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    Clinical Trial Results:
    A Phase 2, Double-Blind, Randomized, Placebo-Controlled Multicenter Study to Determine the Efficacy and Safety of Luspatercept (ACE-536) Versus Placebo in Adults With Non-Transfusion Dependent Beta (β)-Thalassemia (The BEYOND™ Study)

    Summary
    EudraCT number
    		 2015-003225-33
    Trial protocol
    		 GB   GR   IT  
    Global end of trial date
    28 Nov 2022

    Results information
    Results version number
    		 v1(current)
    This version publication date
    14 Dec 2023
    First version publication date
    14 Dec 2023
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    ACE-536-B-THAL-002
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Bristol-Myers Squibb
    Sponsor organisation address
    Chaussee de la Hulpe 185, Brussels, Belgium, 1170
    Public contact
    EU Study Start-Up Unit, Bristol-Myers Squibb International Corporation, Clinical.Trials@bms.com
    Scientific contact
    Bristol-Myers Squibb Study Director, Bristol-Myers Squibb, Clinical.Trials@bms.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    14 Feb 2023
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    28 Nov 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the effect of luspatercept versus placebo on anemia, as measured by mean Hb values in the absence of transfusions over continuous 12-week intervals, from Week 13 to Week 24, compared to baseline
    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
    01 Feb 2018
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety
    Long term follow-up duration
    		 3 Years
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Thailand: 38
    Country: Number of subjects enrolled
    Lebanon: 17
    Country: Number of subjects enrolled
    Greece: 36
    Country: Number of subjects enrolled
    Italy: 43
    Country: Number of subjects enrolled
    United Kingdom: 5
    Country: Number of subjects enrolled
    United States: 6
    Worldwide total number of subjects
    145
    EEA total number of subjects
    79
    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)
    140
    From 65 to 84 years
    5
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 145 subjects were treated

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Luspatercept
    Arm description
    		 Luspatercept was administered as subcutaneous injection once every 3 weeks (administered on Study Day 1 of each 21-day treatment cycle). The starting dose level was 1.00 mg/kg and could be escalated to 1.25 mg/kg and/or reduced to 0.80, 0.60, and 0.45 mg/kg. Participants were treated for a minimum of 48 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Luspatercept
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subcutaneous injection once every 3 weeks for at least 48 weeks. Starting dose 1.00 mg/kg

    Arm title
    		 Placebo
    Arm description
    		 Placebo (0.9% sodium chloride for injection) was administered as subcutaneous injection once every 3 weeks (administered on Study Day 1 of each 21-day treatment cycle) for a minimum of 48 weeks. Eligible participants entered an open-label phase and started Luspatercept treatment for up to approximately 24 months.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subcutaneous injection of 0.9% sodium chloride once every 3 weeks for at least 48 weeks.

    Number of subjects in period 1
    		Luspatercept Placebo
    Started
    96
    49
    Completed
    68
    18
    Not completed
    28
    31
         Adverse event, serious fatal
    1
    -
         Consent withdrawn by subject
    17
    10
         Physician decision
    1
    -
         Adverse event, non-fatal
    5
    4
         Noncompliance with study drug
    1
    -
         Other reasons
    1
    -
         Lack of efficacy
    2
    17
    Period 2
    Period 2 title
    Open-Label Phase
    Is this the baseline period?
    		 No
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Placebo
    Arm description
    		 Placebo (0.9% sodium chloride for injection) was administered as subcutaneous injection once every 3 weeks (administered on Study Day 1 of each 21-day treatment cycle) for a minimum of 48 weeks. Eligible participants entered an open-label phase and started Luspatercept treatment for up to approximately 24 months.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Luspatercept
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subcutaneous injection once every 3 weeks for at least 48 weeks. Starting dose 1.00 mg/kg

    Number of subjects in period 2 [1]
    		Placebo
    Started
    38
    Completed
    27
    Not completed
    11
         Consent withdrawn by subject
    6
         Adverse event, non-fatal
    3
         Other reasons
    1
         Lost to follow-up
    1
    Notes
    [1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: All participants in the Luspatercept arm completed treatment but participants in the placebo arm were eligible to receive Luspatercept treatment

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Luspatercept
    Reporting group description
    		 Luspatercept was administered as subcutaneous injection once every 3 weeks (administered on Study Day 1 of each 21-day treatment cycle). The starting dose level was 1.00 mg/kg and could be escalated to 1.25 mg/kg and/or reduced to 0.80, 0.60, and 0.45 mg/kg. Participants were treated for a minimum of 48 weeks.

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo (0.9% sodium chloride for injection) was administered as subcutaneous injection once every 3 weeks (administered on Study Day 1 of each 21-day treatment cycle) for a minimum of 48 weeks. Eligible participants entered an open-label phase and started Luspatercept treatment for up to approximately 24 months.

    Reporting group values
    		 Luspatercept Placebo Total
    Number of subjects
    		 96 49 145
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        85 years and over
    		 0 0 0
        Adults (18-64 years)
    		 93 47 140
        From 65-84 years
    		 3 2 5
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 39.3 ( 13.24 ) 41.1 ( 11.90 ) -
    Sex: Female, Male
    Units: Participants
        Female
    		 56 26 82
        Male
    		 40 23 63
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 2 1 3
        Not Hispanic or Latino
    		 94 48 142
        Unknown or Not Reported
    		 0 0 0
    Race/Ethnicity, Customized
    Units: Subjects
        Asian
    		 31 13 44
        White
    		 59 28 87
        Other
    		 6 8 14

    End points

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    End points reporting groups
    Reporting group title
    Luspatercept
    Reporting group description
    		 Luspatercept was administered as subcutaneous injection once every 3 weeks (administered on Study Day 1 of each 21-day treatment cycle). The starting dose level was 1.00 mg/kg and could be escalated to 1.25 mg/kg and/or reduced to 0.80, 0.60, and 0.45 mg/kg. Participants were treated for a minimum of 48 weeks.

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo (0.9% sodium chloride for injection) was administered as subcutaneous injection once every 3 weeks (administered on Study Day 1 of each 21-day treatment cycle) for a minimum of 48 weeks. Eligible participants entered an open-label phase and started Luspatercept treatment for up to approximately 24 months.
    Reporting group title
    Placebo
    Reporting group description
    		 Placebo (0.9% sodium chloride for injection) was administered as subcutaneous injection once every 3 weeks (administered on Study Day 1 of each 21-day treatment cycle) for a minimum of 48 weeks. Eligible participants entered an open-label phase and started Luspatercept treatment for up to approximately 24 months.

    Primary: Percentage of Participants Achieving Erythroid Response (Week 13 to Week 24)

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    End point title
    		 Percentage of Participants Achieving Erythroid Response (Week 13 to Week 24)
    End point description
    Erythroid Response is defined as an increase from baseline ≥1.0 g/dL in mean of hemoglobin values over a continuous 12-week interval from Weeks 13 to 24 of treatment in the absence of transfusions. Baseline hemoglobin (Hb) is the average of 2 or more Hb measurements at least 1 week apart within 4 weeks prior to Dose 1.
    End point type
    Primary
    End point timeframe
    From Week 13 to Week 24 of study treatment
    End point values
    		 Luspatercept Placebo
    Number of subjects analysed
    96
    49
    Units: Percent of Participants
        number (confidence interval 95%)
    77.1 (67.4 to 85.0)
    0.0 (0.0 to 7.3)
    Statistical analysis title
    		 Erythroid Response
    Comparison groups
    Luspatercept v Placebo
    Number of subjects included in analysis
    145
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 < 0.0001
    Method
    		 Cochran-Mantel-Haenszel
    Confidence interval
    Statistical analysis title
    		 Erythroid Response
    Comparison groups
    Luspatercept v Placebo
    Number of subjects included in analysis
    145
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Risk difference (RD)
    Point estimate
    77.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 68.7
         upper limit
    		 85.5
    Statistical analysis title
    		 Erythroid Response
    Comparison groups
    Luspatercept v Placebo
    Number of subjects included in analysis
    145
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Difference in proportions
    Point estimate
    77.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 63.4
         upper limit
    		 87

    Secondary: Mean Change From Baseline in Non-Transfusion Dependent β-thalassemia-Patient Reported Outcome (NTDT-PRO) Tiredness and Weakness (T/W) Domain Score (Week 13 to Week 24)

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    End point title
    		 Mean Change From Baseline in Non-Transfusion Dependent β-thalassemia-Patient Reported Outcome (NTDT-PRO) Tiredness and Weakness (T/W) Domain Score (Week 13 to Week 24)
    End point description
    The NTDT-PRO assesses the severity of anemia-related symptoms with a daily recall of symptoms composed of 6 items: 1. Tiredness (lack of energy) when not doing physical activity 2. Tiredness when doing physical activity 3. Weakness (lack of strength) when not doing physical activity 4. Weakness when doing physical activity 5. Shortness of breath when not doing physical activity 6. Shortness of breath when doing physical activity. The Tiredness/Weakness (T/W) domain score is the average score of items 1 through 4 above. T/W domain score ranges from 0 (best outcome, no tiredness/weakness) to 10 (worst outcome, extreme tiredness/weakness). Weekly T/W Scores are the average of daily scores for that week. The mean of weekly scores over a continuous 12-week period (from Week 13 to Week 24) are compared to the T/W Domain Score at baseline. Baseline is defined as the last value taken on or before the first dose of study drug administered in Week 13.
    End point type
    Secondary
    End point timeframe
    Baseline and over a continuous 12 week period (from week 13 through week 24)
    End point values
    		 Luspatercept Placebo
    Number of subjects analysed
    94
    48
    Units: Score on a scale
        least squares mean (standard error)
    -0.68 ( 0.176 )
    -0.20 ( 0.240 )
    Statistical analysis title
    		 NTDT-PRO T/W
    Comparison groups
    Luspatercept v Placebo
    Number of subjects included in analysis
    142
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.0924
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    -0.48
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.03
         upper limit
    		 0.08

