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    Clinical Trial Results:
    A Phase 2, Open-Label, Ascending Dose Study to Evaluate the Effects of ACE-536 in Patients with β-Thalassemia Intermedia

    Summary
    EudraCT number
    		 2012-002499-15
    Trial protocol
    		 IT   GR  
    Global end of trial date
    11 Nov 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    27 Nov 2016
    First version publication date
    27 Nov 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    A536-04
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01749540
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Acceleron Pharma Inc.
    Sponsor organisation address
    128 Sidney Street, CAMBRIDGE, United States, 02139
    Public contact
    Kenneth Attie, Acceleron Pharma Inc., 01 617 649 9200, kattie@acceleronpharma.com
    Scientific contact
    Kenneth Attie, Acceleron Pharma Inc., 01 617 649 9200, kattie@acceleronpharma.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
    17 Oct 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    11 Nov 2015
    Global end of trial reached?
    Yes
    Global end of trial date
    11 Nov 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the proportion of β-thalassemia patients who have an erythroid response, defined as: 1) a hemoglobin increase of ≥ 1.5 g/dL from baseline for ≥ 14 days (in the absence of red blood cell [RBC] transfusions) in non-transfusion dependent patients, or 2) ≥ 20% reduction in RBC transfusion burden compared to pretreatment in transfusion dependent patients.
    Protection of trial subjects
    N/A
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    11 Feb 2013
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Greece: 8
    Country: Number of subjects enrolled
    Italy: 56
    Worldwide total number of subjects
    64
    EEA total number of subjects
    64
    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)
    64
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 35 patients were enrolled in the dose-escalation phase in 6 cohorts of up to 6 patients each at dose levels (dl) of 0.2, 0.4, 0.6, 0.8, 1.0 and 1.25 mg/kg for up to 5 cycles.29 patients were enrolled in the expansion cohort and treated with a starting dose level of 0.8 mg/kg, dl was titrated based on the change in Hgb or patient transfusion burden.

    Pre-assignment
    Screening details
    		 Patients who meet the study eligibility criteria will be enrolled within 28 days of screening.

    Period 1
    Period 1 title
    Overall Trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 0.2 milligrams per kilogram body weight (mg/kg)
    Arm description
    		 Luspatercept 0.2 mg/kg subcutaneously (SC) once every 3 weeks
    Arm type
    		 Experimental

    Investigational medicinal product name
    Luspatercept
    Investigational medicinal product code
    ACE-536
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Patients have received ACE-536, administered subcutaneously (SC), every 3 weeks for up to 5 cycles.

    Arm title
    		 0.4 mg/kg
    Arm description
    		 Luspatercept 0.4 mg/kg subcutaneously (SC) once every 3 weeks
    Arm type
    		 Experimental

    Investigational medicinal product name
    Luspatercept
    Investigational medicinal product code
    Other name
    ACE-536
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Patients have received ACE-536, administered subcutaneously (SC), every 3 weeks for up to 5 cycles.

    Arm title
    		 0.6 mg/kg
    Arm description
    		 Luspatercept 0.6 mg/kg subcutaneously (SC) once every 3 weeks
    Arm type
    		 Experimental

    Investigational medicinal product name
    Luspatercept
    Investigational medicinal product code
    ACE-536
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Patients have received ACE-536, administered subcutaneously (SC), every 3 weeks for up to 5 cycles.

    Arm title
    		 0.8 mg/kg
    Arm description
    		 Luspatercept 0.8 mg/kg subcutaneously (SC) once every 3 weeks
    Arm type
    		 Experimental

    Investigational medicinal product name
    Luspatercept
    Investigational medicinal product code
    ACE-536
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Patients have received ACE-536, administered subcutaneously (SC), every 3 weeks for up to 5 cycles.

    Arm title
    		 1.0 mg/kg
    Arm description
    		 Luspatercept 1.0 mg/kg subcutaneously (SC) once every 3 weeks
    Arm type
    		 Experimental

    Investigational medicinal product name
    Luspatercept
    Investigational medicinal product code
    ACE-536
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Patients have received ACE-536, administered subcutaneously (SC), every 3 weeks for up to 5 cycles.

    Arm title
    		 1.25 mg/kg
    Arm description
    		 Luspatercept 1.25 mg/kg subcutaneously (SC) once every 3 weeks
    Arm type
    		 Experimental

    Investigational medicinal product name
    Luspatercept
    Investigational medicinal product code
    ACE-536
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Patients have received ACE-536, administered subcutaneously (SC), every 3 weeks for up to 5 cycles.

    Arm title
    		 Expansion (0.8 mg/kg)
    Arm description
    		 Luspatercept starting dose 0.8 mg/kg subcutaneously (SC) once every 3 weeks. For each subsequent cycle in the expansion cohort (up to 5 cycles), a patient’s dose level could be titrated based on the change in Hgb or transfusion burden for that patient (the maximum dose level given was 1.25 mg/kg).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Luspatercept
    Investigational medicinal product code
    ACE-536
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    The starting dose level for patients enrolled in the expansion cohort was 0.8 mg/kg subcutaneously (SC) once every 3 weeks. For each subsequent cycle in the expansion cohort (up to 5 cycles), a patient’s dose level could be titrated based on the change in Hgb or transfusion burden for that patient. The maximum dose level given to a subject was 1.25 mg/kg.

