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    Clinical Trial Results:
    A PHASE 3, DOUBLE-BLIND, RANDOMIZED STUDY TO COMPARE THE EFFICACY AND SAFETY OF LUSPATERCEPT (ACE-536) VERSUS PLACEBO FOR THE TREATMENT OF ANEMIA DUE TO IPSS-R VERY LOW, LOW, OR INTERMEDIATE RISK MYELODYSPLASTIC SYNDROMES IN SUBJECTS WITH RING SIDEROBLASTS WHO REQUIRE RED BLOOD CELL TRANSFUSIONS

    Summary
    EudraCT number
    2015-003454-41
    Trial protocol
    DE   ES   NL   BE   SE   IT  
    Global end of trial date
    26 Nov 2020

    Results information
    Results version number
    v2(current)
    This version publication date
    31 Dec 2022
    First version publication date
    05 Dec 2021
    Other versions
    v1
    Version creation reason

    Trial information

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    Trial identification
    Sponsor protocol code
    ACE-536-MDS-001
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    -
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Bristol-Myers Squibb
    Sponsor organisation address
    Chaussée 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
    22 Feb 2021
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    26 Nov 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate RBC transfusion independence (RBC-TI) of luspatercept compared with placebo for the treatment of anemia due to IPSS-R very low, low, or intermediate risk MDS in subjects with ring sideroblasts who require red blood cell (RBC) transfusions.
    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
    09 Feb 2016
    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
    Belgium: 16
    Country: Number of subjects enrolled
    Canada: 14
    Country: Number of subjects enrolled
    France: 36
    Country: Number of subjects enrolled
    Germany: 14
    Country: Number of subjects enrolled
    Italy: 34
    Country: Number of subjects enrolled
    Netherlands: 7
    Country: Number of subjects enrolled
    Spain: 31
    Country: Number of subjects enrolled
    Sweden: 10
    Country: Number of subjects enrolled
    Turkey: 7
    Country: Number of subjects enrolled
    United Kingdom: 24
    Country: Number of subjects enrolled
    United States: 36
    Worldwide total number of subjects
    229
    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)
    45
    From 65 to 84 years
    174
    85 years and over
    10

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    229 participants were randomized and treated.

    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, Monitor, Data analyst, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Luspatercept
    Arm description
    Luspatercept 1.0 mg/Kg SC on Day 1 of each 21-day treatment cycle
    Arm type
    Experimental

    Investigational medicinal product name
    Luspatercept
    Investigational medicinal product code
    Other name
    ACE-536
    Pharmaceutical forms
    Powder and solvent for solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    1.0 mg/kg subcutaneously injection every 3 weeks (administered on Day 1 of each 21-day treatment cycle)

    Arm title
    Placebo
    Arm description
    Placebo (Volume equivalent to experimental arm) SC on Day 1 of each 21-day treatment cycle
    Arm type
    Placebo

    Investigational medicinal product name
    Normal Saline
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Volume equivalent to experimental arm, subcutaneously injection every 3 weeks

    Number of subjects in period 1
    Luspatercept Placebo
    Started
    153
    76
    Completed
    4
    12
    Not completed
    149
    64
         Adverse event, serious fatal
    45
    24
         Consent withdrawn by subject
    35
    13
         Other reasons
    12
    5
         Lost to follow-up
    5
    1
         Transition to rollover protocol
    52
    21

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Luspatercept
    Reporting group description
    Luspatercept 1.0 mg/Kg SC on Day 1 of each 21-day treatment cycle

    Reporting group title
    Placebo
    Reporting group description
    Placebo (Volume equivalent to experimental arm) SC on Day 1 of each 21-day treatment cycle

    Reporting group values
    Luspatercept Placebo Total
    Number of subjects
    153 76 229
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    29 16 45
        From 65-84 years
    120 54 174
        85 years and over
    4 6 10
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    70.5 ± 8.68 70.7 ± 10.88 -
    Sex: Female, Male
    Units: Participants
        Female
    59 26 85
        Male
    94 50 144
    Race/Ethnicity, Customized
    Units: Subjects
        Black or African American
    1 0 1
        White
    107 51 158
        Not Collected or Reported
    44 24 68
        Other
    1 1 2
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    3 4 7
        Not Hispanic or Latino
    115 52 167
        Unknown or Not Reported
    35 20 55

    End points

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    End points reporting groups
    Reporting group title
    Luspatercept
    Reporting group description
    Luspatercept 1.0 mg/Kg SC on Day 1 of each 21-day treatment cycle

    Reporting group title
    Placebo
    Reporting group description
    Placebo (Volume equivalent to experimental arm) SC on Day 1 of each 21-day treatment cycle

    Primary: Percentage Of Participants Who Achieved Red Blood Cell Transfusion Independence (RBC-TI) ≥ 8 Weeks From Week 1 to Week 24

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    End point title
    Percentage Of Participants Who Achieved Red Blood Cell Transfusion Independence (RBC-TI) ≥ 8 Weeks From Week 1 to Week 24
    End point description
    RBC-TI response was defined as the absence of any Red Blood Cells (RBC) transfusion during any consecutive 56-day (8-week) period (ie, Days 1 to 56, Days 2 to 57, Days 3 to 58, etc.) during the first 24 weeks of study treatment. Participants had to have at least 56 days (≥ 8 weeks) of transfusion independence prior to (and including) the Week 24 cut-off date to qualify as a responder. Participants who failed to achieve RBC-TI at least 56 days prior to or on the cut-off date were counted as non-responders.
    End point type
    Primary
    End point timeframe
    From Week 1 through Week 24 of study treatment
    End point values
    Luspatercept Placebo
    Number of subjects analysed
    153
    76
    Units: Percent of Participants
        number (confidence interval 95%)
    37.91 (30.20 to 46.10)
    13.16 (6.49 to 22.87)
    Statistical analysis title
    RBC-TI ≥ 8 weeks_1
    Comparison groups
    Luspatercept v Placebo
    Number of subjects included in analysis
    229
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    < 0.0001
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Common Risk Difference on Response Rate
    Point estimate
    24.56
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    14.48
         upper limit
    34.64
    Statistical analysis title
    RBC-TI ≥ 8 weeks_2
    Comparison groups
    Luspatercept v Placebo
    Number of subjects included in analysis
    229
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    < 0.0001
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Odds ratio (OR)
    Point estimate
    5.065
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    2.278
         upper limit
    11.259

    Secondary: Percentage of Participants Who Achieved Red Blood Cell Transfusion Independence (RBC-TI) ≥ 12 Weeks From Week 1 to Week 24