    Secondary: Mean Change From Baseline in Hemoglobin Values in the Absence of Transfusion (Week 13 to Week 24)

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    End point title
    		 Mean Change From Baseline in Hemoglobin Values in the Absence of Transfusion (Week 13 to Week 24)
    End point description
    Mean change from baseline in mean of hemoglobin (Hb) values over a continuous 12-week interval from Week 13 to Week 24 in the absence of transfusions. Baseline was defined as the average of 2 or more Hb measurements at least 1 week apart within 4 weeks before Dose 1 Day 1.
    End point type
    Secondary
    End point timeframe
    Baseline and over a continuous 12 week period (from week 13 through week 24)
    End point values
    		 Luspatercept Placebo
    Number of subjects analysed
    96
    47
    Units: g/dL
        least squares mean (standard error)
    1.48 ( 0.078 )
    0.07 ( 0.108 )
    Statistical analysis title
    		 Hemoglobin
    Comparison groups
    Luspatercept v Placebo
    Number of subjects included in analysis
    143
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 < 0.0001
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    1.42
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.16
         upper limit
    		 1.67

    Secondary: Percentage of Participants Achieving Erythroid Response (Week 37 to Week 48)

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    End point title
    		 Percentage of Participants Achieving Erythroid Response (Week 37 to Week 48)
    End point description
    Erythroid Response is defined as an increase from baseline ≥1.0 g/dL in mean of hemoglobin values over a continuous 12-week interval from Weeks 37 to 48 of treatment in the absence of transfusions. Baseline hemoglobin (Hb) is the average of 2 or more Hb measurements at least 1 week apart within 4 weeks prior to Dose 1.
    End point type
    Secondary
    End point timeframe
    Assessed over a continuous 12 week period (from week 37 through week 48)
    End point values
    		 Luspatercept Placebo
    Number of subjects analysed
    96
    49
    Units: Percentage of Participants
        number (confidence interval 95%)
    70.8 (60.7 to 79.7)
    2.0 (0.1 to 10.9)
    Statistical analysis title
    		 Erythroid Response
    Comparison groups
    Luspatercept v Placebo
    Number of subjects included in analysis
    145
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 < 0.0001
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Mean difference (net)
    Point estimate
    68.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 54.3
         upper limit
    		 80.4

    Secondary: Mean Change From Baseline in Non-Transfusion Dependent β-thalassemia-Patient Reported Outcome (NTDT-PRO) Shortness of Breath (SoB) Domain Score (Week 13 to Week 24)

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    End point title
    		 Mean Change From Baseline in Non-Transfusion Dependent β-thalassemia-Patient Reported Outcome (NTDT-PRO) Shortness of Breath (SoB) Domain Score (Week 13 to Week 24)
    End point description
    The NTDT-PRO V2.1 assess the severity of anemia-related symptoms associated with NTD β-thalassemia. It is a daily electronic diary with recall of symptoms during the past 24 hours, composed of 6 items: 1. Tiredness (lack of energy) when not doing physical activity 2. Tiredness (lack of energy) when doing physical activity 3. Weakness (lack of strength) when not doing physical activity 4. Weakness (lack of strength) when doing physical activity 5. Shortness of breath when not doing physical activity 6. Shortness of breath when doing physical activity. The Shortness of Breath (SoB) domain score represents the average score of items 5 and 6 above. SoB domain score ranges from 0 (best outcome, no shortness of breath) to 10 (worst outcome, extreme shortness of breath). Weekly SoB Scores represent the average of daily scores for that week. The mean of weekly scores over a continuous 12 week period (from Week 13 to Week 24) are compared to the SoB Domain Score at baseline.
    End point type
    Secondary
    End point timeframe
    Baseline and over a continuous 12 week period (from week 13 through week 24)
    End point values
    		 Luspatercept Placebo
    Number of subjects analysed
    94
    48
    Units: Score on a scale
        least squares mean (standard error)
    -0.46 ( 0.168 )
    0.02 ( 0.228 )
    Statistical analysis title
    		 NTD-PRO
    Comparison groups
    Luspatercept v Placebo
    Number of subjects included in analysis
    142
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.0721
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    -0.49
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.02
         upper limit
    		 0.04

    Secondary: Mean Change from Baseline in Mean Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) Fatigue Subscale Score (Week 13 to Week 24)

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    End point title
    		 Mean Change from Baseline in Mean Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) Fatigue Subscale Score (Week 13 to Week 24)
    End point description
    The FACIT-F is a multidimensional, self-report quality of life instrument which includes the Functional Assessment of Cancer Therapy - General (FACT-G) questionnaire (27 items over 4 different domains), and the Fatigue subscale (FS) component (13 items). FACIT-F version 4 has been used for this study. For the Fatigue subscale, each of the 13 items is scored from 0 (“not at all”) to 4 (“very much”). The scores from individual items are summed to generated the final FS score, which ranges from 0 (best outcome) to 52 (worst outcome). The questionnaire is completed every other dose, and the mean of FS scores from Week 13 to Week 24 is compared to the FS score at baseline (last score available before start of study treatment). Baseline is defined as the last value taken on or before the first dose of study drug administered in Week 13.
    End point type
    Secondary
    End point timeframe
    Baseline and over a continuous 12 week period (from week 13 through week 24)
    End point values
    		 Luspatercept Placebo
    Number of subjects analysed
    90
    43
    Units: Score on a scale
        least squares mean (standard error)
    1.64 ( 0.774 )
    0.26 ( 1.066 )
    Statistical analysis title
    		 FACT-IF
    Comparison groups
    Luspatercept v Placebo
    Number of subjects included in analysis
    133
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.2641
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    1.39
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.06
         upper limit
    		 3.83

    Secondary: Mean Change from Baseline in Mean Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) Fatigue Subscale Score (Week 37 to Week 48)

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    End point title
    		 Mean Change from Baseline in Mean Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) Fatigue Subscale Score (Week 37 to Week 48)
    End point description
    The FACIT-F is a multidimensional, self-report quality of life instrument which includes the Functional Assessment of Cancer Therapy - General (FACT-G) questionnaire (27 items over 4 different domains), and the Fatigue subscale (FS) component (13 items). FACIT-F version 4 has been used for this study. For the Fatigue subscale, each of the 13 items is scored from 0 (“not at all”) to 4 (“very much”). The scores from individual items are summed to generated the final FS score, which ranges from 0 (best outcome) to 52 (worst outcome). The questionnaire is completed every other dose, and the mean of FS scores from Week 37 to Week 48 is compared to the FS score at baseline (last score available before start of study treatment). Baseline is defined as the last value taken on or before the first dose of study drug administered in Week 37.
    End point type
    Secondary
    End point timeframe
    Baseline and over a continuous 12 week period (from week 37 through week 48)
    End point values
    		 Luspatercept Placebo
    Number of subjects analysed
    83
    33
    Units: Score on a scale
        least squares mean (standard error)
    2.43 ( 0.763 )
    0.24 ( 1.150 )
    Statistical analysis title
    		 FACT-IF
    Comparison groups
    Luspatercept v Placebo
    Number of subjects included in analysis
    116
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.0959
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    2.19
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.39
         upper limit
    		 4.78

    Secondary: Mean Change From Baseline in Hemoglobin Values in the Absence of Transfusion (Week 37 to Week 48)

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    End point title
    		 Mean Change From Baseline in Hemoglobin Values in the Absence of Transfusion (Week 37 to Week 48)
    End point description
    Mean change from baseline in mean of hemoglobin (Hb) values over a continuous 12-week interval from Week 37 to Week 48 in the absence of transfusions. Baseline was defined as the average of 2 or more Hb measurements at least 1 week apart within 4 weeks before Dose 1 Day 1.
    End point type
    Secondary
    End point timeframe
    Baseline and over a continuous 12 week period (from week 37 through week 48)
    End point values
    		 Luspatercept Placebo
    Number of subjects analysed
    91
    34
    Units: g/dL
        least squares mean (standard error)
    1.50 ( 0.083 )
    0.01 ( 0.130 )
    Statistical analysis title
    		 Hemoglobin values
    Comparison groups
    Luspatercept v Placebo
    Number of subjects included in analysis
    125
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 < 0.0001
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    1.49
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.2
         upper limit
    		 1.79

    Secondary: Mean Change From Baseline in Non-Transfusion Dependent β-thalassemia-Patient Reported Outcome (NTDT-PRO) Shortness of Breath (SoB) Domain Score (Week 37 to Week 48)

