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    Clinical Trial Results:
    PHASE 3, DOUBLE-BLIND, RANDOMIZED, PLACEBO-CONTROLLED, MULTICENTER STUDY TO DETERMINE THE EFFICACY AND SAFETY OF LUSPATERCEPT (ACE-536) VERSUS PLACEBO IN ADULTS WHO REQUIRE REGULAR RED BLOOD CELL TRANSFUSIONS DUE TO BETA -THALASSEMIA The “BELIEVE” Trial

    Summary
    EudraCT number
    		 2015-003224-31
    Trial protocol
    		 GB   DE   BG   GR   IT  
    Global end of trial date
    05 Jan 2021

    Results information
    Results version number
    		 v2(current)
    This version publication date
    12 Apr 2023
    First version publication date
    11 Jan 2022
    Other versions
    		 v1
    Version creation reason

    Trial information

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    Trial identification
    Sponsor protocol code
    ACE-536-B-Thal-001
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Bristol-Myers Squibb
    Sponsor organisation address
    Chaussée de la Hulpe 185, Brussels, Belgium, 1170
    Public contact
    EU Study Start-Up Unit, Bristol-Myers Squibb International Corporation, Clinical.Trials@bms.com
    Scientific contact
    Bristol-Myers Squibb Study Director, Bristol-Myers Squibb, Clinical.Trials@bms.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    19 Mar 2021
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    05 Jan 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To determine the proportion of subjects treated with Luspatercept + BSC versus placebo + BSC who achieved erythroid response, defined as ≥ 33% reduction from baseline in transfusion burden (units RBCs/time) with a reduction of at least 2 units, from Week 13 to Week 24.
    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
    02 May 2016
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Malaysia: 39
    Country: Number of subjects enrolled
    Australia: 15
    Country: Number of subjects enrolled
    Taiwan: 12
    Country: Number of subjects enrolled
    Thailand: 41
    Country: Number of subjects enrolled
    Israel: 20
    Country: Number of subjects enrolled
    Lebanon: 19
    Country: Number of subjects enrolled
    Tunisia: 17
    Country: Number of subjects enrolled
    Turkey: 22
    Country: Number of subjects enrolled
    Bulgaria: 25
    Country: Number of subjects enrolled
    Canada: 13
    Country: Number of subjects enrolled
    France: 3
    Country: Number of subjects enrolled
    Greece: 24
    Country: Number of subjects enrolled
    Italy: 48
    Country: Number of subjects enrolled
    United Kingdom: 11
    Country: Number of subjects enrolled
    United States: 27
    Worldwide total number of subjects
    336
    EEA total number of subjects
    100
    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)
    335
    From 65 to 84 years
    1
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 336 participants were randomized, 332 participants were treated.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Luspatercept + BSC
    Arm description
    		 Luspatercept (ACE-536) was administered subcutaneously (SC) at a starting dose level of 1 mg/kg once every 21 days. Participants could be dose-titrated to 1.25 mg/kg, but the maximum total dose should not exceed 120 mg, during the Treatment Period, the Long-term Treatment Period, and Open-Label Treatment Period. BSC = Best Supportive Care
    Arm type
    		 Experimental

    Investigational medicinal product name
    Luspatercept
    Investigational medicinal product code
    Other name
    ACE-536
    Pharmaceutical forms
    Powder for solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    1 mg/Kg SC Q3W

    Arm title
    		 Placebo + BSC
    Arm description
    		 Placebo (normal saline) was administered subcutaneously (SC) in volumes to match active treatment once every 21 days. BSC = Best Supportive Care
    Arm type
    		 Placebo

    Investigational medicinal product name
    0.9% Sodium Chloride
    Investigational medicinal product code
    Other name
    Placebo
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Volume equal to investigational drug, SC Q3W

    Number of subjects in period 1
    		Luspatercept + BSC Placebo + BSC
    Started
    224
    112
    Participants Treated
    223
    109
    Completed 24 weeks of treatment
    211
    102
    Completed 48 weeks of treatment
    202
    96
    Completed 96 weeks of treatment
    155
    3 [1]
    Completed 144 weeks of treatment
    125
    0 [2]
    Completed 192 weeks of treatment
    6
    0 [3]
    Completed
    6
    6
    Not completed
    218
    106
         Adverse event, serious fatal
    4
    1
         Consent withdrawn by subject
    37
    16
         Physician decision
    1
    1
         Transition to Rollover Protocol
    169
    82
         Adverse event, non-fatal
    4
    -
         Other reasons
    3
    5
         Lack of efficacy
    -
    1
    Notes
    [1] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: The milestones reflect the number of participants at a particular timepoint
    [2] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: The milestones reflect the number of participants at a particular timepoint
    [3] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: The milestones reflect the number of participants at a particular timepoint

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Luspatercept + BSC
    Reporting group description
    		 Luspatercept (ACE-536) was administered subcutaneously (SC) at a starting dose level of 1 mg/kg once every 21 days. Participants could be dose-titrated to 1.25 mg/kg, but the maximum total dose should not exceed 120 mg, during the Treatment Period, the Long-term Treatment Period, and Open-Label Treatment Period. BSC = Best Supportive Care

    Reporting group title
    Placebo + BSC
    Reporting group description
    		 Placebo (normal saline) was administered subcutaneously (SC) in volumes to match active treatment once every 21 days. BSC = Best Supportive Care

    Reporting group values
    		 Luspatercept + BSC Placebo + BSC Total
    Number of subjects
    		 224 112 336
    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
        Adults (18-64 years)
    		 223 112 335
        From 65-84 years
    		 1 0 1
        85 years and over
    		 0 0 0
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 32.2 ± 10.67 31.9 ± 9.89 -
    Sex: Female, Male
    Units:
        Female
    		 132 63 195
        Male
    		 92 49 141
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 5 2 7
        Not Hispanic or Latino
    		 218 107 325
        Unknown or Not Reported
    		 1 3 4
    Race/Ethnicity, Customized
    Units: Subjects
        Asian
    		 81 36 117
        Black or African American
    		 1 0 1
        White
    		 122 60 182
        Not collected or reported
    		 5 5 10
        Other
    		 15 11 26

    End points

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    End points reporting groups
    Reporting group title
    Luspatercept + BSC
    Reporting group description
    		 Luspatercept (ACE-536) was administered subcutaneously (SC) at a starting dose level of 1 mg/kg once every 21 days. Participants could be dose-titrated to 1.25 mg/kg, but the maximum total dose should not exceed 120 mg, during the Treatment Period, the Long-term Treatment Period, and Open-Label Treatment Period. BSC = Best Supportive Care

    Reporting group title
    Placebo + BSC
    Reporting group description
    		 Placebo (normal saline) was administered subcutaneously (SC) in volumes to match active treatment once every 21 days. BSC = Best Supportive Care

    Primary: Percentage of Participants Who Achieved Erythroid Response - Week 13 to Week 24

