract obstruction
         subjects affected / exposed
    0 / 107 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute kidney injury
         subjects affected / exposed
    2 / 107 (1.87%)
    3 / 109 (2.75%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic kidney disease
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematuria
         subjects affected / exposed
    0 / 107 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pollakiuria
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Prerenal failure
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal colic
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    2 / 107 (1.87%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary retention
         subjects affected / exposed
    1 / 107 (0.93%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Polychondritis
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Muscular weakness
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Back pain
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Abscess limb
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    COVID-19 pneumonia
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atypical pneumonia
         subjects affected / exposed
    2 / 107 (1.87%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bacteraemia
         subjects affected / exposed
    0 / 107 (0.00%)
    2 / 109 (1.83%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    0 / 107 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchopulmonary aspergillosis
         subjects affected / exposed
    2 / 107 (1.87%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arteriovenous fistula site infection
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Klebsiella infection
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronavirus infection
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cystitis escherichia
         subjects affected / exposed
    0 / 107 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 109 (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 / 107 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epididymitis
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Escherichia sepsis
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile infection
         subjects affected / exposed
    1 / 107 (0.93%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis clostridial
         subjects affected / exposed
    0 / 107 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Groin abscess
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemophilus infection
         subjects affected / exposed
    0 / 107 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    0 / 107 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clostridium difficile colitis
         subjects affected / exposed
    0 / 107 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Klebsiella sepsis
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    1 / 107 (0.93%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lymph gland infection
         subjects affected / exposed
    0 / 107 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Meningitis
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Meningitis bacterial
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myringitis
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenic sepsis
         subjects affected / exposed
    5 / 107 (4.67%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    4 / 5
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pharyngeal abscess
         subjects affected / exposed
    0 / 107 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pharyngitis
         subjects affected / exposed
    0 / 107 (0.00%)
    2 / 109 (1.83%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    13 / 107 (12.15%)
    12 / 109 (11.01%)
         occurrences causally related to treatment / all
    5 / 16
    1 / 13
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Pneumonia aspiration
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia fungal
         subjects affected / exposed
    2 / 107 (1.87%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia pneumococcal
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Prostatic abscess
         subjects affected / exposed
    0 / 107 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pseudomonal sepsis
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    1 / 107 (0.93%)
    4 / 109 (3.67%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract infection bacterial
         subjects affected / exposed
    0 / 107 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    8 / 107 (7.48%)
    3 / 109 (2.75%)
         occurrences causally related to treatment / all
    4 / 12
    1 / 3
         deaths causally related to treatment / all
    3 / 5
    0 / 1
    Septic shock
         subjects affected / exposed
    6 / 107 (5.61%)
    3 / 109 (2.75%)
         occurrences causally related to treatment / all
    3 / 6
    1 / 3
         deaths causally related to treatment / all
    3 / 5
    1 / 3
    Skin infection
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Staphylococcal infection
         subjects affected / exposed
    1 / 107 (0.93%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Staphylococcal sepsis
         subjects affected / exposed
    0 / 107 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tooth abscess
         subjects affected / exposed
    0 / 107 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    4 / 107 (3.74%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    2 / 107 (1.87%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection bacterial
         subjects affected / exposed
