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    Clinical Trial Results:
    Prospective, Multicenter, Single-arm Study to Evaluate Efficacy, Safety, and Pharmacokinetics of Denosumab in Children With Osteogenesis Imperfecta

    Summary
    EudraCT number
    		 2014-000184-40
    Trial protocol
    		 CZ   DE   GB   HU   ES   Outside EU/EEA   BG   PL   BE   FR   IT  
    Global end of trial date
    26 Mar 2022

    Results information
    Results version number
    		 v1(current)
    This version publication date
    11 Oct 2022
    First version publication date
    11 Oct 2022
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    20130173
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03638128
    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
    IHQ Medical Info-Clinical Trials, Amgen (EUROPE) GmbH, MedInfoInternational@amgen.com
    Scientific contact
    IHQ Medical Info-Clinical Trials, Amgen (EUROPE) GmbH, 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?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    26 Mar 2022
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    26 Mar 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main objective of the trial was to evaluate the effect of denosumab in lumbar spine bone mineral density (BMD) Z-score at 12 months, as assessed by dual-energy X-ray absorptiometry (DXA), in children 2 to 17 years of age (at the time of screening) with osteogenesis imperfecta (OI) on a 3-month dosing regimen.
    Protection of trial subjects
    This study was conducted in accordance with International Council for Harmonisation Good Clinical Practice regulations/guidelines.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    24 Jun 2015
    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
    Australia: 2
    Country: Number of subjects enrolled
    Belgium: 7
    Country: Number of subjects enrolled
    Bulgaria: 2
    Country: Number of subjects enrolled
    Czechia: 5
    Country: Number of subjects enrolled
    France: 3
    Country: Number of subjects enrolled
    Germany: 40
    Country: Number of subjects enrolled
    Hungary: 13
    Country: Number of subjects enrolled
    Italy: 13
    Country: Number of subjects enrolled
    Poland: 6
    Country: Number of subjects enrolled
    Spain: 6
    Country: Number of subjects enrolled
    United Kingdom: 11
    Country: Number of subjects enrolled
    Canada: 15
    Country: Number of subjects enrolled
    United States: 30
    Worldwide total number of subjects
    153
    EEA total number of subjects
    95
    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)
    106
    Adolescents (12-17 years)
    46
    Adults (18-64 years)
    1
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The study was conducted at 32 centers in North America, Europe, and Australia from June 2015 to March 2022.

    Pre-assignment
    Screening details
    		 Participants were screened within 35 days or rescreened within 42 days prior to receiving the initial dose of investigational product.

    Period 1
    Period 1 title
    6-Month Dosing Period
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Denosumab
    Arm description
    		 Participants received denosumab 1 mg/kg (up to a maximum of 60 mg) subcutaneously every 6 months (Q6M) for up to 36 months. Participants were dose adjusted from Q6M to every 3 months (Q3M) after early efficacy and pharmacokinetic (PK) data were analyzed. Participants enrolled and still receiving denosumab were transitioned from Q6M to Q3M dosing schedule. Participants could transition to Q3M dosing schedule up to and including the date they attended for their Month 36 visit under the Q6M dosing regimen. Those participants received denosumab during the Q3M dosing regimen for 12 months. Participants who transitioned to Q3M at month 18 of the Q6M dosing regimen received denosumab Q3M for up to 18 months.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Denosumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subcutaneous (SC) denosumab 1mg/kg (up to a maximum of 60 mg).

