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    Clinical Trial Results:
    A Phase 2b, Multicentre, Multinational, Double-blind, Dose-finding Study, incorporating an open label substudy, in Adult Patients with Type I, III or IV Osteogenesis Imperfecta Treated with setrusumab (BPS804)

    Summary
    EudraCT number
    2016-005096-27
    Trial protocol
    DK   GB   FR  
    Global end of trial date
    12 Nov 2020

    Results information
    Results version number
    v1(current)
    This version publication date
    01 Mar 2022
    First version publication date
    01 Mar 2022
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    MBPS205
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT03118570
    WHO universal trial number (UTN)
    -
    Other trial identifiers
    IND Number: 113385
    Sponsors
    Sponsor organisation name
    Ultragenyx Pharmaceutical Inc.
    Sponsor organisation address
    60 Leveroni Court, Novato, United States, California 94949
    Public contact
    Medical Information, Ultragenyx Pharmaceutical Inc., 001 888- 756-8567, medinfo@ultragenyx.com
    Scientific contact
    Medical Information, Ultragenyx Pharmaceutical Inc., 001 888- 756-8567, medinfo@ultragenyx.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
    12 Nov 2020
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    12 Nov 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To demonstrate that setrusumab increases radial trabecular volumetric bone mineral density (Tr. vBMD) on high resolution peripheral quantitative computed tomography (HRpQCT) and bone strength on finite element analysis (FEA) in patients with OI Type I, III or IV
    Protection of trial subjects
    The investigator or his/her representative explained the nature of the study to the participant or his/her legally authorised representative and answered all questions regarding the study. Participants was informed that their participation was voluntary. Participants or their legally authorised representative were required to sign a statement of informed consent that meets the requirements of 21 CFR 50, local regulations, ICH guidelines, Health Insurance Portability and Accountability Act (HIPAA) requirements, where applicable, and the IRB/IEC or study centre.
    Background therapy
    For the duration of the study participants receive a daily dose of 500 mg calcium and/or 800 I.U. vitamin D as background treatment. Following the end of setrusumab therapy all participants had the option to receive a dose of zoledronic acid at 12 and 18 months, prescribed at the discretion of the treating physician and in line with local guidelines.
    Evidence for comparator
    -
    Actual start date of recruitment
    11 Sep 2017
    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
    Canada: 8
    Country: Number of subjects enrolled
    United States: 61
    Country: Number of subjects enrolled
    Denmark: 9
    Country: Number of subjects enrolled
    France: 17
    Country: Number of subjects enrolled
    United Kingdom: 17
    Worldwide total number of subjects
    112
    EEA total number of subjects
    26
    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)
    105
    From 65 to 84 years
    7
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Participants were randomized 1:1:1:1 to 3 doses of setrusumab (20 mg/kg, 8 mg/kg and 2 mg/kg) and placebo for a 12-month Treatment Period.

    Pre-assignment
    Screening details
    Per Protocol Amendment 4, participants originally randomized to the placebo group were reassigned to receive 20 mg/kg open-label setrusumab (1 discontinued study prior to the transition). Two participants in the setrusumab 20 mg/kg open-label group were randomized into this group after Amendment 4 and did not receive placebo.

    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
    Blinding implementation details
    With the exception of the open-label treatment arm, investigators and participants remained blinded to each participant’s assigned study treatment throughout the course of the study.

    Arms
    Are arms mutually exclusive
    No

    Arm title
    Setrusumab 20 mg/kg (Blinded)
    Arm description
    Setrusumab 20 mg/kg intravenous (IV) infusion once a month for 12 months plus 500 mg calcium oral tablets and 800 IU vitamin D capsules.
    Arm type
    Experimental

    Investigational medicinal product name
    setrusumab
    Investigational medicinal product code
    BPS804
    Other name
    Pharmaceutical forms
    Powder for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    60-minute infusion

    Investigational medicinal product name
    zoledronic acid
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    15-minute infusion (Following the end of setrusumab therapy all participants had the option to receive a dose of zoledronic acid at 12 and 18 months, prescribed at the discretion of the treating physician and in line with local guidelines.)

    Arm title
    Setrusumab 8 mg/kg (Blinded)
    Arm description
    Setrusumab 8 mg/kg IV infusion once a month for 12 months plus 500 mg calcium oral tablets and 800 IU vitamin D capsules.
    Arm type
    Experimental

    Investigational medicinal product name
    setrusumab
    Investigational medicinal product code
    BPS804
    Other name
    Pharmaceutical forms
    Powder for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    60-minute infusion

    Investigational medicinal product name
    zoledronic acid
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    15-minute infusion (Following the end of setrusumab therapy all participants had the option to receive a dose of zoledronic acid at 12 and 18 months, prescribed at the discretion of the treating physician and in line with local guidelines.)

    Arm title
    Setrusumab 2 mg/kg (Blinded)
    Arm description
    Setrusumab 2 mg/kg IV infusion once a month for 12 months plus 500 mg calcium oral tablets and 800 IU vitamin D capsules.
    Arm type
    Experimental

    Investigational medicinal product name
    setrusumab
    Investigational medicinal product code
    BPS804
    Other name
    Pharmaceutical forms
    Powder for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    60-minute infusion

    Investigational medicinal product name
    zoledronic acid
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    15-minute infusion (Following the end of setrusumab therapy all participants had the option to receive a dose of zoledronic acid at 12 and 18 months, prescribed at the discretion of the treating physician and in line with local guidelines.)

    Arm title
    Setrusumab 20 mg/kg (Open-Label)
    Arm description
    Setrusumab 20 mg/kg IV infusion once a month for 12 months plus 500 mg calcium oral tablets and 800 IU vitamin D capsules. Participants were randomized to this group after amendment 4.
    Arm type
    Experimental

    Investigational medicinal product name
    setrusumab
    Investigational medicinal product code
    BPS804
    Other name
    Pharmaceutical forms
    Powder for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    60-minute infusion

    Investigational medicinal product name
    zoledronic acid
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    15-minute infusion (Following the end of setrusumab therapy all participants had the option to receive a dose of zoledronic acid at 12 and 18 months, prescribed at the discretion of the treating physician and in line with local guidelines.)

    Arm title
    Placebo
    Arm description
    Placebo IV infusion once a month for 12 months plus 500 mg calcium oral tablets and 800 IU vitamin D capsules. Due to a protocol amendment, placebo was actually received for an average of 5 months. Participants originally randomized to the placebo group were reassigned to receive 20 mg/kg open-label setrusumab after amendment 4.
    Arm type
    Experimental

    Investigational medicinal product name
    placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    60-minute infusion

    Number of subjects in period 1
    Setrusumab 20 mg/kg (Blinded) Setrusumab 8 mg/kg (Blinded) Setrusumab 2 mg/kg (Blinded) Setrusumab 20 mg/kg (Open-Label) Placebo
    Started
    31
    29
    30
    2
    20
    Completed
    26
    22
    25
    17
    0
    Not completed
    5
    7
    5
    4
    20
         Other, not specified
    1
    3
    -
    -
    -
         Adverse event
    2
    -
    -
    2
    1
         Transferred to other arm/group
    -
    -
    -
    -
    19
         Consent withdrawn by subject
    -
    1
    4
    1
    -
         Lost to follow-up
    2
    3
    1
    1
    -
    Joined
    0
    0
    0
    19
    0
         Transferred in from other group/arm
    -
    -
    -
    19
    -

    Baseline characteristics

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    Baseline characteristics reporting groups [1]
    Reporting group title
    Setrusumab 20 mg/kg (Blinded)
    Reporting group description
    Setrusumab 20 mg/kg intravenous (IV) infusion once a month for 12 months plus 500 mg calcium oral tablets and 800 IU vitamin D capsules.

    Reporting group title
    Setrusumab 8 mg/kg (Blinded)
    Reporting group description
    Setrusumab 8 mg/kg IV infusion once a month for 12 months plus 500 mg calcium oral tablets and 800 IU vitamin D capsules.

    Reporting group title
    Setrusumab 2 mg/kg (Blinded)
    Reporting group description
    Setrusumab 2 mg/kg IV infusion once a month for 12 months plus 500 mg calcium oral tablets and 800 IU vitamin D capsules.

    Reporting group title
    Setrusumab 20 mg/kg (Open-Label)
    Reporting group description
    Setrusumab 20 mg/kg IV infusion once a month for 12 months plus 500 mg calcium oral tablets and 800 IU vitamin D capsules. Participants were randomized to this group after amendment 4.

    Reporting group title
    Placebo
    Reporting group description
    Placebo IV infusion once a month for 12 months plus 500 mg calcium oral tablets and 800 IU vitamin D capsules. Due to a protocol amendment, placebo was actually received for an average of 5 months. Participants originally randomized to the placebo group were reassigned to receive 20 mg/kg open-label setrusumab after amendment 4.

    Notes
    [1] - The number of subjects reported to be in the baseline period is not equal to the worldwide number of subjects enrolled in the trial. It is expected that these numbers will be the same.
    Justification: The 19 participants who transitioned from the Placebo arm to the Setrusumab 20 mg/kg Open-Label arm are "double-counted" for this analysis. (The total column represents the baseline values only for the n=112 enrolled participants.)
    Reporting group values
    Setrusumab 20 mg/kg (Blinded) Setrusumab 8 mg/kg (Blinded) Setrusumab 2 mg/kg (Blinded) Setrusumab 20 mg/kg (Open-Label) Placebo Total
    Number of subjects
    31 29 30 21 20
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    40.6 ± 13.73 40.4 ± 14.34 47.2 ± 12.42 41.6 ± 14.82 40.9 ± 14.68 -
    Gender categorical
    Units: Subjects
        Female
    17 20 21 15 14 73
        Male
    14 9 9 6 6 39
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    3 1 2 1 1 4
        Not Hispanic or Latino
    27 27 28 20 19 107
        Unknown or Not Reported
    1 1 0 0 0 1
    Race
    Units: Subjects
        Black or African American
    2 1 1 0 0 4
        White
    29 27 29 21 20 107
        Not Collected or Not Reported
    0 1 0 0 0 1

    End points

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    End points reporting groups
    Reporting group title
    Setrusumab 20 mg/kg (Blinded)
    Reporting group description
    Setrusumab 20 mg/kg intravenous (IV) infusion once a month for 12 months plus 500 mg calcium oral tablets and 800 IU vitamin D capsules.

    Reporting group title
    Setrusumab 8 mg/kg (Blinded)
    Reporting group description
    Setrusumab 8 mg/kg IV infusion once a month for 12 months plus 500 mg calcium oral tablets and 800 IU vitamin D capsules.