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    End point title
    		 Percentage of Participants Who Achieved Erythroid Response - Week 13 to Week 24
    End point description
    Erythroid Response was defined as red blood cell (RBC) transfusion burden reduction from baseline ≥ 33% with a reduction of at least 2 units during Week 13 - 24 compared to the 12-week interval on or prior to Dose 1 Day 1.
    End point type
    Primary
    End point timeframe
    Baseline: Day -83 to Day 1; Treatment: Weeks 13 to Week 24
    End point values
    		 Luspatercept + BSC Placebo + BSC
    Number of subjects analysed
    224
    112
    Units: Percentage of participants
        number (not applicable)
    21.0
    4.5
    Statistical analysis title
    		 Response - Week 13 to 24_1
    Statistical analysis description
    Odds ratio 95% confidence intervals (CIs), and p-value were estimated from the Cochran Mantel-Haenszel (CMH) test stratified by the geographical regions defined at randomization.
    Comparison groups
    Luspatercept + BSC v Placebo + BSC
    Number of subjects included in analysis
    336
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 < 0.0001 [1]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    5.62
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 2.17
         upper limit
    		 14.53
    Notes
    [1] - Significance level of 0.050 for 2-sided tests.
    Statistical analysis title
    		 Response - Week 13 to 24_3
    Comparison groups
    Luspatercept + BSC v Placebo + BSC
    Number of subjects included in analysis
    336
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Common Risk Difference
    Point estimate
    16.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 9.9
         upper limit
    		 23.1
    Statistical analysis title
    		 Response - Week 13 to 24_2
    Comparison groups
    Luspatercept + BSC v Placebo + BSC
    Number of subjects included in analysis
    336
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Difference in Proportions
    Point estimate
    16.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 10
         upper limit
    		 23.1

    Secondary: Percentage Of Participants Who Achieved ≥ 33% Reduction from Baseline in Transfusion Burden - Week 37 to Week 48

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    End point title
    		 Percentage Of Participants Who Achieved ≥ 33% Reduction from Baseline in Transfusion Burden - Week 37 to Week 48
    End point description
    Percentage of participants who achieved a red blood cell (RBC) transfusion burden reduction from baseline ≥ 33% with a reduction of at least 2 units during Weeks 37 - 48 compared to the 12-week interval on or prior to Dose 1 Day 1.
    End point type
    Secondary
    End point timeframe
    Baseline: Day -83 to Day 1; Treatment: Weeks 37 to Week 48
    End point values
    		 Luspatercept + BSC Placebo + BSC
    Number of subjects analysed
    224
    112
    Units: Percentage of participants
        number (not applicable)
    19.6
    3.6
    Statistical analysis title
    		 Response - Week 37 to 48
    Statistical analysis description
    Odds ratio 95% CIs, and p-value were estimated from the CMH test stratified by the geographical regions defined at randomization. To control the overall Type 1 error rate for outcomes 2-4, the testing procedure was implemented strictly in order: the test for this outcome was only conducted when there was evidence showing that erythroid response was achieved in the luspatercept group from Week 13 to Week 24 (primary endpoint).
    Comparison groups
    Luspatercept + BSC v Placebo + BSC
    Number of subjects included in analysis
    336
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 < 0.0001 [2]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    6.44
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 2.27
         upper limit
    		 18.26
    Notes
    [2] - Significance level of 0.050 for 2-sided tests.

    Secondary: Percentage Of Participants Who Achieve ≥ 50% Reduction from Baseline in Transfusion Burden - Week 37 to Week 48

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    End point title
    		 Percentage Of Participants Who Achieve ≥ 50% Reduction from Baseline in Transfusion Burden - Week 37 to Week 48
    End point description
    Percentage of participants who achieved a red blood cell (RBC) transfusion burden reduction from baseline ≥ 50% with a reduction of at least 2 units during Week 37 to Week 48 compared to the 12-week interval on or prior to Dose 1 Day 1.
    End point type
    Secondary
    End point timeframe
    Baseline: Day -83 to Day 1; Treatment: Week 37 to Week 48
    End point values
    		 Luspatercept + BSC Placebo + BSC
    Number of subjects analysed
    224
    112
    Units: Percentage of participants
        number (not applicable)
    10.3
    0.9
    Statistical analysis title
    		 ≥ 50% Reduction in transfusion burden_2
    Statistical analysis description
    Odds ratio, 95% CIs, and p-value were estimated from the Cochran-Mantel-Haenszel (CMH) test stratified by the geographical regions defined at randomization. To control the overall Type 1 error rate, the testing procedure was done strictly in order: the test for this outcome was only conducted when there was evidence showing erythroid response was achieved in the luspatercept group for the primary endpoint, and achievement of objective in the luspatercept group in outcomes 2+3.
    Comparison groups
    Luspatercept + BSC v Placebo + BSC
    Number of subjects included in analysis
    336
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.0017 [3]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    11.92
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.65
         upper limit
    		 86.29
    Notes
    [3] - Significance level of 0.050 for 2-sided tests.

    Secondary: Percentage Of Participants Who Achieve ≥ 50% Reduction from Baseline in Transfusion Burden - Week 13 to Week 24

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    End point title
    		 Percentage Of Participants Who Achieve ≥ 50% Reduction from Baseline in Transfusion Burden - Week 13 to Week 24
    End point description
    Percentage of participants who achieved a red blood cell (RBC) transfusion burden reduction from baseline ≥ 50% with a reduction of at least 2 units during Weeks 13 - 24 compared to the 12-week interval on or prior to Dose 1 Day 1.
    End point type
    Secondary
    End point timeframe
    Baseline: Day -83 to Day 1; Treatment: Weeks 13 to Week 24
    End point values
    		 Luspatercept + BSC Placebo + BSC
    Number of subjects analysed
    224
    112
    Units: Percentage of participants
        number (not applicable)
    7.1
    1.8
    Statistical analysis title
    		 ≥ 50% Reduction in transfusion burden
    Statistical analysis description
    Odds ratio, 95% CIs, and p-value were estimated from the Cochran-Mantel-Haenszel (CMH) test stratified by the geographical regions defined at randomization. To control the overall Type 1 error rate, the testing procedure was done strictly in order: the test for this outcome was only conducted when there was evidence showing erythroid response was achieved in the luspatercept group for the primary endpoint, and 33% hematological improvement was achieved in the luspatercept group in outcome 2.
    Comparison groups
    Luspatercept + BSC v Placebo + BSC
    Number of subjects included in analysis
    336
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.0402 [4]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    4.24
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.96
         upper limit
    		 18.79
    Notes
    [4] - Significance level of 0.050 for 2-sided tests.