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    End point title
    		 Mean Change From Baseline in Non-Transfusion Dependent β-thalassemia-Patient Reported Outcome (NTDT-PRO) Shortness of Breath (SoB) Domain Score (Week 37 to Week 48)
    End point description
    NTDT-PRO V2.1 assess the severity of anemia-related symptoms. It is a daily recall of symptoms during the past 24 hours, composed of 6 items: 1. Tiredness (lack of energy) when not doing physical activity 2. Tiredness when doing physical activity 3. Weakness (lack of strength) when not doing physical activity 4. Weakness when doing physical activity 5. Shortness of breath when not doing physical activity 6. Shortness of breath when doing physical activity. The Shortness of Breath (SoB) domain score represents the average score of items 5 and 6 above. SoB domain score ranges from 0 (best outcome, no shortness of breath) to 10 (worst outcome, extreme shortness of breath). Weekly SoB Scores represent the average of daily scores for that week. The mean of weekly scores over a continuous 12-week period (from Week 37 to Week 48) are compared to the SoB Domain Score at baseline. Baseline is defined as the last value taken on or before the first dose of study drug administered in Week 37.
    End point type
    Secondary
    End point timeframe
    Baseline and over a continuous 12 week period (from week 37 through week 48)
    End point values
    		 Luspatercept Placebo
    Number of subjects analysed
    72
    28
    Units: Score on a scale
        least squares mean (standard error)
    -0.59 ( 0.212 )
    0.47 ( 0.320 )
    Statistical analysis title
    		 NTD-PRO SOB
    Comparison groups
    Luspatercept v Placebo
    Number of subjects included in analysis
    100
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.0047
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    -1.07
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.8
         upper limit
    		 -0.33

    Secondary: Mean Change From Baseline in Non-Transfusion Dependent β-thalassemia-Patient Reported Outcome (NTDT-PRO) Tiredness and Weakness (T/W) Domain Score (Week 37 to Week 48)

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    End point title
    		 Mean Change From Baseline in Non-Transfusion Dependent β-thalassemia-Patient Reported Outcome (NTDT-PRO) Tiredness and Weakness (T/W) Domain Score (Week 37 to Week 48)
    End point description
    NTDT-PRO V2.1 assess the severity of anemia-related symptoms. It's a daily recall of symptoms during the past 24 hours, composed of 6 items: 1. Tiredness (lack of energy) when not doing physical activity 2. Tiredness when doing physical activity 3. Weakness (lack of strength) when not doing physical activity 4. Weakness when doing physical activity 5. Shortness of breath when not doing physical activity 6. Shortness of breath when doing physical activity. The Tiredness/Weakness (T/W) domain score represents the average score of items 1 through 4 above. T/W domain score ranges from 0 (best outcome, no tiredness/weakness) to 10 (worst outcome, extreme tiredness/weakness). Weekly T/W Scores represent the average of daily scores for that week. The mean of weekly scores over a continuous 12-week period (from Week 37 to Week 48) are compared to the T/W Domain Score at baseline. Baseline is defined as the last value taken on or before the first dose of study drug administered in Week 37.
    End point type
    Secondary
    End point timeframe
    Baseline and over a continuous 12 week period (from week 37 through week 48)
    End point values
    		 Luspatercept Placebo
    Number of subjects analysed
    72
    28
    Units: Score on a scale
        least squares mean (standard error)
    -0.78 ( 0.229 )
    0.01 ( 0.347 )
    Statistical analysis title
    		 NTD-PRO
    Comparison groups
    Luspatercept v Placebo
    Number of subjects included in analysis
    100
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.051
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    -0.79
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.58
         upper limit
    		 0

    Secondary: Percentage of Participants with an Increase from Baseline ≥ 3 in Mean Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) Fatigue Subscale Score (Week 13 to Week 24)

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    End point title
    		 Percentage of Participants with an Increase from Baseline ≥ 3 in Mean Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) Fatigue Subscale Score (Week 13 to Week 24)
    End point description
    The FACIT-Fatigue, is a multidimensional, self-report quality of life instrument. It consists of 27 core items, the Functional Assessment of Cancer Therapy - General (FACT-G) questionnaire, which assesses patient function in 4 domains: Physical, Social/Family, Emotional, and Functional well-being, which is further supplemented by a 13-item measure designed to capture cancer-related fatigue, the Fatigue subscale (FS). The items are measured on a response scale with five options (0 = not at all to 4 = very much). Participants completed the questionnaire at screening and every other dose. Baseline is defined as the last value taken on or before the first dose of study drug administered in Week 13. Score is calculated by multiplying the sum of item scores by the n of items in the scale, then divided by n of items answered.
    End point type
    Secondary
    End point timeframe
    Baseline and over a continuous 12 week period (from week 13 through week 24)
    End point values
    		 Luspatercept Placebo
    Number of subjects analysed
    94
    47
    Units: Percent of Participants
        number (confidence interval 95%)
    40.4 (30.4 to 51.0)
    27.7 (15.6 to 42.6)
    Statistical analysis title
    		 FACT-IF
    Comparison groups
    Luspatercept v Placebo
    Number of subjects included in analysis
    141
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.1359
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.8
         upper limit
    		 4

    Secondary: Mean Change From Baseline in the Physical Component Summary (PCS) and Mental Component Summary (MCS) Scores of the Medical Outcomes Study 36-Item Short Form (SF-36)

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    End point title
    		 Mean Change From Baseline in the Physical Component Summary (PCS) and Mental Component Summary (MCS) Scores of the Medical Outcomes Study 36-Item Short Form (SF-36)
    End point description
    The SF-36v2 is a 36-item generic PRO questionnaire used to assess patient-reported outcomes. The SF-36 yields scores for 8 domains of health: Physical Functioning (PF), Role-Physical (RP), Bodily Pain (BP), General Health (GH), Vitality (VT), Social Functioning (SF), Role Emotional (RE), and Mental Health (MH) as well as physical component summary (PCS) and mental component summary (MCS) scores. Scores from each of the 8 domains of health are first normalized based on US general population means, then aggregated and transformed so that the scores from each of the 8 domains of health will contribute differently to the determination of PCS and MCS summary scores. PCS and MCS scores range from 0 to 100, with higher scores indicating a better quality of life. Baseline is defined as the last value taken on or before the first dose of study drug administered.
    End point type
    Secondary
    End point timeframe
    From baseline to Week 24 and from baseline to Week 48 of study treatment
    End point values
    		 Luspatercept Placebo
    Number of subjects analysed
    76
    37
    Units: Score on a scale
    least squares mean (standard error)
        Physical Component Summary (PCS) up to Week 24
    1.00 ( 0.499 )
    -0.38 ( 0.684 )
        Physical Component Summary (PCS) up to Week 48
    1.23 ( 0.571 )
    -0.52 ( 0.822 )
        Mental Component Summary (MCS) up to Week 24
    0.83 ( 0.674 )
    -0.71 ( 0.947 )
        Mental Component Summary (MCS) up to Week 48
    0.81 ( 0.784 )
    -1.89 ( 1.152 )
    Statistical analysis title
    		 PCS
    Statistical analysis description
    Mean change from baseline in SF-36 PCS to Week 24
    Comparison groups
    Luspatercept v Placebo
    Number of subjects included in analysis
    113
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.0847
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (net)
    Point estimate
    1.39
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.19
         upper limit
    		 2.96
    Statistical analysis title
    		 PCS
    Statistical analysis description
    Mean change from baseline in SF-36 PCS to Week 48
    Comparison groups
    Luspatercept v Placebo
    Number of subjects included in analysis
    113
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.0712
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (net)
    Point estimate
    1.75
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.15
         upper limit
    		 3.65
    Statistical analysis title
    		 MCS
    Statistical analysis description
    Mean change from baseline in SF-36 MCS to Week 24
    Comparison groups
    Luspatercept v Placebo
    Number of subjects included in analysis
    113
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.1633
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (net)
    Point estimate
    1.54
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.63
         upper limit
    		 3.72
    Statistical analysis title
    		 MCS
    Statistical analysis description
    Mean change from baseline in SF-36 MCS to Week 48
    Comparison groups
    Luspatercept v Placebo
    Number of subjects included in analysis
    113
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.0469
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (net)
    Point estimate
    2.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.04
         upper limit
    		 5.36

    Secondary: Percentage of Participants with an Increase from Baseline ≥ 3 in Mean Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) Fatigue Subscale Score (Week 37 to Week 48)

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    End point title
    		 Percentage of Participants with an Increase from Baseline ≥ 3 in Mean Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) Fatigue Subscale Score (Week 37 to Week 48)
    End point description
    The FACIT-Fatigue, is a multidimensional, self-report quality of life instrument. It consists of 27 core items, the Functional Assessment of Cancer Therapy - General (FACT-G) questionnaire, which assesses patient function in 4 domains: Physical, Social/Family, Emotional, and Functional well-being, which is further supplemented by a 13-item measure designed to capture cancer-related fatigue, the Fatigue subscale (FS). The items are measured on a response scale with five options (0 = not at all to 4 = very much). Participants completed the questionnaire at screening and every other dose. Baseline is defined as the last value taken on or before the first dose of study drug administered in Week 37. Score is calculated by multiplying the sum of item scores by the n of items in the scale, then divided by n of items answered.
    End point type
    Secondary
    End point timeframe
    Baseline and over a continuous 12 week period (from week 37 through week 48)
    End point values
    		 Luspatercept Placebo
    Number of subjects analysed
    94
    47
    Units: Percent of Participants
        number (confidence interval 95%)
    36.2 (26.5 to 46.7)
    21.3 (10.7 to 35.7)
    Statistical analysis title
    		 FACT-IF
    Comparison groups
    Luspatercept v Placebo
    Number of subjects included in analysis
    141
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.0657
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    2.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.9
         upper limit
    		 5.4