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    End point title
    Percentage of Participants Who Achieved Red Blood Cell Transfusion Independence (RBC-TI) ≥ 12 Weeks From Week 1 to Week 24
    End point description
    RBC-TI Response was defined as the absence of any Red Blood Cells (RBC) transfusion during any consecutive 84-day (12-week) period (ie, Days 1 to 84, Days 2 to 85, Days 3 to 86, etc.) during the first 24 weeks of treatment.
    End point type
    Secondary
    End point timeframe
    From Week 1 through Week 24 of study treatment
    End point values
    Luspatercept Placebo
    Number of subjects analysed
    153
    76
    Units: Percent of Participants
        number (confidence interval 95%)
    28.10 (21.14 to 35.93)
    7.89 (2.95 to 16.40)
    Statistical analysis title
    RBC-TI ≥ 12 weeks_2
    Comparison groups
    Luspatercept v Placebo
    Number of subjects included in analysis
    229
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.0002
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Odds ratio (OR)
    Point estimate
    5.071
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    2.002
         upper limit
    12.844
    Statistical analysis title
    RBC-TI ≥ 12 weeks_1
    Comparison groups
    Luspatercept v Placebo
    Number of subjects included in analysis
    229
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.0002
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Common Risk Difference on Response Rate
    Point estimate
    20
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    10.92
         upper limit
    29.08

    Secondary: Percentage of Participants Who Achieved Red Blood Cell Transfusion Independence (RBC-TI) ≥ 12 Weeks From Week 1 to Week 48

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    End point title
    Percentage of Participants Who Achieved Red Blood Cell Transfusion Independence (RBC-TI) ≥ 12 Weeks From Week 1 to Week 48
    End point description
    RBC-TI Response was defined as the absence of any Red Blood Cells (RBC) transfusion during any consecutive 84-day (12-week) period (ie, Days 1 to 84, Days 2 to 85, Days 3 to 86, etc.) during the first 48 weeks of treatment.
    End point type
    Secondary
    End point timeframe
    From Week 1 through Week 48 of study treatment
    End point values
    Luspatercept Placebo
    Number of subjects analysed
    153
    76
    Units: Percent of Participants
        number (confidence interval 95%)
    33.33 (25.93 to 41.40)
    11.84 (5.56 to 21.29)
    Statistical analysis title
    RBC-TI ≥ 12 weeks_4
    Comparison groups
    Luspatercept v Placebo
    Number of subjects included in analysis
    229
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.0003
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Odds ratio (OR)
    Point estimate
    4.045
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.827
         upper limit
    8.956
    Statistical analysis title
    RBC-TI ≥ 12 weeks_3
    Comparison groups
    Luspatercept v Placebo
    Number of subjects included in analysis
    229
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.0003
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Common Risk Difference on Response Rate
    Point estimate
    21.37
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    11.23
         upper limit
    31.51

    Secondary: Percentage of Participants Who Achieved Red Blood Cell Transfusion Independence (RBC-TI) ≥ 8 Weeks From Week 1 Through Week 48

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    End point title
    Percentage of Participants Who Achieved Red Blood Cell Transfusion Independence (RBC-TI) ≥ 8 Weeks From Week 1 Through Week 48
    End point description
    RBC-TI response was defined as the absence of any Red Blood Cells (RBC) transfusion during any consecutive 56-day (8-week) period (ie, Days 1 to 56, Days 2 to 57, Days 3 to 58, etc.) during Week 1 through Week 48. Participants had to have at least 56 days (≥ 8 weeks) of transfusion independence prior to (and including) the Week 48 cut-off date to qualify as a responder. Participants who failed to achieve RBC-TI at least 56 days prior to Week 48 were counted as non-responders.
    End point type
    Secondary
    End point timeframe
    From Week 1 through Week 48 of study treatment
    End point values
    Luspatercept Placebo
    Number of subjects analysed
    153
    76
    Units: Percentage of Participants
        number (confidence interval 95%)
    45.10 (37.05 to 53.34)
    15.79 (8.43 to 25.96)
    Statistical analysis title
    RBC-TI ≥ 8 weeks_3
    Comparison groups
    Luspatercept v Placebo
    Number of subjects included in analysis
    229
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    < 0.0001
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Common Risk Difference on Response Rate
    Point estimate
    29.55
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    18.73
         upper limit
    40.36
    Statistical analysis title
    RBC-TI ≥ 8 weeks_4
    Comparison groups
    Luspatercept v Placebo
    Number of subjects included in analysis
    229
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    < 0.0001
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Odds ratio (OR)
    Point estimate
    5.306
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    2.526
         upper limit
    11.146

    Secondary: Change From Baseline in RBC Units Transfused Over Fixed 16-Week Period

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    End point title
    Change From Baseline in RBC Units Transfused Over Fixed 16-Week Period
    End point description
    Mean change in total number of Red Blood Cells (RBC) units transfused over a fixed 16-week period (Week 9-24 or Week 33-48) from the total number of RBC units transfused in the 16 weeks immediately on or prior to first dose of study treatment.
    End point type
    Secondary
    End point timeframe
    At Baseline (16 weeks prior to first dose of study treatment) and Weeks 9 to 24 or Weeks 33 to 48
    End point values
    Luspatercept Placebo
    Number of subjects analysed
    128
    68
    Units: Units
    arithmetic mean (standard deviation)
        Weeks 9 to 24
    -3.0 ± 5.17
    0.4 ± 4.25
        Weeks 33 to 48
    -4.9 ± 4.22
    -3.9 ± 7.14
    No statistical analyses for this end point

    Secondary: Percentage of Participants who Achieved a Modified Hematologic Erythroid Response (mHI-E) Over any Consecutive 56-Day Period

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    End point title
    Percentage of Participants who Achieved a Modified Hematologic Erythroid Response (mHI-E) Over any Consecutive 56-Day Period
    End point description
    A modified HI-E response was defined as the percentage of participants meeting the modified HI-E per the International Working Group (IWG) sustained over 56-day consecutive period during the Treatment period. For participants with a baseline RBC transfusion burden of ≥ 4 units/8 weeks, a mHI-E was defined as a reduction in RBC transfusion of at least 4 units/8 weeks; for participants with baseline RBC transfusion burden of <4 units/8 weeks, mHI-E, was defined as a mean increase in hemoglobin of ≥ 1.5 g/dL for 8 weeks in the absence of RBC transfusions.
    End point type
    Secondary
    End point timeframe
    Week 1 through 24 or Week 1 Through Week 48
    End point values
    Luspatercept Placebo
    Number of subjects analysed
    153
    76
    Units: Percentage of Participants
    number (confidence interval 95%)
        Week 1 Through Week 24
    52.9 (44.72 to 61.05)
    11.8 (5.56 to 21.29)
        Week 1 Through Week 48
    58.8 (50.59 to 66.71)
    17.1 (9.43 to 27.47)
    Statistical analysis title
    mHI-E_1
    Statistical analysis description
    Week 1 -24
    Comparison groups
    Luspatercept v Placebo
    Number of subjects included in analysis
    229
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    < 0.0001
    Method
    Cochran-Mantel-Haenszel
    Confidence interval
    Statistical analysis title
    mHI-E_2
    Statistical analysis description
    Week 1 - 48
    Comparison groups
    Luspatercept v Placebo
    Number of subjects included in analysis
    229
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    < 0.0001
    Method
    Cochran-Mantel-Haenszel
    Confidence interval

    Secondary: Percentage of Participants Who Achieved a Mean Hemoglobin (Hgb) Increase of at Least 1.0 g/dL Over any Consecutive 56-Day Period in Absence of Red Blood Cells (RBC) Transfusions