    Secondary: Mean Change from Baseline in Transfusion Burden - Week 13 to Week 24

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    End point title
    		 Mean Change from Baseline in Transfusion Burden - Week 13 to Week 24
    End point description
    Baseline was defined as the total number of Red Blood Cells (RBC) units transfused during the 12-week interval on or prior to Dose 1 Day 1. This is compared to the total number of RBC units transfused during the 12-week interval from treatment weeks 13-24.
    End point type
    Secondary
    End point timeframe
    Baseline: Day -83 to Day 1; Treatment: Weeks 13 to Week 24
    End point values
    		 Luspatercept + BSC Placebo + BSC
    Number of subjects analysed
    210
    102
    Units: RBC units
        arithmetic mean (standard deviation)
    -0.67 ± 1.792
    0.66 ± 1.774
    Statistical analysis title
    		 Transfusion burden
    Statistical analysis description
    LSM = least squares mean
    Comparison groups
    Luspatercept + BSC v Placebo + BSC
    Number of subjects included in analysis
    312
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 < 0.0001 [5]
    Method
    		 ANCOVA
    Parameter type
    		 LSM Difference
    Point estimate
    -1.34
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.76
         upper limit
    		 -0.93
    Notes
    [5] - Significance level of 0.050 for 2-sided tests.

    Secondary: Mean Change From Baseline In Liver Iron Concentration (LIC) At Week 48

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    End point title
    		 Mean Change From Baseline In Liver Iron Concentration (LIC) At Week 48
    End point description
    Baseline was defined as the last value on or before the first dose of study drug was administered; if multiple values were present for the same date, the average of these values was used. If a participant had 1 postbaseline assessment, it was used as the Week 48 value. If a participant had multiple postbaseline assessments, the last one was used as the Week 48 value. The value of LIC was collected by magnetic resonance imaging. Participants with a LIC value > 43 mg/g were not included in the analysis.
    End point type
    Secondary
    End point timeframe
    Baseline: Week -12 to Day -1; Treatment: Week 48
    End point values
    		 Luspatercept + BSC Placebo + BSC
    Number of subjects analysed
    185
    99
    Units: mg/g dry weight
        arithmetic mean (standard deviation)
    0.05 ± 5.770
    -0.00 ± 5.329
    Statistical analysis title
    		 LIC - Change from baseline at Week 48
    Statistical analysis description
    Change from baseline at Week 48 P-value ANCOVA model with geographical regions defined at randomization and baseline LIC as covariates. LS = least square
    Comparison groups
    Luspatercept + BSC v Placebo + BSC
    Number of subjects included in analysis
    284
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.7598 [6]
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean of Difference
    Point estimate
    0.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.1
         upper limit
    		 1.51
    Notes
    [6] - Significance level of 0.050 for 2-sided tests.

    Secondary: Mean Change From Baseline In Mean Daily Dose Of Iron Chelation Therapies (ICT) At Week 48

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    End point title
    		 Mean Change From Baseline In Mean Daily Dose Of Iron Chelation Therapies (ICT) At Week 48
    End point description
    Three different types of Iron Chelation Therapy (ICT) were analyzed: 1. Deferasirox 2. Deferiprone 3. Deferoxamine Mesilate/Deferoxamine The baseline mean daily dose was calculated using the ICT dosage during the 12 weeks prior to first study drug administration and the postbaseline mean daily dose was calculated during the last 12 weeks of the 48-week double-blind Treatment Period or the last 12 weeks of the study treatment for early discontinued participants.
    End point type
    Secondary
    End point timeframe
    Baseline: Day -83 to Day 1; Treatment: Week 37 to Week 48
    End point values
    		 Luspatercept + BSC Placebo + BSC
    Number of subjects analysed
    129
    66
    Units: mg
    arithmetic mean (standard deviation)
        Deferasirox
    -105.0 ± 378.67
    -60.4 ± 297.11
        Deferiprone
    -229.1 ± 893.62
    -73.4 ± 614.80
        Deferoxamine Mesilate/Deferoxamine
    84.9 ± 523.45
    274.2 ± 613.05
    Statistical analysis title
    		 ICT_1
    Statistical analysis description
    Change from baseline at Week 48 LS = least squares
    Comparison groups
    Luspatercept + BSC v Placebo + BSC
    Number of subjects included in analysis
    195
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.2552 [7]
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean of Difference
    Point estimate
    -68
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -185.8
         upper limit
    		 49.7
    Notes
    [7] - Significance level of 0.050 for 2-sided tests
    Statistical analysis title
    		 ICT_3
    Statistical analysis description
    Deferoxamine Mesilate / Deferoxamine: Change from baseline at Week 48 LS = least squares
    Comparison groups
    Luspatercept + BSC v Placebo + BSC
    Number of subjects included in analysis
    195
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.5186 [8]
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean of Difference
    Point estimate
    -147.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -673.1
         upper limit
    		 378.5
    Notes
    [8] - Significance level of 0.050 for 2-sided tests
    Statistical analysis title
    		 ICT_2
    Statistical analysis description
    Deferiprone: Change from baseline at Week 48 LS = least squares
    Comparison groups
    Luspatercept + BSC v Placebo + BSC
    Number of subjects included in analysis
    195
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.7746 [9]
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean of Difference
    Point estimate
    -76.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -612.9
         upper limit
    		 460.1
    Notes
    [9] - Significance level of 0.050 for 2-sided tests

    Secondary: Mean Change From Baseline In Mean Serum Ferritin At Week 48

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    End point title
    		 Mean Change From Baseline In Mean Serum Ferritin At Week 48
    End point description
    For each participant, the baseline mean serum ferritin level was calculated during the 12 weeks prior to first study drug administration. The postbaseline mean serum ferritin level was calculated during the last 12 weeks of the 48-week double-blind Treatment Period or last 12 weeks of study treatment, if discontinued early. The change was calculated as the difference of post baseline mean serum ferritin level and baseline mean serum ferritin level.
    End point type
    Secondary
    End point timeframe
    Baseline: Day -83 to Day 1; Treatment: Week 37 to Week 48
    End point values
    		 Luspatercept + BSC Placebo + BSC
    Number of subjects analysed
    207
    101
    Units: μg/L
        arithmetic mean (standard deviation)
    -247.19 ± 713.767
    100.38 ± 522.047
    Statistical analysis title
    		 Ferritin - Change from baseline at Week 48
    Statistical analysis description
    Change from baseline at Week 48 LS = least squares
    Comparison groups
    Luspatercept + BSC v Placebo + BSC
    Number of subjects included in analysis
    308
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 < 0.0001 [10]
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean of Difference
    Point estimate
    -342.59
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -498.3
         upper limit
    		 -186.87
    Notes
    [10] - Significance level of 0.050 for 2-sided tests

    Secondary: Mean Change From Baseline In Total Hip And Lumbar Spine Bone Mineral Density (BMD) At Week 48

