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    Clinical Trial Results:
    A Phase 3 Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study to Evaluate the Safety and Efficacy of Denosumab in Pediatric Subjects With Glucocorticoid-induced Osteoporosis

    Summary
    EudraCT number
    		 2016-003083-39
    Trial protocol
    		 BE   BG   Outside EU/EEA   IT  
    Global end of trial date
    20 Dec 2023

    Results information
    Results version number
    		 v1(current)
    This version publication date
    19 Jun 2024
    First version publication date
    19 Jun 2024
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    20140444
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03164928
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Amgen Inc.
    Sponsor organisation address
    One Amgen Center Drive, Thousand Oaks, CA, United States,
    Public contact
    Amgen (EUROPE) GmbH, IHQ Medical Info-Clinical Trials, MedInfoInternational@amgen.com
    Scientific contact
    Amgen (EUROPE) GmbH, IHQ Medical Info-Clinical Trials, MedInfoInternational@amgen.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-000145-PIP02-12
    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
    15 Feb 2024
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    20 Dec 2023
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the effect of denosumab on lumbar spine bone mineral density (BMD) Z-score as assessed by dual-energy X-ray absorptiometry (DXA) at 12 months in children 5 to 17 year of age with Glucocorticoid (GC)-induced osteoporosis (GiOP).
    Protection of trial subjects
    This study was conducted in accordance with International Council for Harmonisation (ICH) Good Clinical Practice (GCP) regulations/guidelines. Essential documents will be retained in accordance with ICH GCP. The study sponsor declares that the information provided in this report is an accurate representation of the data captured and analyses performed for this study.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    07 May 2018
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    India: 2
    Country: Number of subjects enrolled
    Australia: 2
    Country: Number of subjects enrolled
    Russian Federation: 7
    Country: Number of subjects enrolled
    Türkiye: 1
    Country: Number of subjects enrolled
    Ukraine: 4
    Country: Number of subjects enrolled
    Canada: 4
    Country: Number of subjects enrolled
    United States: 2
    Country: Number of subjects enrolled
    Colombia: 1
    Country: Number of subjects enrolled
    Peru: 1
    Worldwide total number of subjects
    24
    EEA total number of subjects
    0
    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)
    6
    Adolescents (12-17 years)
    18
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 This study was conducted at 12 centers in Australia, Canada, Columbia, India, Peru, Russia, Turkey, Ukraine, and the United States between May 2018 and December 2023.

    Pre-assignment
    Screening details
    		 Participants were randomized in a 2:1 allocation ratio to receive either denosumab or placebo respectively, in a double-blind manner during the 12-month placebo-controlled double-blind Treatment Period. This was followed by a 12-month denosumab Open-label Treatment Period and a 12- month Off-treatment Observation Period.

    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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Denosumab/Denosumab
    Arm description
    		 Participants received 1 mg/kg Denosumab by subcutaneous injection (SC), up to a maximum of 60 mg, every 6 months (Q6M) for 24 months during the Treatment Period. Participants were then followed for an additional 12 months during the Off-treatment Observation Period.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Denosumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    1 mg/kg up to a maximum of 60 mg by SC injection.

    Arm title
    		 Placebo/Denosumab
    Arm description
    		 Participants received matching placebo by SC injection Q6M for the first 12 months of the Treatment Period. This was followed by 1 mg/kg Denosumab administered by SC injection, up to a maximum of 60 mg, Q6M for the second 12 months of the Treatment Period. Participants were then followed for an additional 12 months during the Off-treatment Observation Period.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Denosumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    1 mg/kg up to a maximum of 60 mg by SC injection.

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    1 mg/kg by SC injection.

    Number of subjects in period 1
    		Denosumab/Denosumab Placebo/Denosumab
    Started
    16
    8
    Completed
    15
    8
    Not completed
    1
    0
         Lost to follow-up
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Denosumab/Denosumab
    Reporting group description
    		 Participants received 1 mg/kg Denosumab by subcutaneous injection (SC), up to a maximum of 60 mg, every 6 months (Q6M) for 24 months during the Treatment Period. Participants were then followed for an additional 12 months during the Off-treatment Observation Period.

    Reporting group title
    Placebo/Denosumab
    Reporting group description
    		 Participants received matching placebo by SC injection Q6M for the first 12 months of the Treatment Period. This was followed by 1 mg/kg Denosumab administered by SC injection, up to a maximum of 60 mg, Q6M for the second 12 months of the Treatment Period. Participants were then followed for an additional 12 months during the Off-treatment Observation Period.

    Reporting group values
    		 Denosumab/Denosumab Placebo/Denosumab Total
    Number of subjects
    		 16 8 24
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 3 3 6
        Adolescents (12-17 years)
    		 13 5 18
        Adults (18-64 years)
    		 0 0 0
        From 65-84 years
    		 0 0 0
        85 years and over
    		 0 0 0
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 13.8 ( 2.3 ) 12.8 ( 2.1 ) -
    Sex: Female, Male
    Units: participants
        Female
    		 6 4 10
        Male
    		 10 4 14
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 1 3 4
        Not Hispanic or Latino
    		 15 5 20
        Unknown or Not Reported
    		 0 0 0
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 0 0 0
        Asian
    		 3 0 3
        Native Hawaiian or Other Pacific Islander
    		 0 0 0
        Black or African American
    		 0 0 0
        White
    		 13 5 18
        More than one race
    		 0 0 0
        Other
    		 0 3 3
    Lumbar Spine Bone Mineral Density (BMD) Z-score at Baseline
    Units: Z-score
        arithmetic mean (standard deviation)
    		 -1.95 ( 1.03 ) -3.60 ( 1.77 ) -
    Femoral Neck BMD Z-score at Baseline
    Units: Z-score
        arithmetic mean (standard deviation)
    		 -3.35 ( 1.91 ) -4.78 ( 2.80 ) -
    Total Hip BMD Z-score at Baseline
    Units: Z-score
        arithmetic mean (standard deviation)
    		 -3.14 ( 1.70 ) -4.56 ( 2.08 ) -

    End points

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    End points reporting groups
    Reporting group title
    Denosumab/Denosumab
    Reporting group description
    		 Participants received 1 mg/kg Denosumab by subcutaneous injection (SC), up to a maximum of 60 mg, every 6 months (Q6M) for 24 months during the Treatment Period. Participants were then followed for an additional 12 months during the Off-treatment Observation Period.