    Reporting group title
    Setrusumab 2 mg/kg (Blinded)
    Reporting group description
    Setrusumab 2 mg/kg IV infusion once a month for 12 months plus 500 mg calcium oral tablets and 800 IU vitamin D capsules.

    Reporting group title
    Setrusumab 20 mg/kg (Open-Label)
    Reporting group description
    Setrusumab 20 mg/kg IV infusion once a month for 12 months plus 500 mg calcium oral tablets and 800 IU vitamin D capsules. Participants were randomized to this group after amendment 4.

    Reporting group title
    Placebo
    Reporting group description
    Placebo IV infusion once a month for 12 months plus 500 mg calcium oral tablets and 800 IU vitamin D capsules. Due to a protocol amendment, placebo was actually received for an average of 5 months. Participants originally randomized to the placebo group were reassigned to receive 20 mg/kg open-label setrusumab after amendment 4.

    Primary: Change From Baseline in Radial Trabecular Volumetric Bone Mineral Density (Tr vBMD) at Month 12

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    End point title
    Change From Baseline in Radial Trabecular Volumetric Bone Mineral Density (Tr vBMD) at Month 12 [1] [2]
    End point description
    Assessed by high resolution peripheral quantitative computed tomography (HRpQCT). HRpQCT scans were performed on the participant's distal non-dominant arm. In cases of an arm that had been supported with rods or had significant deformity, the dominant limb was selected. Data presents the ratio of the means between the visit and Baseline from analysis of covariance (ANCOVA). Full Analysis Set: all participants who are randomized to one of the blinded treatment arms and took at least 1 dose of study treatment (per protocol almost all efficacy endpoints were to be analyzed only in the blinded treatment arms). Participants with an assessment at given time point.
    End point type
    Primary
    End point timeframe
    Full Analysis Set: all participants who are randomized to one of the blinded treatment arms and took at least 1 dose of study treatment. Participants with an assessment at given time point.
    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: Statistical analyses are attached in a word document due to system limitations.
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Per protocol almost all efficacy endpoints were to be analyzed only in the blinded treatment arms.
    End point values
    Setrusumab 20 mg/kg (Blinded) Setrusumab 8 mg/kg (Blinded) Setrusumab 2 mg/kg (Blinded)
    Number of subjects analysed
    31
    29
    30
    Units: ratio
        number (confidence interval 95%)
    1.004 (0.987 to 1.021)
    0.993 (0.975 to 1.012)
    0.992 (0.974 to 1.011)
    Attachments
    Untitled (Filename: Endpoint 1 Stat Analyses.docx)
    No statistical analyses for this end point

    Primary: Change From Baseline in Radial Bone Strength (Failure Load) at Month 12

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    End point title
    Change From Baseline in Radial Bone Strength (Failure Load) at Month 12 [3] [4]
    End point description
    Assessed by finite element analysis (FEA) of models generated from HRpQCT images of the distal radius. Full Analysis Set: all participants who are randomized to one of the blinded treatment arms and took at least 1 dose of study treatment. Participants with an assessment at given time point.
    End point type
    Primary
    End point timeframe
    Baseline, Month 12 (EOT)
    Notes
    [3] - 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: Statistical analyses are attached in a word document due to system limitations.
    [4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Per protocol almost all efficacy endpoints were to be analyzed only in the blinded treatment arms.
    End point values
    Setrusumab 20 mg/kg (Blinded) Setrusumab 8 mg/kg (Blinded) Setrusumab 2 mg/kg (Blinded)
    Number of subjects analysed
    28
    22
    25
    Units: newton (N)
        least squares mean (standard error)
    61.25 ± 21.669
    32.25 ± 24.342
    8.86 ± 23.200
    Attachments
    Untitled (Filename: Endpoint 2 Stat Analyses.docx)
    No statistical analyses for this end point

    Primary: Change From Baseline in Radial Bone Strength (Stiffness) at Month 12

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    End point title
    Change From Baseline in Radial Bone Strength (Stiffness) at Month 12 [5] [6]
    End point description
    Assessed by FEA of models generated from HRpQCT images of the distal radius. Full Analysis Set: all participants who are randomized to one of the blinded treatment arms and took at least 1 dose of study treatment. Participants with an assessment at given time point.
    End point type
    Primary
    End point timeframe
    Baseline, Month 12 (EOT)
    Notes
    [5] - 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: Statistical analyses are attached in a word document due to system limitations.
    [6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Per protocol almost all efficacy endpoints were to be analyzed only in the blinded treatment arms.
    End point values
    Setrusumab 20 mg/kg (Blinded) Setrusumab 8 mg/kg (Blinded) Setrusumab 2 mg/kg (Blinded)
    Number of subjects analysed
    28
    22
    25
    Units: N/mm
        least squares mean (standard error)
    1638.70 ± 625.808
    1422.00 ± 703.275
    209.89 ± 671.777
    Attachments
    Untitled (Filename: Endpoint 3 Stat Analyses.docx)
    No statistical analyses for this end point

    Secondary: Change From Baseline in Radial and Tibial Tr VBMD Over Time: Full Analysis Set

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    End point title
    Change From Baseline in Radial and Tibial Tr VBMD Over Time: Full Analysis Set [7]
    End point description
    Assessed by HRpQCT. HRpQCT scans were performed on the participant's distal non-dominant arm. In cases of an arm that had been supported with rods or had significant deformity, the dominant limb was selected. Data presented is the ratio of the means between the Visit and Baseline from ANCOVA. Full Analysis Set: all participants who are randomized to one of the blinded treatment arms and took at least 1 dose of study treatment. n=participants with an assessment at given time point.
    End point type
    Secondary
    End point timeframe
    Baseline, Months 6, 12 (EOT), 18, 24
    Notes
    [7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Per protocol almost all efficacy endpoints were to be analyzed only in the blinded treatment arms. Open-Label arm data for this endpoint are presented as a separate endpoint.
    End point values
    Setrusumab 20 mg/kg (Blinded) Setrusumab 8 mg/kg (Blinded) Setrusumab 2 mg/kg (Blinded)
    Number of subjects analysed
    31
    29
    30
    Units: ratio
    number (confidence interval 95%)
        Radial: Month 6; n=26, 25, 25
    1.007 (0.993 to 1.021)
    1.000 (0.986 to 1.015)
    0.998 (0.984 to 1.013)
        Radial: Month 12; n=28, 22, 24
    1.004 (0.987 to 1.021)
    0.993 (0.975 to 1.012)
    0.992 (0.974 to 1.011)
        Radial: Month 18; n=23, 17, 23
    1.002 (0.984 to 1.020)
    0.992 (0.973 to 1.013)
    0.979 (0.962 to 0.997)
        Radial: Month 24; n=21, 16, 16
    0.997 (0.972 to 1.023)
    0.998 (0.970 to 1.027)
    0.979 (0.951 to 1.008)
        Tibial: Month 6; n=23, 20, 17
    1.004 (0.986 to 1.022)
    1.016 (0.996 to 1.036)
    0.990 (0.969 to 1.012)
        Tibial: Month 12; n=24, 17, 15
    0.991 (0.940 to 1.046)
    1.018 (0.955 to 1.086)
    0.973 (0.909 to 1.042)
        Tibial: Month 18; n=20, 13, 16
    0.989 (0.945 to 1.035)
    1.042 (0.985 to 1.102)
    0.983 (0.933 to 1.036)
        Tibial: Month 24; n=19, 12, 11
    1.000 (0.949 to 1.054)
    1.062 (0.995 to 1.133)
    1.017 (0.949 to 1.090)
    Attachments
    Untitled (Filename: Endpoint 4 Stat Analyses.docx)
    No statistical analyses for this end point

    Secondary: Changes From Baseline in Radial and Tibial Tr VBMD at Months 6 and 12: Open-Label Arm

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    End point title
    Changes From Baseline in Radial and Tibial Tr VBMD at Months 6 and 12: Open-Label Arm [8]
    End point description
    Assessed by HRpQCT. HRpQCT scans were performed on the participant's distal non-dominant arm. In cases of an arm that had been supported with rods or had significant deformity, the dominant limb was selected. Data presented is the ratio of the means between the Visit and Baseline from ANCOVA. Analysis Population: All participants in the open-label arm who took at least 1 dose of study treatment. n=participants with an assessment at given time point.
    End point type
    Secondary
    End point timeframe
    Baseline, Months 6, 12 (EOT)
    Notes
    [8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Per protocol almost all efficacy endpoints were to be analyzed only in the blinded treatment arms. Full Analysis Set data for this endpoint are presented as a separate endpoint.
    End point values
    Setrusumab 20 mg/kg (Open-Label)
    Number of subjects analysed
    21
    Units: ratio
    number (confidence interval 95%)
        Radial: Month 6; n=17
    0.994 (0.972 to 1.017)
        Radial: Month 12; n=16
    1.011 (0.986 to 1.036)
        Tibial: Month 6; n=15
    1.013 (0.991 to 1.035)
        Tibial: Month 12; n=15
    1.035 (0.975 to 1.099)
    Attachments
    Untitled (Filename: Endpoint 5 Stat Analyses.docx)
    No statistical analyses for this end point

    Secondary: Changes From Baseline in Radial and Tibial Bone Strength (Failure Load) Over Time: Full Analysis Set

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    End point title
    Changes From Baseline in Radial and Tibial Bone Strength (Failure Load) Over Time: Full Analysis Set [9]
    End point description
    Assessed by FEA of models generated from HRpQCT images of the distal radius. Full Analysis Set: all participants who are randomized to one of the blinded treatment arms and took at least 1 dose of study treatment. n=participants with an assessment at given time point.
    End point type
    Secondary
    End point timeframe
    Baseline, Months 6, 12 (EOT), 18, 24
    Notes
    [9] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Per protocol almost all efficacy endpoints were to be analyzed only in the blinded treatment arms.
    End point values
    Setrusumab 20 mg/kg (Blinded) Setrusumab 8 mg/kg (Blinded) Setrusumab 2 mg/kg (Blinded)
    Number of subjects analysed
    31
    29
    30
    Units: newton
    least squares mean (confidence interval 95%)
        Radial: Month 6; n=26, 25, 26
    31.22 (-1.80 to 64.23)
    39.95 (6.63 to 73.27)
    -3.28 (-36.57 to 30.00)
        Radial: Month 12; n=28, 22, 25
    61.25 (18.03 to 104.46)
    32.25 (-16.30 to 80.80)
    8.86 (-37.41 to 55.13)
        Radial: Month 18; n=23, 17, 24
    50.39 (19.11 to 81.68)
    43.11 (6.79 to 79.42)
    -10.53 (-41.86 to 20.80)
        Radial: Month 24; n=21, 16, 17
    -19.59 (-72.66 to 33.47)
    45.03 (-14.40 to 104.47)
    -50.65 (-108.69 to 7.39)
        Tibial: Month 6; n=23, 20, 17
    46.00 (-24.91 to 116.92)
    45.91 (-28.16 to 119.98)
    -65.33 (-146.39 to 15.72)
        Tibial: Month 12; n=24, 17, 15
    76.15 (-11.23 to 163.54)
    60.20 (-42.63 to 163.04)
    -65.96 (-175.43 to 43.51)
        Tibial: Month 18; n=20, 13, 16
    50.69 (-34.55 to 135.93)
    88.33 (-13.67 to 190.32)
    -49.50 (-144.93 to 45.94)
        Tibial: Month 24; n=19, 12, 11
    -24.75 (-126.76 to 77.27)
    41.37 (-86.68 to 169.43)
    -74.94 (-208.22 to 58.34)
    Attachments
    Untitled (Filename: Endpoint 6 Stat Analyses.docx)
    No statistical analyses for this end point