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    End point title
    		 Mean Change From Baseline In Total Hip And Lumbar Spine Bone Mineral Density (BMD) At Week 48
    End point description
    For BMD, the lumbar spine and total hip were measured at baseline and 48 weeks by dual energy x-ray absorptiometry (DXA). Baseline was defined as the last value on or before the first dose of study drug is administered; if multiple values are present for the same date, the average of these values was used. If during the 48 week double-blinded treatment period, a participant has only one assessment, it is counted as 'Week 48' visit; if a participant has multiple assessments, the last one is used as 'Week 48' visit. The analysis was done on the population that had at least 2 measurements.
    End point type
    Secondary
    End point timeframe
    Baseline: Day 1; Treatment: Week 48
    End point values
    		 Luspatercept + BSC Placebo + BSC
    Number of subjects analysed
    190
    95
    Units: gm/cm^2
    arithmetic mean (standard deviation)
        Total Hip
    0.01 ± 0.050
    0.01 ± 0.057
        Lumbar Spine
    -0.00 ± 0.063
    0.00 ± 0.078
    Statistical analysis title
    		 Hip BMD - Change from baseline at Week 48
    Statistical analysis description
    LS = least squares
    Comparison groups
    Luspatercept + BSC v Placebo + BSC
    Number of subjects included in analysis
    285
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.9201 [11]
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean of Difference
    Point estimate
    0
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.01
         upper limit
    		 0.01
    Notes
    [11] - Significance level of 0.050 for 2-sided tests.
    Statistical analysis title
    		 Spine BMD - Change from baseline at Week 48
    Statistical analysis description
    Lumbar Spine Bone Mineral Density: Change from baseline at Week 48 LS = least squares
    Comparison groups
    Luspatercept + BSC v Placebo + BSC
    Number of subjects included in analysis
    285
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.462 [12]
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean of Difference
    Point estimate
    -0.01
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.02
         upper limit
    		 0.01
    Notes
    [12] - Significance level of 0.050 for 2-sided tests.

    Secondary: Mean Change From Baseline In Myocardial Iron At Week 48

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    End point title
    		 Mean Change From Baseline In Myocardial Iron At Week 48
    End point description
    Myocardial Iron levels were measured by Magnetic Resonance Imaging (MRI), using MRI parameter T2* (Unit: ms). T2* values correlates with heart failure (HF) risk (e.g. T2*<6ms: high HF risk).
    End point type
    Secondary
    End point timeframe
    Baseline: Day 1; Treatment: Week 48
    End point values
    		 Luspatercept + BSC Placebo + BSC
    Number of subjects analysed
    201
    102
    Units: ms
        arithmetic mean (standard deviation)
    -1.83 ± 15.084
    -0.01 ± 6.780
    Statistical analysis title
    		 Myocardial Iron - Change from baseline at Week 48
    Statistical analysis description
    Change from baseline at Week 48 LS = least square
    Comparison groups
    Luspatercept + BSC v Placebo + BSC
    Number of subjects included in analysis
    303
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.0543 [13]
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean of Difference
    Point estimate
    -2.22
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.48
         upper limit
    		 0.04
    Notes
    [13] - Significance level of 0.050 for 2-sided tests.

    Secondary: Mean Change From Baseline in the Transfusion-dependent Quality of Life (TranQol) Questionnaire At Week 24

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    End point title
    		 Mean Change From Baseline in the Transfusion-dependent Quality of Life (TranQol) Questionnaire At Week 24
    End point description
    The TranQol is a self-administered quality of life tool developed for beta-thalassemia patients. The adult self-report version used in this study, includes 36 questions assessed on a 5-point response, that are grouped into 5 domains (Physical Health, Emotional Health, Sexual Health, Family Functioning, School/Career Functioning). Scores are calculated according to specific scoring algorithms developed by the authors. Both individual domains score and the total score range from 0 (worst) to 100 (best). Total Score and Physical Health domain score are reported. Positive change from baseline values indicate improvement.
    End point type
    Secondary
    End point timeframe
    Baseline: 4 weeks prior to Day 1; Treatment: Week 24
    End point values
    		 Luspatercept + BSC Placebo + BSC
    Number of subjects analysed
    200
    94
    Units: Score on a scale
    arithmetic mean (standard deviation)
        Physical Health Domain Score
    -1.5 ± 14.26
    -0.7 ± 14.24
        Total Score
    0.8 ± 11.56
    -0.4 ± 11.62
    Statistical analysis title
    		 Physical Health Domain Score
    Comparison groups
    Luspatercept + BSC v Placebo + BSC
    Number of subjects included in analysis
    294
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.666 [14]
    Method
    		 t-test, 2-sided
    Confidence interval
    Notes
    [14] - Significance level of 0.050 for 2-sided tests.
    Statistical analysis title
    		 Total Score
    Comparison groups
    Luspatercept + BSC v Placebo + BSC
    Number of subjects included in analysis
    294
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.384 [15]
    Method
    		 t-test, 2-sided
    Confidence interval
    Notes
    [15] - Significance level of 0.050 for 2-sided tests.

    Secondary: Mean Change From Baseline in the 36-item Short Form Health Survey (SF-36) Questionnaire At Weeks 24

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    End point title
    		 Mean Change From Baseline in the 36-item Short Form Health Survey (SF-36) Questionnaire At Weeks 24
    End point description
    The SF-36 (version 2) is a generic, self-administered instrument consisting of 8 multi-item scales that assess 8 health domains. The raw score for each health domain is transformed into a 0 (worst) to 100 (best) domain score. The 0–100 scale score for each health domain is further converted to normbased scores using a T-score transformation, with a mean of 50 and a standard deviation (SD) of 10. Higher norm-based T-scores indicate better heath/QoL. The domains/summaries reported are: 1. Physical Functioning (Range of possible T-scores is 19.26 – 57.54) 2. General Health (Range of possible T-scores is 18.95 – 66.50) 3. Physical Component summary (PCS) (Range of possible T-scores is 5.02 – 79.78). Positive change from baseline values indicate improvement.
    End point type
    Secondary
    End point timeframe
    Baseline: 4 weeks prior to Day 1; Treatment: Weeks 24
    End point values
    		 Luspatercept + BSC Placebo + BSC
    Number of subjects analysed
    210
    103
    Units: T-score
    arithmetic mean (standard deviation)
        Physical Functioning Domain Score
    -0.3 ± 6.93
    -0.2 ± 7.86
        General Health Domain Score
    0.4 ± 7.18
    0.3 ± 7.03
        PCS
    -0.4 ± 7.01
    -0.3 ± 7.97
    Statistical analysis title
    		 Physical Functioning Domain
    Comparison groups
    Luspatercept + BSC v Placebo + BSC
    Number of subjects included in analysis
    313
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.918 [16]
    Method
    		 t-test, 2-sided
    Confidence interval
    Notes
    [16] - Significance level of 0.050 for 2-sided tests.
    Statistical analysis title
    		 General Health Domain
    Comparison groups
    Luspatercept + BSC v Placebo + BSC
    Number of subjects included in analysis
    313
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.857 [17]
    Method
    		 t-test, 2-sided
    Confidence interval
    Notes
    [17] - Significance level of 0.050 for 2-sided tests.
    Statistical analysis title
    		 PCS
    Comparison groups
    Luspatercept + BSC v Placebo + BSC
    Number of subjects included in analysis
    313
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.839 [18]
    Method
    		 t-test, 2-sided
    Confidence interval
    Notes
    [18] - Significance level of 0.050 for 2-sided tests.