    Reporting group title
    Placebo/Denosumab
    Reporting group description
    		 Participants received matching placebo by SC injection Q6M for the first 12 months of the Treatment Period. This was followed by 1 mg/kg Denosumab administered by SC injection, up to a maximum of 60 mg, Q6M for the second 12 months of the Treatment Period. Participants were then followed for an additional 12 months during the Off-treatment Observation Period.

    Primary: Change From Baseline in Lumbar Spine BMD Z-score as Assessed by DXA at 12 Months

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    End point title
    		 Change From Baseline in Lumbar Spine BMD Z-score as Assessed by DXA at 12 Months
    End point description
    Lumbar spine BMD was assessed by DXA and analyzed by analysis of covariance (ANCOVA) including treatment (denosumab vs placebo), baseline age, and baseline BMD z-score. DXA results were converted to z-scores, indicating number of standard deviations from the reference population's mean, with 0 denoting the mean. Positive changes from baseline signify lumbar spine BMD improvement. Primary DXA Analysis Set: all participants in the FAS with baseline and ≥ 1 postbaseline DXA of lumbar spine provided by the central imaging vendor during the first 12 months.
    End point type
    Primary
    End point timeframe
    Baseline and 12 Months
    End point values
    		 Denosumab/Denosumab Placebo/Denosumab
    Number of subjects analysed
    15
    8
    Units: Z-score
        least squares mean (confidence interval 95%)
    0.23 (-0.054 to 0.506)
    0.11 (-0.304 to 0.532)
    Statistical analysis title
    		 ANCOVA Primary DXA Analysis Set
    Comparison groups
    Denosumab/Denosumab v Placebo/Denosumab
    Number of subjects included in analysis
    23
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [1]
    P-value
    		 = 0.68
    Method
    		 ANCOVA
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    0.11
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.45
         upper limit
    		 0.673
    Notes
    [1] - Analysis of covariance (ANCOVA) model including treatment (denosumab vs placebo), baseline age, and baseline BMD Z-score, with no imputation for missing data.

    Secondary: Change From Baseline in Lumbar Spine BMD Z-score as Assessed by DXA at 6, 18, 24, and 36 Months

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    End point title
    		 Change From Baseline in Lumbar Spine BMD Z-score as Assessed by DXA at 6, 18, 24, and 36 Months
    End point description
    Lumbar spine BMD was assessed by DXA and analyzed by repeated measures analysis with randomization group, visit, baseline age, and baseline BMD z-score as fixed effects. Treatment-by-visit was included as an interaction term. DXA results were converted to z-scores, indicating number of standard deviations from the reference population's mean, with 0 denoting the mean. Positive changes from baseline signify lumbar spine BMD improvement. DXA Analysis Set: all participants in the FAS with baseline and ≥ 1 postbaseline valid DXA assessment for lumbar spine as provided by the central imaging vendor.
    End point type
    Secondary
    End point timeframe
    Baseline and 6, 18, 24, and 36 Months
    End point values
    		 Denosumab/Denosumab Placebo/Denosumab
    Number of subjects analysed
    15
    8
    Units: Z-score
    least squares mean (confidence interval 95%)
        Month 6 n= 14, 6
    0.28 (0.095 to 0.468)
    0.11 (-0.176 to 0.391)
        Month 18 n= 15, 7
    0.32 (-0.034 to 0.679)
    0.30 (-0.206 to 0.800)
        Month 24 n= 13, 7
    0.37 (-0.017 to 0.755)
    0.26 (-0.285 to 0.801)
        Month 36 n= 9, 5
    -0.23 (-0.833 to 0.372)
    0.57 (-0.268 to 1.416)
    Statistical analysis title
    		 Repeated Measures Model DXA Analysis Set
    Statistical analysis description
    Month 6
    Comparison groups
    Denosumab/Denosumab v Placebo/Denosumab
    Number of subjects included in analysis
    23
    Analysis specification
    Pre-specified
    Analysis type
    		 [2]
    P-value
    		 = 0.34
    Method
    		 Repeated Measures Model
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    0.17
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.194
         upper limit
    		 0.542
    Notes
    [2] - Repeated measures model including treatment (denosumab vs placebo), study visit (6, 12, 18, 24, and 36 months), baseline age, baseline BMD Z-score, and treatment-by visit included as an interaction with no imputation for missing data.
    Statistical analysis title
    		 Repeated Measures Model DXA Analysis Set
    Statistical analysis description
    Month 18
    Comparison groups
    Denosumab/Denosumab v Placebo/Denosumab
    Number of subjects included in analysis
    23
    Analysis specification
    Pre-specified
    Analysis type
    		 [3]
    P-value
    		 = 0.93
    Method
    		 Repeated Measures Model
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    0.03
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.609
         upper limit
    		 0.661
    Notes
    [3] - Repeated measures model including treatment (denosumab vs placebo), study visit (6, 12, 18, 24, and 36 months), baseline age, baseline BMD Z-score, and treatment-by visit included as an interaction with no imputation for missing data.
    Statistical analysis title
    		 Repeated Measures Model DXA Analysis Set
    Statistical analysis description
    Month 24
    Comparison groups
    Denosumab/Denosumab v Placebo/Denosumab
    Number of subjects included in analysis
    23
    Analysis specification
    Pre-specified
    Analysis type
    		 [4]
    P-value
    		 = 0.74
    Method
    		 Repeated Measures Model
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    0.11
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.572
         upper limit
    		 0.795
    Notes
    [4] - Repeated measures model including treatment (denosumab vs placebo), study visit (6, 12, 18, 24, and 36 months), baseline age, baseline BMD Z-score, and treatment-by visit included as an interaction with no imputation for missing data.
    Statistical analysis title
    		 Repeated Measures Model DXA Analysis Set
    Statistical analysis description
    Month 36
    Comparison groups
    Denosumab/Denosumab v Placebo/Denosumab
    Number of subjects included in analysis
    23
    Analysis specification
    Pre-specified
    Analysis type
    		 [5]
    P-value
    		 = 0.12
    Method
    		 Repeated Measures Model
    Parameter type
    		 Least Squares Means Difference
    Point estimate
    -0.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.848
         upper limit
    		 0.239
    Notes
    [5] - Repeated measures model including treatment (denosumab vs placebo), study visit (6, 12, 18, 24, and 36 months), baseline age, baseline BMD Z-score, and treatment-by visit included as an interaction with no imputation for missing data.