    Secondary: Percentage of Participants With Improvement of Iron Overload

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    End point title
    		 Percentage of Participants With Improvement of Iron Overload
    End point description
    Iron overload was measured by Liver Iron Concentration (LIC) and Iron Chelation Therapy (ICT) daily dose. Improvement is defined as: - For participants with baseline LIC ≥3 mg/g: ≥20% reduction in LIC or ≥ 33% decrease in ICT daily dose - For participants with baseline LIC <3 mg/g: no increase in LIC >1 mg/g and not starting treatment with ICT, or no increase in ICT daily dose ≥ 33% (if on ICT at baseline)
    End point type
    Secondary
    End point timeframe
    Week 24 and Week 48 of study treatment
    End point values
    		 Luspatercept Placebo
    Number of subjects analysed
    96
    49
    Units: Percent of participants
    number (not applicable)
        Week 24
    44.8
    49.0
        Week 48
    34.4
    49.0
    Statistical analysis title
    		 LIC/ICT
    Statistical analysis description
    Percentage of participants with improvement of iron overload (LIC/ICT responders) at Week 24
    Comparison groups
    Luspatercept v Placebo
    Number of subjects included in analysis
    145
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.4787
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Mean difference (net)
    Point estimate
    -4.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -21.4
         upper limit
    		 13
    Statistical analysis title
    		 LIC/ICT
    Statistical analysis description
    Percentage of participants with improvement of iron overload (LIC/ICT responders) at Week 48
    Comparison groups
    Luspatercept v Placebo
    Number of subjects included in analysis
    145
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.0827
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Mean difference (net)
    Point estimate
    -14.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -31.5
         upper limit
    		 2.4

    Secondary: Mean Change From Baseline in Serum Ferritin

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    End point title
    		 Mean Change From Baseline in Serum Ferritin
    End point description
    Baseline mean serum ferritin is calculated during the 24 weeks on or prior to dose 1 day 1. Post-baseline mean serum ferritin is calculated as mean of ferritin values during the last 24 weeks on or prior to the end date of the first 24 week or 48 week treatment
    End point type
    Secondary
    End point timeframe
    Week 24 and Week 48 of study treatment
    End point values
    		 Luspatercept Placebo
    Number of subjects analysed
    92
    44
    Units: ug/L
    least squares mean (standard error)
        Week 24
    29.32 ( 22.949 )
    2.18 ( 32.217 )
        Week 48
    84.94 ( 23.120 )
    71.48 ( 32.457 )
    Statistical analysis title
    		 Serum Ferritin
    Statistical analysis description
    Mean change from baseline in serum ferritin at Week 48
    Comparison groups
    Luspatercept v Placebo
    Number of subjects included in analysis
    136
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.3454
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    13.46
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -61.01
         upper limit
    		 87.93
    Statistical analysis title
    		 Serum Ferritin
    Statistical analysis description
    Mean change from baseline in serum ferritin at Week 24
    Comparison groups
    Luspatercept v Placebo
    Number of subjects included in analysis
    136
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.5949
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    27.14
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -46.77
         upper limit
    		 101.06

    Secondary: Mean Change From Baseline in Liver Iron Concentration (LIC)

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    End point title
    		 Mean Change From Baseline in Liver Iron Concentration (LIC)
    End point description
    LIC was measured by Magnetic Resonance Imaging (MRI). Baseline is defined as the last value on or before the first dose of study drug is administered; Postbaseline is defined as the closest visit at Week 24 or Week 48. Participants with LIC value >43 are not included in the analysis.
    End point type
    Secondary
    End point timeframe
    Week 24 and Week 48 of study treatment
    End point values
    		 Luspatercept Placebo
    Number of subjects analysed
    87
    45
    Units: mg/g dry weight
    least squares mean (standard error)
        Week 24
    -0.30 ( 0.125 )
    -0.21 ( 0.169 )
        Week 48
    -0.34 ( 0.233 )
    -1.00 ( 0.329 )
    Statistical analysis title
    		 LIC
    Statistical analysis description
    Mean change from baseline in LIC at Week 48
    Comparison groups
    Luspatercept v Placebo
    Number of subjects included in analysis
    132
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.0859
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.66
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.09
         upper limit
    		 1.42
    Statistical analysis title
    		 LIC
    Statistical analysis description
    Mean change from baseline in LIC at Week 24
    Comparison groups
    Luspatercept v Placebo
    Number of subjects included in analysis
    132
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.6628
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    -0.09
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.47
         upper limit
    		 0.3

    Secondary: Percentage of Participants Who are Transfusion-Free Over 48 Weeks

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    End point title
    		 Percentage of Participants Who are Transfusion-Free Over 48 Weeks
    End point description
    Transfusion free is defined as the absence of any transfusion during Week 1-48 of study treatment. Participants who discontinued treatment prior to Week 48 were not considered as transfusion free during Week 1-48.
    End point type
    Secondary
    End point timeframe
    From first dose to Week 48
    End point values
    		 Luspatercept Placebo
    Number of subjects analysed
    96
    49
    Units: Percent of Participants
        number (not applicable)
    82.3
    44.9
    Statistical analysis title
    		 Transfusion-Free
    Statistical analysis description
    Percentage of Participants Who are Transfusion-Free Over 48 Weeks
    Comparison groups
    Luspatercept v Placebo
    Number of subjects included in analysis
    145
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 < 0.0001
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Mean difference (net)
    Point estimate
    37.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 20.9
         upper limit
    		 53

    Secondary: Percentage of Participants Who are Transfusion-Free Over 24 Weeks

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    End point title
    		 Percentage of Participants Who are Transfusion-Free Over 24 Weeks
    End point description
    Transfusion free is defined as the absence of any transfusion during Week 1-24 of study treatment. Participants who discontinued treatment prior to Week 24 were not considered as transfusion free during Week 1-24.
    End point type
    Secondary
    End point timeframe
    From first dose to Week 24
    End point values
    		 Luspatercept Placebo
    Number of subjects analysed
    96
    49
    Units: Percent of Participants
        number (not applicable)
    89.6
    67.3
    Statistical analysis title
    		 Tranfusion Free
    Statistical analysis description
    Percentage of participants who were transfusion free over 24 weeks
    Comparison groups
    Luspatercept v Placebo
    Number of subjects included in analysis
    145
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.0013
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Mean difference (net)
    Point estimate
    22.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 5
         upper limit
    		 38.6

    Secondary: Duration of the Mean Hemoglobin Increase From Baseline ≥1.0 g/dL

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    End point title
    		 Duration of the Mean Hemoglobin Increase From Baseline ≥1.0 g/dL
    End point description
    This outcome measure is the cumulative mean of the duration of hemoglobin response for the ≥ 1.0 g/dL during any 12-week rolling period. Any hemoglobin values within 21 days after a transfusion were excluded from the analysis.
    End point type
    Secondary
    End point timeframe
    From baseline up to approximately 56 months
    End point values
    		 Luspatercept Placebo
    Number of subjects analysed
    91
    11
    Units: Days
        arithmetic mean (standard deviation)
    1136.0 ( 491.86 )
    203.3 ( 170.82 )
    No statistical analyses for this end point

    Secondary: Mean Change From Baseline in the 6-Minute Walk Test (6MWT) Distance

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    End point title
    		 Mean Change From Baseline in the 6-Minute Walk Test (6MWT) Distance
    End point description
    The 6MWT is typically used to objectively assess functional exercise capacity and response to medical interventions in patients with various moderate to severe diseases. Particiapnts are asked to walk as quickly as possible without running along a 30-meter corridor for six minutes, and the total distance covered during that time is measured. Baseline is defined as the last value on or before the first dose of study drug is administered. Postbaseline is defined as the closest visit at Week 24 or Week 48.
    End point type
    Secondary
    End point timeframe
    From baseline to Week 24 and from baseline to Week 48 of study treatment
    End point values
    		 Luspatercept Placebo
    Number of subjects analysed
    87
    47
    Units: Meters
    least squares mean (standard error)
        24 Weeks
    7.20 ( 7.017 )
    -8.96 ( 9.297 )
        48 Weeks
    8.82 ( 5.907 )
    -3.62 ( 8.141 )
    Statistical analysis title
    		 6MWT
    Statistical analysis description
    Mean change from baseline in 6MWT distance at Week 48
    Comparison groups
    Luspatercept v Placebo
    Number of subjects included in analysis
    134
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.2011
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    12.44
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.72
         upper limit
    		 31.59
    Statistical analysis title
    		 6MWT
    Statistical analysis description
    Mean change from baseline in 6MWT distance at Week 24
    Comparison groups
    Luspatercept v Placebo
    Number of subjects included in analysis
    134
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.1466
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    16.15
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.73
         upper limit
    		 38.04