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    End point title
    Percentage of Participants Who Achieved a Mean Hemoglobin (Hgb) Increase of at Least 1.0 g/dL Over any Consecutive 56-Day Period in Absence of Red Blood Cells (RBC) Transfusions
    End point description
    A mean hgb increase of ≥ 1.0 g/dL was analyzed as the percentage of participants with a hgb increase ≥ 1.0 g/dL compared with baseline (after applying the 14/3 day rule) that was sustained over any consecutive 56-day (8-week) period in the absence of RBC transfusions during the treatment period. (Week 1 through Week 24 and Week 1 through Week 48).
    End point type
    Secondary
    End point timeframe
    Week 1 though Week 24 and Week 1 through 48
    End point values
    Luspatercept Placebo
    Number of subjects analysed
    153
    76
    Units: Percentage of Participants
    number (confidence interval 95%)
        Week 1 Through Week 24
    35.3 (27.75 to 43.42)
    7.9 (2.95 to 16.40)
        Week 1 Through Week 48
    41.2 (33.29 to 49.41)
    10.5 (4.66 to 19.69)
    Statistical analysis title
    Hgb increase_1
    Statistical analysis description
    Week 1 Through Week 24
    Comparison groups
    Luspatercept v Placebo
    Number of subjects included in analysis
    229
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    < 0.0001
    Method
    Fisher exact
    Confidence interval
    Statistical analysis title
    Hgb increase_2
    Statistical analysis description
    Week 1 Through Week 48
    Comparison groups
    Luspatercept v Placebo
    Number of subjects included in analysis
    229
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    < 0.0001
    Method
    Fisher exact
    Confidence interval

    Secondary: Duration of Red Blood Cell Transfusion Independence (RBC-TI) - Week 1 through Week 24

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    End point title
    Duration of Red Blood Cell Transfusion Independence (RBC-TI) - Week 1 through Week 24
    End point description
    Duration of RBC-TI was defined as the longest duration of response for participants who achieved RBC-TI of ≥ 8 weeks during the treatment period Week 1 through Week 24. Participants who maintained RBC-TI through the end of the treatment period were censored at the date of IP discontinuation or death, whichever occurred first. Median was estimated from unstratified Kaplan Meier method.
    End point type
    Secondary
    End point timeframe
    From start of study treatment to 16 weeks after last dose, up to approximately 70 weeks
    End point values
    Luspatercept Placebo
    Number of subjects analysed
    58
    10
    Units: Weeks
        median (confidence interval 95%)
    30.6 (20.6 to 40.6)
    13.6 (9.1 to 54.9)
    Statistical analysis title
    RBC-TI Duration_1
    Comparison groups
    Luspatercept v Placebo
    Number of subjects included in analysis
    68
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.0445
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.446
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.196
         upper limit
    1.013

    Secondary: Duration of Red Blood Cell Transfusion Independence (RBC-TI) - Week 1 through Week 48

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    End point title
    Duration of Red Blood Cell Transfusion Independence (RBC-TI) - Week 1 through Week 48
    End point description
    Duration of RBC-TI was defined as the longest duration of response for participants who achieved RBC-TI of ≥ 8 weeks during the treatment period Week 1 through Week 48. Participants who maintained RBC-TI through the end of the treatment period were censored at the date of IP discontinuation or death, whichever occurred first. Median was estimated from unstratified Kaplan Meier method.
    End point type
    Secondary
    End point timeframe
    From start of study treatment to 16 weeks after last dose, up to approximately 76 weeks
    End point values
    Luspatercept Placebo
    Number of subjects analysed
    69
    12
    Units: Weeks
        median (confidence interval 95%)
    30.6 (20.6 to 50.9)
    18.6 (10.9 to 99999)
    Statistical analysis title
    RBC-TI Duration_2
    Comparison groups
    Luspatercept v Placebo
    Number of subjects included in analysis
    81
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.5121
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.784
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.362
         upper limit
    1.699

    Secondary: Mean Change From Baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) Global Quality of Life Score

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    End point title
    Mean Change From Baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) Global Quality of Life Score
    End point description
    The EORTC questionnaire is a validated health-related quality of life (HRQoL) measure applicable to participants with any cancer diagnosis. Version 3.0 of the questionnaire was used in the study. It is composed of 30 items that address 15 domains, including one global health status, functional domains, and symptom domains. Domain scores are transformed to a 0 to 100 scale, where higher scores on the global quality of life score indicate better function. As such, a positive change from Baseline score indicates an improvement in quality of life.
    End point type
    Secondary
    End point timeframe
    Baseline and Cycle 3, Day 1 (C3 D1), C5 D1, C7 D1, Week 25, every other cycle during extension phase (C1 D1, C3 D1, C5 D1, etc. up to C59 D1) and end of treatment. Each cycle is composed of 21 days.
    End point values
    Luspatercept Placebo
    Number of subjects analysed
    149
    76
    Units: Score on a scale
    arithmetic mean (standard deviation)
        Cycle 3 Day 1 (C3 D1)
    -4.1 ± 21.01
    0.1 ± 15.95
        C5 D1
    -2.4 ± 20.73
    2.2 ± 17.13
        C7 D1
    -2.1 ± 23.04
    -0.6 ± 18.63
        Week 25
    -1.8 ± 21.75
    0.2 ± 18.88
        Extension Phase C1 D1
    0.0 ± 25.32
    6.3 ± 14.60
        Extension Phase C3 D1
    2.0 ± 19.68
    -3.9 ± 26.86
        Extension Phase C5 D1
    0.8 ± 18.40
    0.6 ± 20.04
        Extension Phase C7 D1
    -0.5 ± 20.03
    3.8 ± 20.87
        Extension Phase C9 D1
    -2.4 ± 18.42
    11.9 ± 19.75
        Extension Phase C11 D1
    -1.8 ± 19.53
    4.8 ± 24.47
        Extension Phase C13 D1
    -2.6 ± 20.84
    8.3 ± 24.15
        Extension Phase C15 D1
    3.1 ± 18.27
    4.2 ± 27.26
        Extension Phase C17 D1
    -0.6 ± 19.03
    13.9 ± 26.79
        Extension Phase C19 D1
    -1.6 ± 18.78
    -16.7 ± 14.43
        Extension Phase C21 D1
    3.1 ± 18.32
    4.2 ± 17.68
        Extension Phase C23 D1
    0.9 ± 17.84
    16.7 ± 99999
        Extension Phase C25 D1
    -2.0 ± 18.15
    16.7 ± 99999
        Extension Phase C27 D1 0 subjects in Placebo.
    2.5 ± 20.40
    99999 ± 99999
        Extension Phase C29 D1 0 subjects in Placebo.
    2.1 ± 21.12
    99999 ± 99999
        Extension Phase C31 D1 0 subjects in Placebo.
    -0.3 ± 15.93
    99999 ± 99999
        Extension Phase C33 D1 0 subjects in Placebo.
    -1.5 ± 19.41
    99999 ± 99999
        Extension Phase C35 D1 0 subjects in Placebo.
    3.6 ± 23.33
    99999 ± 99999
        Extension Phase C37 D1 0 subjects in Placebo.
    0.5 ± 22.04
    99999 ± 99999
        Extension Phase C39 D1 0 subjects in Placebo.
    0.3 ± 23.63
    99999 ± 99999
        Extension Phase C41 D1 0 subjects in Placebo.
    6.6 ± 20.11
    99999 ± 99999
        Extension Phase C43 D1 0 subjects in Placebo.
    4.8 ± 15.29
    99999 ± 99999
        Extension Phase C45 D1 0 subjects in Placebo.
    -2.2 ± 21.24
    99999 ± 99999
        Extension Phase C47 D1 0 subjects in Placebo.
    1.4 ± 19.08
    99999 ± 99999
        Extension Phase C49 D1 0 subjects in Placebo.
    -3.8 ± 16.40
    99999 ± 99999
        Extension Phase C51 D1 0 subjects in Placebo.
    8.3 ± 8.33
    99999 ± 99999
        Extension Phase C53 D1 0 subjects in Placebo.
    12.5 ± 10.76
    99999 ± 99999
        Extension Phase C55 D1 0 subjects in Placebo.
    2.8 ± 17.35
    99999 ± 99999
        Extension Phase C57 D1 0 subjects in Placebo.
    12.5 ± 5.89
    99999 ± 99999
        Extension Phase C59 D1 0 subjects in Placebo.
    16.7 ± 99999
    99999 ± 99999
        End of Treatment
    -9.2 ± 23.97
    -0.8 ± 23.07
    No statistical analyses for this end point