    Number of subjects in period 1
    		0.2 milligrams per kilogram body weight (mg/kg) 0.4 mg/kg 0.6 mg/kg 0.8 mg/kg 1.0 mg/kg 1.25 mg/kg Expansion (0.8 mg/kg)
    Started
    6
    6
    6
    6
    6
    5
    29
    Completed
    6
    6
    5
    4
    6
    3
    26
    Not completed
    0
    0
    1
    2
    0
    2
    3
         Adverse event, non-fatal
    -
    -
    1
    2
    -
    -
    2
         Use of prohibited medications
    -
    -
    -
    -
    -
    1
    -
         Protocol deviation
    -
    -
    -
    -
    -
    1
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall Trial
    Reporting group description
    		 -

    Reporting group values
    		 Overall Trial Total
    Number of subjects
    		 64 64
    Age categorical
    Units: Subjects
        In utero
    		 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0
        Newborns (0-27 days)
    		 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0
        Children (2-11 years)
    		 0 0
        Adolescents (12-17 years)
    		 0 0
        Adults (18-64 years)
    		 64 64
        From 65-84 years
    		 0 0
        85 years and over
    		 0 0
    Age continuous
    Units: years
        arithmetic mean (full range (min-max))
    		 38.1 (20 to 62) -
    Gender categorical
    Units: Subjects
        Female
    		 31 31
        Male
    		 33 33

    End points

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    End points reporting groups
    Reporting group title
    0.2 milligrams per kilogram body weight (mg/kg)
    Reporting group description
    		 Luspatercept 0.2 mg/kg subcutaneously (SC) once every 3 weeks

    Reporting group title
    0.4 mg/kg
    Reporting group description
    		 Luspatercept 0.4 mg/kg subcutaneously (SC) once every 3 weeks

    Reporting group title
    0.6 mg/kg
    Reporting group description
    		 Luspatercept 0.6 mg/kg subcutaneously (SC) once every 3 weeks

    Reporting group title
    0.8 mg/kg
    Reporting group description
    		 Luspatercept 0.8 mg/kg subcutaneously (SC) once every 3 weeks

    Reporting group title
    1.0 mg/kg
    Reporting group description
    		 Luspatercept 1.0 mg/kg subcutaneously (SC) once every 3 weeks

    Reporting group title
    1.25 mg/kg
    Reporting group description
    		 Luspatercept 1.25 mg/kg subcutaneously (SC) once every 3 weeks

    Reporting group title
    Expansion (0.8 mg/kg)
    Reporting group description
    		 Luspatercept starting dose 0.8 mg/kg subcutaneously (SC) once every 3 weeks. For each subsequent cycle in the expansion cohort (up to 5 cycles), a patient’s dose level could be titrated based on the change in Hgb or transfusion burden for that patient (the maximum dose level given was 1.25 mg/kg).

    Subject analysis set title
    Non-Transfusion Dependent
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All treated patients who are Non-Transfusion Dependent at baseline. Non-Transfusion Dependence is defined as having received < 4 units of RBCs within 8 weeks prior to Cycle 1 Day 1. In this study, Efficacy Evaluable population is the same as Intention-to-treat population.

    Subject analysis set title
    Transfusion Dependent
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All treated patients who are Transfusion Dependent at baseline. Transfusion Dependence is defined as requiring >= 4 units of RBCs every 8 weeks (confirmed over 6 months prior to Cycle 1 Day 1). In this study, Efficacy Evaluable population is the same as Intention-to-treat population.

    Subject analysis set title
    Overall
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All treated patients In this study, Efficacy Evaluable population is the same as Intention-to-treat population.

    Primary: Hemoglobin Response

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    End point title
    		 Hemoglobin Response [1]
    End point description
    Consecutive change from baseline Hemoglobin >= 1.5 for >= 14 days in Non-Transfusion Dependent subjects.
    End point type
    Primary
    End point timeframe
    From first dose to last dose + 56 days.
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: The response rate for each dose group is reported in earlier section of EudraCT results posting, however, per protocol, no statistical testing is performed to compare the dose groups. Consequently, no p-value is reported in this section.
    End point values
    		 0.2 milligrams per kilogram body weight (mg/kg) 0.4 mg/kg 0.6 mg/kg 0.8 mg/kg 1.0 mg/kg 1.25 mg/kg Expansion (0.8 mg/kg) Non-Transfusion Dependent
    Number of subjects analysed
    6
    6
    5
    3
    2
    1
    10
    33
    Units: percent
        number (confidence interval 95%)
    0 (0 to 45.9)
    0 (0 to 45.9)
    0 (0 to 52.2)
    66.7 (9.4 to 99.2)
    50 (1.3 to 98.7)
    0 (0 to 97.5)
    60 (26.2 to 87.8)
    27.3 (13.3 to 45.5)
    No statistical analyses for this end point