    Secondary: Change From Baseline in Proximal Femur BMD Z-score as Assessed by DXA at 6, 12, 18, 24, and 36 Months

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    End point title
    		 Change From Baseline in Proximal Femur BMD Z-score as Assessed by DXA at 6, 12, 18, 24, and 36 Months
    End point description
    Proximal femur (total hip and femoral neck) BMD was assessed by DXA and analyzed by repeated measures analysis with randomization group, visit, baseline age, and baseline BMD z-score as fixed effects. Treatment-by-visit was included as an interaction term. DXA results were converted to z-scores, indicating number of standard deviations from the reference population's mean, with 0 denoting the mean. Positive changes from baseline signify proximal femur BMD improvement. DXA Analysis Set: all participants in the FAS with baseline and ≥ 1 postbaseline valid DXA assessment for total hip and femoral neck as provided by the central imaging vendor.
    End point type
    Secondary
    End point timeframe
    Baseline and 6, 12, 18, 24, and 36 Months
    End point values
    		 Denosumab/Denosumab Placebo/Denosumab
    Number of subjects analysed
    15
    7
    Units: Z-score
    least squares mean (confidence interval 95%)
        Month 6 (Total Hip) n= 13, 5
    0.22 (-0.103 to 0.552)
    0.64 (0.104 to 1.171)
        Month 12 (Total Hip) n= 14, 7
    0.24 (-0.079 to 0.554)
    0.30 (-0.168 to 0.759)
        Month 18 (Total Hip) n= 15, 6
    0.48 (0.015 to 0.937)
    0.75 (0.061 to 1.434)
        Month 24 (Total Hip) n= 13, 6
    0.52 (0.000 to 1.033)
    0.69 (-0.062 to 1.447)
        Month 36 (Total Hip) n= 9, 5
    0.64 (-0.149 to 1.436)
    0.73 (-0.384 to 1.850)
        Month 6 (Femoral Neck) n= 13, 5
    0.42 (0.000 to 0.849)
    0.60 (-0.037 to 1.241)
        Month 12 (Femoral Neck) n= 14, 7
    0.53 (0.029 to 1.030)
    0.43 (-0.294 to 1.161)
        Month 18 (Femoral Neck) n= 15, 6
    0.85 (0.261 to 1.446)
    0.48 (-0.387 to 1.350)
        Month 24 (Femoral Neck) n= 13, 6
    0.75 (0.000 to 1.495)
    0.64 (-0.449 to 1.724)
        Month 36 (Femoral Neck) n= 9, 5
    1.00 (-0.008 to 2.012)
    0.63 (-0.798 to 2.050)
    Statistical analysis title
    		 Repeated Measures Model DXA Analysis Set
    Statistical analysis description
    Month 18 (Total Hip)
    Comparison groups
    Denosumab/Denosumab v Placebo/Denosumab
    Number of subjects included in analysis
    22
    Analysis specification
    Pre-specified
    Analysis type
    		 [6]
    P-value
    		 = 0.51
    Method
    		 Repeated Measures Model
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    -0.27
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.108
         upper limit
    		 0.565
    Notes
    [6] - Repeated measures model including treatment (denosumab vs placebo), study visit (6, 12, 18, 24, and 36 months), baseline age, baseline BMD Z-score, and treatment-by visit included as an interaction with no imputation for missing data.
    Statistical analysis title
    		 Repeated Measures Model DXA Analysis Set
    Statistical analysis description
    Month 12 (Total Hip)
    Comparison groups
    Denosumab/Denosumab v Placebo/Denosumab
    Number of subjects included in analysis
    22
    Analysis specification
    Pre-specified
    Analysis type
    		 [7]
    P-value
    		 = 0.83
    Method
    		 Repeated Measures Model
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    -0.06
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.631
         upper limit
    		 0.515
    Notes
    [7] - Repeated measures model including treatment (denosumab vs placebo), study visit (6, 12, 18, 24, and 36 months), baseline age, baseline BMD Z-score, and treatment-by visit included as an interaction with no imputation for missing data.
    Statistical analysis title
    		 Repeated Measures Model DXA Analysis Set
    Statistical analysis description
    Month 6 (Total Hip)
    Comparison groups
    Denosumab/Denosumab v Placebo/Denosumab
    Number of subjects included in analysis
    22
    Analysis specification
    Pre-specified
    Analysis type
    		 [8]
    P-value
    		 = 0.19
    Method
    		 Repeated Measures Model
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    -0.41
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.05
         upper limit
    		 0.223
    Notes
    [8] - Repeated measures model including treatment (denosumab vs placebo), study visit (6, 12, 18, 24, and 36 months), baseline age, baseline BMD Z-score, and treatment-by visit included as an interaction with no imputation for missing data.
    Statistical analysis title
    		 Repeated Measures Model DXA Analysis Set
    Statistical analysis description
    Month 12 (Femoral Neck)
    Comparison groups
    Denosumab/Denosumab v Placebo/Denosumab
    Number of subjects included in analysis
    22
    Analysis specification
    Pre-specified
    Analysis type
    		 [9]
    P-value
    		 = 0.83
    Method
    		 Repeated Measures Model
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    0.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.808
         upper limit
    		 1
    Notes
    [9] - Repeated measures model including treatment (denosumab vs placebo), study visit (6, 12, 18, 24, and 36 months), baseline age, baseline BMD Z-score, and treatment-by visit included as an interaction with no imputation for missing data.
    Statistical analysis title
    		 Repeated Measures Model DXA Analysis Set
    Statistical analysis description
    Month 18 (Femoral Neck)
    Comparison groups
    Denosumab/Denosumab v Placebo/Denosumab
    Number of subjects included in analysis
    22
    Analysis specification
    Pre-specified
    Analysis type
    		 [10]
    P-value
    		 = 0.48
    Method
    		 Repeated Measures Model
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    0.37
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.697
         upper limit
    		 1.442
    Notes
    [10] - Repeated measures model including treatment (denosumab vs placebo), study visit (6, 12, 18, 24, and 36 months), baseline age, baseline BMD Z-score, and treatment-by visit included as an interaction with no imputation for missing data.
    Statistical analysis title
    		 Repeated Measures Model DXA Analysis Set
    Statistical analysis description
    Month 24 (Femoral Neck)
    Comparison groups
    Denosumab/Denosumab v Placebo/Denosumab
    Number of subjects included in analysis
    22
    Analysis specification
    Pre-specified
    Analysis type
    		 [11]
    P-value
    		 = 0.86
    Method
    		 Repeated Measures Model
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    0.11
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.222
         upper limit
    		 1.443
    Notes
    [11] - Repeated measures model including treatment (denosumab vs placebo), study visit (6, 12, 18, 24, and 36 months), baseline age, baseline BMD Z-score, and treatment-by visit included as an interaction with no imputation for missing data.
    Statistical analysis title
    		 Repeated Measures Model DXA Analysis Set
    Statistical analysis description
    Month 6 (Femoral Neck)
    Comparison groups
    Denosumab/Denosumab v Placebo/Denosumab
    Number of subjects included in analysis
    22
    Analysis specification
    Pre-specified
    Analysis type
    		 [12]
    P-value
    		 = 0.64
    Method
    		 Repeated Measures Model
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    -0.18
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.969
         upper limit
    		 0.614
    Notes
    [12] - Repeated measures model including treatment (denosumab vs placebo), study visit (6, 12, 18, 24, and 36 months), baseline age, baseline BMD Z-score, and treatment-by visit included as an interaction with no imputation for missing data.
    Statistical analysis title
    		 Repeated Measures Model DXA Analysis Set
    Statistical analysis description
    Month 36 (Femoral Neck)
    Comparison groups
    Denosumab/Denosumab v Placebo/Denosumab
    Number of subjects included in analysis
    22
    Analysis specification
    Pre-specified
    Analysis type
    		 [13]
    P-value
    		 = 0.66
    Method
    		 Repeated Measures Model
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    0.38
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.378
         upper limit
    		 2.13
    Notes
    [13] - Repeated measures model including treatment (denosumab vs placebo), study visit (6, 12, 18, 24, and 36 months), baseline age, baseline BMD Z-score, and treatment-by visit included as an interaction with no imputation for missing data.
    Statistical analysis title
    		 Repeated Measures Model DXA Analysis Set
    Statistical analysis description
    Month 24 (Total Hip)
    Comparison groups
    Denosumab/Denosumab v Placebo/Denosumab
    Number of subjects included in analysis
    22
    Analysis specification
    Pre-specified
    Analysis type
    		 [14]
    P-value
    		 = 0.69
    Method
    		 Repeated Measures Model
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    -0.18
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.098
         upper limit
    		 0.746
    Notes
    [14] - Repeated measures model including treatment (denosumab vs placebo), study visit (6, 12, 18, 24, and 36 months), baseline age, baseline BMD Z-score, and treatment-by visit included as an interaction with no imputation for missing data.
    Statistical analysis title
    		 Repeated Measures Model DXA Analysis Set
    Statistical analysis description
    Month 36 (Total Hip)
    Comparison groups
    Denosumab/Denosumab v Placebo/Denosumab
    Number of subjects included in analysis
    22
    Analysis specification
    Pre-specified
    Analysis type
    		 [15]
    P-value
    		 = 0.89
    Method
    		 Repeated Measures Model
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    -0.09
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.465
         upper limit
    		 1.286
    Notes
    [15] - Repeated measures model including treatment (denosumab vs placebo), study visit (6, 12, 18, 24, and 36 months), baseline age, baseline BMD Z-score, and treatment-by visit included as an interaction with no imputation for missing data.