    Secondary: Percentage of Participants who Achieved a Hematologic Improvement in Neutrophil Response (HI-N) over any Consecutive 56-day Period

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    End point title
    Percentage of Participants who Achieved a Hematologic Improvement in Neutrophil Response (HI-N) over any Consecutive 56-day Period
    End point description
    Percentage of participants who achieved a hematologic improvement in neutrophil response (HI-N) per IWG criteria sustained over any consecutive 56-day (8-week) period, during the treatment period (Week 1 to Week 24 and Week 1 to Week 48) HI-N was defined as at least a 100% increase and an absolute increase > 0.5 X 10^9/L.
    End point type
    Secondary
    End point timeframe
    Week 1 through Week 24 or Week 1 Through Week 48 of study treatment
    End point values
    Luspatercept Placebo
    Number of subjects analysed
    15
    10
    Units: Percentage of Participants
    number (confidence interval 95%)
        Week 1 Through Week 24
    13.3 (1.66 to 40.46)
    0 (0.00 to 30.85)
        Week 1 Through Week 48
    20.0 (4.33 to 48.09)
    10.0 (0.25 to 44.50)
    Statistical analysis title
    HI-N_1
    Statistical analysis description
    Week 1 -24
    Comparison groups
    Luspatercept v Placebo
    Number of subjects included in analysis
    25
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.2382
    Method
    Cochran-Mantel-Haenszel
    Confidence interval
    Statistical analysis title
    HI-N_2
    Statistical analysis description
    Week 1 - 48
    Comparison groups
    Luspatercept v Placebo
    Number of subjects included in analysis
    25
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.5127
    Method
    Cochran-Mantel-Haenszel
    Confidence interval

    Secondary: Percentage of Participants who Achieved a Hematologic Improvement in Platelet Response (HI-P) Over any Consecutive 56-day Period

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    End point title
    Percentage of Participants who Achieved a Hematologic Improvement in Platelet Response (HI-P) Over any Consecutive 56-day Period
    End point description
    Percentage of participants who achieved a hematologic improvement platelet response (HI-P) was defined as the percentage of participants meeting the HI-P criteria per the IWG sustained over any consecutive 56-day (8-week) period (Week 1 to Week 24 and Week 1 to Week 48) during the treatment period. HI – P reponse was defined as: • Absolute increase of ≥ 30 X 10^9/L in platelets for participants starting with > 20 X 10^9/L platelets • Increase in platelets from < 20 X 10^9/L to > 20 X 10^9/L and by at least 100%
    End point type
    Secondary
    End point timeframe
    Week 1 through Week 24 or Week 1 Through Week 48 of study treatment
    End point values
    Luspatercept Placebo
    Number of subjects analysed
    8
    6
    Units: Percentage of Participants
    number (confidence interval 95%)
        Week 1 Through Week 24
    50.0 (15.70 to 84.30)
    33.3 (4.33 to 77.72)
        Week 1 Through Week 48
    62.5 (24.49 to 91.48)
    33.3 (4.33 to 77.72)
    Statistical analysis title
    HI-P_2
    Statistical analysis description
    Week 1 - 48
    Comparison groups
    Luspatercept v Placebo
    Number of subjects included in analysis
    14
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.298
    Method
    Cochran-Mantel-Haenszel
    Confidence interval
    Statistical analysis title
    HI-P_1
    Statistical analysis description
    Week 1 -24
    Comparison groups
    Luspatercept v Placebo
    Number of subjects included in analysis
    14
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.5479
    Method
    Cochran-Mantel-Haenszel
    Confidence interval

    Secondary: Change from Baseline in Mean Serum Ferritin

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    End point title
    Change from Baseline in Mean Serum Ferritin
    End point description
    Mean change from baseline in mean serum ferritin was calculated as the difference of postbaseline mean serum ferritin (averaged over the specified timepoints) and baseline mean serum ferritin.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 9 through Week 24 and Week 33 through Week 48
    End point values
    Luspatercept Placebo
    Number of subjects analysed
    148
    74
    Units: ug/L
    least squares mean (standard error)
        Weeks 9-24
    -2.7 ± 54.05
    226.5 ± 68.02
        Weeks 33-48
    -72.0 ± 74.76
    247.4 ± 140.96
    Statistical analysis title
    Ferritin_1
    Statistical analysis description
    Week 9 Through 24
    Comparison groups
    Luspatercept v Placebo
    Number of subjects included in analysis
    222
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.0024
    Method
    ANCOVA
    Parameter type
    LS Mean Difference
    Point estimate
    -229.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -375.8
         upper limit
    -82.4
    Variability estimate
    Standard error of the mean
    Dispersion value
    74.43
    Statistical analysis title
    Ferritin_2
    Statistical analysis description
    Week 33 Through 48
    Comparison groups
    Luspatercept v Placebo
    Number of subjects included in analysis
    222
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.0294
    Method
    ANCOVA
    Parameter type
    LS Mean Difference
    Point estimate
    -319.5
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -606.3
         upper limit
    -32.7
    Variability estimate
    Standard error of the mean
    Dispersion value
    144.57

    Secondary: Change from Baseline in Mean Daily Dose of Iron Chelation Therapy (ICT)