    1 / 107 (0.93%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viral sepsis
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 109 (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
    Dehydration
         subjects affected / exposed
    1 / 107 (0.93%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetic metabolic decompensation
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetes mellitus
         subjects affected / exposed
    0 / 107 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetes mellitus inadequate control
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    0 / 107 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    1 / 107 (0.93%)
    0 / 109 (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 / 107 (0.93%)
    0 / 109 (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
    CC-486 Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    107 / 107 (100.00%)
    104 / 109 (95.41%)
    Vascular disorders
    Haematoma
         subjects affected / exposed
    11 / 107 (10.28%)
    11 / 109 (10.09%)
         occurrences all number
    11
    17
    Hypertension
         subjects affected / exposed
    5 / 107 (4.67%)
    7 / 109 (6.42%)
         occurrences all number
    5
    7
    Hypotension
         subjects affected / exposed
    6 / 107 (5.61%)
    3 / 109 (2.75%)
         occurrences all number
    7
    3
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    25 / 107 (23.36%)
    20 / 109 (18.35%)
         occurrences all number
    35
    26
    Fatigue
         subjects affected / exposed
    25 / 107 (23.36%)
    22 / 109 (20.18%)
         occurrences all number
    32
    29
    Pyrexia
         subjects affected / exposed
    32 / 107 (29.91%)
    15 / 109 (13.76%)
         occurrences all number
    48
    27
    Oedema peripheral
         subjects affected / exposed
    30 / 107 (28.04%)
    17 / 109 (15.60%)
         occurrences all number
    40
    20
    Respiratory, thoracic and mediastinal disorders
    Epistaxis
         subjects affected / exposed
    28 / 107 (26.17%)
    21 / 109 (19.27%)
         occurrences all number
    58
    34
    Dyspnoea
         subjects affected / exposed
    14 / 107 (13.08%)
    15 / 109 (13.76%)
         occurrences all number
    16
    15
    Cough
         subjects affected / exposed
    16 / 107 (14.95%)
    15 / 109 (13.76%)
         occurrences all number
    21
    19
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    11 / 107 (10.28%)
    6 / 109 (5.50%)
         occurrences all number
    13
    6
    Anxiety
         subjects affected / exposed
    9 / 107 (8.41%)
    4 / 109 (3.67%)
         occurrences all number
    10
    5
    Confusional state
         subjects affected / exposed
    6 / 107 (5.61%)
    1 / 109 (0.92%)
         occurrences all number
    6
    1
    Depression
         subjects affected / exposed
    7 / 107 (6.54%)
    2 / 109 (1.83%)
         occurrences all number
    7
    2
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    10 / 107 (9.35%)
    6 / 109 (5.50%)
         occurrences all number
    11
    10
    Weight decreased
         subjects affected / exposed
    11 / 107 (10.28%)
    3 / 109 (2.75%)
         occurrences all number
    13
    3
    Serum ferritin increased
         subjects affected / exposed
    6 / 107 (5.61%)
    5 / 109 (4.59%)
         occurrences all number
    6
    5
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    6 / 107 (5.61%)
    1 / 109 (0.92%)
         occurrences all number
    9
    1
    Contusion
         subjects affected / exposed
    16 / 107 (14.95%)
    3 / 109 (2.75%)
         occurrences all number
    21
    3
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    7 / 107 (6.54%)
    2 / 109 (1.83%)
         occurrences all number
    10
    2
    Cardiac failure
         subjects affected / exposed
    6 / 107 (5.61%)
    1 / 109 (0.92%)
         occurrences all number
    6
    1
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    8 / 107 (7.48%)
    9 / 109 (8.26%)
         occurrences all number
    9
    10
    Syncope
         subjects affected / exposed
    6 / 107 (5.61%)
    1 / 109 (0.92%)
         occurrences all number
    12
    1
    Blood and lymphatic system disorders
    Thrombocytopenia
         subjects affected / exposed
    30 / 107 (28.04%)
    18 / 109 (16.51%)
         occurrences all number
    59
    29
    Neutropenia
         subjects affected / exposed
    52 / 107 (48.60%)
    16 / 109 (14.68%)
         occurrences all number
    116
    25
    Leukopenia
         subjects affected / exposed
    10 / 107 (9.35%)
    3 / 109 (2.75%)
         occurrences all number
    18
    3
    Anaemia
         subjects affected / exposed
    23 / 107 (21.50%)
    17 / 109 (15.60%)
         occurrences all number
    65
    41
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    16 / 107 (14.95%)
    14 / 109 (12.84%)
         occurrences all number
    30
    17
    Constipation
         subjects affected / exposed
    51 / 107 (47.66%)
    24 / 109 (22.02%)
         occurrences all number
    80
    39
    Gastrooesophageal reflux disease
         subjects affected / exposed
    6 / 107 (5.61%)
    1 / 109 (0.92%)
         occurrences all number
    6
    1
    Diarrhoea
         subjects affected / exposed
    73 / 107 (68.22%)
    26 / 109 (23.85%)
         occurrences all number
    152
    32
    Gingival bleeding
         subjects affected / exposed
    7 / 107 (6.54%)
    4 / 109 (3.67%)
         occurrences all number
    13
    8
    Nausea
         subjects affected / exposed
    81 / 107 (75.70%)
    25 / 109 (22.94%)
         occurrences all number
    132
    33