    Secondary: Changes From Baseline in Radial and Tibial Bone Strength (Failure Load) at Months 6 and 12: Open-Label Arm

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    End point title
    Changes From Baseline in Radial and Tibial Bone Strength (Failure Load) at Months 6 and 12: Open-Label Arm [10]
    End point description
    Assessed by FEA of models generated from HRpQCT images of the distal radius. All participants in the open-label arm who took at least 1 dose of study treatment. n=participants with an assessment at given time point.
    End point type
    Secondary
    End point timeframe
    Baseline, Months 6, 12 (EOT)
    Notes
    [10] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Per protocol almost all efficacy endpoints were to be analyzed only in the blinded treatment arms.
    End point values
    Setrusumab 20 mg/kg (Open-Label)
    Number of subjects analysed
    21
    Units: newton
    least squares mean (confidence interval 95%)
        Radial: Month 6; n=16
    110.16 (61.30 to 159.01)
        Radial: Month 12; n=15
    88.32 (28.55 to 148.09)
        Tibial: Month 6; n=15
    69.78 (-8.61 to 148.18)
        Tibial: Month 12; n=15
    112.92 (10.76 to 215.07)
    Attachments
    Untitled (Filename: Endpoint 7 Stat Analyses.docx)
    No statistical analyses for this end point

    Secondary: Changes From Baseline in Radial and Tibial Bone Strength (Stiffness) Over Time: Full Analysis Set

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    End point title
    Changes From Baseline in Radial and Tibial Bone Strength (Stiffness) Over Time: Full Analysis Set [11]
    End point description
    Assessed by FEA of models generated from HRpQCT images of the distal radius. Full Analysis Set: all participants who are randomized to one of the blinded treatment arms and took at least 1 dose of study treatment. n=participants with an assessment at given time point.
    End point type
    Secondary
    End point timeframe
    Baseline, Months 6, 12 (EOT), 18, 24
    Notes
    [11] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Per protocol almost all efficacy endpoints were to be analyzed only in the blinded treatment arms.
    End point values
    Setrusumab 20 mg/kg (Blinded) Setrusumab 8 mg/kg (Blinded) Setrusumab 2 mg/kg (Blinded)
    Number of subjects analysed
    31
    29
    30
    Units: N/mm
    least squares mean (confidence interval 95%)
        Radial: Month 6; n=26, 25, 26
    795.67 (-34.71 to 1626.04)
    1048.61 (209.47 to 1887.75)
    109.65 (-728.52 to 947.82)
        Radial: Month 12; n=28, 22, 25
    1638.70 (390.57 to 2886.83)
    1422.00 (19.37 to 2824.64)
    209.89 (-1129.93 to 1549.71)
        Radial: Month 18; n=23, 17, 24
    1295.98 (390.54 to 2201.42)
    803.50 (-263.21 to 1870.21)
    -215.92 (-1132.78 to 700.94)
        Radial: Month 24; n=21, 16, 17
    -625.46 (-1888.53 to 637.60)
    1172.45 (-265.87 to 2610.76)
    -1258.55 (-2663.69 to 146.60)
        Tibial: Month 6; n=23, 20, 17
    1344.84 (-296.83 to 2986.52)
    1051.40 (-708.46 to 2811.25)
    -1356.71 (-3284.14 to 570.73)
        Tibial: Month 12; n=24, 17, 15
    2326.63 (221.71 to 4431.55)
    1543.85 (-973.70 to 4061.40)
    -1428.87 (-4118.78 to 1261.03)
        Tibial: Month 18; n=20, 13, 16
    1047.16 (-1070.79 to 3165.11)
    1697.21 (-861.80 to 4256.23)
    -815.38 (-3247.85 to 1617.09)
        Tibial: Month 24; n=19, 12, 11
    -1250.69 (-4131.64 to 1630.26)
    622.77 (-2966.46 to 4212.01)
    -1844.84 (-5695.04 to 2005.37)
    Attachments
    Untitled (Filename: Endpoint 8 Stat Analyses.docx)
    No statistical analyses for this end point

    Secondary: Changes From Baseline in Radial and Tibial Bone Strength (Stiffness) at Months 6 and 12: Open-Label Arm

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    End point title
    Changes From Baseline in Radial and Tibial Bone Strength (Stiffness) at Months 6 and 12: Open-Label Arm [12]
    End point description
    Assessed by FEA of models generated from HRpQCT images of the distal radius. All participants in the open-label arm who took at least 1 dose of study treatment. n=participants with an assessment at given time point.
    End point type
    Secondary
    End point timeframe
    Baseline, Months 6, 12 (EOT)
    Notes
    [12] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Per protocol almost all efficacy endpoints were to be analyzed only in the blinded treatment arms.
    End point values
    Setrusumab 20 mg/kg (Open-Label)
    Number of subjects analysed
    21
    Units: N/mm
    least squares mean (confidence interval 95%)
        Radial: Month 6; n=16
    5056.51 (3404.58 to 6708.45)
        Radial: Month 12; n=15
    4992.82 (3056.80 to 6928.84)
        Tibial: Month 6; n=15
    4225.92 (1840.16 to 6611.68)
        Tibial: Month 12; n=15
    5827.81 (2601.54 to 9054.08)
    Attachments
    Untitled (Filename: Endpoint 9 Stat Analyses.docx)
    No statistical analyses for this end point

    Secondary: Percentage of Participants With at Least 1 New Fracture (Peripheral, Vertebral, Long-Bone, Any) at Month 12

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    End point title
    Percentage of Participants With at Least 1 New Fracture (Peripheral, Vertebral, Long-Bone, Any) at Month 12 [13]
    End point description
    Fracture assessment, confirmed by central radiographic reading, was carried out for peripheral including all major long bones, minor bone (digits, ribs) and vertebral fractures. Fractures without clinical symptoms, detected only by means of radiographic investigations, were not included in the analysis. Full Analysis Set: all participants who are randomized to one of the blinded treatment arms and took at least 1 dose of study treatment.
    End point type
    Secondary
    End point timeframe
    Month 12 (EOT)
    Notes
    [13] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Per protocol almost all efficacy endpoints were to be analyzed only in the blinded treatment arms.
    End point values
    Setrusumab 20 mg/kg (Blinded) Setrusumab 8 mg/kg (Blinded) Setrusumab 2 mg/kg (Blinded)
    Number of subjects analysed
    31
    29
    30
    Units: percentage of participants
    number (not applicable)
        Peripheral
    6.5
    17.2
    13.3
        Vertebral
    0
    0
    0
        Long-Bone
    3.2
    13.8
    3.3
        Any
    16.1
    34.5
    23.3
    No statistical analyses for this end point

    Secondary: Change From Baseline in Lumbar, Total Body, and Femoral Neck Bone Mineral Density (BMD) T-score at Month 6

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    End point title
    Change From Baseline in Lumbar, Total Body, and Femoral Neck Bone Mineral Density (BMD) T-score at Month 6 [14]
    End point description
    BMD was evaluated by dual-energy x-ray absorptiometry (DXA). T-Score was calculated based on actual measured bone density value. T-scores are standardized scores that reflect the standard deviations (SDs) above/below the normal mean for young adults. A score of 50 indicates the population mean with a standard deviation of 10. A positive change in DXA T-score indicates an improvement in BMD. Full Analysis Set: all participants who are randomized to one of the blinded treatment arms and took at least 1 dose of study treatment. n=participants with an assessment at given timepoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Month 6
    Notes
    [14] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Per protocol almost all efficacy endpoints were to be analyzed only in the blinded treatment arms.
    End point values
    Setrusumab 20 mg/kg (Blinded) Setrusumab 8 mg/kg (Blinded) Setrusumab 2 mg/kg (Blinded)
    Number of subjects analysed
    31
    29
    30
    Units: T-score
    least squares mean (confidence interval 95%)
        Lumbar; n=24, 25, 26
    0.273 (0.142 to 0.405)
    0.338 (0.213 to 0.464)
    0.110 (-0.014 to 0.233)
        Total Body; n=23, 24, 27
    0.072 (-0.049 to 0.194)
    0.071 (-0.048 to 0.189)
    0.122 (0.009 to 0.235)
        Femoral Neck; n=21, 19, 24
    -0.024 (-0.143 to 0.095)
    0.102 (-0.023 to 0.226)
    0.087 (-0.026 to 0.199)
    Attachments
    Untitled (Filename: Endpoint 11 Stat Analyses.docx)
    No statistical analyses for this end point

    Secondary: Change From Baseline in Lumbar, Total Body, and Femoral Neck BMD at Month 6

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    End point title
    Change From Baseline in Lumbar, Total Body, and Femoral Neck BMD at Month 6 [15]
    End point description
    BMD was evaluated by DXA. Full Analysis Set: all participants who are randomized to one of the blinded treatment arms and took at least 1 dose of study treatment. n=participants with an assessment at given timepoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Month 6
    Notes
    [15] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Per protocol almost all efficacy endpoints were to be analyzed only in the blinded treatment arms.
    End point values
    Setrusumab 20 mg/kg (Blinded) Setrusumab 8 mg/kg (Blinded) Setrusumab 2 mg/kg (Blinded)
    Number of subjects analysed
    31
    29
    30
    Units: g/cm^2
    least squares mean (confidence interval 95%)
        Lumbar; n=24, 25, 26
    4.06 (2.12 to 6.00)
    4.70 (2.86 to 6.55)
    1.58 (-0.24 to 3.40)
        Total Body; n=23, 24, 27
    0.77 (-0.38 to 1.92)
    0.83 (-0.29 to 1.94)
    1.21 (0.14 to 2.28)
        Femoral Neck; n=21, 19, 24
    -0.42 (-2.51 to 1.68)
    1.64 (-0.57 to 3.84)
    1.61 (-0.38 to 3.59)
    Attachments
    Untitled (Filename: Endpoint 12 Stat Analyses.docx)
    No statistical analyses for this end point