    Secondary: Percentage of Participants with an Increase From Baseline ≥1.5 g/dL in Mean Hemoglobin Values in the Absence of Transfusion

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    End point title
    		 Percentage of Participants with an Increase From Baseline ≥1.5 g/dL in Mean Hemoglobin Values in the Absence of Transfusion
    End point description
    Percentage of participants who have an increase from baseline ≥1.5 g/dL in mean of hemoglobin (Hb) values over a continuous 12-week interval from Week 13 to Week 24 in the absence of transfusions. Baseline was defined as the average of 2 or more Hb measurements at least 1 week apart within 4 weeks before Dose 1 Day 1.
    End point type
    Secondary
    End point timeframe
    From Week 13 to Week 24 of study treatment
    End point values
    		 Luspatercept Placebo
    Number of subjects analysed
    96
    49
    Units: Percentage of Participants
        number (confidence interval 95%)
    52.1 (41.6 to 62.4)
    0.0 (0.0 to 7.3)
    Statistical analysis title
    		 Hemoglobin Values
    Statistical analysis description
    Percentage of Participants with an Increase From Baseline ≥1.5 g/dL in Mean Hemoglobin Values in the Absence of Transfusion
    Comparison groups
    Luspatercept v Placebo
    Number of subjects included in analysis
    145
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 < 0.0001
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Mean difference (net)
    Point estimate
    52.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 36.2
         upper limit
    		 66.2

    Secondary: Percentage of Participants With a Decrease From Baseline ≥ RD (= 1) in the Non-Transfusion Dependent β-thalassemia-Patient Reported Outcome (NTDT-PRO) Tiredness and Weakness (T/W) Domain Score

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    End point title
    		 Percentage of Participants With a Decrease From Baseline ≥ RD (= 1) in the Non-Transfusion Dependent β-thalassemia-Patient Reported Outcome (NTDT-PRO) Tiredness and Weakness (T/W) Domain Score
    End point description
    The responder definition (RD) threshold is the individual participant score change over a predetermined time period that will be interpreted as a treatment benefit. The RD for the NTDT-PRO T/W domain score was defined as ≥ 1-point decrease (ie, RD = -1) from baseline over the time from Week 13 to Week 24 or from Week 37 to Week 48. Participants with missing NTDT-PRO T/W scores at the indicated 12-week period are classified as non-responders in the analysis.
    End point type
    Secondary
    End point timeframe
    From Week 13 to Week 24 and from Week 37 to Week 48 of study treatment
    End point values
    		 Luspatercept Placebo
    Number of subjects analysed
    96
    49
    Units: Percent of participants
    number (confidence interval 95%)
        Week 13 to week 24
    37.5 (27.8 to 48.0)
    28.6 (16.6 to 43.3)
        Week 37 to week 48
    31.3 (22.2 to 41.5)
    18.4 (8.8 to 32.0)
    Statistical analysis title
    		 NTDT-PRO
    Statistical analysis description
    Percentage of Participants With a Decrease From Baseline ≥ RD (= 1) in the Non-Transfusion Dependent β-thalassemia-Patient Reported Outcome (NTDT-PRO) Tiredness and Weakness (T/W) Domain Score Week 37 to Week 48
    Comparison groups
    Luspatercept v Placebo
    Number of subjects included in analysis
    145
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.0733
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Mean difference (net)
    Point estimate
    2.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.9
         upper limit
    		 5
    Statistical analysis title
    		 NTDT-PRO
    Statistical analysis description
    Percentage of Participants With a Decrease From Baseline ≥ RD (= 1) in the Non-Transfusion Dependent β-thalassemia-Patient Reported Outcome (NTDT-PRO) Tiredness and Weakness (T/W) Domain Score Week 13 to Week 24
    Comparison groups
    Luspatercept v Placebo
    Number of subjects included in analysis
    145
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.1989
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Mean difference (net)
    Point estimate
    1.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.8
         upper limit
    		 3.7

    Secondary: Number of Participants Experiencing Adverse Events

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    End point title
    		 Number of Participants Experiencing Adverse Events
    End point description
    An Adverse Event (AE) is defined as any new untoward medical occurrence or worsening of a pre-existing medical condition in a clinical investigation participant administered study treatment and that does not necessarily have a causal relationship with this treatment. Adverse events are graded on a scale from 1 to 5, with Grade 1 being mild and asymptomatic; Grade 2 is moderate requiring minimal, local or noninvasive intervention; Grade 3 is severe or medically significant but not immediately life-threatening; Grade 4 events are usually severe enough to require hospitalization; Grade 5 events are fatal.
    End point type
    Secondary
    End point timeframe
    From first dose to 63 days after last dose (up to approximately 56 months)
    End point values
    		 Luspatercept Placebo
    Number of subjects analysed
    96
    49
    Units: Participants
        Treatment-emergent adverse-event (TEAE)
    96
    48
        Serious TEAE
    23
    13
        Treatment-related TEAE
    79
    18
        Treatment-related Serious TEAE
    4
    0
        TEAE Leading to Death
    1
    0
        TEAE Leading to Dose Reduction
    11
    0
        TEAE Leading to Dose Delay
    47
    11
        TEAE Leading to Study Drug Discontinuation
    5
    4
        Treatment-related TEAE Leading to Death
    0
    0
        Treatment-related TEAE Leading to Dose Reduction
    11
    0
        Treatment-related TEAE Leading to Dose Delay
    10
    0
        Treatment-related TEAE Study Drug Discontinuation
    4
    0
    No statistical analyses for this end point

    Secondary: Number of Participants with Anti-drug Antibody (ADA) Positive Test for Luspatercept

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    End point title
    		 Number of Participants with Anti-drug Antibody (ADA) Positive Test for Luspatercept
    End point description
    Presence of anti-drug (ACE-536/Luspatercept) antibodies was assessed every 24 weeks from serum samples. A participant is counted as ‘positive’ if there is any positive result captured during the study.
    End point type
    Secondary
    End point timeframe
    From first dose and up to 2 years following last dose, up to approximately 56 months
    End point values
    		 Luspatercept Placebo
    Number of subjects analysed
    96
    49
    Units: Participants
    5
    3
    No statistical analyses for this end point

    Secondary: Apparent Clearance (CL/F) of Luspatercept

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    End point title
    		 Apparent Clearance (CL/F) of Luspatercept [1]
    End point description
    Apparent Clearance (CL/F) of Luspatercept
    End point type
    Secondary
    End point timeframe
    Doses 1 to 16: at predose (must be collected before first dose), Dose 2 Day 1, Dose 4 Day 1, Dose 6 Day 1, Dose 8 Day 1, Dose 12 Day 1, Dose 16 Day 1, Dose 6 Day 8, Dose 6 Day 15, and every 6 doses (at Dose 22, 28, etc.), up to approx. 48 months
    Notes
    [1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Pharmacokinetic data can not be assessed for the placebo arm. Thus, no data was evaluate for the placebo arm, nor was it ever planned to be according to the protocol
    End point values
    		 Luspatercept
    Number of subjects analysed
    96
    Units: L/day
        geometric mean (geometric coefficient of variation)
    0.458 ( 33.8 )
    No statistical analyses for this end point

    Secondary: Apparent Volume of Distribution of the Central Compartment (V1/F) of Luspatercept

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    End point title
    		 Apparent Volume of Distribution of the Central Compartment (V1/F) of Luspatercept [2]
    End point description
    Apparent Volume of Distribution of the Central Compartment (V1/F) of Luspatercept
    End point type
    Secondary
    End point timeframe
    Doses 1 to 16: at predose (must be collected before first dose), Dose 2 Day 1, Dose 4 Day 1, Dose 6 Day 1, Dose 8 Day 1, Dose 12 Day 1, Dose 16 Day 1, Dose 6 Day 8, Dose 6 Day 15, and every 6 doses (at Dose 22, 28, etc.), up to approx. 48 months
    Notes
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Pharmacokinetic data can not be assessed for the placebo arm. Thus, no data was evaluate for the placebo arm, nor was it ever planned to be according to the protocol
    End point values
    		 Luspatercept
    Number of subjects analysed
    96
    Units: Liters
        geometric mean (geometric coefficient of variation)
    7.79 ( 19.6 )
    No statistical analyses for this end point

    Secondary: Maximum Concentration (Cmax) of Luspatercept

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    End point title
    		 Maximum Concentration (Cmax) of Luspatercept [3]
    End point description
    Maximum Concentration (Cmax) of Luspatercept
    End point type
    Secondary
    End point timeframe
    Doses 1 to 16: at predose (must be collected before first dose), Dose 2 Day 1, Dose 4 Day 1, Dose 6 Day 1, Dose 8 Day 1, Dose 12 Day 1, Dose 16 Day 1, Dose 6 Day 8, Dose 6 Day 15, and every 6 doses (at Dose 22, 28, etc.), up to approx. 48 months
    Notes
    [3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Pharmacokinetic data can not be assessed for the placebo arm. Thus, no data was evaluate for the placebo arm, nor was it ever planned to be according to the protocol
    End point values
    		 Luspatercept
    Number of subjects analysed
    96
    Units: μg/mL
        geometric mean (geometric coefficient of variation)
    5.55 ( 16.9 )
    No statistical analyses for this end point