    Secondary: Number of Participants with X-ray Confirmed Long-bone Fractures and/or Vertebral Fractures at 12, 24, and 36 Months

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    End point title
    		 Number of Participants with X-ray Confirmed Long-bone Fractures and/or Vertebral Fractures at 12, 24, and 36 Months
    End point description
    Number of participants who have at least one long bone fracture or vertebral fracture, and number of participants who have more than one long bone fracture or vertebral fracture. FAS: all participants randomized into the study.
    End point type
    Secondary
    End point timeframe
    Month 12, 24, and 36
    End point values
    		 Denosumab/Denosumab Placebo/Denosumab
    Number of subjects analysed
    16
    8
    Units: Participants
        Month 12 (at least 1 fracture)
    2
    2
        Month 24 (at least 1 fracture)
    3
    3
        Month 36 (at least 1 fracture)
    3
    3
        Month 12 (more than 1 fracture)
    2
    1
        Month 24 (more than 1 fracture)
    2
    0
        Month 36 (more than 1 fracture)
    3
    1
    No statistical analyses for this end point

    Secondary: Number of Participants with Improving Vertebral Fractures at 12, 24, and 36 Months

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    End point title
    		 Number of Participants with Improving Vertebral Fractures at 12, 24, and 36 Months
    End point description
    Vertebral Fracture Analysis Set: all participants in the FAS who have a non-missing baseline and ≥ 1 non missing postbaseline X-ray vertebral evaluation as provided by the central imaging vendor, on or before the time point under consideration.
    End point type
    Secondary
    End point timeframe
    Month 12, 24, and 36
    End point values
    		 Denosumab/Denosumab Placebo/Denosumab
    Number of subjects analysed
    15
    7
    Units: Participants
        Month 12
    3
    1
        Month 24
    2
    1
        Month 36
    1
    2
    No statistical analyses for this end point

    Secondary: Number of Participants with New and Worsening Vertebral and Non-vertebral Fractures at 12, 24, and 36 Months

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    End point title
    		 Number of Participants with New and Worsening Vertebral and Non-vertebral Fractures at 12, 24, and 36 Months
    End point description
    Number of participants who have at least one vertebral fracture or non-vertebral fracture, and number of participants who have more than one vertebral fracture or non-vertebral fracture. FAS: all participants randomized into the study.
    End point type
    Secondary
    End point timeframe
    Month 12, 24, and 36
    End point values
    		 Denosumab/Denosumab Placebo/Denosumab
    Number of subjects analysed
    16
    8
    Units: Participants
        Month 12 (at least 1 fracture)
    2
    2
        Month 24 (at least 1 fracture)
    3
    3
        Month 36 (at least 1 fracture)
    3
    3
        Month 12 (more than 1 fracture)
    2
    1
        Month 24 (more than 1 fracture)
    2
    0
        Month 36 (more than 1 fracture)
    3
    1
    No statistical analyses for this end point

    Secondary: Change From Baseline in Child Health Questionnaire-Parent Form-50 (CHQ-PF-50) Physical Summary Score at 12, 24, and 36 Months