    Secondary: Change From Baseline in Lumbar, Total Body, and Femoral Neck BMD T-score at Month 12

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    End point title
    Change From Baseline in Lumbar, Total Body, and Femoral Neck BMD T-score at Month 12 [16]
    End point description
    BMD was evaluated by DXA. T-Score was calculated based on actual measured bone density value. T-scores are standardized scores that reflect the standard deviations (SDs) above/below the normal mean for young adults. A score of 50 indicates the population mean with a standard deviation of 10. A positive change in DXA T-score indicates an improvement in BMD. Full Analysis Set: all participants who are randomized to one of the blinded treatment arms and took at least 1 dose of study treatment. n=participants with an assessment at given timepoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Month 12 (EOT)
    Notes
    [16] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Per protocol almost all efficacy endpoints were to be analyzed only in the blinded treatment arms.
    End point values
    Setrusumab 20 mg/kg (Blinded) Setrusumab 8 mg/kg (Blinded) Setrusumab 2 mg/kg (Blinded)
    Number of subjects analysed
    31
    29
    30
    Units: T-score
    least squares mean (confidence interval 95%)
        Lumbar; n=24, 22, 25
    0.587 (0.427 to 0.746)
    0.486 (0.324 to 0.648)
    0.174 (0.022 to 0.327)
        Total Body; n=23, 22, 26
    0.181 (0.051 to 0.310)
    0.199 (0.068 to 0.330)
    0.108 (-0.015 to 0.231)
        Femoral Neck; n=21, 18, 22
    0.163 (0.008 to 0.319)
    0.159 (-0.007 to 0.326)
    0.104 (-0.053 to 0.260)
    Attachments
    Untitled (Filename: Endpoint 13 Stat Analyses.docx)
    No statistical analyses for this end point

    Secondary: Change From Baseline in Lumbar, Total Body, and Femoral Neck BMD at Month 12

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    End point title
    Change From Baseline in Lumbar, Total Body, and Femoral Neck BMD at Month 12 [17]
    End point description
    BMD was evaluated by DXA. Full Analysis Set: all participants who are randomized to one of the blinded treatment arms and took at least 1 dose of study treatment. n=participants with an assessment at given timepoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Month 12 (EOT)
    Notes
    [17] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Per protocol almost all efficacy endpoints were to be analyzed only in the blinded treatment arms.
    End point values
    Setrusumab 20 mg/kg (Blinded) Setrusumab 8 mg/kg (Blinded) Setrusumab 2 mg/kg (Blinded)
    Number of subjects analysed
    31
    29
    30
    Units: g/cm^2
    least squares mean (confidence interval 95%)
        Lumbar; n=24, 22, 25
    8.55 (6.13 to 10.97)
    6.79 (4.34 to 9.25)
    2.50 (0.19 to 4.81)
        Total Body; n=23, 22, 26
    1.98 (0.70 to 3.25)
    2.03 (0.73 to 3.33)
    1.06 (-0.16 to 2.27)
        Femoral Neck; n= 21, 18, 22
    3.30 (0.64 to 5.96)
    2.65 (-0.20 to 5.51)
    1.90 (-0.77 to 4.56)
    Attachments
    Untitled (Filename: Endpoint 14 Stat Analyses.docx)
    No statistical analyses for this end point

    Secondary: Change From Baseline in Total vBMD (Radial and Tibial) Over Time

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    End point title
    Change From Baseline in Total vBMD (Radial and Tibial) Over Time [18]
    End point description
    Assessed by HRpQCT. HRpQCT scans were performed on the participant's distal non-dominant arm. In cases of an arm that had been supported with rods or had significant deformity, the dominant limb was selected. Data presented is the ratio of the means between the Visit and Baseline from ANCOVA. Full Analysis Set: all participants who are randomized to one of the blinded treatment arms and took at least 1 dose of study treatment. n=participants with an assessment at given timepoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Months 6, 12 (EOT), 18, and 24
    Notes
    [18] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Per protocol almost all efficacy endpoints were to be analyzed only in the blinded treatment arms.
    End point values
    Setrusumab 20 mg/kg (Blinded) Setrusumab 8 mg/kg (Blinded) Setrusumab 2 mg/kg (Blinded)
    Number of subjects analysed
    31
    29
    30
    Units: ratio
    number (confidence interval 95%)
        Radial, Month 6; n=26, 25, 26
    1.011 (0.999 to 1.022)
    0.995 (0.984 to 1.007)
    1.000 (0.989 to 1.012)
        Radial, Month 12; n=28, 22, 25
    1.017 (1.006 to 1.029)
    1.008 (0.995 to 1.021)
    0.999 (0.986 to 1.011)
        Radial, Month 18; n=23, 17, 24
    1.013 (1.000 to 1.026)
    0.992 (0.978 to 1.007)
    0.996 (0.983 to 1.009)
        Radial, Month 24; n=21, 16, 17
    0.998 (0.984 to 1.012)
    1.009 (0.994 to 1.025)
    0.985 (0.969 to 1.000)
        Tibial, Month 6; n=23, 20, 17
    1.017 (1.001 to 1.033)
    1.011 (0.995 to 1.028)
    0.995 (0.977 to 1.031)
        Tibial, Month 12; n=24, 17, 15
    1.024 (1.004 to 1.045)
    1.011 (0.988 to 1.035)
    0.989 (0.965 to 1.014)
        Tibial, Month 18; n=20, 13, 16
    1.020 (0.997 to 1.045)
    1.021 (0.992 to 1.050)
    0.987 (0.961 to 1.014)
        Tibial, Month 24; n=19, 12, 11
    1.001 (0.982 to 1.021)
    1.025 (1.001 to 1.050)
    0.994 (0.970 to 1.019)
    Attachments
    Untitled (Filename: Endpoint 15 Stat Analyses.docx)
    No statistical analyses for this end point

    Secondary: Change From Baseline in Cortical vBMD (Radial and Tibial) Over Time

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    End point title
    Change From Baseline in Cortical vBMD (Radial and Tibial) Over Time [19]
    End point description
    Assessed by HRpQCT. HRpQCT scans were performed on the participant's distal non-dominant arm. In cases of an arm that had been supported with rods or had significant deformity, the dominant limb was selected. Data presented is the ratio of the means between the Visit and Baseline from ANCOVA. Full Analysis Set: all participants who are randomized to one of the blinded treatment arms and took at least 1 dose of study treatment. n=participants with an assessment at given timepoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Months 6, 12 (EOT), 18, and 24
    Notes
    [19] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Per protocol almost all efficacy endpoints were to be analyzed only in the blinded treatment arms.
    End point values
    Setrusumab 20 mg/kg (Blinded) Setrusumab 8 mg/kg (Blinded) Setrusumab 2 mg/kg (Blinded)
    Number of subjects analysed
    31
    29
    30
    Units: ratio
    number (confidence interval 95%)
        Radial, Month 6; n=26, 25, 26
    1.004 (0.997 to 1.010)
    1.002 (0.996 to 1.009)
    0.998 (0.992 to 1.005)
        Radial, Month 12; n=28, 22, 25
    1.005 (0.998 to 1.012)
    1.003 (0.995 to 1.010)
    1.001 (0.993 to 1.008)
        Radial, Month 18; n=23, 17, 24
    1.011 (1.001 to 1.021)
    1.001 (0.989 to 1.012)
    1.007 (0.997 to 1.017)
        Radial, Month 24; n=21, 16, 17
    1.011 (0.999 to 1.022)
    1.018 (1.005 to 1.031)
    1.002 (0.989 to 1.015)
        Tibial, Month 6; n=23, 20, 17
    1.012 (1.003 to 1.022)
    0.997 (0.987 to 1.007)
    0.998 (0.987 to 1.008)
        Tibial, Month 12; n=24, 17, 15
    1.017 (1.008 to 1.026)
    1.004 (0.993 to 1.014)
    0.998 (0.987 to 1.009)
        Tibial, Month 18; n=20, 13, 16
    1.024 (1.009 to 1.039)
    1.004 (0.986 to 1.022)
    0.993 (0.976 to 1.009)
        Tibial, Month 24; n=19, 12, 11
    1.020 (1.004 to 1.035)
    1.017 (0.998 to 1.036)
    0.996 (0.976 to 1.017)
    Attachments
    Untitled (Filename: Endpoint 16 Stat Analyses.docx)
    No statistical analyses for this end point

    Secondary: Number of Participants With Clinically Significant Changes From Baseline in Body Height, Weight and Body Mass Index (BMI) at 6 and 12 Months: Full Analysis Set

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    End point title
    Number of Participants With Clinically Significant Changes From Baseline in Body Height, Weight and Body Mass Index (BMI) at 6 and 12 Months: Full Analysis Set [20]
    End point description
    Full Analysis Set: all participants who are randomized to one of the blinded treatment arms and took at least 1 dose of study treatment.
    End point type
    Secondary
    End point timeframe
    Baseline, Month 6, Month 12 (EOT)
    Notes
    [20] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Per protocol almost all efficacy endpoints were to be analyzed only in the blinded treatment arms.
    End point values
    Setrusumab 20 mg/kg (Blinded) Setrusumab 8 mg/kg (Blinded) Setrusumab 2 mg/kg (Blinded)
    Number of subjects analysed
    31
    29
    30
    Units: participants
        Month 6: Body Height
    0
    0
    0
        Month 6: Weight
    0
    0
    0
        Month 6: BMI
    0
    0
    0
        Month 12: Body Height
    0
    0
    0
        Month 12: Weight
    0
    0
    0
        Month 12: BMI
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Change From Baseline in Lean and Fat Body Mass From Whole Body at Months 6 and 12

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    End point title
    Change From Baseline in Lean and Fat Body Mass From Whole Body at Months 6 and 12 [21]
    End point description
    Lean and fat body mass was evaluated using whole body DXA (including the head). Full Analysis Set: all participants who are randomized to one of the blinded treatment arms and took at least 1 dose of study treatment. n=participants with an assessment at given timepoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Months 6, 12 (EOT)
    Notes
    [21] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Per protocol almost all efficacy endpoints were to be analyzed only in the blinded treatment arms.
    End point values
    Setrusumab 20 mg/kg (Blinded) Setrusumab 8 mg/kg (Blinded) Setrusumab 2 mg/kg (Blinded)
    Number of subjects analysed
    31
    29
    30
    Units: grams
    least squares mean (confidence interval 95%)
        Month 6: Lean; n=23, 24, 27
    519.152 (13.020 to 1025.284)
    -410.664 (-903.724 to 82.395)
    168.206 (-306.981 to 643.393)
        Month 12: Lean; n=23, 22, 26
    867.668 (204.535 to 1530.801)
    -225.474 (-901.083 to 450.136)
    184.164 (-448.625 to 816.953)
        Month 6: Fat; n=23, 24, 27
    42.567 (-771.815 to 856.949)
    105.420 (-676.720 to 887.561)
    426.388 (-326.298 to 1179.074)
        Month 12: Fat; n=23, 22, 26
    421.266 (-629.870 to 1472.401)
    -85.495 (-1136.234 to 965.245)
    792.485 (-191.238 to 1776.208)
    Attachments
    Untitled (Filename: Endpoint 18 Stat Analyses.docx)
    No statistical analyses for this end point