    Primary: Transfusion Response

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    End point title
    		 Transfusion Response [2]
    End point description
    >= 20% reduction in RBC transfusion burden over 12 weeks, compared to pre-treatment, in transfusion dependent subjects
    End point type
    Primary
    End point timeframe
    First dose to last dose + 56 days
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: The response rate for each dose group is reported in earlier section of EudraCT result posting, however, per protocol, no statistical testing is performed to compare the dose groups. Consequently, no p-value is reported in this section.
    End point values
    		 0.2 milligrams per kilogram body weight (mg/kg) 0.4 mg/kg 0.6 mg/kg 0.8 mg/kg 1.0 mg/kg 1.25 mg/kg Expansion (0.8 mg/kg) Transfusion Dependent
    Number of subjects analysed
    0 [3]
    0 [4]
    1
    3
    4
    4
    19
    31
    Units: percent
        number (confidence interval 95%)
    ( to )
    ( to )
    100 (2.5 to 100)
    66.7 (9.4 to 99.2)
    100 (39.8 to 100)
    75 (19.4 to 99.4)
    78.9 (54.4 to 93.9)
    80.6 (62.5 to 92.5)
    Notes
    [3] - No subjects
    [4] - No subjects
    No statistical analyses for this end point

    Secondary: BSAP - End of Treatment - Percent Change from Baseline

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    End point title
    		 BSAP - End of Treatment - Percent Change from Baseline
    End point description
    End point type
    Secondary
    End point timeframe
    First dose to End of Treatment visit
    End point values
    		 0.2 milligrams per kilogram body weight (mg/kg) 0.4 mg/kg 0.6 mg/kg 0.8 mg/kg 1.0 mg/kg 1.25 mg/kg Expansion (0.8 mg/kg) Overall
    Number of subjects analysed
    5
    5
    6
    6
    6
    3
    20
    51
    Units: percent
        arithmetic mean (standard deviation)
    -35.09 ± 10.94
    15.45 ± 56.2
    17.7 ± 9.31
    20.08 ± 20.77
    0.65 ± 10.18
    -0.17 ± 17.15
    19.01 ± 41.1
    10.04 ± 35.39
    No statistical analyses for this end point

    Secondary: CTX - End of Treatment - Percent Change from Baseline

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    End point title
    		 CTX - End of Treatment - Percent Change from Baseline
    End point description
    End point type
    Secondary
    End point timeframe
    First dose to End of treatment visit.
    End point values
    		 0.2 milligrams per kilogram body weight (mg/kg) 0.4 mg/kg 0.6 mg/kg 0.8 mg/kg 1.0 mg/kg 1.25 mg/kg Expansion (0.8 mg/kg) Overall
    Number of subjects analysed
    2
    3
    4
    6
    6
    3
    20
    44
    Units: percent
        arithmetic mean (standard deviation)
    42.56 ± 14.52
    3.39 ± 53.02
    8.43 ± 31.32
    23.61 ± 33.31
    12.67 ± 53.27
    -20.87 ± 31.86
    22.62 ± 59.97
    16.74 ± 49.73
    No statistical analyses for this end point

    Secondary: Erythropoietin - End of Treatment - Change from Baseline

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    End point title
    		 Erythropoietin - End of Treatment - Change from Baseline
    End point description
    End point type
    Secondary
    End point timeframe
    First dose to End of treatment visit.
    End point values
    		 0.2 milligrams per kilogram body weight (mg/kg) 0.4 mg/kg 0.6 mg/kg 0.8 mg/kg 1.0 mg/kg 1.25 mg/kg Expansion (0.8 mg/kg) Overall
    Number of subjects analysed
    6
    6
    6
    6
    6
    4
    22
    56
    Units: IU/L
        arithmetic mean (standard deviation)
    -18.67 ± 42.95
    6.85 ± 41.82
    21.88 ± 66.23
    37.1 ± 48.79
    71.62 ± 104.86
    64.58 ± 94.47
    40.92 ± 109.54
    33.41 ± 87.47
    No statistical analyses for this end point

    Secondary: Reticulocytes - End of Treatment - Change from Baseline

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    End point title
    		 Reticulocytes - End of Treatment - Change from Baseline
    End point description
    End point type
    Secondary
    End point timeframe
    First dose to End of treatment visit.
    End point values
    		 0.2 milligrams per kilogram body weight (mg/kg) 0.4 mg/kg 0.6 mg/kg 0.8 mg/kg 1.0 mg/kg 1.25 mg/kg Expansion (0.8 mg/kg) Overall
    Number of subjects analysed
    3
    6
    6
    5
    6
    4
    28
    58
    Units: 10^9/L
        arithmetic mean (standard deviation)
    -10.8 ± 28.69
    0.63 ± 1.63
    -34.42 ± 73.88
    15.77 ± 17.45
    16.9 ± 46.62
    297.57 ± 330.75
    39.87 ± 219.87
    38.82 ± 187.14
    No statistical analyses for this end point