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    End point title
    Change from Baseline in Mean Daily Dose of Iron Chelation Therapy (ICT)
    End point description
    Mean change from baseline in mean daily dose of ICT averaged over Week 9 to Week 24 or Week 33 to Week 48. For each participant, the mean change in daily dose of ICT was calculated as the difference of postbaseline mean daily dose and baseline mean daily dose.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 9 through Week 24 and Week 33 through Week 48 of study treatment
    End point values
    Luspatercept Placebo
    Number of subjects analysed
    128
    68
    Units: mg/day
    least squares mean (standard error)
        Weeks 9-24
    10.0 ± 29.25
    51.0 ± 35.92
        Weeks 33-48
    -148.8 ± 46.13
    -123.8 ± 92.19
    Statistical analysis title
    ICT_2
    Statistical analysis description
    Weeks 33 Through 48
    Comparison groups
    Luspatercept v Placebo
    Number of subjects included in analysis
    196
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.7903
    Method
    ANCOVA
    Parameter type
    LS Mean Difference
    Point estimate
    -24.9
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -210.7
         upper limit
    160.8
    Variability estimate
    Standard error of the mean
    Dispersion value
    93.42
    Statistical analysis title
    ICT_1
    Statistical analysis description
    Weeks 9 Through 24
    Comparison groups
    Luspatercept v Placebo
    Number of subjects included in analysis
    196
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.3087
    Method
    ANCOVA
    Parameter type
    LS Mean Difference
    Point estimate
    -41
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -120.3
         upper limit
    38.2
    Variability estimate
    Standard error of the mean
    Dispersion value
    40.18

    Secondary: Time to Red Blood Cell Transfusion Independence (RBC-TI) - Week 1 Through Week 48

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    End point title
    Time to Red Blood Cell Transfusion Independence (RBC-TI) - Week 1 Through Week 48
    End point description
    Time to RBC-TI was defined as the time between first dose date and the date of onset of RBC-TI first observed for participants who achieved RBC-TI of ≥ 8 weeks during Week 1 through Week 48
    End point type
    Secondary
    End point timeframe
    From first dose to Week 48 of study treatment
    End point values
    Luspatercept Placebo
    Number of subjects analysed
    69
    12
    Units: Days
        arithmetic mean (standard deviation)
    40.3 ± 61.03
    57.2 ± 79.18
    No statistical analyses for this end point

    Secondary: Time to Red Blood Cell Transfusion Independence (RBC-TI) - Week 1 Through Week 24

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    End point title
    Time to Red Blood Cell Transfusion Independence (RBC-TI) - Week 1 Through Week 24
    End point description
    Time to RBC-TI was defined as the time between first dose date and the date of onset of RBC-TI first observed for participants who achieved RBC-TI of ≥ 8 weeks during Week 1 through Week 24
    End point type
    Secondary
    End point timeframe
    From first dose to Week 24 of study treatment
    End point values
    Luspatercept Placebo
    Number of subjects analysed
    58
    10
    Units: Days
        arithmetic mean (standard deviation)
    17.2 ± 29.40
    26.0 ± 31.83
    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
    Percentage of participants progressing to AML throughout the course of the study
    End point type
    Secondary
    End point timeframe
    From randomization to study completion (up to approximately 57 months)
    End point values
    Luspatercept Placebo
    Number of subjects analysed
    153
    76
    Units: Percentage of Participants
        number (not applicable)
    2.6
    3.9
    No statistical analyses for this end point

    Secondary: Time to Acute Myeloid Leukemia (AML) Progression

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    End point title
    Time to Acute Myeloid Leukemia (AML) Progression
    End point description
    Time to AML progression was defined as the time between randomization date and the first diagnosis of AML as per World Health Organization (WHO) classification of ≥ 20% blasts in peripheral blood or bone marrow. Participants with a diagnosis of AML were considered to have had an event, participants who did not progress to AML at the time of analysis were censored at the last assessment date which did not indicate progression to AML. Median was not reached because of insufficient number of events
    End point type
    Secondary
    End point timeframe
    From randomization to study completion (up to approximately 57 months)
    End point values
    Luspatercept Placebo
    Number of subjects analysed
    4 [1]
    3 [2]
    Units: Months
        median (confidence interval 95%)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    Notes
    [1] - Median was not reached because of insufficient number of events
    [2] - Median was not reached because of insufficient number of events
    No statistical analyses for this end point

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

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    End point title
    Number of Participants with Treatment Emergent Adverse Events (TEAEs)
    End point description
    The outcome measure describes the number of participants who experienced different types of Treatment-emergent adverse events (TEAEs). TEAEs were defined as Adverse Events (AEs) that started on or after the day of the first dose and on or before 42 days after the last dose of IP. 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 date of first dose up to 42 days after the last dose (up to approximately 66 weeks)
    End point values
    Luspatercept Placebo
    Number of subjects analysed
    153
    76
    Units: Participants
        ≥ 1 TEAE
    151
    70
        ≥ 1 Suspected Related TEAE
    71
    26
        ≥ 1 Serious TEAE
    66
    23
        ≥ 1 Suspected Related Serious TEAE
    6
    0
        ≥ 1 TEAE CTCAE Toxicity Grade (GR) 5
    8
    4
        ≥ 1 Suspected Related TEAE With CTCAE GR 5
    0
    0
        ≥ 1 TEAE with CTCAE GR 3 or 4
    86
    34
        ≥ 1 Suspected Related TEAE With CTCAE GR 3 or 4
    13
    3
        ≥ 1 TEAE Leading to Dose Interruption
    42
    4
        ≥ 1 TEAE Leading to Dose Reduction
    9
    0
        ≥ 1 TEAE Leading to Study Drug Discontinuation
    22
    6
    No statistical analyses for this end point

    Secondary: Overall Survival

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    End point title
    Overall Survival
    End point description
    Overall Survival was defined as the time from the date of study drug randomization to death due to any cause. Overall survival was censored at the last date that the participant was known to be alive for participants who were alive at the time of analysis and for those who discontinued from the study or were lost to follow-up.
    End point type
    Secondary
    End point timeframe
    From randomization to study completion (up to approximately 57 months)
    End point values
    Luspatercept Placebo
    Number of subjects analysed
    153
    76 [3]
    Units: Months
        median (confidence interval 95%)
    46.0 (42.0 to 99999)
    99999 (43.1 to 99999)
    Notes
    [3] - Median not reached because of insufficient number of events
    Statistical analysis title
    OS
    Comparison groups
    Luspatercept v Placebo
    Number of subjects included in analysis
    229
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.958
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.986
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.595
         upper limit
    1.636

    Secondary: Pharmacokinetic (PK) Parameters: Bayesian Estimate of Apparent Clearance (CL/F)

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    End point title
    Pharmacokinetic (PK) Parameters: Bayesian Estimate of Apparent Clearance (CL/F)
    End point description
    Apparent total plasma clearance was calculated as Dose/Area Under the Curve to infinity (ꝏ).
    End point type
    Secondary
    End point timeframe
    Blood serum samples taken pre-dose at Cycle 1 Day 1 (C1, D1), C1 D8, C1 D15, C2 D1, C4 D1, C5 D8, C6 D1 and Week 25 visit, extension phase C4 D1 and Day 1 of every fourth treatment cycle thereafter.
    End point values
    Luspatercept Placebo
    Number of subjects analysed
    153
    0 [4]
    Units: L/day
        geometric mean (geometric coefficient of variation)
    0.516 ± 41.2
    ±
    Notes
    [4] - Subjects did not receive investigational drug product
    No statistical analyses for this end point