    Secondary: Change From Baseline in Amino-Terminal Propeptide of Type 1 Procollagen (P1NP) up to Month 12

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    End point title
    Change From Baseline in Amino-Terminal Propeptide of Type 1 Procollagen (P1NP) up to Month 12 [22]
    End point description
    Full Analysis Set: all participants who are randomized to one of the blinded treatment arms and took at least 1 dose of study treatment. n=participants with an assessment at given timepoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Months 1, 3, 6, 9, 12 (EOT)
    Notes
    [22] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Per protocol almost all efficacy endpoints were to be analyzed only in the blinded treatment arms.
    End point values
    Setrusumab 20 mg/kg (Blinded) Setrusumab 8 mg/kg (Blinded) Setrusumab 2 mg/kg (Blinded)
    Number of subjects analysed
    31
    29
    30
    Units: μg/L
    least squares mean (confidence interval 95%)
        Month 1; n=30, 27, 29
    24.349 (18.604 to 30.095)
    14.288 (8.221 to 20.354)
    0.060 (-5.827 to 5.948)
        Month 3; n=29, 27, 25
    17.903 (11.412 to 24.395)
    6.735 (0.015 to 13.455)
    0.640 (-6.389 to 7.670)
        Month 6; n=27, 28, 27
    13.096 (5.468 to 20.725)
    6.665 (-0.788 to 14.118)
    -0.429 (-8.116 to 7.258)
        Month 9; n=27, 25, 26
    7.265 (-0.115 to 14.644)
    0.238 (-7.353 to 7.830)
    -2.254 (-9.820 to 5.312)
        Month 12; n=25, 20, 20
    5.452 (-3.362 to 14.267)
    4.172 (-5.529 to 13.874)
    4.428 (-5.689 to 14.545)
    Attachments
    Untitled (Filename: Endpoint 19 Stat Analyses.docx)
    No statistical analyses for this end point

    Secondary: Change From Baseline in Carboxy-Terminal Telo-Peptide [CTX-1] up to Month 12

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    End point title
    Change From Baseline in Carboxy-Terminal Telo-Peptide [CTX-1] up to Month 12 [23]
    End point description
    Full Analysis Set: all participants who are randomized to one of the blinded treatment arms and took at least 1 dose of study treatment. n=participants with an assessment at given timepoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Months 1, 3, 6, 9, 12 (EOT)
    Notes
    [23] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Per protocol almost all efficacy endpoints were to be analyzed only in the blinded treatment arms.
    End point values
    Setrusumab 20 mg/kg (Blinded) Setrusumab 8 mg/kg (Blinded) Setrusumab 2 mg/kg (Blinded)
    Number of subjects analysed
    31
    29
    30
    Units: μg/L
    least squares mean (confidence interval 95%)
        Month 1; n=30, 27, 29
    -0.077 (-0.100 to -0.054)
    -0.047 (-0.071 to -0.022)
    -0.041 (-0.064 to -0.017)
        Month 3; n=29, 27, 25
    -0.044 (-0.071 to -0.016)
    -0.029 (-0.058 to 0.000)
    -0.043 (-0.073 to -0.013)
        Month 6; n=27, 28, 27
    -0.013 (-0.055 to 0.028)
    -0.025 (-0.065 to 0.016)
    -0.028 (-0.069 to 0.014)
        Month 9; n=27, 25, 26
    -0.020 (-0.067 to 0.026)
    -0.039 (-0.087 to 0.009)
    -0.031 (-0.079 to 0.017)
        Month 12; n=25, 20, 20
    -0.037 (-0.083 to 0.010)
    -0.002 (-0.053 to 0.049)
    -0.034 (-0.087 to 0.019)
    Attachments
    Untitled (Filename: Endpoint 20 Stat Analyses.docx)
    No statistical analyses for this end point

    Secondary: Change From Baseline in Short Form 12 Health Survey (SF-12) Physical Component Summary Score at Months 6 and 12

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    End point title
    Change From Baseline in Short Form 12 Health Survey (SF-12) Physical Component Summary Score at Months 6 and 12 [24]
    End point description
    The SF-12 is a generic, 12-item survey that measures 8 domains of health: physical functioning, role limitations due to physical health, bodily pain, general health perceptions, vitality, social functioning, role limitations due to emotional problems, and mental health. It yields scale scores for each of these 8 domains and 2 summary measures of physical and mental health: The Physical Component Summary and the Mental Component Summary. The total score for the Physical Component Summary ranges from 0 to 100, where higher scores reflect better physical functioning. Full Analysis Set: all participants who are randomized to one of the blinded treatment arms and took at least 1 dose of study treatment. n=participants with an assessment at given timepoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Months 6, 12 (EOT)
    Notes
    [24] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Per protocol almost all efficacy endpoints were to be analyzed only in the blinded treatment arms.
    End point values
    Setrusumab 20 mg/kg (Blinded) Setrusumab 8 mg/kg (Blinded) Setrusumab 2 mg/kg (Blinded)
    Number of subjects analysed
    31
    29
    30
    Units: score on a scale
    least squares mean (confidence interval 95%)
        Month 6; n=27, 29, 27
    0.672 (-1.788 to 3.132)
    -0.463 (-2.821 to 1.895)
    1.342 (-1.129 to 3.814)
        Month 12; n=26, 26, 26
    -1.178 (-3.698 to 1.341)
    -0.994 (-3.488 to 1.501)
    2.171 (-0.352 to 4.695)
    Attachments
    Untitled (Filename: Endpoint 21 Stat Analyses.docx)
    No statistical analyses for this end point

    Secondary: Change From Baseline in SF-12 Mental Component Summary Score at Months 6 and 12

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    End point title
    Change From Baseline in SF-12 Mental Component Summary Score at Months 6 and 12 [25]
    End point description
    The SF-12 is a generic, 12-item survey that measures 8 domains of health: physical functioning, role limitations due to physical health, bodily pain, general health perceptions, vitality, social functioning, role limitations due to emotional problems, and mental health. It yields scale scores for each of these 8 domains and 2 summary measures of physical and mental health: The Physical Component Summary and the Mental Component Summary. The total score for the Mental Component Summary ranges from 0 to 100, where higher scores reflect better mental health functioning. Full Analysis Set: all participants who are randomized to one of the blinded treatment arms and took at least 1 dose of study treatment. n=participants with an assessment at given timepoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Months 6, 12 (EOT)
    Notes
    [25] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Per protocol almost all efficacy endpoints were to be analyzed only in the blinded treatment arms.
    End point values
    Setrusumab 20 mg/kg (Blinded) Setrusumab 8 mg/kg (Blinded) Setrusumab 2 mg/kg (Blinded)
    Number of subjects analysed
    31
    29
    30
    Units: score on a scale
    least squares mean (confidence interval 95%)
        Month 6; n=27, 29, 27
    0.966 (-2.064 to 3.996)
    -0.492 (-3.411 to 2.427)
    -1.133 (-4.202 to 1.936)
        Month 12; n=26, 26, 26
    2.807 (-0.216 to 5.831)
    -1.473 (-4.457 to 1.511)
    -1.664 (-4.694 to 1.366)
    Attachments
    Untitled (Filename: Endpoint 22 Stat Analyses.docx)
    No statistical analyses for this end point

    Secondary: Change From Baseline in Index (Utility) Score on EuroQol 5-Dimension 5-Level Descriptive System (EQ-5D-5L) Score at Months 6 and 12

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    End point title
    Change From Baseline in Index (Utility) Score on EuroQol 5-Dimension 5-Level Descriptive System (EQ-5D-5L) Score at Months 6 and 12 [26]
    End point description
    The EQ-5D-5L is a standardised measure of health status comprised of a descriptive system of 5 health-related quality of life states (i.e., mobility, self-care, usual activities, pain/discomfort, and anxiety/depression) and a Visual Analogue Scale (VAS) of overall health. Each dimension is rated on a 5-point response scale indicating severity of problems, where 1 is “no problems” and 5 is “extreme problems”. The 5 questions are scored and together contribute to the EQ-5D index (utility) score between 0 and 1 (1 being perfect health). Full Analysis Set: all participants who are randomized to one of the blinded treatment arms and took at least 1 dose of study treatment. n=participants with an assessment at given timepoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Months 6 and 12 (EOT)
    Notes
    [26] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Per protocol almost all efficacy endpoints were to be analyzed only in the blinded treatment arms.
    End point values
    Setrusumab 20 mg/kg (Blinded) Setrusumab 8 mg/kg (Blinded) Setrusumab 2 mg/kg (Blinded)
    Number of subjects analysed
    31
    29
    30
    Units: score on a scale
    least squares mean (confidence interval 95%)
        Month 6; n=27, 28, 26
    0.0627 (-0.0105 to 0.1359)
    0.0362 (-0.0343 to 0.1067)
    -0.0383 (-0.1121 to 0.0354)
        Month 12; n=26, 25, 26
    0.0424 (-0.0163 to 0.1012)
    0.0252 (-0.0332 to 0.0837)
    0.0214 (-0.0365 to 0.0793)
    Attachments
    Untitled (Filename: Endpoint 23 Stat Analyses.docx)
    No statistical analyses for this end point

    Secondary: Change From Baseline in Osteogenesis Imperfecta Specific Quality of Life Questionnaire for Adults (OIQoL-A) Total Score at Months 6 and 12

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    End point title
    Change From Baseline in Osteogenesis Imperfecta Specific Quality of Life Questionnaire for Adults (OIQoL-A) Total Score at Months 6 and 12 [27]
    End point description
    The OIQoL-A measures 5 areas of quality of life related to OI (Physical Function, Pain, Hearing Loss, Taking Care/Concerns, Social and Family Life and Activities). The total score is calculated on a 0-100 scale, where higher scores indicate a greater (negative) impact on quality of life. Full Analysis Set: all participants who are randomized to one of the blinded treatment arms and took at least 1 dose of study treatment. n=participants with an assessment at given timepoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Months 6, 12 (EOT)
    Notes
    [27] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Per protocol almost all efficacy endpoints were to be analyzed only in the blinded treatment arms.
    End point values
    Setrusumab 20 mg/kg (Blinded) Setrusumab 8 mg/kg (Blinded) Setrusumab 2 mg/kg (Blinded)
    Number of subjects analysed
    31
    29
    30
    Units: score on a scale
    least squares mean (confidence interval 95%)
        Month 6; n=27, 25, 26
    -3.584 (-8.491 to 1.324)
    -1.848 (-6.899 to 3.203)
    -0.649 (-5.751 to 4.452)
        Month 12; n=25, 24, 25
    -1.668 (-7.395 to 4.059)
    -0.587 (-6.310 to 5.137)
    -3.846 (-9.592 to 1.901)
    Attachments
    Untitled (Filename: Endpoint 24 Stat Analyses.docx)
    No statistical analyses for this end point