    Secondary: Maximum Concentration From Steady State (Cmax,ss) of Luspatercept

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    End point title
    		 Maximum Concentration From Steady State (Cmax,ss) of Luspatercept [4]
    End point description
    Maximum Concentration From Steady State (Cmax,ss) of Luspatercept
    End point type
    Secondary
    End point timeframe
    Doses 1 to 16: at predose (must be collected before first dose), Dose 2 Day 1, Dose 4 Day 1, Dose 6 Day 1, Dose 8 Day 1, Dose 12 Day 1, Dose 16 Day 1, Dose 6 Day 8, Dose 6 Day 15, and every 6 doses (at Dose 22, 28, etc.), up to approx. 48 months
    Notes
    [4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Pharmacokinetic data can not be assessed for the placebo arm. Thus, no data was evaluate for the placebo arm, nor was it ever planned to be according to the protocol
    End point values
    		 Luspatercept
    Number of subjects analysed
    96
    Units: μg/mL
        geometric mean (geometric coefficient of variation)
    8.36 ( 27.7 )
    No statistical analyses for this end point

    Secondary: Area Under the Curve From Steady State (AUCss) of Luspatercept

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    End point title
    		 Area Under the Curve From Steady State (AUCss) of Luspatercept [5]
    End point description
    Area Under the Curve From Steady State (AUCss) of Luspatercept
    End point type
    Secondary
    End point timeframe
    Doses 1 to 16: at predose (must be collected before first dose), Dose 2 Day 1, Dose 4 Day 1, Dose 6 Day 1, Dose 8 Day 1, Dose 12 Day 1, Dose 16 Day 1, Dose 6 Day 8, Dose 6 Day 15, and every 6 doses (at Dose 22, 28, etc.), up to approx. 48 months
    Notes
    [5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Pharmacokinetic data can not be assessed for the placebo arm. Thus, no data was evaluate for the placebo arm, nor was it ever planned to be according to the protocol
    End point values
    		 Luspatercept
    Number of subjects analysed
    96
    Units: day*μg/mL
        geometric mean (geometric coefficient of variation)
    130 ( 34.4 )
    No statistical analyses for this end point

    Secondary: Time to Reach Maximum Concentration (Tmax) of Luspatercept

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    End point title
    		 Time to Reach Maximum Concentration (Tmax) of Luspatercept [6]
    End point description
    Time to Reach Maximum Concentration (Tmax) of Luspatercept
    End point type
    Secondary
    End point timeframe
    Doses 1 to 16: at predose (must be collected before first dose), Dose 2 Day 1, Dose 4 Day 1, Dose 6 Day 1, Dose 8 Day 1, Dose 12 Day 1, Dose 16 Day 1, Dose 6 Day 8, Dose 6 Day 15, and every 6 doses (at Dose 22, 28, etc.), up to approx. 48 months
    Notes
    [6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Pharmacokinetic data can not be assessed for the placebo arm. Thus, no data was evaluate for the placebo arm, nor was it ever planned to be according to the protocol
    End point values
    		 Luspatercept
    Number of subjects analysed
    96
    Units: Days
        median (full range (min-max))
    5.50 (4.33 to 6.42)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From first dose to 63 days after last dose (up to approximately 56 months)
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    25.1
    Reporting groups
    Reporting group title
    Luspatercept
    Reporting group description
    		 Luspatercept was administered as subcutaneous injection once every 3 weeks (administered on Study Day 1 of each 21-day treatment cycle). The starting dose level was 1.00 mg/kg and could be escalated to 1.25 mg/kg and/or reduced to 0.80, 0.60, and 0.45 mg/kg. Participants were treated for a minimum of 48 weeks.

    Reporting group title
    Placebo-Luspatercept
    Reporting group description
    		 Open-label phase in which participants switched from placebo and started Luspatercept treatment for up to approximately 24 months.

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo (0.9% sodium chloride for injection) was administered as subcutaneous injection once every 3 weeks (administered on Study Day 1 of each 21-day treatment cycle) for a minimum of 48 weeks. Eligible participants entered an open-label phase and started Luspatercept treatment for up to approximately 24 months.