    Secondary: Number of Days Spent in Higher Care Hospital Units

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    End point title
    		 Number of Days Spent in Higher Care Hospital Units
    End point description
    Types of hospitals units considered to be 'higher care' are: - Intensive Care Unit - Coronary Care Unit
    End point type
    Secondary
    End point timeframe
    From informed consent signing (up to 12 weeks before start of treatment) to end of treatment (up to approximately 227 weeks)
    End point values
    		 Luspatercept + BSC Placebo + BSC
    Number of subjects analysed
    43
    5
    Units: Days
        arithmetic mean (standard deviation)
    8.0 ± 23.70
    0.6 ± 0.55
    No statistical analyses for this end point

    Secondary: Number of Participants Who Utilized Healthcare Resources During Study

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    End point title
    		 Number of Participants Who Utilized Healthcare Resources During Study
    End point description
    Number of participants who had any of the following types of Healthcare Resource Utilization (HRU): - a doctor office visit (non-study scheduled) - an emergency department visit - a hospitalization
    End point type
    Secondary
    End point timeframe
    From informed consent signing (up to 12 weeks before start of treatment) to end of treatment (up to approximately 227 weeks)
    End point values
    		 Luspatercept + BSC Placebo + BSC
    Number of subjects analysed
    224
    112
    Units: Participants
        Doctor Office Visit
    186
    69
        Emergency Department Visit
    71
    22
        Hospital Admission
    61
    5
    No statistical analyses for this end point

    Secondary: Duration of Reduction in Transfusion Burden

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    End point title
    		 Duration of Reduction in Transfusion Burden
    End point description
    Responders were defined as subjects who achieved ≥ 33% reduction or ≥ 50% reduction in Red Blood Cells Transfusion (RBC-T) burden from baseline with a reduction of at least 2 RBC units during any rolling 12-week interval. The duration of reduction is calculated as Last Day of Response - First day of response +1
    End point type
    Secondary
    End point timeframe
    From first dose to end of study treatment (up to approximately 215 weeks)
    End point values
    		 Luspatercept + BSC Placebo + BSC
    Number of subjects analysed
    173
    39
    Units: Days
    arithmetic mean (standard deviation)
        Number of participants analyzed for 33%
    627.3 ± 390.54
    224.0 ± 155.15
        Number of participants analyzed for 50%
    491.1 ± 386.37
    193.0 ± 142.51
    No statistical analyses for this end point

    Secondary: Percentage Of Participants Who Were Transfusion Independent For ≥ 8 Weeks During Treatment

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    End point title
    		 Percentage Of Participants Who Were Transfusion Independent For ≥ 8 Weeks During Treatment
    End point description
    Transfusion independence was defined as the absence of any transfusion during any consecutive “rolling” 8-week time interval within the treatment period, i.e, Days 1 to 56, Days 2 to 57 and so on.
    End point type
    Secondary
    End point timeframe
    From first dose through 3 weeks post last dose (up to approximately 218 weeks)
    End point values
    		 Luspatercept + BSC Placebo + BSC
    Number of subjects analysed
    224
    112
    Units: Percentage of participants
        number (not applicable)
    12.1
    1.8
    Statistical analysis title
    		 Transfusion independence >8 weeks
    Statistical analysis description
    Odds ratio 95% confidence intervals (CIs), and p-value were estimated from the Cochran Mantel-Haenszel (CMH) test stratified by the geographical regions defined at randomization.
    Comparison groups
    Luspatercept + BSC v Placebo + BSC
    Number of subjects included in analysis
    336
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.0015 [19]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    7.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.8
         upper limit
    		 32.9
    Notes
    [19] - Significance level of 0.050 for 2-sided tests.

    Secondary: Longest Duration of Transfusion Independence

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    End point title
    		 Longest Duration of Transfusion Independence
    End point description
    Transfusion independence was defined as the absence of any transfusion during any consecutive “rolling” 8-week time interval within the treatment period, ie, Days 1 to 56, Days 2 to 57 and so on. Longest duration of transfusion independence was estimated based on Kaplan-Meier model. "99999"=N/A
    End point type
    Secondary
    End point timeframe
    From first dose through 3 weeks post last dose (up to approximately 218 weeks)
    End point values
    		 Luspatercept + BSC Placebo + BSC
    Number of subjects analysed
    27
    2
    Units: Days
        median (confidence interval 95%)
    72.0 (62.0 to 103.0)
    71.5 (62.0 to 99999)
    No statistical analyses for this end point

    Secondary: Time to Erythroid Response

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    End point title
    		 Time to Erythroid Response
    End point description
    Time to erythroid response was defined as the time from first dose of the study drug to first erythroid response. This is reported for participants with a ≥ 33% reduction from baseline in RBC transfusion burden (with a reduction of at least 2 units) for any 12-week interval., as well as participants with a ≥ 50% reduction from baseline in RBC transfusion burden (with a reduction of at least 2 units) for any 12-week interval.
    End point type
    Secondary
    End point timeframe
    From first dose to 48 weeks following first dose
    End point values
    		 Luspatercept + BSC Placebo + BSC
    Number of subjects analysed
    173
    39
    Units: Days
    arithmetic mean (standard deviation)
        ≥ 33% Transfusion Burden Reduction
    96.3 ± 163.92
    163.5 ± 148.78
        ≥ 50% Transfusion Burden Reduction
    189.1 ± 257.69
    160.9 ± 160.17
    Statistical analysis title
    		 ≥ 50% Transfusion Burden Reduction
    Comparison groups
    Luspatercept + BSC v Placebo + BSC
    Number of subjects included in analysis
    212
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.7473 [20]
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    28.24
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -144.87
         upper limit
    		 201.34
    Notes
    [20] - Significance level of 0.050 for 2-sided tests.
    Statistical analysis title
    		 ≥ 33% Transfusion Burden Reduction
    Comparison groups
    Luspatercept + BSC v Placebo + BSC
    Number of subjects included in analysis
    212
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.0195 [21]
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -67.27
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -123.63
         upper limit
    		 -10.91
    Notes
    [21] - Significance level of 0.050 for 2-sided tests.

    Secondary: Post-Baseline Transfusion Event Frequency

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    End point title
    		 Post-Baseline Transfusion Event Frequency
    End point description
    The number of transfusion events after start of study treatment were evaluated. For the definition of transfusion events, if multiple transfusions happen on the same date, they are counted as one event; if multiple transfusions happen on two consecutive dates, they are counted as one event; if multiple transfusions happen on three consecutive dates, they are counted as two events. Results are presented in 24-week intervals, up to 96 weeks after start of study treatment
    End point type
    Secondary
    End point timeframe
    From first dose through 3 weeks post last dose (up to approximately 218 weeks)
    End point values
    		 Luspatercept + BSC Placebo + BSC
    Number of subjects analysed
    210
    102
    Units: Number of transfusions
    arithmetic mean (standard deviation)
        Week 1 - 24
    7.1 ± 2.03
    7.9 ± 1.65
        Week 25 - 48
    7.0 ± 2.02
    7.6 ± 1.61
        Week 49 - 72
    7.0 ± 2.04
    7.5 ± 1.28
        Week 73 - 96
    7.0 ± 2.13
    7.0 ± 1.00
    No statistical analyses for this end point