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    End point title
    		 Change From Baseline in Child Health Questionnaire-Parent Form-50 (CHQ-PF-50) Physical Summary Score at 12, 24, and 36 Months
    End point description
    The CHQ-PF-50 is a 5O-item questionnaire to be completed by the parents or guardians of children between 5 and 18 years of age. The physical summary score ranges from 0-100 with higher scores indicating better physical health. Patient Reported Outcomes (PRO) Analysis Set: all participants in the FAS with baseline and at least one valid CHQ-PF-50 response at postbaseline.
    End point type
    Secondary
    End point timeframe
    Baseline and Month 12, 24, and 36
    End point values
    		 Denosumab/Denosumab Placebo/Denosumab
    Number of subjects analysed
    14
    7
    Units: Scores on a scale
    arithmetic mean (standard deviation)
        Month 12 n= 12, 7
    5.26 ( 8.88 )
    8.53 ( 16.39 )
        Month 24 n= 13, 5
    5.62 ( 7.39 )
    19.88 ( 15.20 )
        Month 36 n= 9, 5
    4.48 ( 8.89 )
    14.18 ( 8.14 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in CHQ-PF-50 Psychological Summary Score at 12, 24, and 36 Months

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    End point title
    		 Change From Baseline in CHQ-PF-50 Psychological Summary Score at 12, 24, and 36 Months
    End point description
    The CHQ-PF-50 is a 5O-item questionnaire to be completed by the parents or guardians of children between 5 and 18 years of age. The psychological summary score ranges from 0-100 with higher scores indicating better psychological health. PRO Analysis Set: all participants in the FAS with baseline and at least one valid CHQ-PF-50 response at postbaseline.
    End point type
    Secondary
    End point timeframe
    Baseline and Month 12, 24, and 36
    End point values
    		 Denosumab/Denosumab Placebo/Denosumab
    Number of subjects analysed
    14
    7
    Units: Scores on a scale
    arithmetic mean (standard deviation)
        Month 12 n= 12, 7
    0.71 ( 9.15 )
    -0.10 ( 12.52 )
        Month 24 n= 13, 5
    2.58 ( 12.58 )
    1.90 ( 9.76 )
        Month 36 n= 9, 5
    5.20 ( 10.09 )
    2.00 ( 9.33 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in Childhood Health Assessment Questionnaire (CHAQ) Disability Index Score at 12, 24, and 36 Months

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    End point title
    		 Change From Baseline in Childhood Health Assessment Questionnaire (CHAQ) Disability Index Score at 12, 24, and 36 Months
    End point description
    The CHAQ was developed to measure the physical functioning in children 6 months to 18 years of age. It consists of 54 questions related to the child's ability to perform various activities of daily living. Depending on the question asked, each question is scored either 0 to 3 based on the level of difficulty experienced by the child or 0-1 based on whether the child required assistance from another person or used an aid or other device. All CHAQ questions were scored and converted to a total index score ranging from 0-3, where higher scores indicate greater disability. PRO Analysis Set: all participants in the FAS with baseline and at least one valid CHAQ response at postbaseline.
    End point type
    Secondary
    End point timeframe
    Baseline and Month 12, 24, and 36
    End point values
    		 Denosumab/Denosumab Placebo/Denosumab
    Number of subjects analysed
    14
    7
    Units: Scores on a scale
    arithmetic mean (standard deviation)
        Month 12 n= 12, 7
    -0.06 ( 0.32 )
    -0.29 ( 0.44 )
        Month 24 n= 13, 5
    -0.09 ( 0.33 )
    -0.30 ( 0.49 )
        Month 36 n= 8, 5
    -0.12 ( 0.45 )
    -0.43 ( 0.45 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in Wong-Baker FACES Pain Rating Scale (WBFPRS) at 12, 24, and 36 Months

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    End point title
    		 Change From Baseline in Wong-Baker FACES Pain Rating Scale (WBFPRS) at 12, 24, and 36 Months
    End point description
    WBFPRS is a horizontal pain scale for children from 3 to 18 years, which consists of 6 hand-drawn faces that range from a smiling “no hurt” face with a score of 0 to a crying “hurts most” face with a score of 10. PRO Analysis Set: all participants in the FAS with baseline and at least one valid WBFPRS response at postbaseline.
    End point type
    Secondary
    End point timeframe
    Baseline and Month 12, 24, and 36
    End point values
    		 Denosumab/Denosumab Placebo/Denosumab
    Number of subjects analysed
    14
    7
    Units: Scores on a scale
    arithmetic mean (standard deviation)
        Month 12 n= 11, 7
    -0.7 ( 3.3 )
    -0.3 ( 3.9 )
        Month 24 n= 13, 5
    -0.6 ( 2.9 )
    -2.4 ( 0.9 )
        Month 36 n= 8, 5
    -2.5 ( 1.8 )
    0.0 ( 1.4 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in Growth Velocity Z-score (height) at 12, 24, and 36 Months

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    End point title
    		 Change From Baseline in Growth Velocity Z-score (height) at 12, 24, and 36 Months
    End point description
    Growth velocity was determined by calculating age-adjusted z-scores for height, weight, and body mass index (BMI). Z-scores represent the number of standard deviations from the reference population's mean, with 0 denoting the mean. Positive changes from baseline signify increased growth velocity. Growth Velocity Analysis Set: all participants in the FAS who have non-missing height and age in total months at baseline and postbaseline. Only participants with available data for growth velocity (height) are included. All participants included in the Overall Number of Participants Analyzed contributed data to this outcome measure.
    End point type
    Secondary
    End point timeframe
    Baseline and Month 12, 24, and 36
    End point values
    		 Denosumab/Denosumab Placebo/Denosumab
    Number of subjects analysed
    15
    8
    Units: Z-score
    arithmetic mean (standard deviation)
        Month 12 n= 13, 8
    -0.18 ( 0.46 )
    -0.07 ( 0.84 )
        Month 24 n= 12, 7
    -0.11 ( 0.90 )
    -0.27 ( 1.17 )
        Month 36 n= 12, 7
    -0.33 ( 0.84 )
    0.01 ( 1.35 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in Growth Velocity Z-score (weight) at 12, 24, and 36 Months