    Secondary: Serum Iron - End of Treatment - Percent Change from Baseline

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    End point title
    		 Serum Iron - End of Treatment - Percent Change from Baseline
    End point description
    End point type
    Secondary
    End point timeframe
    First dose to End of treatment visit.
    End point values
    		 0.2 milligrams per kilogram body weight (mg/kg) 0.4 mg/kg 0.6 mg/kg 0.8 mg/kg 1.0 mg/kg 1.25 mg/kg Expansion (0.8 mg/kg) Overall
    Number of subjects analysed
    6
    6
    6
    6
    6
    4
    24
    58
    Units: percent
        arithmetic mean (standard deviation)
    -15.78 ± 26.9
    -8.99 ± 38.02
    7.81 ± 15.09
    -12.93 ± 31.55
    -5.37 ± 35.75
    -12.38 ± 18.35
    2.67 ± 41.64
    -3.4 ± 34.51
    No statistical analyses for this end point

    Secondary: Total Iron Binding Capacity(TIBC) - End of Treatment - Percent Change from Baseline

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    End point title
    		 Total Iron Binding Capacity(TIBC) - End of Treatment - Percent Change from Baseline
    End point description
    End point type
    Secondary
    End point timeframe
    First dose to End of treatment visit.
    End point values
    		 0.2 milligrams per kilogram body weight (mg/kg) 0.4 mg/kg 0.6 mg/kg 0.8 mg/kg 1.0 mg/kg 1.25 mg/kg Expansion (0.8 mg/kg) Overall
    Number of subjects analysed
    6
    6
    6
    6
    6
    4
    24
    58
    Units: percent
        arithmetic mean (standard deviation)
    2.91 ± 7.02
    -1.53 ± 7.37
    3.53 ± 7.85
    -4.86 ± 11.67
    -2.13 ± 6.18
    -0.76 ± 4.3
    1.25 ± 12.7
    0.25 ± 10.09
    No statistical analyses for this end point

    Secondary: Transferrin - End of Treatment - Percent Change from Baseline

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    End point title
    		 Transferrin - End of Treatment - Percent Change from Baseline
    End point description
    End point type
    Secondary
    End point timeframe
    First dose to End of treatment visit.
    End point values
    		 0.2 milligrams per kilogram body weight (mg/kg) 0.4 mg/kg 0.6 mg/kg 0.8 mg/kg 1.0 mg/kg 1.25 mg/kg Expansion (0.8 mg/kg) Overall
    Number of subjects analysed
    6
    6
    6
    6
    6
    4
    24
    58
    Units: percent
        arithmetic mean (standard deviation)
    3.96 ± 6.73
    -1.54 ± 6.04
    3.04 ± 8.51
    -4.71 ± 11.26
    -0.99 ± 7.51
    -1.64 ± 5.59
    0.98 ± 12.01
    0.27 ± 9.76
    No statistical analyses for this end point

    Secondary: Soluble Transferrin Receptor - End of Treatment - Percent Change from Baseline

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    End point title
    		 Soluble Transferrin Receptor - End of Treatment - Percent Change from Baseline
    End point description
    End point type
    Secondary
    End point timeframe
    First dose to End of treatment visit.
    End point values
    		 0.2 milligrams per kilogram body weight (mg/kg) 0.4 mg/kg 0.6 mg/kg 0.8 mg/kg 1.0 mg/kg 1.25 mg/kg Expansion (0.8 mg/kg) Overall
    Number of subjects analysed
    6
    6
    6
    6
    6
    4
    24
    58
    Units: percent
        arithmetic mean (standard deviation)
    3.61 ± 10.91
    -10.6 ± 12.29
    10.55 ± 34.45
    36.29 ± 41.28
    68.17 ± 60.44
    83.34 ± 90.42
    53.25 ± 57.3
    38.96 ± 56.06
    No statistical analyses for this end point

    Secondary: Ferritin - End of Treatment - Percent Change from Baseline

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    End point title
    		 Ferritin - End of Treatment - Percent Change from Baseline
    End point description
    End point type
    Secondary
    End point timeframe
    First dose to End of treatment visit.
    End point values
    		 0.2 milligrams per kilogram body weight (mg/kg) 0.4 mg/kg 0.6 mg/kg 0.8 mg/kg 1.0 mg/kg 1.25 mg/kg Expansion (0.8 mg/kg) Overall
    Number of subjects analysed
    6
    6
    6
    6
    6
    4
    24
    58
    Units: percent
        arithmetic mean (standard deviation)
    -18.48 ± 17.77
    8.43 ± 27.22
    -4.5 ± 14.92
    -23.73 ± 27.83
    -23.17 ± 19.41
    -25.18 ± 22.75
    -27.46 ± 18.67
    -19.46 ± 22.79
    No statistical analyses for this end point