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

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    End point title
    		 Pharmacokinetic (PK) Parameters: Bayesian Estimate of Apparent Clearance (CL/F)
    End point description
    End point type
    Secondary
    End point timeframe
    Blood serum samples taken pre-dose and on Days 1, 22, 64, 85, 106, 127, 169, 211, 253, 295, 337
    End point values
    		 Luspatercept + BSC Placebo + BSC
    Number of subjects analysed
    221
    0 [22]
    Units: L/day
        geometric mean (geometric coefficient of variation)
    0.437 ± 38.5
    ±
    Notes
    [22] - No study drug administered in this cohort
    No statistical analyses for this end point

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

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    End point title
    		 Pharmacokinetic (PK) Parameters: Bayesian Estimate of Apparent Volume of Distribution of the Central Compartment (V1/F)
    End point description
    End point type
    Secondary
    End point timeframe
    Blood serum samples taken pre-dose and on Days 1, 22, 64, 85, 106, 127, 169, 211, 253, 295, 337
    End point values
    		 Luspatercept + BSC Placebo + BSC
    Number of subjects analysed
    221
    0 [23]
    Units: Liters
        geometric mean (geometric coefficient of variation)
    7.08 ± 26.7
    ±
    Notes
    [23] - No study drug administered in this cohort
    No statistical analyses for this end point

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

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    End point title
    		 Pharmacokinetic (PK) Parameters: Bayesian Estimate of Elimination Half-life (t1/2)
    End point description
    End point type
    Secondary
    End point timeframe
    Blood serum samples taken pre-dose and on Days 1, 22, 64, 85, 106, 127, 169, 211, 253, 295, 337
    End point values
    		 Luspatercept + BSC Placebo + BSC
    Number of subjects analysed
    221
    0 [24]
    Units: days
        geometric mean (geometric coefficient of variation)
    11.2 ± 25.7
    ±
    Notes
    [24] - No study drug administered in this cohort
    No statistical analyses for this end point

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

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    End point title
    		 Pharmacokinetic (PK) Parameters: Bayesian Estimate of Maximum Concentration for the Starting Dose (Cmax)
    End point description
    End point type
    Secondary
    End point timeframe
    Blood serum samples taken pre-dose and on Days 1, 22, 64, 85, 106, 127, 169, 211, 253, 295, 337
    End point values
    		 Luspatercept + BSC Placebo + BSC
    Number of subjects analysed
    221
    0 [25]
    Units: μg/mL
        geometric mean (geometric coefficient of variation)
    5.64 ± 25.1
    ±
    Notes
    [25] - No study drug administered in this cohort
    No statistical analyses for this end point

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

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    End point title
    		 Pharmacokinetic (PK) Parameters: Bayesian Estimate of Maximum Concentration at Steady State for the Starting Dose (Cmax,ss)
    End point description
    End point type
    Secondary
    End point timeframe
    Blood serum samples taken pre-dose and on Days 1, 22, 64, 85, 106, 127, 169, 211, 253, 295, 337
    End point values
    		 Luspatercept + BSC Placebo + BSC
    Number of subjects analysed
    221
    0 [26]
    Units: μg/mL
        geometric mean (geometric coefficient of variation)
    8.31 ± 30.1
    ±
    Notes
    [26] - No study drug administered in this cohort
    No statistical analyses for this end point

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

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    End point title
    		 Pharmacokinetic (PK) Parameters: Bayesian Estimate of Time to Reach Maximum Concentration (Tmax)
    End point description
    End point type
    Secondary
    End point timeframe
    Blood serum samples taken pre-dose and on Days 1, 22, 64, 85, 106, 127, 169, 211, 253, 295, 337
    End point values
    		 Luspatercept + BSC Placebo + BSC
    Number of subjects analysed
    221
    0 [27]
    Units: Days
        median (full range (min-max))
    5.48 (3.35 to 7.74)
    ( to )
    Notes
    [27] - No study drug administered in this cohort
    No statistical analyses for this end point

    Secondary: Pharmacokinetic (PK) Parameters: Bayesian Estimate of Area Under the Concentration-Time Curve at Steady State for the Starting Dose (AUCss)

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    End point title
    		 Pharmacokinetic (PK) Parameters: Bayesian Estimate of Area Under the Concentration-Time Curve at Steady State for the Starting Dose (AUCss)
    End point description
    End point type
    Secondary
    End point timeframe
    Blood serum samples taken pre-dose and on Days 1, 22, 64, 85, 106, 127, 169, 211, 253, 295, 337
    End point values
    		 Luspatercept + BSC Placebo + BSC
    Number of subjects analysed
    221
    0 [28]
    Units: day*μg/mL
        geometric mean (geometric coefficient of variation)
    129 ± 36.0
    ±
    Notes
    [28] - No study drug administered in this cohort
    No statistical analyses for this end point

    Secondary: Participants with Treatment-Emergent Adverse Events (TEAE)

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    End point title
    		 Participants with Treatment-Emergent Adverse Events (TEAE)
    End point description
    An AE is any noxious, unintended, or untoward medical occurrence that may appear or worsen during the course of a study. A serious AE is any AE occurring at any dose that - Results in death - Is life-threatening - Requires or prolongs existing inpatient hospitalization - Results in persistent or significant disability/incapacity - Is a congenital anomaly/birth defect - Constitutes an important medical event. The Investigator assessed the relationship of each AE to study drug and graded the severity according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE, Version 4.03): - Grade 1 = Mild - Grade 2 = Moderate (some limitation in activity; no/minimal medical intervention) - Grade 3 = Severe (limitation in activity; medical intervention required) - Grade 4 = Life-threatening - Grade 5 = Death
    End point type
    Secondary
    End point timeframe
    From first dose to 90 days following last dose (up to approximately 52 months)
    End point values
    		 Luspatercept + BSC Placebo + BSC
    Number of subjects analysed
    223
    109
    Units: Participants
        ≥ 1 Treatment-emergent adverse event (TEAE)
    219
    102
        Serious TEAE
    53
    8
        Grade ≥ 3 TEAE
    84
    19
        Treatment-related TEAE
    135
    31
        Treatment-related Serious TEAE
    13
    0
        Treatment-related TEAE ≥ Grade 3
    27
    1
        TEAE leading to death
    2
    1
        Trt-related TEAE leading to death
    0
    0
        TEAE leading to dose reduction
    10
    3
        TEAE leading to dose delay
    46
    11
        TEAE leading to drug discontinuation
    25
    2
        Trt-related TEAE leading to dose reduction
    9
    2
        Trt-related TEAE leading to dose delay
    15
    3
        Trt-related TEAE leading to drug discontinuation
    20
    1
    No statistical analyses for this end point