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    End point title
    		 Change From Baseline in Growth Velocity Z-score (weight) at 12, 24, and 36 Months
    End point description
    Growth velocity was determined by calculating age-adjusted z-scores for height, weight, and BMI. Z-scores represent the number of standard deviations from the reference population's mean, with 0 denoting the mean. Positive changes from baseline signify increased growth velocity. Growth Velocity Analysis Set: all participants in the FAS who have non-missing weight and age in total months at baseline and postbaseline. Only participants with available data for growth velocity (weight) are included.
    End point type
    Secondary
    End point timeframe
    Baseline and Month 12, 24, and 36
    End point values
    		 Denosumab/Denosumab Placebo/Denosumab
    Number of subjects analysed
    16
    8
    Units: Z-score
    arithmetic mean (standard deviation)
        Month 12 n= 15, 8
    -0.12 ( 0.44 )
    -0.10 ( 0.49 )
        Month 24 n= 12, 7
    -0.22 ( 0.73 )
    -0.68 ( 0.62 )
        Month 36 n= 12, 7
    -0.32 ( 0.90 )
    -0.44 ( 0.60 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in Growth Velocity Z-score (BMI) at 12, 24, and 36 Months

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    End point title
    		 Change From Baseline in Growth Velocity Z-score (BMI) at 12, 24, and 36 Months
    End point description
    Growth velocity was determined by calculating age-adjusted z-scores for height, weight, and BMI. Z-scores represent the number of standard deviations from the reference population's mean, with 0 denoting the mean. Positive changes from baseline signify increased growth velocity. Growth Velocity Analysis Set: all participants in the FAS who have non-missing BMI and age in total months at baseline and postbaseline. Only participants with available data for growth velocity (BMI) are included. All participants included in the Overall Number of Participants Analyzed contributed data to this outcome measure
    End point type
    Secondary
    End point timeframe
    Baseline and Month 12, 24, and 36
    End point values
    		 Denosumab/Denosumab Placebo/Denosumab
    Number of subjects analysed
    15
    8
    Units: Z-score
    arithmetic mean (standard deviation)
        Month 12 n= 13, 8
    -0.03 ( 0.53 )
    -0.14 ( 0.54 )
        Month 24 n= 12, 7
    -0.12 ( 0.80 )
    -0.75 ( 1.02 )
        Month 36 n= 12, 7
    -0.12 ( 0.84 )
    -0.72 ( 0.97 )
    No statistical analyses for this end point

    Secondary: Serum Concentration of Denosumab

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    End point title
    		 Serum Concentration of Denosumab [16]
    End point description
    Participants were randomized to receive 1 mg/kg Denosumab or Placebo by SC injection up to a maximum of 60 mg, Q6M for 12 months during the Treatment Period. All participants then received 1 mg/kg Denosumab, up to a maximum of 60 mg, Q6M, for the second 12 months of the Treatment Period. Participants were then followed for an additional 12 months during the Off-treatment Observation Period. PK Analysis Set: all participants in the FAS who have ≥ 1 denosumab reported result.
    End point type
    Secondary
    End point timeframe
    Day 1, Day 10, Day 30, Month 3, and Month 6
    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: Arms were pooled for serum concentration analysis.
    End point values
    		 Denosumab/Denosumab
    Number of subjects analysed
    14
    Units: ng/mL
    arithmetic mean (standard deviation)
        Day 1 n= 14
    0.00 ( 0.00 )
        Day 10 n= 11
    10300 ( 7900 )
        Day 30 n= 9
    6830 ( 4770 )
        Month 3 n= 10
    1100 ( 935 )
        Month 6 n= 12
    141 ( 338 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From enrollment through last dose, up to 36 months.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    26.1
    Reporting groups
    Reporting group title
    Baseline-Month 12: Placebo
    Reporting group description
    		 Participants received placebo by SC injection during the first 12 months of the Treatment Period.

    Reporting group title
    Baseline-Month 12: Denosumab
    Reporting group description
    		 Participants received 1 mg/kg Denosumab up to a maximum of 60 mg, Q6M by SC injection during the first 12 months of the Treatment Period.

    Reporting group title
    Baseline-Month 36: Denosumab/Denosumab
    Reporting group description
    		 Participants received 1 mg/kg Denosumab by SC injection up to a maximum of 60 mg, Q6M for 24 months during the Treatment Period. Participants were then followed for an additional 12 months during the Off-treatment Observation Period.

    Reporting group title
    Baseline-Month 24: Denosumab/Denosumab
    Reporting group description
    		 Participants received 1 mg/kg Denosumab by SC injection up to a maximum of 60 mg, Q6M for 24 months during the Treatment Period.

    Reporting group title
    Baseline-Month 36: Placebo/Denosumab
    Reporting group description
    		 Participants received matching placebo by SC injection Q6M for the first 12 months of the Treatment Period. This was followed by 1 mg/kg Denosumab up to a maximum of 60 mg, Q6M administered by SC injection for the second 12 months of the Treatment Period. Participants were then followed for an additional 12 months during the Off-treatment Observation Period.

    Reporting group title
    Baseline-Month 24: Placebo/Denosumab
    Reporting group description
    		 Participants received matching placebo by SC injection Q6M for the first 12 months of the Treatment Period. This was followed by 1 mg/kg Denosumab administered by SC injection Q6M for the second 12 months of the Treatment Period.