    Secondary: Pharmacokinetic (PK) Parameters: Bayesian Estimate of Apparent Volume of Distribution of the Central Compartment (V1/F)

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    End point title
    Pharmacokinetic (PK) Parameters: Bayesian Estimate of Apparent Volume of Distribution of the Central Compartment (V1/F)
    End point description
    Apparent volume of distribution of luspatercept was calculated according to the equation Vz = (CL)/λ.
    End point type
    Secondary
    End point timeframe
    Blood serum samples taken pre-dose at Cycle 1 Day 1 (C1, D1), C1 D8, C1 D15, C2 D1, C4 D1, C5 D8, C6 D1 and Week 25 visit, extension phase C4 D1 and Day 1 of every fourth treatment cycle thereafter.
    End point values
    Luspatercept Placebo
    Number of subjects analysed
    153
    0 [5]
    Units: Liters
        geometric mean (geometric coefficient of variation)
    9.68 ± 26.5
    ±
    Notes
    [5] - Subjects did not receive investigational drug product
    No statistical analyses for this end point

    Secondary: Pharmacokinetic (PK) Parameters: Bayesian Estimate of Time to Reach Maximum Concentration (Tmax)

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    End point title
    Pharmacokinetic (PK) Parameters: Bayesian Estimate of Time to Reach Maximum Concentration (Tmax)
    End point description
    Tmax was defined as the observed time to maximum plasma concentration of luspatercept.
    End point type
    Secondary
    End point timeframe
    Blood serum samples taken pre-dose at Cycle 1 Day 1 (C1, D1), C1 D8, C1 D15, C2 D1, C4 D1, C5 D8, C6 D1 and Week 25 visit, extension phase C4 D1 and Day 1 of every fourth treatment cycle thereafter.
    End point values
    Luspatercept Placebo
    Number of subjects analysed
    153
    0 [6]
    Units: Day
        median (full range (min-max))
    5.40 (3.12 to 6.69)
    ( to )
    Notes
    [6] - Subjects did not receive investigational drug product
    No statistical analyses for this end point

    Secondary: Pharmacokinetic (PK) Parameters: Bayesian Estimate of Elimination Half-life (t1/2)

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    End point title
    Pharmacokinetic (PK) Parameters: Bayesian Estimate of Elimination Half-life (t1/2)
    End point description
    Terminal phase half-life was calculated according to the following equation: t1/2 = 0.693/λz.
    End point type
    Secondary
    End point timeframe
    Blood serum samples taken pre-dose at Cycle 1 Day 1 (C1, D1), C1 D8, C1 D15, C2 D1, C4 D1, C5 D8, C6 D1 and Week 25 visit, extension phase C4 D1 and Day 1 of every fourth treatment cycle thereafter.
    End point values
    Luspatercept Placebo
    Number of subjects analysed
    153
    0 [7]
    Units: Day
        geometric mean (geometric coefficient of variation)
    13.0 ± 31.6
    ±
    Notes
    [7] - Subjects did not receive investigational drug product
    No statistical analyses for this end point

    Secondary: Pharmacokinetic (PK) Parameters: Bayesian Estimate of Maximum Concentration for the Starting Dose (Cmax) at Steady State

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    End point title
    Pharmacokinetic (PK) Parameters: Bayesian Estimate of Maximum Concentration for the Starting Dose (Cmax) at Steady State
    End point description
    Cmax was defined as the observed maximum plasma concentration, obtained directly from the observed concentration at a steady state.
    End point type
    Secondary
    End point timeframe
    Blood serum samples taken pre-dose at Cycle 1 Day 1 (C1, D1), C1 D8, C1 D15, C2 D1, C4 D1, C5 D8, C6 D1 and Week 25 visit, extension phase C4 D1 and Day 1 of every fourth treatment cycle thereafter.
    End point values
    Luspatercept Placebo
    Number of subjects analysed
    153
    0 [8]
    Units: μg/mL
        geometric mean (geometric coefficient of variation)
    9.17 ± 29.9
    ±
    Notes
    [8] - Subjects did not receive investigational drug product
    No statistical analyses for this end point

    Secondary: Pharmacokinetic (PK) Parameters: Bayesian Estimate of Maximum Concentration for the First Dose (Cmax)

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    End point title
    Pharmacokinetic (PK) Parameters: Bayesian Estimate of Maximum Concentration for the First Dose (Cmax)
    End point description
    Cmax was defined as the observed maximum plasma concentration, obtained directly from the observed concentration versus time.
    End point type
    Secondary
    End point timeframe
    Blood serum samples taken pre-dose at Cycle 1 Day 1 (C1, D1), C1 D8, C1 D15, C2 D1, C4 D1, C5 D8, C6 D1 and Week 25 visit, extension phase C4 D1 and Day 1 of every fourth treatment cycle thereafter.
    End point values
    Luspatercept Placebo
    Number of subjects analysed
    153
    0 [9]
    Units: μg/mL
        geometric mean (geometric coefficient of variation)
    5.77 ± 20.5
    ±
    Notes
    [9] - Subjects did not receive investigational drug product
    No statistical analyses for this end point

    Secondary: Pharmacokinetic (PK) Parameters: Bayesian Estimate of Maximum Concentration for the Area Under the Curve at Steady State for Starting Dose (AUC^ss)

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    End point title
    Pharmacokinetic (PK) Parameters: Bayesian Estimate of Maximum Concentration for the Area Under the Curve at Steady State for Starting Dose (AUC^ss)
    End point description
    Area under the curve steady state was defined as the area under the plasma concentration-time curve for a steady state. calculated by the linear trapezoidal rule.
    End point type
    Secondary
    End point timeframe
    Blood serum samples taken pre-dose at Cycle 1 Day 1 (C1, D1), C1 D8, C1 D15, C2 D1, C4 D1, C5 D8, C6 D1 and Week 25 visit, extension phase C4 D1 and Day 1 of every fourth treatment cycle thereafter.
    End point values
    Luspatercept Placebo
    Number of subjects analysed
    153
    0 [10]
    Units: day/μg/mL
        geometric mean (geometric coefficient of variation)
    145 ± 38.3
    ±
    Notes
    [10] - Subjects did not receive investigational drug product
    No statistical analyses for this end point

    Secondary: Participants with Pre-Existing and/or Treatment-Emergent Antidrug Antibodies (ADA)

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    End point title
    Participants with Pre-Existing and/or Treatment-Emergent Antidrug Antibodies (ADA)
    End point description
    Number of participants with positive ADA prior to taking study drug and/or during study. A participant was counted as “treatment-emergent” if there was a positive post-baseline sample while the baseline sample was ADA negative, or there was a positive post-baseline sample with a titer ≥ 4-fold of the baseline titer while the baseline sample was ADA positive. A participant was counted as “preexisting” if the baseline sample was ADA positive and the participant was not qualified for “treatment-emergent.”
    End point type
    Secondary
    End point timeframe
    From randomization to 1 year post first dose
    End point values
    Luspatercept Placebo
    Number of subjects analysed
    153
    76
    Units: Participants
        Pre-Existing ADA
    7
    2
        Treatment Emergent ADA
    11
    3
        Treatment Emergent Neutralizing ADA
    5
    2
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All-cause mortality was assessed from first dose to study completion (up to approximately 57 months). SAEs and Other AEs were assessed from first dose to 100 days following last dose (up to approximately 91 weeks)
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    23.0
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Placebo (Volume equivalent to experimental arm) SC on Day 1 of each 21-day treatment cycle. Placebo is with a median duration of treatment of 168 days