    Secondary: Hepcidin - End of Treatment - Percent Change from Baseline

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    End point title
    		 Hepcidin - End of Treatment - Percent Change from Baseline
    End point description
    End point type
    Secondary
    End point timeframe
    First dose to End of treatment visit.
    End point values
    		 0.2 milligrams per kilogram body weight (mg/kg) 0.4 mg/kg 0.6 mg/kg 0.8 mg/kg 1.0 mg/kg 1.25 mg/kg Expansion (0.8 mg/kg) Overall
    Number of subjects analysed
    5
    6
    5
    5
    4
    1
    5
    31
    Units: percent
        arithmetic mean (standard deviation)
    7.48 ± 41.12
    58.35 ± 140.97
    -4.81 ± 27.81
    0.67 ± 83.3
    -41.16 ± 12.73
    -13.58 ± 0
    -12.54 ± 23.44
    4.06 ± 74.77
    No statistical analyses for this end point

    Secondary: LIC - End of Treatment - Change from Baseline

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    End point title
    		 LIC - End of Treatment - Change from Baseline
    End point description
    End point type
    Secondary
    End point timeframe
    First dose to End of treatment visit.
    End point values
    		 0.2 milligrams per kilogram body weight (mg/kg) 0.4 mg/kg 0.6 mg/kg 0.8 mg/kg 1.0 mg/kg 1.25 mg/kg Expansion (0.8 mg/kg) Overall
    Number of subjects analysed
    6
    5
    5
    5
    6
    3
    25
    55
    Units: mg/g dw
        arithmetic mean (standard deviation)
    -0.01 ± 0.61
    -0.46 ± 1.17
    -1.25 ± 1.54
    -0.88 ± 0.97
    -1.7 ± 3.57
    -0.1 ± 0.7
    0.16 ± 1.02
    -0.35 ± 1.58
    No statistical analyses for this end point

    Secondary: Hb A - End of Treatment - Change from Baseline

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    End point title
    		 Hb A - End of Treatment - Change from Baseline
    End point description
    End point type
    Secondary
    End point timeframe
    First dose to End of treatment visit.
    End point values
    		 0.2 milligrams per kilogram body weight (mg/kg) 0.4 mg/kg 0.6 mg/kg 0.8 mg/kg 1.0 mg/kg 1.25 mg/kg Expansion (0.8 mg/kg) Overall
    Number of subjects analysed
    6
    4
    5
    5
    6
    4
    22
    64
    Units: g/dL
        arithmetic mean (standard deviation)
    -0.07 ± 0.61
    0.27 ± 0.57
    0.04 ± 2.11
    -0.35 ± 1.98
    -1.11 ± 1.45
    -0.76 ± 0.5
    -0.57 ± 1.11
    -0.44 ± 1.26
    No statistical analyses for this end point

    Secondary: Hb A2 - End of Treatment - Change from Baseline

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    End point title
    		 Hb A2 - End of Treatment - Change from Baseline
    End point description
    End point type
    Secondary
    End point timeframe
    First dose to End of treatment visit.
    End point values
    		 0.2 milligrams per kilogram body weight (mg/kg) 0.4 mg/kg 0.6 mg/kg 0.8 mg/kg 1.0 mg/kg 1.25 mg/kg Expansion (0.8 mg/kg) Overall
    Number of subjects analysed
    6
    5
    5
    5
    6
    4
    22
    53
    Units: g/dL
        arithmetic mean (standard deviation)
    0 ± 0.1
    -0.18 ± 0.5
    0.1 ± 0.13
    -0.06 ± 0.31
    0.06 ± 0.05
    0.04 ± 0.03
    0.03 ± 0.06
    0.01 ± 0.19
    No statistical analyses for this end point

    Secondary: Hb C - End of Treatment - Change from Baseline

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    End point title
    		 Hb C - End of Treatment - Change from Baseline
    End point description
    End point type
    Secondary
    End point timeframe
    First dose to End of treatment visit.
    End point values
    		 0.2 milligrams per kilogram body weight (mg/kg) 0.4 mg/kg 0.6 mg/kg 0.8 mg/kg 1.0 mg/kg 1.25 mg/kg Expansion (0.8 mg/kg) Overall
    Number of subjects analysed
    6
    5
    5
    5
    6
    4
    22
    53
    Units: g/dL
        arithmetic mean (standard deviation)
    0 ± 0
    0 ± 0
    0 ± 0
    0 ± 0
    0 ± 0
    0 ± 0
    0 ± 0
    0 ± 0
    No statistical analyses for this end point

    Secondary: Hb D - End of Treatment - Change from Baseline

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    End point title
    		 Hb D - End of Treatment - Change from Baseline
    End point description
    End point type
    Secondary
    End point timeframe
    First dose to End of treatment visit.
    End point values
    		 0.2 milligrams per kilogram body weight (mg/kg) 0.4 mg/kg 0.6 mg/kg 0.8 mg/kg 1.0 mg/kg 1.25 mg/kg Expansion (0.8 mg/kg) Overall
    Number of subjects analysed
    6
    5
    5
    5
    6
    4
    22
    53
    Units: g/dL
        arithmetic mean (standard deviation)
    0 ± 0
    0 ± 0
    0 ± 0
    0 ± 0
    0 ± 0
    0 ± 0
    0 ± 0
    0 ± 0
    No statistical analyses for this end point