    Secondary: Change From Baseline in OIQoL-A Pain Subscale Score at Months 6 and 12

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    End point title
    Change From Baseline in OIQoL-A Pain Subscale Score at Months 6 and 12 [28]
    End point description
    The OIQoL-A measures 5 areas of quality of life related to OI (Physical Function, Pain, Hearing Loss, Taking Care/Concerns, Social and Family Life and Activities). The Pain subscale ranges from 0 to 10, with higher value representing worse pain. Full Analysis Set: all participants who are randomized to one of the blinded treatment arms and took at least 1 dose of study treatment. n=participants with an assessment at given timepoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Months 6, 12 (EOT)
    Notes
    [28] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Per protocol almost all efficacy endpoints were to be analyzed only in the blinded treatment arms.
    End point values
    Setrusumab 20 mg/kg (Blinded) Setrusumab 8 mg/kg (Blinded) Setrusumab 2 mg/kg (Blinded)
    Number of subjects analysed
    31
    29
    30
    Units: score on a scale
    least squares mean (confidence interval 95%)
        Month 6; n=27, 26, 26
    -3.990 (-11.267 to 3.287)
    -3.906 (-11.239 to 3.426)
    -6.003 (-13.495 to 1.489)
        Month 12; n=26, 26, 25
    -3.655 (-11.505 to 4.195)
    -4.968 (-12.709 to 2.772)
    -7.178 (-15.183 to 0.827)
    Attachments
    Untitled (Filename: Endpoint 25 Stat Analyses.docx)
    No statistical analyses for this end point

    Secondary: Change From Baseline in OIQoL-A Activity Subscale Score at Months 6 and 12

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    End point title
    Change From Baseline in OIQoL-A Activity Subscale Score at Months 6 and 12 [29]
    End point description
    The OIQoL-A measures 5 areas of quality of life related to OI (Physical Function, Pain, Hearing Loss, Taking Care/Concerns, Social and Family Life and Activities). The Activities subscale ranges from 0 to 100, with higher value representing increased difficulty. Full Analysis Set: all participants who are randomized to one of the blinded treatment arms and took at least 1 dose of study treatment. n=participants with an assessment at given timepoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Months 6, 12 (EOT)
    Notes
    [29] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Per protocol almost all efficacy endpoints were to be analyzed only in the blinded treatment arms.
    End point values
    Setrusumab 20 mg/kg (Blinded) Setrusumab 8 mg/kg (Blinded) Setrusumab 2 mg/kg (Blinded)
    Number of subjects analysed
    31
    29
    30
    Units: score on a scale
    least squares mean (confidence interval 95%)
        Month 6; n=27, 26, 26
    -5.980 (-11.597 to -0.363)
    -2.722 (-8.397 to 2.953)
    1.907 (-3.906 to 7.719)
        Month 12; n=26, 25, 25
    -0.964 (-8.006 to 6.079)
    4.489 (-2.620 to 11.598)
    -1.630 (-8.869 to 5.609)
    Attachments
    Untitled (Filename: Endpoint 26 Stat Analyses.docx)
    No statistical analyses for this end point

    Secondary: Percentage of Participants Who Were Positive for Anti-Setrusumab Antibodies at Any Time During the Study up to Month 14

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    End point title
    Percentage of Participants Who Were Positive for Anti-Setrusumab Antibodies at Any Time During the Study up to Month 14
    End point description
    Serum samples were screened for antibodies binding to setrusumab using a validated assay method by or under the supervision of the sponsor. Safety Population: all participants who received at least 1 dose of study drug. The 19 participants who transitioned from the Placebo arm to the Setrusumab 20 mg/kg Open-Label arm are reflected in both arms for this analysis.
    End point type
    Secondary
    End point timeframe
    up to Month 14
    End point values
    Setrusumab 20 mg/kg (Blinded) Setrusumab 8 mg/kg (Blinded) Setrusumab 2 mg/kg (Blinded) Setrusumab 20 mg/kg (Open-Label) Placebo
    Number of subjects analysed
    31
    29
    30
    21
    20
    Units: percentage of participants
    number (not applicable)
        Binding Antibodies
    16.1
    17.2
    16.7
    9.5
    15.0
        Neutralizing Antibodies
    16.1
    17.2
    16.7
    0
    0
        Both Binding and Neutralizing Antibodies
    16.1
    17.2
    16.7
    0
    0
    No statistical analyses for this end point

    Secondary: Percentage of Participants With Adverse Events (AEs), Treatment-Emergent AEs (TEAEs), Serious TEAEs, and TEAEs Leading to Discontinuation or Death

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    End point title
    Percentage of Participants With Adverse Events (AEs), Treatment-Emergent AEs (TEAEs), Serious TEAEs, and TEAEs Leading to Discontinuation or Death
    End point description
    An AE is any untoward medical occurrence, which does not necessarily have a causal relationship with treatment. A SAE is defined as any untoward medical occurrence that, at any dose: results in death; is life-threatening; requires inpatient hospitalization or prolongation of existing hospitalization; results in persistent disability/incapacity; is a congenital anomaly/birth defect; is another important medical event. The intensity for each AE was graded as mild, moderate or severe, according to the investigator's judgement. An event was considered related to study drug if there were a "reasonable possibility" of a relationship, according to the investigator's clinical judgment. A TEAE was defined as an event occurring or worsening on or after the first dose of study medication. Safety Population: all participants who received at least 1 dose of study drug. The 19 participants who transitioned from the Placebo arm to the Setrusumab 20 mg/kg Open-Label arm are reflected in both arms
    End point type
    Secondary
    End point timeframe
    Non-serious AEs: up to Month 14; Serious AEs: up to Month 24. (Average duration of exposure to placebo was 5 months and for setrusumab was 11 month plus follow-up to 24 months.)
    End point values
    Setrusumab 20 mg/kg (Blinded) Setrusumab 8 mg/kg (Blinded) Setrusumab 2 mg/kg (Blinded) Setrusumab 20 mg/kg (Open-Label) Placebo
    Number of subjects analysed
    31
    29
    30
    21
    20
    Units: percentage of participants
    number (not applicable)
        All AEs
    100.0
    96.6
    90.0
    100.0
    90.0
        TEAEs
    100.0
    96.6
    90.0
    95.2
    80.0
        Treatment-Related TEAEs
    71.0
    41.4
    36.7
    42.9
    25.0
        Serious TEAEs
    12.9
    24.1
    23.3
    23.8
    10.0
        Treatment-Related Serious TEAEs
    6.5
    0
    0
    9.5
    0
        TEAEs Leading to Death
    0
    0
    0
    0
    0
        TEAEs Leading to Permanent Study Treatment Discon.
    6.5
    0
    0
    9.5
    5.0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Non-serious AEs: up to Month 14; Serious AEs: up to Month 24. (Average duration of exposure to placebo was 5 months and for setrusumab was 11 month plus follow-up to 24 months.)
    Adverse event reporting additional description
    Safety Population: all participants who received at least 1 dose of study drug. The 19 participants who transitioned from the Placebo arm to the Setrusumab 20 mg/kg Open-Label arm are reflected in both arms for this analysis.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    23.1
    Reporting groups
    Reporting group title
    Setrusumab 20 mg/kg (Blinded)
    Reporting group description
    Setrusumab 20 mg/kg intravenous (IV) infusion once a month for 12 months plus 500 mg calcium oral tablets and 800 IU vitamin D capsules.

    Reporting group title
    Setrusumab 8 mg/kg (Blinded)
    Reporting group description
    Setrusumab 8 mg/kg IV infusion once a month for 12 months plus 500 mg calcium oral tablets and 800 IU vitamin D capsules.

    Reporting group title
    Setrusumab 2 mg/kg (Blinded)
    Reporting group description
    Setrusumab 2 mg/kg IV infusion once a month for 12 months plus 500 mg calcium oral tablets and 800 IU vitamin D capsules.

    Reporting group title
    Setrusumab 20 mg/kg (Open-Label)
    Reporting group description
    Setrusumab 20 mg/kg IV infusion once a month for 12 months plus 500 mg calcium oral tablets and 800 IU vitamin D capsules.

    Reporting group title
    Placebo
    Reporting group description
    Placebo IV infusion once a month for 12 months plus 500 mg calcium oral tablets and 800 IU vitamin D capsules. Due to a protocol amendment, placebo was actually received for an average of 5 months.