    Reporting group title
    Luspatercept
    Reporting group description
    Luspatercept 1.0 mg/Kg SC on Day 1 of each 21-day treatment cycle. Luspatercept is with a median duration of treatment of 356 days

    Serious adverse events
    Placebo Luspatercept
    Total subjects affected by serious adverse events
         subjects affected / exposed
    23 / 76 (30.26%)
    66 / 153 (43.14%)
         number of deaths (all causes)
    24
    45
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Colon adenoma
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 153 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Basal cell carcinoma
         subjects affected / exposed
    0 / 76 (0.00%)
    3 / 153 (1.96%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intraductal papillary mucinous neoplasm
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 153 (0.65%)
         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
    1 / 76 (1.32%)
    2 / 153 (1.31%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transformation to acute myeloid leukaemia
         subjects affected / exposed
    1 / 76 (1.32%)
    3 / 153 (1.96%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Refractory anaemia with an excess of blasts
         subjects affected / exposed
    0 / 76 (0.00%)
    4 / 153 (2.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Squamous cell carcinoma of skin
         subjects affected / exposed
    0 / 76 (0.00%)
    3 / 153 (1.96%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Squamous cell carcinoma
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 153 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Systemic mastocytosis
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 153 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Granulomatosis with polyangiitis
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 153 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Orthostatic hypotension
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 153 (0.65%)
         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
    0 / 76 (0.00%)
    1 / 153 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Aortic stenosis
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 153 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 153 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 153 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Generalised oedema
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 153 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gait disturbance
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 153 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 153 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 153 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chest pain
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 153 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multiple organ dysfunction syndrome
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 153 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pyrexia
         subjects affected / exposed
    2 / 76 (2.63%)
    3 / 153 (1.96%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory distress syndrome
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 153 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    1 / 76 (1.32%)
    1 / 153 (0.65%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea exertional
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 153 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    0 / 76 (0.00%)
    2 / 153 (1.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epistaxis
         subjects affected / exposed
    0 / 76 (0.00%)
    2 / 153 (1.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary fibrosis
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 153 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 153 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Psychiatric disorders
    Confusional state
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 153 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Delirium
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 153 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Suicide attempt
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 153 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Product issues
    Thrombosis in device
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 153 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    General physical condition abnormal
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 153 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Ankle fracture
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 153 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clavicle fracture
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 153 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    3 / 76 (3.95%)
    7 / 153 (4.58%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    0 / 76 (0.00%)
    6 / 153 (3.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Head injury
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 153 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Joint dislocation
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 153 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Humerus fracture
         subjects affected / exposed
    1 / 76 (1.32%)
    2 / 153 (1.31%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    3 / 76 (3.95%)
    0 / 153 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Joint injury
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 153 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rib fracture
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 153 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Road traffic accident
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 153 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Spinal column injury
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 153 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thoracic vertebral fracture
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 153 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pelvic bone injury
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 153 (0.65%)
         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
    0 / 76 (0.00%)
    1 / 153 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal fracture
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 153 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Angina pectoris
         subjects affected / exposed
    0 / 76 (0.00%)
    3 / 153 (1.96%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aortic valve stenosis
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 153 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arteriosclerosis coronary artery
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 153 (0.65%)
         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
    0 / 76 (0.00%)
    1 / 153 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrioventricular block
         subjects affected / exposed
    0 / 76 (0.00%)
    2 / 153 (1.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    0 / 76 (0.00%)
    2 / 153 (1.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrioventricular block second degree
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 153 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bradycardia
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 153 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    0 / 76 (0.00%)
    2 / 153 (1.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure acute
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 153 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 153 (0.65%)
         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 / 76 (1.32%)
    0 / 153 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Supraventricular tachycardia
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 153 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebral haemorrhage
         subjects affected / exposed
    0 / 76 (0.00%)
    2 / 153 (1.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cerebral ischaemia
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 153 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 153 (0.65%)
         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
    1 / 76 (1.32%)
    0 / 153 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebrospinal fluid leakage
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 153 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 76 (0.00%)
    3 / 153 (1.96%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Disseminated intravascular coagulation
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 153 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anaemia
         subjects affected / exposed
    0 / 76 (0.00%)
    3 / 153 (1.96%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 153 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 153 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ascites
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 153 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 153 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Duodenal ulcer
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 153 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dysphagia
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 153 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Duodenal ulcer haemorrhage
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 153 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 153 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 153 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 153 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 153 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 153 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholelithiasis
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 153 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperbilirubinaemia
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 153 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholangitis
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 153 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 76 (0.00%)
    2 / 153 (1.31%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal colic
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 153 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    1 / 76 (1.32%)
    1 / 153 (0.65%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Urinary retention
         subjects affected / exposed
    1 / 76 (1.32%)
    1 / 153 (0.65%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urethral stenosis
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 153 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    0 / 76 (0.00%)
    3 / 153 (1.96%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chondritis
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 153 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gouty arthritis
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 153 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Flank pain
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 153 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Muscle haemorrhage
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 153 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Muscular weakness
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 153 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Polymyalgia rheumatica