    Secondary: Hb F - End of Treatment - Change from Baseline

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    End point title
    		 Hb F - End of Treatment - Change from Baseline
    End point description
    End point type
    Secondary
    End point timeframe
    First dose to End of treatment visit.
    End point values
    		 0.2 milligrams per kilogram body weight (mg/kg) 0.4 mg/kg 0.6 mg/kg 0.8 mg/kg 1.0 mg/kg 1.25 mg/kg Expansion (0.8 mg/kg) Overall
    Number of subjects analysed
    6
    5
    4
    5
    5
    3
    22
    50
    Units: g/dL
        arithmetic mean (standard deviation)
    0.09 ± 0.1
    -0.23 ± 0.43
    0.87 ± 1.57
    0.24 ± 0.53
    1.54 ± 1.31
    0.84 ± 0.16
    0.6 ± 0.78
    0.55 ± 0.9
    No statistical analyses for this end point

    Secondary: Hb S - End of Treatment - Change from Baseline

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    End point title
    		 Hb S - End of Treatment - Change from Baseline
    End point description
    End point type
    Secondary
    End point timeframe
    First dose to End of treatment visit.
    End point values
    		 0.2 milligrams per kilogram body weight (mg/kg) 0.4 mg/kg 0.6 mg/kg 0.8 mg/kg 1.0 mg/kg 1.25 mg/kg Expansion (0.8 mg/kg) Overall
    Number of subjects analysed
    6
    5
    5
    5
    6
    4
    22
    53
    Units: g/dL
        arithmetic mean (standard deviation)
    0 ± 0
    0 ± 0
    0 ± 0
    0 ± 0
    0 ± 0
    0 ± 0
    0 ± 0
    0 ± 0
    No statistical analyses for this end point

    Secondary: HBA12 - End of Treatment - Change from Baseline

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    End point title
    		 HBA12 - End of Treatment - Change from Baseline
    End point description
    End point type
    Secondary
    End point timeframe
    First dose to End of treatment visit.
    End point values
    		 0.2 milligrams per kilogram body weight (mg/kg) 0.4 mg/kg 0.6 mg/kg 0.8 mg/kg 1.0 mg/kg 1.25 mg/kg Expansion (0.8 mg/kg) Overall
    Number of subjects analysed
    6
    5
    2
    5
    6
    4
    12
    40
    Units: g/dL
        arithmetic mean (standard deviation)
    0.69 ± 0.64
    -2.58 ± 2.01
    0.67 ± 0.51
    0.41 ± 0.78
    3.55 ± 2.4
    -1.96 ± 3.78
    2.13 ± 1.57
    0.84 ± 2.65
    No statistical analyses for this end point

    Secondary: HBB - End of Treatment - Change from Baseline

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    End point title
    		 HBB - End of Treatment - Change from Baseline
    End point description
    End point type
    Secondary
    End point timeframe
    First dose to End of treatment visit.
    End point values
    		 0.2 milligrams per kilogram body weight (mg/kg) 0.4 mg/kg 0.6 mg/kg 0.8 mg/kg 1.0 mg/kg 1.25 mg/kg Expansion (0.8 mg/kg) Overall
    Number of subjects analysed
    6
    5
    2
    5
    6
    4
    12
    40
    Units: g/dL
        arithmetic mean (standard deviation)
    0.12 ± 0.12
    -0.15 ± 0.16
    0.06 ± 0.08
    0.06 ± 0.25
    0.33 ± 0.51
    -0.41 ± 0.72
    0.46 ± 0.34
    0.16 ± 0.45
    No statistical analyses for this end point

    Secondary: nRBC Smear - End of Treatment - Change from Baseline

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    End point title
    		 nRBC Smear - End of Treatment - Change from Baseline
    End point description
    End point type
    Secondary
    End point timeframe
    First dose to End of treatment visit.
    End point values
    		 0.2 milligrams per kilogram body weight (mg/kg) 0.4 mg/kg 0.6 mg/kg 0.8 mg/kg 1.0 mg/kg 1.25 mg/kg Expansion (0.8 mg/kg) Overall
    Number of subjects analysed
    4
    6
    6
    6
    5
    4
    23
    54
    Units: /100 WBC
        arithmetic mean (standard deviation)
    38.75 ± 57.64
    -4 ± 70.52
    16.67 ± 26.03
    20.67 ± 55.72
    37 ± 46.92
    44.5 ± 44.17
    57.48 ± 93.65
    37.78 ± 73.38
    No statistical analyses for this end point