    Mouth haemorrhage
         subjects affected / exposed
    10 / 107 (9.35%)
    7 / 109 (6.42%)
         occurrences all number
    13
    12
    Haemorrhoids
         subjects affected / exposed
    4 / 107 (3.74%)
    6 / 109 (5.50%)
         occurrences all number
    4
    6
    Rectal haemorrhage
         subjects affected / exposed
    3 / 107 (2.80%)
    8 / 109 (7.34%)
         occurrences all number
    3
    11
    Vomiting
         subjects affected / exposed
    67 / 107 (62.62%)
    11 / 109 (10.09%)
         occurrences all number
    109
    13
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    6 / 107 (5.61%)
    8 / 109 (7.34%)
         occurrences all number
    6
    10
    Petechiae
         subjects affected / exposed
    21 / 107 (19.63%)
    20 / 109 (18.35%)
         occurrences all number
    30
    23
    Ecchymosis
         subjects affected / exposed
    6 / 107 (5.61%)
    10 / 109 (9.17%)
         occurrences all number
    6
    17
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    4 / 107 (3.74%)
    6 / 109 (5.50%)
         occurrences all number
    4
    7
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    15 / 107 (14.02%)
    13 / 109 (11.93%)
         occurrences all number
    17
    16
    Arthralgia
         subjects affected / exposed
    11 / 107 (10.28%)
    12 / 109 (11.01%)
         occurrences all number
    15
    15
    Pain in extremity
         subjects affected / exposed
    8 / 107 (7.48%)
    4 / 109 (3.67%)
         occurrences all number
    9
    4
    Infections and infestations
    Cellulitis
         subjects affected / exposed
    6 / 107 (5.61%)
    3 / 109 (2.75%)
         occurrences all number
    7
    3
    Oral herpes
         subjects affected / exposed
    6 / 107 (5.61%)
    3 / 109 (2.75%)
         occurrences all number
    6
    3
    Urinary tract infection
         subjects affected / exposed
    12 / 107 (11.21%)
    5 / 109 (4.59%)
         occurrences all number
    15
    5
    Upper respiratory tract infection
         subjects affected / exposed
    7 / 107 (6.54%)
    4 / 109 (3.67%)
         occurrences all number
    11
    4
    Pneumonia
         subjects affected / exposed
    10 / 107 (9.35%)
    4 / 109 (3.67%)
         occurrences all number
    13
    6
    Metabolism and nutrition disorders
    Iron overload
         subjects affected / exposed
    7 / 107 (6.54%)
    11 / 109 (10.09%)
         occurrences all number
    8
    11
    Hypomagnesaemia
         subjects affected / exposed
    11 / 107 (10.28%)
    5 / 109 (4.59%)
         occurrences all number
    16
    5
    Hypokalaemia
         subjects affected / exposed
    12 / 107 (11.21%)
    10 / 109 (9.17%)
         occurrences all number
    21
    11
    Hyperkalaemia
         subjects affected / exposed
    6 / 107 (5.61%)
    0 / 109 (0.00%)
         occurrences all number
    6
    0
    Hyperglycaemia
         subjects affected / exposed
    6 / 107 (5.61%)
    2 / 109 (1.83%)
         occurrences all number
    7
    2
    Decreased appetite
         subjects affected / exposed
    27 / 107 (25.23%)
    10 / 109 (9.17%)
         occurrences all number
    36
    10

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    21 Feb 2018
    The duration of the study and enrollment period was extended due to slow enrollment; Based on Food and Drug Administration (FDA) recommendation, for subjects in Cycle 1 or 2 as of 31 Jan 2018, dose schedule was reduced to 14 days; Based on DMC recommendation to enhance hematotoxicity monitoring, the following information was added to Section 8.2.4. Dose Modifications: “Any subject who experiences febrile neutropenia ≥ Grade 3 will have IP held until fever has resolved; must be afebrile for 3 days before re-starting study drug. Administration of antibiotic, antiviral and antifungal therapy is strongly recommended"; Based on DMC recommendation, to enhance hematotoxicity monitoring, dose modification for neutropenia Grade 4 was updated; Based on DMC recommendation, to enhance hematotoxicity monitoring for Febrile Neutropenia, the following wording “Secondary prophylaxis with G-CSF may be considered” was changed to “Secondary prophylaxis with G-CSF is strongly recommended"; Based on DMC recommendation, to enhance hematotoxicity monitoring, Section 8.2.5. Re-treatment Criteria was updated to reflect that for subjects that experience hematotoxicity (absolute neutrophil count [ANC] or platelet drop to Grade 4, or 50% drop within Grade 4), hematologic recovery is required before starting the next cycle at Day 28. Hematology recovery is defined and a decision tree for hematologic recovery presents the rules in a friendly manner; Based on DMC recommendation, to enhance hematotoxicity monitoring, the following sentences were added: “Consider platelet transfusion if platelet counts are < 25 x 109/L; Based on DMC recommendation, add information to enhance hematotoxicity monitoring.
    06 Aug 2018
    This protocol is being amended to address the sponsor’s decision to close enrollment into the study and revise sample size.
    28 Nov 2018
    This protocol was amended to change the primary endpoint to RBC transfusion independence with duration ≥ 56 days (8 weeks) and to add an extension phase of CC-486 treatment once the trial is unblinded.
    24 May 2022
    Updated contact details for the Medical Monitor of the study; Therapeutic Area Head and their title were updated; New section added; Survival follow-up (FU) was updated by reducing the duration of survival FU to 35 days (± 7 days) after treatment discontinuation.

    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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