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 153 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myositis
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 153 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rheumatoid arthritis
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 153 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Abdominal infection
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 153 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bacteraemia
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 153 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    0 / 76 (0.00%)
    2 / 153 (1.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    1 / 76 (1.32%)
    1 / 153 (0.65%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocarditis
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 153 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 153 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterocolitis infectious
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 153 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epididymitis
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 153 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Escherichia urinary tract infection
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 153 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 153 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Localised infection
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 153 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 76 (0.00%)
    2 / 153 (1.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Parainfluenzae virus infection
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 153 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Orchitis
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 153 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metapneumovirus infection
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 153 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pharyngitis
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 153 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    2 / 76 (2.63%)
    8 / 153 (5.23%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 14
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia staphylococcal
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 153 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    1 / 76 (1.32%)
    1 / 153 (0.65%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 76 (1.32%)
    4 / 153 (2.61%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Soft tissue infection
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 153 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Staphylococcal infection
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 153 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Streptococcal infection
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 153 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 153 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection bacterial
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 153 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    1 / 76 (1.32%)
    1 / 153 (0.65%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 76 (1.32%)
    4 / 153 (2.61%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia moraxella
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 153 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 153 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 153 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Type 2 diabetes mellitus
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 153 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lactic acidosis
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 153 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Placebo Luspatercept
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    63 / 76 (82.89%)
    145 / 153 (94.77%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    6 / 76 (7.89%)
    16 / 153 (10.46%)
         occurrences all number
    8
    53
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    9 / 76 (11.84%)
    40 / 153 (26.14%)
         occurrences all number
    9
    74
    Influenza like illness
         subjects affected / exposed
    3 / 76 (3.95%)
    9 / 153 (5.88%)
         occurrences all number
    4
    11
    Malaise
         subjects affected / exposed
    3 / 76 (3.95%)
    8 / 153 (5.23%)
         occurrences all number
    3
    11
    Pyrexia
         subjects affected / exposed
    6 / 76 (7.89%)
    19 / 153 (12.42%)
         occurrences all number
    7
    24
    Oedema peripheral
         subjects affected / exposed
    13 / 76 (17.11%)
    37 / 153 (24.18%)
         occurrences all number
    14
    45
    Fatigue
         subjects affected / exposed
    11 / 76 (14.47%)
    46 / 153 (30.07%)
         occurrences all number
    14
    70
    Reproductive system and breast disorders
    Benign prostatic hyperplasia
         subjects affected / exposed
    0 / 76 (0.00%)
    8 / 153 (5.23%)
         occurrences all number
    0
    8
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    5 / 76 (6.58%)
    30 / 153 (19.61%)
         occurrences all number
    6
    39
    Cough
         subjects affected / exposed
    10 / 76 (13.16%)
    35 / 153 (22.88%)
         occurrences all number
    13
    50
    Epistaxis
         subjects affected / exposed
    3 / 76 (3.95%)
    12 / 153 (7.84%)
         occurrences all number
    3
    13
    Oropharyngeal pain
         subjects affected / exposed
    6 / 76 (7.89%)
    6 / 153 (3.92%)
         occurrences all number
    6
    6
    Psychiatric disorders
    Depression
         subjects affected / exposed
    5 / 76 (6.58%)
    9 / 153 (5.88%)
         occurrences all number
    5
    10
    Confusional state
         subjects affected / exposed
    0 / 76 (0.00%)
    9 / 153 (5.88%)
         occurrences all number
    0
    10
    Insomnia
         subjects affected / exposed
    4 / 76 (5.26%)
    13 / 153 (8.50%)
         occurrences all number
    4
    14
    Anxiety
         subjects affected / exposed
    1 / 76 (1.32%)
    9 / 153 (5.88%)
         occurrences all number
    1
    9
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    3 / 76 (3.95%)
    9 / 153 (5.88%)
         occurrences all number
    7
    17
    Weight decreased
         subjects affected / exposed
    5 / 76 (6.58%)
    9 / 153 (5.88%)
         occurrences all number
    5
    16
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 76 (1.32%)
    10 / 153 (6.54%)
         occurrences all number
    3
    22
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    7 / 76 (9.21%)
    25 / 153 (16.34%)
         occurrences all number
    8
    34
    Cardiac disorders
    Palpitations
         subjects affected / exposed
    5 / 76 (6.58%)
    11 / 153 (7.19%)
         occurrences all number
    5
    12
    Tachycardia
         subjects affected / exposed
    0 / 76 (0.00%)
    8 / 153 (5.23%)
         occurrences all number
    0
    9
    Nervous system disorders
    Headache
         subjects affected / exposed
    5 / 76 (6.58%)
    27 / 153 (17.65%)
         occurrences all number
    7
    32
    Syncope
         subjects affected / exposed
    1 / 76 (1.32%)
    10 / 153 (6.54%)
         occurrences all number
    1
    11
    Dizziness
         subjects affected / exposed
    4 / 76 (5.26%)
    35 / 153 (22.88%)
         occurrences all number
    4
    52
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    6 / 76 (7.89%)
    14 / 153 (9.15%)
         occurrences all number
    9
    36
    Neutropenia
         subjects affected / exposed
    7 / 76 (9.21%)
    8 / 153 (5.23%)
         occurrences all number
    13
    15
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    0 / 76 (0.00%)
    12 / 153 (7.84%)
         occurrences all number
    0
    14
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    4 / 76 (5.26%)
    11 / 153 (7.19%)
         occurrences all number
    5
    14
    Diarrhoea
         subjects affected / exposed
    8 / 76 (10.53%)
    44 / 153 (28.76%)
         occurrences all number
    9
    63
    Vomiting
         subjects affected / exposed
    5 / 76 (6.58%)
    14 / 153 (9.15%)
         occurrences all number
    5
    21
    Nausea
         subjects affected / exposed
    6 / 76 (7.89%)
    35 / 153 (22.88%)
         occurrences all number
    7
    53
    Abdominal pain upper
         subjects affected / exposed
    2 / 76 (2.63%)
    11 / 153 (7.19%)
         occurrences all number
    2
    12
    Constipation
         subjects affected / exposed
    7 / 76 (9.21%)
    21 / 153 (13.73%)
         occurrences all number
    11
    28
    Skin and subcutaneous tissue disorders
    Erythema
         subjects affected / exposed
    4 / 76 (5.26%)
    2 / 153 (1.31%)
         occurrences all number
    4
    2
    Pruritus
         subjects affected / exposed
    3 / 76 (3.95%)
    11 / 153 (7.19%)
         occurrences all number
    3
    14
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    9 / 76 (11.84%)
    13 / 153 (8.50%)
         occurrences all number
    14
    14
    Back pain
         subjects affected / exposed
    6 / 76 (7.89%)
    32 / 153 (20.92%)
         occurrences all number
    8
    47
    Myalgia
         subjects affected / exposed
    5 / 76 (6.58%)
    13 / 153 (8.50%)
         occurrences all number
    6
    14
    Infections and infestations
    Upper respiratory tract infection
         subjects affected / exposed
    4 / 76 (5.26%)
    19 / 153 (12.42%)
         occurrences all number
    5
    27
    Influenza
         subjects affected / exposed
    0 / 76 (0.00%)
    11 / 153 (7.19%)
         occurrences all number
    0
    17
    Urinary tract infection
         subjects affected / exposed
    4 / 76 (5.26%)
    21 / 153 (13.73%)
         occurrences all number
    7
    37
    Bronchitis
         subjects affected / exposed
    1 / 76 (1.32%)
    19 / 153 (12.42%)
         occurrences all number
    1
    29
    Nasopharyngitis
         subjects affected / exposed
    4 / 76 (5.26%)
    18 / 153 (11.76%)
         occurrences all number
    5
    26
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    3 / 76 (3.95%)
    14 / 153 (9.15%)
         occurrences all number
    4
    14
    Hyperuricaemia
         subjects affected / exposed
    2 / 76 (2.63%)
    12 / 153 (7.84%)
         occurrences all number
    2
    22
    Hyperglycaemia
         subjects affected / exposed
    3 / 76 (3.95%)
    12 / 153 (7.84%)
         occurrences all number
    3
    14
    Hyperkalaemia
         subjects affected / exposed
    1 / 76 (1.32%)
    10 / 153 (6.54%)
         occurrences all number
    1
    19
    Iron overload
         subjects affected / exposed
    3 / 76 (3.95%)
    9 / 153 (5.88%)
         occurrences all number
    3
    9

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    21 Sep 2016
    - Updates to criteria related to contraception measures - Added sites guidance for sample collection - Added language to exploratory markers - Updates to eligibility criteria - Updates to benefits/risk section
    09 May 2017
    - Updates to discontinuation criteria and dose modification - Clarification on sample collection modalities - Follow up period extension

    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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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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