    Secondary: Haptoglobin - End of Treatment - Change from Baseline

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    End point title
    		 Haptoglobin - End of Treatment - Change from Baseline
    End point description
    End point type
    Secondary
    End point timeframe
    First dose to End of treatment visit.
    End point values
    		 0.2 milligrams per kilogram body weight (mg/kg) 0.4 mg/kg 0.6 mg/kg 0.8 mg/kg 1.0 mg/kg 1.25 mg/kg Expansion (0.8 mg/kg) Overall
    Number of subjects analysed
    5
    4
    5
    3
    4
    4
    13
    38
    Units: mg/dL
        arithmetic mean (standard deviation)
    1.2 ± 5.63
    3.8 ± 4.06
    -0.56 ± 0.93
    -3 ± 3
    -9 ± 8.29
    -15.75 ± 12.37
    -8.15 ± 14.11
    -5.15 ± 11.05
    No statistical analyses for this end point

    Secondary: LDH - End of Treatment - Percent Change from Baseline

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    End point title
    		 LDH - End of Treatment - Percent Change from Baseline
    End point description
    End point type
    Secondary
    End point timeframe
    First dose to End of treatment visit.
    End point values
    		 0.2 milligrams per kilogram body weight (mg/kg) 0.4 mg/kg 0.6 mg/kg 0.8 mg/kg 1.0 mg/kg 1.25 mg/kg Expansion (0.8 mg/kg) Overall
    Number of subjects analysed
    6
    6
    6
    6
    6
    4
    28
    62
    Units: percent
        arithmetic mean (standard deviation)
    0.43 ± 17.52
    -0.95 ± 10.49
    8.68 ± 25.13
    29.17 ± 25.18
    37.38 ± 64.52
    53.79 ± 68.18
    44.95 ± 68.53
    31 ± 56.18
    No statistical analyses for this end point

    Secondary: Indirect Bilirubin - End of Treatment - Percent Change from Baseline

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    End point title
    		 Indirect Bilirubin - End of Treatment - Percent Change from Baseline
    End point description
    End point type
    Secondary
    End point timeframe
    First dose to End of treatment visit.
    End point values
    		 0.2 milligrams per kilogram body weight (mg/kg) 0.4 mg/kg 0.6 mg/kg 0.8 mg/kg 1.0 mg/kg 1.25 mg/kg Expansion (0.8 mg/kg) Overall
    Number of subjects analysed
    6
    6
    6
    6
    6
    4
    29
    63
    Units: percent
        arithmetic mean (standard deviation)
    13.88 ± 23.72
    -25.18 ± 18.27
    4.77 ± 8.68
    6.29 ± 20.29
    3.68 ± 21.42
    2.76 ± 53.64
    18.33 ± 38.67
    8.94 ± 33.57
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse Events collected from first dose to end of study.
    Adverse event reporting additional description
    Non-Serious Adverse Events reported in >= 5% of subjects overall (N=64) are shown.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    15.1
    Reporting groups
    Reporting group title
    0.2 mg/kg
    Reporting group description
    		 -