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

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    End point title
    		 Participants with Pre-Existing and/or Treatment-Emergent Antidrug Antibodies (ADA)
    End point description
    Number of participants with positive ADA prior to taking study drug and/or during study. A participant was counted as “treatment-emergent” if there was a positive post-baseline sample while the baseline sample was ADA negative, or there was a positive post-baseline sample with a titer ≥ 4-fold of the baseline titer while the baseline sample was ADA positive. A participant was counted as “preexisting” if the baseline sample was ADA positive and the participant was not qualified for “treatment-emergent.”
    End point type
    Secondary
    End point timeframe
    Timeframe: pre-dose, Day 1, Days 22, 64, 106, 148, 232, 316
    End point values
    		 Luspatercept + BSC Placebo + BSC
    Number of subjects analysed
    221
    109
    Units: Participants
        Pre-existing
    2
    1
        Treatment-emergent
    4
    2
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All-cause mortality was assessed from first dose to study completion (approximately 56 months) SAEs and NSAEs were assessed from first dose to 90 days following last dose (up to approximately 52 months)
    Adverse event reporting additional description
    Adverse events were collected in all participants who received at least 1 dose of study drug.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    23.0
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Placebo (normal saline) was administered subcutaneously (SC) in volumes to match active treatment once every 21 days. BSC = Best Supportive Care

    Reporting group title
    Luspatercept
    Reporting group description
    		 Luspatercept (ACE-536) was administered subcutaneously (SC) at a starting dose level of 1 mg/kg once every 21 days. Participants could be dose-titrated to 1.25 mg/kg, but the maximum total dose should not exceed 120 mg, during the Treatment Period, the Long-term Treatment Period, and Open-Label Treatment Period. BSC = Best Supportive Care