    Serious adverse events
    		 Baseline-Month 12: Placebo Baseline-Month 12: Denosumab Baseline-Month 36: Denosumab/Denosumab Baseline-Month 24: Denosumab/Denosumab Baseline-Month 36: Placebo/Denosumab Baseline-Month 24: Placebo/Denosumab
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 8 (12.50%)
    3 / 16 (18.75%)
    4 / 16 (25.00%)
    3 / 16 (18.75%)
    2 / 8 (25.00%)
    1 / 8 (12.50%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    Injury, poisoning and procedural complications
    Tibia fracture
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 16 (6.25%)
    1 / 16 (6.25%)
    1 / 16 (6.25%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 16 (6.25%)
    1 / 16 (6.25%)
    1 / 16 (6.25%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Brain contusion
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 16 (6.25%)
    1 / 16 (6.25%)
    1 / 16 (6.25%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Cardiomyopathy
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    1 / 8 (12.50%)
    1 / 8 (12.50%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Uterine haemorrhage
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 16 (6.25%)
    1 / 16 (6.25%)
    1 / 16 (6.25%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Autoimmune hepatitis
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 16 (6.25%)
    1 / 16 (6.25%)
    1 / 16 (6.25%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Ureterolithiasis
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    1 / 8 (12.50%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Infections and infestations
    Urinary tract infection
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    1 / 16 (6.25%)
    0 / 16 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Baseline-Month 12: Placebo Baseline-Month 12: Denosumab Baseline-Month 36: Denosumab/Denosumab Baseline-Month 24: Denosumab/Denosumab Baseline-Month 36: Placebo/Denosumab Baseline-Month 24: Placebo/Denosumab
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    5 / 8 (62.50%)
    11 / 16 (68.75%)
    13 / 16 (81.25%)
    12 / 16 (75.00%)
    5 / 8 (62.50%)
    5 / 8 (62.50%)
    General disorders and administration site conditions
    Hyperthermia
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    1 / 8 (12.50%)
    1 / 8 (12.50%)
         occurrences all number
    1
    0
    0
    0
    1
    1
    Fatigue
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 16 (6.25%)
    1 / 16 (6.25%)
    1 / 16 (6.25%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    1
    1
    0
    0
    Asthenia
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    1 / 16 (6.25%)
    1 / 16 (6.25%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    0
    Injection site pain
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 16 (6.25%)
    1 / 16 (6.25%)
    1 / 16 (6.25%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    1
    1
    0
    0
    Pyrexia
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 16 (6.25%)
    2 / 16 (12.50%)
    1 / 16 (6.25%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    2
    1
    0
    0
    Reproductive system and breast disorders
    Dysmenorrhoea
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    1 / 8 (12.50%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Central sleep apnoea syndrome
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 16 (6.25%)
    1 / 16 (6.25%)
    1 / 16 (6.25%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    1
    1
    0
    0
    Cough
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    1 / 8 (12.50%)
    1 / 8 (12.50%)
         occurrences all number
    1
    0
    0
    0
    1
    1
    Epistaxis
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 16 (6.25%)
    1 / 16 (6.25%)
    1 / 16 (6.25%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    1
    1
    0
    0
    Nasal septum deviation
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    1 / 16 (6.25%)
    1 / 16 (6.25%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    0
    Obstructive sleep apnoea syndrome
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    1 / 16 (6.25%)
    1 / 16 (6.25%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    0
    Oropharyngeal pain
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    1 / 16 (6.25%)
    0 / 16 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Pleural effusion
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    1 / 8 (12.50%)
    1 / 8 (12.50%)
         occurrences all number
    1
    0
    0
    0
    1
    1
    Rhinorrhoea
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    1 / 8 (12.50%)
    1 / 8 (12.50%)
         occurrences all number
    1
    0
    0
    0
    1
    1
    Vasomotor rhinitis
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    1 / 8 (12.50%)
    1 / 8 (12.50%)
         occurrences all number
    1
    0
    0
    0
    1
    1
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 16 (6.25%)
    1 / 16 (6.25%)
    1 / 16 (6.25%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    1
    1
    0
    0
    Investigations
    Bone density decreased
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    1 / 8 (12.50%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Injury, poisoning and procedural complications
    Femur fracture
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 16 (6.25%)
    1 / 16 (6.25%)
    1 / 16 (6.25%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    1
    1
    0
    0
    Tooth fracture
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    1 / 8 (12.50%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Congenital, familial and genetic disorders
    Intracranial lipoma
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    1 / 8 (12.50%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Cardiac disorders
    Cardiac failure
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    1 / 16 (6.25%)
    1 / 16 (6.25%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    0
    Cardiomyopathy
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    1 / 8 (12.50%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Tachycardia
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 16 (6.25%)
    2 / 16 (12.50%)
    2 / 16 (12.50%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    2
    2
    0
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    1 / 8 (12.50%)
    2 / 16 (12.50%)
    3 / 16 (18.75%)
    2 / 16 (12.50%)
    1 / 8 (12.50%)
    1 / 8 (12.50%)
         occurrences all number
    1
    5
    8
    6
    1
    1
    Hypoaesthesia
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    1 / 16 (6.25%)
    0 / 16 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Myelopathy
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    1 / 8 (12.50%)
    1 / 8 (12.50%)
         occurrences all number
    1
    0
    0
    0
    1
    1
    Syncope
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 16 (6.25%)
    1 / 16 (6.25%)
    1 / 16 (6.25%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    1
    1
    0
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 8 (0.00%)
    2 / 16 (12.50%)
    2 / 16 (12.50%)
    2 / 16 (12.50%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    2
    2
    2
    0
    0
    Iron deficiency anaemia
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    1 / 8 (12.50%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    Eye disorders
    Cataract subcapsular
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    1 / 8 (12.50%)
    1 / 8 (12.50%)
         occurrences all number
    1
    0
    0
    0
    1
    1
    Cataract
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 16 (6.25%)
    1 / 16 (6.25%)
    1 / 16 (6.25%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    1
    1
    0
    0
    Astigmatism
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    1 / 8 (12.50%)
    1 / 8 (12.50%)
         occurrences all number
    1
    0
    0
    0
    1
    1
    Gastrointestinal disorders
    Abdominal discomfort
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 16 (6.25%)
    1 / 16 (6.25%)
    1 / 16 (6.25%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    1
    1
    0
    0
    Constipation
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    1 / 8 (12.50%)
    1 / 8 (12.50%)
         occurrences all number
    1
    0
    0
    0
    1
    1
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    1 / 16 (6.25%)
    1 / 16 (6.25%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    0
    Gastrointestinal disorder
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 16 (6.25%)
    2 / 16 (12.50%)
    2 / 16 (12.50%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    2
    2
    0
    0
    Duodenogastric reflux
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 16 (6.25%)
    2 / 16 (12.50%)
    2 / 16 (12.50%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    2
    2
    0
    0
    Duodenal bulb deformity
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    1 / 16 (6.25%)
    1 / 16 (6.25%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    0
    Diarrhoea
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    1 / 8 (12.50%)
    1 / 8 (12.50%)
         occurrences all number
    1
    0
    0
    0
    1
    1
    Dental caries
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    1 / 8 (12.50%)
    1 / 8 (12.50%)
         occurrences all number
    1
    0
    0
    0
    1
    1
    Oesophagitis
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 16 (6.25%)
    1 / 16 (6.25%)
    1 / 16 (6.25%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    1
    1
    0
    0
    Vomiting
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    1 / 8 (12.50%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Hepatobiliary disorders
    Autoimmune hepatitis
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    1 / 16 (6.25%)
    1 / 16 (6.25%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    0
    Biliary tract disorder
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    1 / 8 (12.50%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Skin and subcutaneous tissue disorders
    Dry skin
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 16 (6.25%)
    1 / 16 (6.25%)
    1 / 16 (6.25%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    1
    1
    0
    0
    Dermal cyst
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    1 / 8 (12.50%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Acne
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    1 / 16 (6.25%)
    0 / 16 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Chronic spontaneous urticaria
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 16 (6.25%)
    1 / 16 (6.25%)
    1 / 16 (6.25%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    1
    1
    0
    0
    Erythema
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 16 (6.25%)
    1 / 16 (6.25%)
    1 / 16 (6.25%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    1
    1
    0
    0
    Eczema
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 16 (6.25%)
    1 / 16 (6.25%)
    1 / 16 (6.25%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    1
    1
    0
    0
    Ingrowing nail
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 16 (6.25%)
    1 / 16 (6.25%)
    1 / 16 (6.25%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    1
    1
    0
    0
    Renal and urinary disorders
    Metabolic nephropathy
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    1 / 8 (12.50%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Endocrine disorders
    Delayed puberty
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 16 (6.25%)
    2 / 16 (12.50%)
    1 / 16 (6.25%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    2
    1
    0
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    1 / 16 (6.25%)
    1 / 16 (6.25%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    0
    Autoimmune arthritis
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 16 (6.25%)
    1 / 16 (6.25%)
    1 / 16 (6.25%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    1
    1
    0
    0
    Back pain
         subjects affected / exposed
    0 / 8 (0.00%)
    2 / 16 (12.50%)
    2 / 16 (12.50%)
    2 / 16 (12.50%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    2
    2
    2
    0
    0
    Costochondritis
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    1 / 8 (12.50%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Dwarfism
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    1 / 8 (12.50%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Musculoskeletal chest pain
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 16 (6.25%)
    1 / 16 (6.25%)
    1 / 16 (6.25%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    1
    1
    0
    0
    Osteonecrosis
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    1 / 16 (6.25%)
    0 / 16 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Myalgia
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    1 / 16 (6.25%)
    1 / 16 (6.25%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    0
    Infections and infestations
    Balanitis candida
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    1 / 16 (6.25%)
    1 / 16 (6.25%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    0
    COVID-19
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    1 / 16 (6.25%)
    1 / 16 (6.25%)
    1 / 8 (12.50%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    1
    1
    1
    1
    Hordeolum
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    1 / 16 (6.25%)
    1 / 16 (6.25%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    0
    Chronic tonsillitis
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 16 (6.25%)
    1 / 16 (6.25%)
    1 / 16 (6.25%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    1
    1
    0
    0
    Coronavirus infection
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    1 / 16 (6.25%)
    0 / 16 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Gingivitis
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 16 (6.25%)
    1 / 16 (6.25%)
    1 / 16 (6.25%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    1
    1
    0
    0
    Gastrointestinal infection
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 16 (6.25%)
    1 / 16 (6.25%)
    1 / 16 (6.25%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    1
    1
    0
    0
    Fungal skin infection
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    1 / 16 (6.25%)
    1 / 16 (6.25%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    0
    Epstein-Barr virus infection
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    1 / 16 (6.25%)
    0 / 16 (0.00%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    COVID-19 pneumonia
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    1 / 8 (12.50%)
    1 / 8 (12.50%)
         occurrences all number
    1
    0
    0
    0
    1
    1
    Influenza
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    1 / 8 (12.50%)
    1 / 8 (12.50%)
         occurrences all number
    1
    0
    0
    0
    2
    1
    Nasopharyngitis
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 16 (0.00%)
    3 / 16 (18.75%)
    0 / 16 (0.00%)
    1 / 8 (12.50%)
    1 / 8 (12.50%)
         occurrences all number
    1
    0
    4
    0
    1
    1
    Respiratory tract infection
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    1 / 8 (12.50%)
    1 / 8 (12.50%)
         occurrences all number
    1
    0
    0
    0
    2
    2
    Rhinitis
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 16 (6.25%)
    1 / 16 (6.25%)
    1 / 16 (6.25%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    1
    1
    0
    0
    Skin infection
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 16 (6.25%)
    1 / 16 (6.25%)
    1 / 16 (6.25%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    1
    1
    0
    0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 16 (6.25%)
    1 / 16 (6.25%)
    1 / 16 (6.25%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    1
    1
    0
    0
    Varicella
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 16 (6.25%)
    1 / 16 (6.25%)
    1 / 16 (6.25%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    1
    1
    0
    0
    Viral tonsillitis
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 16 (6.25%)
    1 / 16 (6.25%)
    1 / 16 (6.25%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    1
    1
    0
    0
    Vulvitis
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    1 / 8 (12.50%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Metabolism and nutrition disorders
    Iron deficiency
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    1 / 8 (12.50%)
    1 / 8 (12.50%)
         occurrences all number
    1
    0
    0
    0
    1
    1
    Vitamin D deficiency
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 16 (6.25%)
    1 / 16 (6.25%)
    1 / 16 (6.25%)
    0 / 8 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    1
    1
    0
    0