    Reporting group title
    0.4 mg/kg
    Reporting group description
    		 -

    Reporting group title
    0.6 mg/kg
    Reporting group description
    		 -

    Reporting group title
    0.8 mg/kg
    Reporting group description
    		 -

    Reporting group title
    1.0 mg/kg
    Reporting group description
    		 -

    Reporting group title
    1.25 mg/kg
    Reporting group description
    		 -

    Reporting group title
    Expansion
    Reporting group description
    		 -

    Serious adverse events
    		 0.2 mg/kg 0.4 mg/kg 0.6 mg/kg 0.8 mg/kg 1.0 mg/kg 1.25 mg/kg Expansion
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 29 (0.00%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    0
    0
    Blood and lymphatic system disorders
    Bone marrow failure
    Additional description: 'Occurrences all number' equal to subjects affected number.
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 29 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 0.2 mg/kg 0.4 mg/kg 0.6 mg/kg 0.8 mg/kg 1.0 mg/kg 1.25 mg/kg Expansion
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    5 / 6 (83.33%)
    6 / 6 (100.00%)
    5 / 6 (83.33%)
    6 / 6 (100.00%)
    6 / 6 (100.00%)
    5 / 5 (100.00%)
    26 / 29 (89.66%)
    Injury, poisoning and procedural complications
    Post-traumatic pain
    Additional description: 'Occurrences all number' equal to subjects affected number.
         subjects affected / exposed
    2 / 6 (33.33%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 5 (20.00%)
    1 / 29 (3.45%)
         occurrences all number
    2
    0
    1
    0
    0
    1
    1
    Nervous system disorders
    Headache
    Additional description: 'Occurrences all number' equal to subjects affected number.
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    3 / 6 (50.00%)
    3 / 6 (50.00%)
    4 / 6 (66.67%)
    2 / 5 (40.00%)
    8 / 29 (27.59%)
         occurrences all number
    0
    1
    3
    3
    4
    2
    8
    General disorders and administration site conditions
    Asthenia
    Additional description: 'Occurrences all number' equal to subjects affected number.
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    3 / 6 (50.00%)
    2 / 6 (33.33%)
    2 / 5 (40.00%)
    11 / 29 (37.93%)
         occurrences all number
    0
    0
    1
    3
    2
    2
    11
    Oedema peripheral
    Additional description: 'Occurrences all number' equal to subjects affected number.
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    3 / 29 (10.34%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    3
    Pyrexia
    Additional description: 'Occurrences all number' equal to subjects affected number.
         subjects affected / exposed
    1 / 6 (16.67%)
    2 / 6 (33.33%)
    2 / 6 (33.33%)
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    0 / 5 (0.00%)
    4 / 29 (13.79%)
         occurrences all number
    1
    2
    2
    1
    1
    0
    4
    Gastrointestinal disorders
    Diarrhoea
    Additional description: 'Occurrences all number' equal to subjects affected number.
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    0 / 5 (0.00%)
    4 / 29 (13.79%)
         occurrences all number
    1
    0
    1
    1
    1
    0
    4
    Nausea
    Additional description: 'Occurrences all number' equal to subjects affected number.
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    4 / 29 (13.79%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    4
    Respiratory, thoracic and mediastinal disorders
    Cough
    Additional description: 'Occurrences all number' equal to subjects affected number.
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    2 / 5 (40.00%)
    2 / 29 (6.90%)
         occurrences all number
    0
    0
    1
    1
    1
    2
    2
    Oropharyngeal pain
    Additional description: 'Occurrences all number' equal to subjects affected number.
         subjects affected / exposed
    0 / 6 (0.00%)
    2 / 6 (33.33%)
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    1 / 5 (20.00%)
    3 / 29 (10.34%)
         occurrences all number
    0
    2
    1
    1
    1
    1
    3
    Musculoskeletal and connective tissue disorders
    Arthralgia
    Additional description: 'Occurrences all number' equal to subjects affected number.
         subjects affected / exposed
    0 / 6 (0.00%)
    2 / 6 (33.33%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    2 / 5 (40.00%)
    7 / 29 (24.14%)
         occurrences all number
    0
    2
    0
    1
    0
    2
    7
    Back pain
    Additional description: 'Occurrences all number' equal to subjects affected number.
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    6 / 29 (20.69%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    6
    Bone pain
    Additional description: 'Occurrences all number' equal to subjects affected number.
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    4 / 6 (66.67%)
    2 / 6 (33.33%)
    3 / 5 (60.00%)
    14 / 29 (48.28%)
         occurrences all number
    0
    0
    1
    4
    2
    3
    14
    Musculoskeletal pain
    Additional description: 'Occurrences all number' equal to subjects affected number.
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 5 (20.00%)
    7 / 29 (24.14%)
         occurrences all number
    0
    0
    1
    0
    0
    1
    7
    Myalgia
    Additional description: 'Occurrences all number' equal to subjects affected number.
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    2 / 6 (33.33%)
    3 / 6 (50.00%)
    0 / 6 (0.00%)
    2 / 5 (40.00%)
    6 / 29 (20.69%)
         occurrences all number
    1
    1
    2
    3
    0
    2
    6
    Infections and infestations
    Influenza
    Additional description: 'Occurrences all number' equal to subjects affected number.
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    2 / 6 (33.33%)
    2 / 5 (40.00%)
    1 / 29 (3.45%)
         occurrences all number
    0
    1
    0
    0
    2
    2
    1
    Nasopharyngitis
    Additional description: 'Occurrences all number' equal to subjects affected number.
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    2 / 29 (6.90%)
         occurrences all number
    0
    0
    1
    1
    0
    0
    2
    Pharyngitis
    Additional description: 'Occurrences all number' equal to subjects affected number.
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    0 / 5 (0.00%)
    0 / 29 (0.00%)
         occurrences all number
    1
    0
    1
    1
    1
    0
    0
    Rhinitis
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    2 / 5 (40.00%)
    2 / 29 (6.90%)
         occurrences all number
    0
    1
    1
    0
    0
    2
    2

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    07 Sep 2012
    AMENDMENT 01: revise inclusion criteria to be consistent with the accepted standard definition of the β-thalassemia intermedia patient population; addition of Urinalysis to the end of study visit.
    09 Apr 2013
    AMENDMENT 02: addition of patients with transfusion dependent β-thalassemia intermedia, including eligibility, revising endpoints and collection of transfusion data; eligibility to exclude prior treatment with ACE-011 (sotatercept) or ACE-536 (luspatercept).
    27 Nov 2013
    AMENDMENT 03: allow enrollment of patients with β-thalassemia major in the expansion cohort; add two further dose levels, increase total number of planned patients.
    07 Nov 2014
    AMENDMENT 04: add exploratory objectives, provide clarification on required birth control methods (revised inclusion criterion #7); increase the whashout from hydroxyurea (revised exclusion criterion #15), include additional evaluations and safety criteria; include expanded dose modification rules.

    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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