    Serious adverse events
    		 Placebo Luspatercept
    Total subjects affected by serious adverse events
         subjects affected / exposed
    8 / 109 (7.34%)
    53 / 223 (23.77%)
         number of deaths (all causes)
    1
    4
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Acute erythroid leukaemia
         subjects affected / exposed
    0 / 109 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatocellular carcinoma
         subjects affected / exposed
    0 / 109 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Meningioma
         subjects affected / exposed
    0 / 109 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    0 / 109 (0.00%)
    3 / 223 (1.35%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombophlebitis superficial
         subjects affected / exposed
    0 / 109 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    0 / 109 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    0 / 109 (0.00%)
    2 / 223 (0.90%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain
         subjects affected / exposed
    0 / 109 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperpyrexia
         subjects affected / exposed
    0 / 109 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pulmonary hypertension
         subjects affected / exposed
    0 / 109 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    0 / 109 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Coombs direct test positive
         subjects affected / exposed
    1 / 109 (0.92%)
    0 / 223 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood uric acid increased
         subjects affected / exposed
    0 / 109 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urine albumin/creatinine ratio increased
         subjects affected / exposed
    0 / 109 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Femur fracture
         subjects affected / exposed
    0 / 109 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Radius fracture
         subjects affected / exposed
    0 / 109 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thoracic vertebral fracture
         subjects affected / exposed
    0 / 109 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thermal burn
         subjects affected / exposed
    0 / 109 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Traumatic fracture
         subjects affected / exposed
    0 / 109 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Cardiac arrest
         subjects affected / exposed
    0 / 109 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cardiac failure congestive
         subjects affected / exposed
    0 / 109 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac iron overload
         subjects affected / exposed
    1 / 109 (0.92%)
    0 / 223 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Left ventricular dysfunction
         subjects affected / exposed
    0 / 109 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial ischaemia
         subjects affected / exposed
    0 / 109 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Transient ischaemic attack
         subjects affected / exposed
    0 / 109 (0.00%)
    3 / 223 (1.35%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombotic stroke
         subjects affected / exposed
    0 / 109 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal cord compression
         subjects affected / exposed
    0 / 109 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral venous sinus thrombosis
         subjects affected / exposed
    0 / 109 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Depressed level of consciousness
         subjects affected / exposed
    0 / 109 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    0 / 109 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intracranial aneurysm
         subjects affected / exposed
    0 / 109 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhage intracranial
         subjects affected / exposed
    0 / 109 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Neuritis
         subjects affected / exposed
    0 / 109 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Pancytopenia
         subjects affected / exposed
    0 / 109 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    0 / 109 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    0 / 109 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Extramedullary haemopoiesis
         subjects affected / exposed
    0 / 109 (0.00%)
    2 / 223 (0.90%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anaemia
         subjects affected / exposed
    0 / 109 (0.00%)
    4 / 223 (1.79%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    0 / 109 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Pancreatitis acute
         subjects affected / exposed
    0 / 109 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    0 / 109 (0.00%)
    2 / 223 (0.90%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    0 / 109 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Food poisoning
         subjects affected / exposed
    0 / 109 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Drug-induced liver injury
         subjects affected / exposed
    0 / 109 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    0 / 109 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis acute
         subjects affected / exposed
    2 / 109 (1.83%)
    3 / 223 (1.35%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cholangitis
         subjects affected / exposed
    0 / 109 (0.00%)
    2 / 223 (0.90%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gallbladder obstruction
         subjects affected / exposed
    0 / 109 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Portal vein thrombosis
         subjects affected / exposed
    0 / 109 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatitis acute
         subjects affected / exposed
    0 / 109 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal colic
         subjects affected / exposed
    0 / 109 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nephrolithiasis
         subjects affected / exposed
    0 / 109 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal injury
         subjects affected / exposed
    0 / 109 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    0 / 109 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Epstein-Barr virus infection
         subjects affected / exposed
    1 / 109 (0.92%)
    0 / 223 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dengue fever
         subjects affected / exposed
    0 / 109 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    0 / 109 (0.00%)
    3 / 223 (1.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bacteraemia
         subjects affected / exposed
    1 / 109 (0.92%)
    0 / 223 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    0 / 109 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute sinusitis
         subjects affected / exposed
    0 / 109 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gallbladder empyema
         subjects affected / exposed
    0 / 109 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 109 (0.92%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Large intestine infection
         subjects affected / exposed
    1 / 109 (0.92%)
    0 / 223 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenic sepsis
         subjects affected / exposed
    0 / 109 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Parotid abscess
         subjects affected / exposed
    0 / 109 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pharyngitis bacterial
         subjects affected / exposed
    0 / 109 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    1 / 109 (0.92%)
    0 / 223 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 109 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tonsillitis
         subjects affected / exposed
    0 / 109 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Splenic abscess
         subjects affected / exposed
    0 / 109 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    0 / 109 (0.00%)
    2 / 223 (0.90%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    0 / 109 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary sepsis
         subjects affected / exposed
    0 / 109 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 109 (0.00%)
    2 / 223 (0.90%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    0 / 109 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viral infection
         subjects affected / exposed
    0 / 109 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vestibular neuronitis
         subjects affected / exposed
    0 / 109 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viral sepsis
         subjects affected / exposed
    0 / 109 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viral upper respiratory tract infection
         subjects affected / exposed
    0 / 109 (0.00%)
    2 / 223 (0.90%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound infection
         subjects affected / exposed
    0 / 109 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    0 / 109 (0.00%)
    1 / 223 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Placebo Luspatercept
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    95 / 109 (87.16%)
    211 / 223 (94.62%)
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    4 / 109 (3.67%)
    12 / 223 (5.38%)
         occurrences all number
    11
    28
    Liver iron concentration increased
         subjects affected / exposed
    2 / 109 (1.83%)
    12 / 223 (5.38%)
         occurrences all number
    2
    13
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    8 / 109 (7.34%)
    8 / 223 (3.59%)
         occurrences all number
    8
    8
    Transfusion reaction
         subjects affected / exposed
    5 / 109 (4.59%)
    12 / 223 (5.38%)
         occurrences all number
    6
    14
    Vascular disorders
    Hypertension
         subjects affected / exposed
    3 / 109 (2.75%)
    23 / 223 (10.31%)
         occurrences all number
    3
    43
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    5 / 109 (4.59%)
    29 / 223 (13.00%)
         occurrences all number
    6
    56
    Lethargy
         subjects affected / exposed
    4 / 109 (3.67%)
    12 / 223 (5.38%)
         occurrences all number
    11
    27
    Headache
         subjects affected / exposed
    27 / 109 (24.77%)
    78 / 223 (34.98%)
         occurrences all number
    69
    265
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    11 / 109 (10.09%)
    26 / 223 (11.66%)
         occurrences all number
    35
    55
    Fatigue
         subjects affected / exposed
    16 / 109 (14.68%)
    38 / 223 (17.04%)
         occurrences all number
    21
    96
    Influenza like illness
         subjects affected / exposed
    8 / 109 (7.34%)
    21 / 223 (9.42%)
         occurrences all number
    12
    31
    Injection site pain
         subjects affected / exposed
    3 / 109 (2.75%)
    12 / 223 (5.38%)
         occurrences all number
    3
    22
    Pyrexia
         subjects affected / exposed
    24 / 109 (22.02%)
    47 / 223 (21.08%)
         occurrences all number
    37
    68
    Pain
         subjects affected / exposed
    4 / 109 (3.67%)
    14 / 223 (6.28%)
         occurrences all number
    4
    17
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    4 / 109 (3.67%)
    12 / 223 (5.38%)
         occurrences all number
    6
    14
    Abdominal pain
         subjects affected / exposed
    7 / 109 (6.42%)
    30 / 223 (13.45%)
         occurrences all number
    11
    42
    Abdominal pain upper
         subjects affected / exposed
    8 / 109 (7.34%)
    25 / 223 (11.21%)
         occurrences all number
    14
    36
    Diarrhoea
         subjects affected / exposed
    14 / 109 (12.84%)
    41 / 223 (18.39%)
         occurrences all number
    17
    61
    Vomiting
         subjects affected / exposed
    8 / 109 (7.34%)
    30 / 223 (13.45%)
         occurrences all number
    15
    44
    Dyspepsia
         subjects affected / exposed
    1 / 109 (0.92%)
    19 / 223 (8.52%)
         occurrences all number
    2
    21
    Nausea
         subjects affected / exposed
    6 / 109 (5.50%)
    29 / 223 (13.00%)
         occurrences all number
    8
    43
    Toothache
         subjects affected / exposed
    5 / 109 (4.59%)
    15 / 223 (6.73%)
         occurrences all number
    7
    17
    Reproductive system and breast disorders
    Menstruation irregular
         subjects affected / exposed
    6 / 109 (5.50%)
    12 / 223 (5.38%)
         occurrences all number
    7
    21
    Respiratory, thoracic and mediastinal disorders
    Nasal congestion
         subjects affected / exposed
    3 / 109 (2.75%)
    21 / 223 (9.42%)
         occurrences all number
    4
    32
    Cough
         subjects affected / exposed
    13 / 109 (11.93%)
    48 / 223 (21.52%)
         occurrences all number
    17
    82
    Oropharyngeal pain
         subjects affected / exposed
    13 / 109 (11.93%)
    41 / 223 (18.39%)
         occurrences all number
    13
    54
    Skin and subcutaneous tissue disorders
    Urticaria
         subjects affected / exposed
    4 / 109 (3.67%)
    17 / 223 (7.62%)
         occurrences all number
    5
    36
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    15 / 109 (13.76%)
    51 / 223 (22.87%)
         occurrences all number
    26
    113
    Back pain
         subjects affected / exposed
    33 / 109 (30.28%)
    72 / 223 (32.29%)
         occurrences all number
    60
    196
    Musculoskeletal chest pain
         subjects affected / exposed
    8 / 109 (7.34%)
    8 / 223 (3.59%)
         occurrences all number
    11
    8
    Musculoskeletal pain
         subjects affected / exposed
    11 / 109 (10.09%)
    21 / 223 (9.42%)
         occurrences all number
    13
    24
    Bone pain
         subjects affected / exposed
    9 / 109 (8.26%)
    50 / 223 (22.42%)
         occurrences all number
    14
    124
    Neck pain
         subjects affected / exposed
    9 / 109 (8.26%)
    14 / 223 (6.28%)
         occurrences all number
    12
    28
    Myalgia
         subjects affected / exposed
    11 / 109 (10.09%)
    28 / 223 (12.56%)
         occurrences all number
    17
    35
    Osteoporosis
         subjects affected / exposed
    7 / 109 (6.42%)
    13 / 223 (5.83%)
         occurrences all number
    7
    13
    Pain in extremity
         subjects affected / exposed
    12 / 109 (11.01%)
    33 / 223 (14.80%)
         occurrences all number
    13
    89
    Spinal pain
         subjects affected / exposed
    5 / 109 (4.59%)
    12 / 223 (5.38%)
         occurrences all number
    7
    15
    Infections and infestations
    Gastroenteritis
         subjects affected / exposed
    9 / 109 (8.26%)
    18 / 223 (8.07%)
         occurrences all number
    11
    22
    Nasopharyngitis
         subjects affected / exposed
    4 / 109 (3.67%)
    17 / 223 (7.62%)
         occurrences all number
    4
    21
    Influenza
         subjects affected / exposed
    8 / 109 (7.34%)
    25 / 223 (11.21%)
         occurrences all number
    12
    36
    Pharyngitis
         subjects affected / exposed
    15 / 109 (13.76%)
    36 / 223 (16.14%)
         occurrences all number
    16
    57
    Tonsillitis
         subjects affected / exposed
    2 / 109 (1.83%)
    16 / 223 (7.17%)
         occurrences all number
    2
    24
    Urinary tract infection
         subjects affected / exposed
    6 / 109 (5.50%)
    13 / 223 (5.83%)
         occurrences all number
    7
    15
    Upper respiratory tract infection
         subjects affected / exposed
    43 / 109 (39.45%)
    93 / 223 (41.70%)
         occurrences all number
    65
    212
    Metabolism and nutrition disorders
    Hyperuricaemia
         subjects affected / exposed
    0 / 109 (0.00%)
    16 / 223 (7.17%)
         occurrences all number
    0
    23

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    25 Aug 2015
    -Exploratory endpoints changes -Study design changes -Eligibility criteria changes
    21 Apr 2017
    -Dose modification changes

    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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