    Serious adverse events
    		 Luspatercept Placebo-Luspatercept Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    23 / 96 (23.96%)
    3 / 38 (7.89%)
    13 / 49 (26.53%)
         number of deaths (all causes)
    1
    0
    0
         number of deaths resulting from adverse events
    1
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Uterine leiomyoma
         subjects affected / exposed
    1 / 96 (1.04%)
    0 / 38 (0.00%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatocellular carcinoma
         subjects affected / exposed
    0 / 96 (0.00%)
    0 / 38 (0.00%)
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diffuse large B-cell lymphoma
         subjects affected / exposed
    0 / 96 (0.00%)
    0 / 38 (0.00%)
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pregnancy, puerperium and perinatal conditions
    Pregnancy
         subjects affected / exposed
    0 / 96 (0.00%)
    1 / 38 (2.63%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Abortion spontaneous
         subjects affected / exposed
    0 / 96 (0.00%)
    1 / 38 (2.63%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Oedema peripheral
         subjects affected / exposed
    1 / 96 (1.04%)
    0 / 38 (0.00%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Ovarian cyst ruptured
         subjects affected / exposed
    0 / 96 (0.00%)
    0 / 38 (0.00%)
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Prostatic obstruction
         subjects affected / exposed
    1 / 96 (1.04%)
    0 / 38 (0.00%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Haemoptysis
         subjects affected / exposed
    0 / 96 (0.00%)
    0 / 38 (0.00%)
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    2 / 96 (2.08%)
    0 / 38 (0.00%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary arterial hypertension
         subjects affected / exposed
    1 / 96 (1.04%)
    0 / 38 (0.00%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary oedema
         subjects affected / exposed
    1 / 96 (1.04%)
    0 / 38 (0.00%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Haemothorax
         subjects affected / exposed
    1 / 96 (1.04%)
    0 / 38 (0.00%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Haemoglobin decreased
         subjects affected / exposed
    0 / 96 (0.00%)
    1 / 38 (2.63%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Hip fracture
         subjects affected / exposed
    1 / 96 (1.04%)
    0 / 38 (0.00%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rib fracture
         subjects affected / exposed
    1 / 96 (1.04%)
    0 / 38 (0.00%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary contusion
         subjects affected / exposed
    1 / 96 (1.04%)
    0 / 38 (0.00%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Traumatic fracture
         subjects affected / exposed
    5 / 96 (5.21%)
    0 / 38 (0.00%)
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Myocardial ischaemia
         subjects affected / exposed
    1 / 96 (1.04%)
    0 / 38 (0.00%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    1 / 96 (1.04%)
    0 / 38 (0.00%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure acute
         subjects affected / exposed
    1 / 96 (1.04%)
    0 / 38 (0.00%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ventricular hypokinesia
         subjects affected / exposed
    1 / 96 (1.04%)
    0 / 38 (0.00%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Transient ischaemic attack
         subjects affected / exposed
    1 / 96 (1.04%)
    0 / 38 (0.00%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Spinal cord compression
         subjects affected / exposed
    1 / 96 (1.04%)
    0 / 38 (0.00%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Splenomegaly
         subjects affected / exposed
    1 / 96 (1.04%)
    0 / 38 (0.00%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Anaemia
         subjects affected / exposed
    2 / 96 (2.08%)
    0 / 38 (0.00%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Extramedullary haemopoiesis
         subjects affected / exposed
    1 / 96 (1.04%)
    0 / 38 (0.00%)
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 96 (0.00%)
    0 / 38 (0.00%)
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Biliary colic
         subjects affected / exposed
    0 / 96 (0.00%)
    0 / 38 (0.00%)
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bile duct stone
         subjects affected / exposed
    1 / 96 (1.04%)
    0 / 38 (0.00%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis acute
         subjects affected / exposed
    1 / 96 (1.04%)
    0 / 38 (0.00%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    0 / 96 (0.00%)
    1 / 38 (2.63%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cholangitis
         subjects affected / exposed
    1 / 96 (1.04%)
    0 / 38 (0.00%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Skin ulcer
         subjects affected / exposed
    1 / 96 (1.04%)
    0 / 38 (0.00%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Proteinuria
         subjects affected / exposed
    1 / 96 (1.04%)
    0 / 38 (0.00%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal colic
         subjects affected / exposed
    0 / 96 (0.00%)
    0 / 38 (0.00%)
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Abscess limb
         subjects affected / exposed
    0 / 96 (0.00%)
    0 / 38 (0.00%)
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    COVID-19
         subjects affected / exposed
    2 / 96 (2.08%)
    0 / 38 (0.00%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    COVID-19 pneumonia
         subjects affected / exposed
    2 / 96 (2.08%)
    0 / 38 (0.00%)
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    0 / 96 (0.00%)
    0 / 38 (0.00%)
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    0 / 96 (0.00%)
    0 / 38 (0.00%)
    2 / 49 (4.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dengue haemorrhagic fever
         subjects affected / exposed
    1 / 96 (1.04%)
    0 / 38 (0.00%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pilonidal disease
         subjects affected / exposed
    1 / 96 (1.04%)
    0 / 38 (0.00%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyelonephritis acute
         subjects affected / exposed
    0 / 96 (0.00%)
    0 / 38 (0.00%)
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    1 / 96 (1.04%)
    0 / 38 (0.00%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tonsillitis
         subjects affected / exposed
    0 / 96 (0.00%)
    0 / 38 (0.00%)
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Viral upper respiratory tract infection
         subjects affected / exposed
    0 / 96 (0.00%)
    0 / 38 (0.00%)
    2 / 49 (4.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pharyngitis
         subjects affected / exposed
    0 / 96 (0.00%)
    0 / 38 (0.00%)
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Steroid diabetes
         subjects affected / exposed
    1 / 96 (1.04%)
    0 / 38 (0.00%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diabetes mellitus
         subjects affected / exposed
    1 / 96 (1.04%)
    0 / 38 (0.00%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypovolaemia
         subjects affected / exposed
    1 / 96 (1.04%)
    0 / 38 (0.00%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Luspatercept Placebo-Luspatercept Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    96 / 96 (100.00%)
    38 / 38 (100.00%)
    48 / 49 (97.96%)
    Vascular disorders
    Prehypertension
         subjects affected / exposed
    23 / 96 (23.96%)
    3 / 38 (7.89%)
    7 / 49 (14.29%)
         occurrences all number
    39
    3
    10
    Hypertension
         subjects affected / exposed
    21 / 96 (21.88%)
    7 / 38 (18.42%)
    1 / 49 (2.04%)
         occurrences all number
    45
    7
    1
    General disorders and administration site conditions
    Malaise
         subjects affected / exposed
    6 / 96 (6.25%)
    1 / 38 (2.63%)
    1 / 49 (2.04%)
         occurrences all number
    8
    1
    1
    Injection site erythema
         subjects affected / exposed
    5 / 96 (5.21%)
    3 / 38 (7.89%)
    0 / 49 (0.00%)
         occurrences all number
    6
    14
    0
    Influenza like illness
         subjects affected / exposed
    25 / 96 (26.04%)
    2 / 38 (5.26%)
    3 / 49 (6.12%)
         occurrences all number
    38
    2
    3
    Fatigue
         subjects affected / exposed
    23 / 96 (23.96%)
    8 / 38 (21.05%)
    10 / 49 (20.41%)
         occurrences all number
    26
    10
    12
    Asthenia
         subjects affected / exposed
    19 / 96 (19.79%)
    0 / 38 (0.00%)
    5 / 49 (10.20%)
         occurrences all number
    34
    0
    8
    Oedema peripheral
         subjects affected / exposed
    6 / 96 (6.25%)
    1 / 38 (2.63%)
    2 / 49 (4.08%)
         occurrences all number
    10
    1
    2
    Pyrexia
         subjects affected / exposed
    30 / 96 (31.25%)
    11 / 38 (28.95%)
    9 / 49 (18.37%)
         occurrences all number
    49
    17
    9
    Pain
         subjects affected / exposed
    4 / 96 (4.17%)
    2 / 38 (5.26%)
    0 / 49 (0.00%)
         occurrences all number
    4
    2
    0
    Immune system disorders
    Immunisation reaction
         subjects affected / exposed
    18 / 96 (18.75%)
    5 / 38 (13.16%)
    0 / 49 (0.00%)
         occurrences all number
    25
    6
    0
    Reproductive system and breast disorders
    Ovarian cyst
         subjects affected / exposed
    3 / 96 (3.13%)
    3 / 38 (7.89%)
    1 / 49 (2.04%)
         occurrences all number
    3
    3
    1
    Menstruation irregular
         subjects affected / exposed
    13 / 96 (13.54%)
    2 / 38 (5.26%)
    3 / 49 (6.12%)
         occurrences all number
    29
    2
    4
    Dysmenorrhoea
         subjects affected / exposed
    8 / 96 (8.33%)
    1 / 38 (2.63%)
    1 / 49 (2.04%)
         occurrences all number
    38
    1
    1
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    5 / 96 (5.21%)
    1 / 38 (2.63%)
    0 / 49 (0.00%)
         occurrences all number
    8
    1
    0
    Cough
         subjects affected / exposed
    24 / 96 (25.00%)
    2 / 38 (5.26%)
    1 / 49 (2.04%)
         occurrences all number
    39
    2
    1
    Rhinorrhoea
         subjects affected / exposed
    4 / 96 (4.17%)
    1 / 38 (2.63%)
    3 / 49 (6.12%)
         occurrences all number
    5
    1
    3
    Rhinitis allergic
         subjects affected / exposed
    7 / 96 (7.29%)
    0 / 38 (0.00%)
    3 / 49 (6.12%)
         occurrences all number
    10
    0
    3
    Pulmonary hypertension
         subjects affected / exposed
    0 / 96 (0.00%)
    2 / 38 (5.26%)
    2 / 49 (4.08%)
         occurrences all number
    0
    2
    2
    Pleuritic pain
         subjects affected / exposed
    0 / 96 (0.00%)
    2 / 38 (5.26%)
    0 / 49 (0.00%)
         occurrences all number
    0
    2
    0
    Oropharyngeal pain
         subjects affected / exposed
    23 / 96 (23.96%)
    1 / 38 (2.63%)
    6 / 49 (12.24%)
         occurrences all number
    34
    1
    10
    Epistaxis
         subjects affected / exposed
    12 / 96 (12.50%)
    1 / 38 (2.63%)
    1 / 49 (2.04%)
         occurrences all number
    20
    1
    5
    Nasal congestion
         subjects affected / exposed
    8 / 96 (8.33%)
    1 / 38 (2.63%)
    2 / 49 (4.08%)
         occurrences all number
    12