    Serious adverse events
    Setrusumab 20 mg/kg (Blinded) Setrusumab 8 mg/kg (Blinded) Setrusumab 2 mg/kg (Blinded) Setrusumab 20 mg/kg (Open-Label) Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    4 / 31 (12.90%)
    7 / 29 (24.14%)
    7 / 30 (23.33%)
    5 / 21 (23.81%)
    2 / 20 (10.00%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    Injury, poisoning and procedural complications
    Femur fracture
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 29 (3.45%)
    1 / 30 (3.33%)
    0 / 21 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pelvic fracture
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 29 (0.00%)
    1 / 30 (3.33%)
    0 / 21 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tibia fracture
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 29 (3.45%)
    0 / 30 (0.00%)
    1 / 21 (4.76%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ankle fracture
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 29 (0.00%)
    1 / 30 (3.33%)
    0 / 21 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fibula fracture
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 29 (0.00%)
    0 / 30 (0.00%)
    1 / 21 (4.76%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fracture of penis
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 29 (0.00%)
    1 / 30 (3.33%)
    0 / 21 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hand fracture
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 29 (0.00%)
    1 / 30 (3.33%)
    0 / 21 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ilium fracture
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 29 (0.00%)
    0 / 30 (0.00%)
    0 / 21 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lumbar vertebral fracture
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 29 (0.00%)
    0 / 30 (0.00%)
    1 / 21 (4.76%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Radius fracture
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 29 (0.00%)
    1 / 30 (3.33%)
    0 / 21 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rib fracture
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 29 (0.00%)
    0 / 30 (0.00%)
    0 / 21 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Subcutaneous haematoma
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 29 (0.00%)
    1 / 30 (3.33%)
    0 / 21 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Wound
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 29 (0.00%)
    0 / 30 (0.00%)
    0 / 21 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Scapula fracture
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 29 (0.00%)
    0 / 30 (0.00%)
    0 / 21 (0.00%)
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Squamous cell carcinoma
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 29 (0.00%)
    0 / 30 (0.00%)
    1 / 21 (4.76%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Platybasia
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 29 (0.00%)
    0 / 30 (0.00%)
    1 / 21 (4.76%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Anaphylactic reaction
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 29 (0.00%)
    0 / 30 (0.00%)
    0 / 21 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory failure
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 29 (0.00%)
    0 / 30 (0.00%)
    0 / 21 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 29 (0.00%)
    0 / 30 (0.00%)
    0 / 21 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 29 (0.00%)
    0 / 30 (0.00%)
    0 / 21 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary hypertension
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 29 (0.00%)
    0 / 30 (0.00%)
    1 / 21 (4.76%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 29 (3.45%)
    0 / 30 (0.00%)
    0 / 21 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Headache
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 29 (0.00%)
    0 / 30 (0.00%)
    1 / 21 (4.76%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hydrocephalus
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 29 (0.00%)
    0 / 30 (0.00%)
    0 / 21 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neuritis
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 29 (0.00%)
    1 / 30 (3.33%)
    0 / 21 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Blindness unilateral
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 29 (0.00%)
    1 / 30 (3.33%)
    0 / 21 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Visual impairment
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 29 (0.00%)
    0 / 30 (0.00%)
    1 / 21 (4.76%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Chills
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 29 (0.00%)
    0 / 30 (0.00%)
    1 / 21 (4.76%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Noninfective sialoadenitis
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 29 (0.00%)
    1 / 30 (3.33%)
    0 / 21 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rectal haemorrhage
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 29 (3.45%)
    0 / 30 (0.00%)
    0 / 21 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholelithiasis
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 29 (3.45%)
    0 / 30 (0.00%)
    0 / 21 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 29 (3.45%)
    0 / 30 (0.00%)
    0 / 21 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bone pain
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 29 (3.45%)
    0 / 30 (0.00%)
    0 / 21 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fracture nonunion
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 29 (0.00%)
    1 / 30 (3.33%)
    0 / 21 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Anal abscess
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 29 (0.00%)
    1 / 30 (3.33%)
    0 / 21 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 29 (3.45%)
    0 / 30 (0.00%)
    0 / 21 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 29 (0.00%)
    0 / 30 (0.00%)
    1 / 21 (4.76%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Joint abscess
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 29 (0.00%)
    0 / 30 (0.00%)
    1 / 21 (4.76%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 29 (0.00%)
    0 / 30 (0.00%)
    0 / 21 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Wound infection
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 29 (3.45%)
    0 / 30 (0.00%)
    0 / 21 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyelonephritis acute
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 29 (0.00%)
    0 / 30 (0.00%)
    0 / 21 (0.00%)
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Setrusumab 20 mg/kg (Blinded) Setrusumab 8 mg/kg (Blinded) Setrusumab 2 mg/kg (Blinded) Setrusumab 20 mg/kg (Open-Label) Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    29 / 31 (93.55%)
    28 / 29 (96.55%)
    27 / 30 (90.00%)
    19 / 21 (90.48%)
    16 / 20 (80.00%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 29 (0.00%)
    2 / 30 (6.67%)
    1 / 21 (4.76%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    2
    1
    0
    Immune system disorders
    Seasonal allergy
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 29 (0.00%)
    2 / 30 (6.67%)
    1 / 21 (4.76%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    2
    1
    0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 29 (0.00%)
    0 / 30 (0.00%)
    0 / 21 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    0
    0
    1
    Chest pain
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 29 (3.45%)
    0 / 30 (0.00%)
    2 / 21 (9.52%)
    0 / 20 (0.00%)
         occurrences all number
    0
    1
    0
    2
    0
    Fatigue
         subjects affected / exposed
    3 / 31 (9.68%)
    2 / 29 (6.90%)
    7 / 30 (23.33%)
    3 / 21 (14.29%)
    0 / 20 (0.00%)
         occurrences all number
    4
    2
    7
    4
    0
    Influenza like illness
         subjects affected / exposed
    1 / 31 (3.23%)
    2 / 29 (6.90%)
    0 / 30 (0.00%)
    0 / 21 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    1
    2
    0
    0
    0
    Injection site extravasation
         subjects affected / exposed
    1 / 31 (3.23%)
    1 / 29 (3.45%)
    0 / 30 (0.00%)
    1 / 21 (4.76%)
    1 / 20 (5.00%)
         occurrences all number
    1
    1
    0
    1
    1
    Malaise
         subjects affected / exposed
    0 / 31 (0.00%)
    2 / 29 (6.90%)
    0 / 30 (0.00%)
    0 / 21 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    16
    0
    0
    0
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 31 (0.00%)
    2 / 29 (6.90%)
    0 / 30 (0.00%)
    0 / 21 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    Pain
         subjects affected / exposed
    2 / 31 (6.45%)
    0 / 29 (0.00%)
    2 / 30 (6.67%)
    1 / 21 (4.76%)
    0 / 20 (0.00%)
         occurrences all number
    2
    0
    2
    1
    0
    Peripheral swelling
         subjects affected / exposed
    0 / 31 (0.00%)
    2 / 29 (6.90%)
    0 / 30 (0.00%)
    0 / 21 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    2
    0
    0
    1
    Pyrexia
         subjects affected / exposed
    1 / 31 (3.23%)
    2 / 29 (6.90%)
    2 / 30 (6.67%)
    2 / 21 (9.52%)
    2 / 20 (10.00%)
         occurrences all number
    5
    3
    2
    3
    2
    Reproductive system and breast disorders
    Dysmenorrhoea
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 29 (0.00%)
    0 / 30 (0.00%)
    1 / 21 (4.76%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    0
    3
    1
    Menorrhagia
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 29 (0.00%)
    0 / 30 (0.00%)
    0 / 21 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    0
    0
    1
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    1 / 31 (3.23%)
    2 / 29 (6.90%)
    1 / 30 (3.33%)
    3 / 21 (14.29%)
    0 / 20 (0.00%)
         occurrences all number
    1
    3
    1
    5
    0
    Fall
         subjects affected / exposed
    6 / 31 (19.35%)
    4 / 29 (13.79%)
    3 / 30 (10.00%)
    2 / 21 (9.52%)
    2 / 20 (10.00%)
         occurrences all number
    8
    4
    5
    3
    3
    Foot fracture
         subjects affected / exposed
    3 / 31 (9.68%)
    4 / 29 (13.79%)
    3 / 30 (10.00%)
    6 / 21 (28.57%)
    1 / 20 (5.00%)
         occurrences all number
    3
    5
    3
    8
    2
    Hand fracture
         subjects affected / exposed
    1 / 31 (3.23%)
    3 / 29 (10.34%)
    2 / 30 (6.67%)
    0 / 21 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    1
    3
    2
    0
    0
    Infusion related reaction
         subjects affected / exposed
    4 / 31 (12.90%)
    3 / 29 (10.34%)
    1 / 30 (3.33%)
    2 / 21 (9.52%)
    0 / 20 (0.00%)
         occurrences all number
    12
    9
    1
    2
    0
    Joint dislocation
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 29 (0.00%)
    1 / 30 (3.33%)
    3 / 21 (14.29%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    2
    9
    0
    Joint injury
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 29 (0.00%)
    0 / 30 (0.00%)
    1 / 21 (4.76%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    0
    3
    1
    Ligament sprain
         subjects affected / exposed
    3 / 31 (9.68%)
    1 / 29 (3.45%)
    2 / 30 (6.67%)
    1 / 21 (4.76%)
    2 / 20 (10.00%)
         occurrences all number
    3
    1
    2
    1
    2
    Limb injury
         subjects affected / exposed
    0 / 31 (0.00%)
    3 / 29 (10.34%)
    1 / 30 (3.33%)
    0 / 21 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    4
    1
    0
    0
    Muscle strain
         subjects affected / exposed
    1 / 31 (3.23%)
    2 / 29 (6.90%)
    0 / 30 (0.00%)
    0 / 21 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    1
    3
    0
    0
    0
    Procedural pain
         subjects affected / exposed
    2 / 31 (6.45%)
    0 / 29 (0.00%)
    1 / 30 (3.33%)
    0 / 21 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    2
    0
    1
    0
    0
    Rib fracture
         subjects affected / exposed
    2 / 31 (6.45%)
    3 / 29 (10.34%)
    3 / 30 (10.00%)
    0 / 21 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    2
    4
    5
    0
    0
    Tooth fracture
         subjects affected / exposed
    3 / 31 (9.68%)
    2 / 29 (6.90%)
    6 / 30 (20.00%)
    0 / 21 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    4
    3
    12
    0
    0
    Wound
         subjects affected / exposed
    0 / 31 (0.00%)
    2 / 29 (6.90%)
    0 / 30 (0.00%)