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    14 Feb 2017
    Amendment 1: - Updated placebo arm to transition to open-label denosumab at 12 months and continue open-label denosumab for an additional 12 months. - Updated primary analysis to be conducted at the time of the final analysis. - Updated primary analysis to use an ANCOVA model, replacing the repeated measures analysis, which was updated to be included as a sensitivity analysis. - Updated protocol to include imputation rules for primary endpoint analysis.
    25 May 2018
    Amendment 2: - Updated exclusion criteria to include any causes of primary or secondary osteoporosis (other than GC use), or previous exposure to non-GC medications, which the investigator considers to have been a major factor contributing to the patient’s fracture(s). - Updated schedule of assessments to include blood sampling for immunogenicity assessments at months 1, 3, and 6. - Added description of additional sensitivity analysis to assess impact of short stature on BMD Z-scores in response to FDA. - Changed description of placebo to reflect the fact that with the new XGEVA formulation, the placebo will no longer be identical in composition.
    20 Apr 2021
    Amendment 3: - Updated the number of subjects enrolled in the study to 24 from an initial plan to enroll 150 subjects. - Updated close of enrollment to January 2021 because too few children with disease or condition to study.
    10 Jul 2023
    Amendment 4: - Updated "from pre-treatment to post-treatment" to "compared to baseline" to clarify that the determination of improving vertebral fracture is to compare with baseline spine X-ray. - Removed subgroup analyses because of low enrollment. - Updated language to clarify that new and worsening vertebral and non-vertebral fractures will be used to evaluate the effect of denosumab in children with GiOP.

    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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