    1
    2
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    14 / 96 (14.58%)
    1 / 38 (2.63%)
    1 / 49 (2.04%)
         occurrences all number
    20
    1
    1
    Anxiety
         subjects affected / exposed
    10 / 96 (10.42%)
    1 / 38 (2.63%)
    0 / 49 (0.00%)
         occurrences all number
    10
    1
    0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    6 / 96 (6.25%)
    0 / 38 (0.00%)
    1 / 49 (2.04%)
         occurrences all number
    6
    0
    3
    Injury, poisoning and procedural complications
    Muscle strain
         subjects affected / exposed
    5 / 96 (5.21%)
    0 / 38 (0.00%)
    0 / 49 (0.00%)
         occurrences all number
    5
    0
    0
    Ligament sprain
         subjects affected / exposed
    5 / 96 (5.21%)
    0 / 38 (0.00%)
    0 / 49 (0.00%)
         occurrences all number
    5
    0
    0
    Fall
         subjects affected / exposed
    2 / 96 (2.08%)
    3 / 38 (7.89%)
    0 / 49 (0.00%)
         occurrences all number
    3
    3
    0
    Traumatic fracture
         subjects affected / exposed
    6 / 96 (6.25%)
    0 / 38 (0.00%)
    0 / 49 (0.00%)
         occurrences all number
    6
    0
    0
    Cardiac disorders
    Palpitations
         subjects affected / exposed
    9 / 96 (9.38%)
    4 / 38 (10.53%)
    6 / 49 (12.24%)
         occurrences all number
    14
    4
    6
    Tachycardia
         subjects affected / exposed
    6 / 96 (6.25%)
    2 / 38 (5.26%)
    2 / 49 (4.08%)
         occurrences all number
    6
    3
    3
    Nervous system disorders
    Sciatica
         subjects affected / exposed
    5 / 96 (5.21%)
    1 / 38 (2.63%)
    0 / 49 (0.00%)
         occurrences all number
    6
    1
    0
    Dizziness
         subjects affected / exposed
    19 / 96 (19.79%)
    3 / 38 (7.89%)
    4 / 49 (8.16%)
         occurrences all number
    26
    3
    4
    Headache
         subjects affected / exposed
    44 / 96 (45.83%)
    10 / 38 (26.32%)
    10 / 49 (20.41%)
         occurrences all number
    175
    17
    20
    Migraine
         subjects affected / exposed
    9 / 96 (9.38%)
    0 / 38 (0.00%)
    0 / 49 (0.00%)
         occurrences all number
    22
    0
    0
    Blood and lymphatic system disorders
    Extramedullary haemopoiesis
         subjects affected / exposed
    9 / 96 (9.38%)
    2 / 38 (5.26%)
    2 / 49 (4.08%)
         occurrences all number
    9
    3
    3
    Ear and labyrinth disorders
    Ear pain
         subjects affected / exposed
    3 / 96 (3.13%)
    0 / 38 (0.00%)
    4 / 49 (8.16%)
         occurrences all number
    3
    0
    5
    Vertigo
         subjects affected / exposed
    3 / 96 (3.13%)
    0 / 38 (0.00%)
    3 / 49 (6.12%)
         occurrences all number
    4
    0
    3
    Gastrointestinal disorders
    Abdominal pain upper
         subjects affected / exposed
    15 / 96 (15.63%)
    5 / 38 (13.16%)
    3 / 49 (6.12%)
         occurrences all number
    22
    8
    3
    Abdominal pain
         subjects affected / exposed
    18 / 96 (18.75%)
    4 / 38 (10.53%)
    5 / 49 (10.20%)
         occurrences all number
    20
    5
    6
    Dyspepsia
         subjects affected / exposed
    18 / 96 (18.75%)
    3 / 38 (7.89%)
    2 / 49 (4.08%)
         occurrences all number
    20
    3
    2
    Dental caries
         subjects affected / exposed
    5 / 96 (5.21%)
    0 / 38 (0.00%)
    2 / 49 (4.08%)
         occurrences all number
    5
    0
    2
    Diarrhoea
         subjects affected / exposed
    25 / 96 (26.04%)
    5 / 38 (13.16%)
    6 / 49 (12.24%)
         occurrences all number
    43
    9
    7
    Vomiting
         subjects affected / exposed
    11 / 96 (11.46%)
    1 / 38 (2.63%)
    1 / 49 (2.04%)
         occurrences all number
    12
    1
    1
    Toothache
         subjects affected / exposed
    15 / 96 (15.63%)
    0 / 38 (0.00%)
    1 / 49 (2.04%)
         occurrences all number
    22
    0
    1
    Nausea
         subjects affected / exposed
    14 / 96 (14.58%)
    1 / 38 (2.63%)
    6 / 49 (12.24%)
         occurrences all number
    21
    1
    11
    Gastrooesophageal reflux disease
         subjects affected / exposed
    5 / 96 (5.21%)
    0 / 38 (0.00%)
    3 / 49 (6.12%)
         occurrences all number
    5
    0
    3
    Hepatobiliary disorders
    Biliary colic
         subjects affected / exposed
    5 / 96 (5.21%)
    0 / 38 (0.00%)
    0 / 49 (0.00%)
         occurrences all number
    6
    0
    0
    Skin and subcutaneous tissue disorders
    Skin ulcer
         subjects affected / exposed
    7 / 96 (7.29%)
    1 / 38 (2.63%)
    1 / 49 (2.04%)
         occurrences all number
    15
    1
    1
    Pruritus
         subjects affected / exposed
    3 / 96 (3.13%)
    2 / 38 (5.26%)
    0 / 49 (0.00%)
         occurrences all number
    3
    2
    0
    Erythema
         subjects affected / exposed
    7 / 96 (7.29%)
    1 / 38 (2.63%)
    0 / 49 (0.00%)
         occurrences all number
    7
    2
    0
    Renal and urinary disorders
    Renal cyst
         subjects affected / exposed
    1 / 96 (1.04%)
    0 / 38 (0.00%)
    3 / 49 (6.12%)
         occurrences all number
    1
    0
    3
    Dysuria
         subjects affected / exposed
    6 / 96 (6.25%)
    0 / 38 (0.00%)
    1 / 49 (2.04%)
         occurrences all number
    8
    0
    1
    Albuminuria
         subjects affected / exposed
    2 / 96 (2.08%)
    2 / 38 (5.26%)
    0 / 49 (0.00%)
         occurrences all number
    2
    2
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    37 / 96 (38.54%)
    11 / 38 (28.95%)
    8 / 49 (16.33%)
         occurrences all number
    82
    19
    15
    Back pain
         subjects affected / exposed
    38 / 96 (39.58%)
    14 / 38 (36.84%)
    6 / 49 (12.24%)
         occurrences all number
    77
    29
    7
    Bone pain
         subjects affected / exposed
    42 / 96 (43.75%)
    8 / 38 (21.05%)
    3 / 49 (6.12%)
         occurrences all number
    103
    13
    3
    Muscle spasms
         subjects affected / exposed
    3 / 96 (3.13%)
    2 / 38 (5.26%)
    1 / 49 (2.04%)
         occurrences all number
    4
    3
    1
    Muscular weakness
         subjects affected / exposed
    3 / 96 (3.13%)
    1 / 38 (2.63%)
    3 / 49 (6.12%)
         occurrences all number
    3
    1
    4
    Musculoskeletal chest pain
         subjects affected / exposed
    6 / 96 (6.25%)
    0 / 38 (0.00%)
    1 / 49 (2.04%)
         occurrences all number
    8
    0
    1
    Musculoskeletal pain
         subjects affected / exposed
    6 / 96 (6.25%)
    1 / 38 (2.63%)
    1 / 49 (2.04%)
         occurrences all number
    6
    1
    1
    Myalgia
         subjects affected / exposed
    16 / 96 (16.67%)
    3 / 38 (7.89%)
    5 / 49 (10.20%)
         occurrences all number
    25
    5
    5
    Neck pain
         subjects affected / exposed
    12 / 96 (12.50%)
    1 / 38 (2.63%)
    2 / 49 (4.08%)
         occurrences all number
    17
    1
    4
    Osteoporosis
         subjects affected / exposed
    6 / 96 (6.25%)
    1 / 38 (2.63%)
    0 / 49 (0.00%)
         occurrences all number
    6
    1
    0
    Pain in extremity
         subjects affected / exposed
    29 / 96 (30.21%)
    6 / 38 (15.79%)
    5 / 49 (10.20%)
         occurrences all number
    47
    8
    6
    Pain in jaw
         subjects affected / exposed
    1 / 96 (1.04%)
    3 / 38 (7.89%)
    0 / 49 (0.00%)
         occurrences all number
    1
    3
    0
    Spinal pain
         subjects affected / exposed
    6 / 96 (6.25%)
    0 / 38 (0.00%)
    1 / 49 (2.04%)
         occurrences all number
    8
    0
    1
    Tendonitis
         subjects affected / exposed
    5 / 96 (5.21%)
    1 / 38 (2.63%)
    1 / 49 (2.04%)
         occurrences all number
    6
    1
    1
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    6 / 96 (6.25%)
    1 / 38 (2.63%)
    1 / 49 (2.04%)
         occurrences all number
    6
    1
    1
    COVID-19
         subjects affected / exposed
    34 / 96 (35.42%)
    15 / 38 (39.47%)
    0 / 49 (0.00%)
         occurrences all number
    36
    15
    0
    Gastroenteritis
         subjects affected / exposed
    12 / 96 (12.50%)
    2 / 38 (5.26%)
    2 / 49 (4.08%)
         occurrences all number
    15
    2
    3
    Helicobacter infection
         subjects affected / exposed
    0 / 96 (0.00%)
    2 / 38 (5.26%)
    0 / 49 (0.00%)
         occurrences all number
    0
    3
    0
    Influenza
         subjects affected / exposed
    15 / 96 (15.63%)
    1 / 38 (2.63%)
    5 / 49 (10.20%)
         occurrences all number
    18
    1
    7
    Nasopharyngitis
         subjects affected / exposed
    7 / 96 (7.29%)
    0 / 38 (0.00%)
    0 / 49 (0.00%)
         occurrences all number
    10
    0
    0
    Pharyngitis
         subjects affected / exposed
    21 / 96 (21.88%)
    1 / 38 (2.63%)
    6 / 49 (12.24%)
         occurrences all number
    30
    1
    13
    Rhinitis
         subjects affected / exposed
    9 / 96 (9.38%)
    0 / 38 (0.00%)
    6 / 49 (12.24%)
         occurrences all number
    11
    0
    6
    Sinusitis
         subjects affected / exposed
    4 / 96 (4.17%)
    2 / 38 (5.26%)
    1 / 49 (2.04%)
         occurrences all number
    7
    2
    1
    Tonsillitis
         subjects affected / exposed
    4 / 96 (4.17%)
    1 / 38 (2.63%)
    6 / 49 (12.24%)
         occurrences all number
    5
    2
    7
    Tooth abscess
         subjects affected / exposed
    6 / 96 (6.25%)
    0 / 38 (0.00%)
    1 / 49 (2.04%)
         occurrences all number
    9
    0
    1
    Upper respiratory tract infection
         subjects affected / exposed
    23 / 96 (23.96%)
    1 / 38 (2.63%)
    11 / 49 (22.45%)
         occurrences all number
    42
    1
    32
    Metabolism and nutrition disorders
    Folate deficiency
         subjects affected / exposed
    5 / 96 (5.21%)
    0 / 38 (0.00%)
    1 / 49 (2.04%)
         occurrences all number
    5
    0
    1
    Hyperuricaemia
         subjects affected / exposed
    8 / 96 (8.33%)
    1 / 38 (2.63%)
    2 / 49 (4.08%)
         occurrences all number
    9
    1
    2
    Iron overload
         subjects affected / exposed
    14 / 96 (14.58%)
    0 / 38 (0.00%)
    5 / 49 (10.20%)
         occurrences all number
    15
    0
    5
    Vitamin D deficiency
         subjects affected / exposed
    9 / 96 (9.38%)
    2 / 38 (5.26%)
    4 / 49 (8.16%)
         occurrences all number
    11
    2
    4

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    21 Dec 2018
    Added additional criteria for dose modification; description of TRV and EMH masses measurements have been clarified for consistency; exclusion criterion clarified.
    12 Jun 2020
    Open-Label Phase (OLP) added to study design; modification to PRO Minimum Clinical Important Difference (MCID) and Responder Definition (RD)Thresholds); Table of Events, Treatment Schedule and Procedures was updated to include the OLP; rationale for the key secondary endpoints were updated; clarified use of the Quality of Life questionnaire; monitoring of thromboembolic events has been added as event of interest; correction of typos.
    27 Apr 2022
    Updated morbidity-free parameters; changed open-label duration; added COVID-19 guidelines; modify medical monitor; added modification of monitoring extramedullary masses.

    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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