    0 / 21 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    Investigations
    Alanine aminotransferase abnormal
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 29 (0.00%)
    0 / 30 (0.00%)
    0 / 21 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    0
    0
    1
    Alanine aminotransferase increased
         subjects affected / exposed
    2 / 31 (6.45%)
    0 / 29 (0.00%)
    1 / 30 (3.33%)
    0 / 21 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    2
    0
    1
    0
    0
    Aspartate aminotransferase abnormal
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 29 (0.00%)
    0 / 30 (0.00%)
    0 / 21 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    0
    0
    1
    Aspartate aminotransferase increased
         subjects affected / exposed
    2 / 31 (6.45%)
    1 / 29 (3.45%)
    1 / 30 (3.33%)
    1 / 21 (4.76%)
    0 / 20 (0.00%)
         occurrences all number
    2
    1
    1
    1
    0
    Blood alkaline phosphatase increased
         subjects affected / exposed
    2 / 31 (6.45%)
    0 / 29 (0.00%)
    0 / 30 (0.00%)
    0 / 21 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    International normalised ratio increased
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 29 (3.45%)
    3 / 30 (10.00%)
    1 / 21 (4.76%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    3
    1
    1
    Lipase increased
         subjects affected / exposed
    1 / 31 (3.23%)
    1 / 29 (3.45%)
    0 / 30 (0.00%)
    0 / 21 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    1
    2
    0
    0
    1
    Prothrombin time prolonged
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 29 (3.45%)
    3 / 30 (10.00%)
    1 / 21 (4.76%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    3
    2
    1
    Vitamin D decreased
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 29 (3.45%)
    2 / 30 (6.67%)
    2 / 21 (9.52%)
    0 / 20 (0.00%)
         occurrences all number
    0
    1
    3
    2
    0
    Cardiac disorders
    Tachycardia
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 29 (0.00%)
    3 / 30 (10.00%)
    0 / 21 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    3
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    2 / 31 (6.45%)
    2 / 29 (6.90%)
    2 / 30 (6.67%)
    3 / 21 (14.29%)
    0 / 20 (0.00%)
         occurrences all number
    2
    2
    2
    4
    0
    Dyspnoea
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 29 (3.45%)
    2 / 30 (6.67%)
    0 / 21 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    1
    2
    0
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 29 (0.00%)
    2 / 30 (6.67%)
    2 / 21 (9.52%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    3
    2
    0
    Increased tendency to bruise
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 29 (0.00%)
    0 / 30 (0.00%)
    0 / 21 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    0
    0
    1
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    2 / 31 (6.45%)
    0 / 29 (0.00%)
    3 / 30 (10.00%)
    0 / 21 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    2
    0
    3
    0
    1
    Headache
         subjects affected / exposed
    4 / 31 (12.90%)
    5 / 29 (17.24%)
    6 / 30 (20.00%)
    7 / 21 (33.33%)
    2 / 20 (10.00%)
         occurrences all number
    4
    13
    8
    11
    4
    Hypoaesthesia
         subjects affected / exposed
    3 / 31 (9.68%)
    0 / 29 (0.00%)
    1 / 30 (3.33%)
    0 / 21 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    3
    0
    1
    0
    0
    Migraine
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 29 (0.00%)
    3 / 30 (10.00%)
    0 / 21 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    3
    0
    0
    Paraesthesia
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 29 (0.00%)
    0 / 30 (0.00%)
    0 / 21 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    0
    0
    1
    Trigeminal neuralgia
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 29 (0.00%)
    0 / 30 (0.00%)
    0 / 21 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    0
    0
    1
    Eye disorders
    Blepharospasm
         subjects affected / exposed
    2 / 31 (6.45%)
    0 / 29 (0.00%)
    0 / 30 (0.00%)
    0 / 21 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    Ear and labyrinth disorders
    Ear pain
         subjects affected / exposed
    0 / 31 (0.00%)
    2 / 29 (6.90%)
    0 / 30 (0.00%)
    0 / 21 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    Middle ear effusion
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 29 (0.00%)
    0 / 30 (0.00%)
    0 / 21 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    0
    0
    1
    Gastrointestinal disorders
    Dental caries
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 29 (3.45%)
    0 / 30 (0.00%)
    1 / 21 (4.76%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    0
    1
    1
    Diarrhoea
         subjects affected / exposed
    4 / 31 (12.90%)
    3 / 29 (10.34%)
    2 / 30 (6.67%)
    1 / 21 (4.76%)
    1 / 20 (5.00%)
         occurrences all number
    4
    4
    2
    1
    1
    Dyspepsia
         subjects affected / exposed
    2 / 31 (6.45%)
    0 / 29 (0.00%)
    0 / 30 (0.00%)
    0 / 21 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    1 / 31 (3.23%)
    2 / 29 (6.90%)
    1 / 30 (3.33%)
    0 / 21 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    1
    2
    1
    0
    0
    Nausea
         subjects affected / exposed
    2 / 31 (6.45%)
    3 / 29 (10.34%)
    5 / 30 (16.67%)
    2 / 21 (9.52%)
    2 / 20 (10.00%)
         occurrences all number
    2
    4
    10
    2
    2
    Toothache
         subjects affected / exposed
    2 / 31 (6.45%)
    0 / 29 (0.00%)
    1 / 30 (3.33%)
    1 / 21 (4.76%)
    0 / 20 (0.00%)
         occurrences all number
    2
    0
    1
    1
    0
    Vomiting
         subjects affected / exposed
    3 / 31 (9.68%)
    1 / 29 (3.45%)
    1 / 30 (3.33%)
    3 / 21 (14.29%)
    1 / 20 (5.00%)
         occurrences all number
    3
    1
    1
    3
    1
    Renal and urinary disorders
    Nephrolithiasis
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 29 (0.00%)
    2 / 30 (6.67%)
    1 / 21 (4.76%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    2
    1
    0
    Renal colic
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 29 (0.00%)
    0 / 30 (0.00%)
    0 / 21 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    0
    0
    1
    Skin and subcutaneous tissue disorders
    Ecchymosis
         subjects affected / exposed
    1 / 31 (3.23%)
    1 / 29 (3.45%)
    0 / 30 (0.00%)
    0 / 21 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    1
    1
    0
    0
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    15 / 31 (48.39%)
    8 / 29 (27.59%)
    9 / 30 (30.00%)
    8 / 21 (38.10%)
    5 / 20 (25.00%)
         occurrences all number
    29
    17
    24
    12
    5
    Back pain
         subjects affected / exposed
    6 / 31 (19.35%)
    4 / 29 (13.79%)
    8 / 30 (26.67%)
    4 / 21 (19.05%)
    1 / 20 (5.00%)
         occurrences all number
    7
    4
    13
    5
    1
    Bone pain
         subjects affected / exposed
    4 / 31 (12.90%)
    3 / 29 (10.34%)
    4 / 30 (13.33%)
    2 / 21 (9.52%)
    0 / 20 (0.00%)
         occurrences all number
    4
    3
    6
    3
    0
    Muscle spasms
         subjects affected / exposed
    2 / 31 (6.45%)
    1 / 29 (3.45%)
    2 / 30 (6.67%)
    1 / 21 (4.76%)
    0 / 20 (0.00%)
         occurrences all number
    2
    2
    2
    1
    0
    Musculoskeletal chest pain
         subjects affected / exposed
    2 / 31 (6.45%)
    1 / 29 (3.45%)
    3 / 30 (10.00%)
    2 / 21 (9.52%)
    0 / 20 (0.00%)
         occurrences all number
    2
    1
    4
    4
    0
    Musculoskeletal discomfort
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 29 (0.00%)
    0 / 30 (0.00%)
    0 / 21 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    1
    0
    0
    0
    1
    Myalgia
         subjects affected / exposed
    2 / 31 (6.45%)
    1 / 29 (3.45%)
    0 / 30 (0.00%)
    1 / 21 (4.76%)
    1 / 20 (5.00%)
         occurrences all number
    3
    2
    0
    1
    1
    Neck pain
         subjects affected / exposed
    1 / 31 (3.23%)
    1 / 29 (3.45%)
    4 / 30 (13.33%)
    1 / 21 (4.76%)
    0 / 20 (0.00%)
         occurrences all number
    1
    1
    10
    1
    0
    Pain in extremity
         subjects affected / exposed
    5 / 31 (16.13%)
    5 / 29 (17.24%)
    3 / 30 (10.00%)
    4 / 21 (19.05%)
    1 / 20 (5.00%)
         occurrences all number
    5
    8
    3
    8
    1
    Metabolism and nutrition disorders
    Hypokalaemia
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 29 (0.00%)
    0 / 30 (0.00%)
    2 / 21 (9.52%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    0
    2
    1
    Type 2 diabetes mellitus
         subjects affected / exposed
    0 / 31 (0.00%)
    2 / 29 (6.90%)
    0 / 30 (0.00%)
    0 / 21 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    2
    0
    0
    1
    Vitamin D deficiency
         subjects affected / exposed
    2 / 31 (6.45%)
    0 / 29 (0.00%)
    1 / 30 (3.33%)
    1 / 21 (4.76%)
    0 / 20 (0.00%)
         occurrences all number
    2
    0
    1
    1
    0
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    1 / 31 (3.23%)
    1 / 29 (3.45%)
    0 / 30 (0.00%)
    1 / 21 (4.76%)
    1 / 20 (5.00%)
         occurrences all number
    1
    1
    0
    1
    1
    Cystitis
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 29 (3.45%)
    0 / 30 (0.00%)
    0 / 21 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    0
    0
    1
    Ear infection
         subjects affected / exposed
    3 / 31 (9.68%)
    1 / 29 (3.45%)
    0 / 30 (0.00%)
    1 / 21 (4.76%)
    0 / 20 (0.00%)
         occurrences all number
    3
    1
    0
    1
    0
    Gastroenteritis
         subjects affected / exposed
    3 / 31 (9.68%)
    2 / 29 (6.90%)
    0 / 30 (0.00%)
    0 / 21 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    3
    3
    0
    0
    1
    Herpes zoster
         subjects affected / exposed
    2 / 31 (6.45%)
    1 / 29 (3.45%)
    0 / 30 (0.00%)
    0 / 21 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    2
    1
    0
    0
    0
    Influenza
         subjects affected / exposed
    2 / 31 (6.45%)
    0 / 29 (0.00%)
    0 / 30 (0.00%)
    4 / 21 (19.05%)
    1 / 20 (5.00%)
         occurrences all number
    2
    0
    0
    4
    3
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 29 (0.00%)
    1 / 30 (3.33%)
    0 / 21 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    1
    0
    1
    Nasopharyngitis
         subjects affected / exposed
    5 / 31 (16.13%)
    3 / 29 (10.34%)
    4 / 30 (13.33%)
    5 / 21 (23.81%)
    3 / 20 (15.00%)
         occurrences all number
    5
    4
    4
    9
    5
    Sinusitis
         subjects affected / exposed
    2 / 31 (6.45%)
    3 / 29 (10.34%)
    4 / 30 (13.33%)
    0 / 21 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    2
    3
    6
    0
    0
    Tooth abscess
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 29 (0.00%)
    2 / 30 (6.67%)
    0 / 21 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    4
    0
    0
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 29 (0.00%)
    1 / 30 (3.33%)
    1 / 21 (4.76%)
    1 / 20 (5.00%)
         occurrences all number
    1
    0
    1
    1
    1
    Urinary tract infection
         subjects affected / exposed
    3 / 31 (9.68%)
    3 / 29 (10.34%)
    2 / 30 (6.67%)
    3 / 21 (14.29%)
    1 / 20 (5.00%)
         occurrences all number
    4
    4
    3
    4
    1

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    27 Jan 2017
    • Change to OI-QoL-A endpoints
    02 May 2017
    • Added 60-day Follow-up Period per UK regulatory agency • Clarified the schedule of activities
    18 Jan 2018
    • Adjusted the primary analysis to 12 months • Removed DXA vertebral fracture assessment as study endpoint
    18 May 2018
    • Placebo arm was replaced by 20 mg/kg of setrusumab open-label treatment arm • Addition of 12-month Follow-up Period following the double-blind Treatment Period
    12 Dec 2018
    • Addition of optional zoledronic acid therapy during Follow-up Period
    19 Jul 2019
    • Clarified open-label data on Tr. vBMD (tibia & radius) on HRpQCT and bone strength on FEA would be assessed up to Month 12

    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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