    Number of subjects in period 1
    		Denosumab
    Started
    153
    Received investigational product
    153
    Completed
    115
    Not completed
    38
         Consent withdrawn by subject
    34
         Lost to follow-up
    2
         Decision by sponsor
    2
    Period 2
    Period 2 title
    3-Month Dosing Period
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Denosumab
    Arm description
    		 Participants received denosumab 1 mg/kg (up to a maximum of 60 mg) subcutaneously every 6 months (Q6M) for up to 36 months. Participants were dose adjusted from Q6M to every 3 months (Q3M) after early efficacy and pharmacokinetic (PK) data were analyzed. Participants enrolled and still receiving denosumab were transitioned from Q6M to Q3M dosing schedule. Participants could transition to Q3M dosing schedule up to and including the date they attended for their Month 36 visit under the Q6M dosing regimen. Those participants received denosumab during the Q3M dosing regimen for 12 months. Participants who transitioned to Q3M at month 18 of the Q6M dosing regimen received denosumab Q3M for up to 18 months.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Denosumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subcutaneous (SC) denosumab 1mg/kg (up to a maximum of 60 mg).

    Number of subjects in period 2 [1]
    		Denosumab
    Started
    60
    Received Investigational Product
    60
    Completed
    40
    Not completed
    20
         Consent withdrawn by subject
    6
         Decision by sponsor
    14
    Notes
    [1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: 55 participants completed Q6M and did not continue into the Q3M dosing regimen. Only 60 participants were transitioned to Q3M dosing regimen.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Denosumab
    Reporting group description
    		 Participants received denosumab 1 mg/kg (up to a maximum of 60 mg) subcutaneously every 6 months (Q6M) for up to 36 months. Participants were dose adjusted from Q6M to every 3 months (Q3M) after early efficacy and pharmacokinetic (PK) data were analyzed. Participants enrolled and still receiving denosumab were transitioned from Q6M to Q3M dosing schedule. Participants could transition to Q3M dosing schedule up to and including the date they attended for their Month 36 visit under the Q6M dosing regimen. Those participants received denosumab during the Q3M dosing regimen for 12 months. Participants who transitioned to Q3M at month 18 of the Q6M dosing regimen received denosumab Q3M for up to 18 months.

    Reporting group values
    		 Denosumab Total
    Number of subjects
    		 153 153
    Age categorical
    Units: Subjects
        Children (2-11 years)
    		 106 106
        Adolescents (12-17 years)
    		 46 46
        Adults (18-64 years)
    		 1 1
        From 65-84 years
    		 0 0
        In utero
    		 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0
        Newborns (0-27 days)
    		 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0
        85 years and over
    		 0 0
    Age Continuous
    Data presented is the age at Q6M dosing regimen enrolment.
    Units: Years
        arithmetic mean (standard deviation)
    		 9.3 ( 3.9 ) -
    Sex: Female, Male
    Units: Participants
        Female
    		 73 73
        Male
    		 80 80
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 15 15
        Not Hispanic or Latino
    		 138 138
        Unknown or Not Reported
    		 0 0
    Race/Ethnicity, Customized
    Units: Subjects
        Asian
    		 4 4
        Black or African American
    		 2 2
        White
    		 135 135
        Other
    		 8 8
        Multiple
    		 4 4
    Subject analysis sets

    Subject analysis set title
    6-Month Dosing Regimen Safety Analysis Set
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    All participants who were enrolled in the study who received at least 1 dose of denosumab in the Q6M dosing regimen.

    Subject analysis set title
    3-Month Dosing Regimen Safety Analysis Set
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    All participants who were enrolled in the study who received at least 1 dose of denosumab in the Q3M dosing regimen.

    Subject analysis sets values
    		 6-Month Dosing Regimen Safety Analysis Set 3-Month Dosing Regimen Safety Analysis Set
    Number of subjects
    153
    60
    Age categorical
    Units: Subjects
        Children (2-11 years)
        Adolescents (12-17 years)
        Adults (18-64 years)
        From 65-84 years
        In utero
        Preterm newborn infants (gestational age < 37 wks)
        Newborns (0-27 days)
        Infants and toddlers (28 days-23 months)
        85 years and over
    Age Continuous
    Data presented is the age at Q6M dosing regimen enrolment.
    Units: Years
        arithmetic mean (standard deviation)
    9.3 ( 3.9 )
    11.0 ( 4.4 )
    Sex: Female, Male
    Units: Participants
        Female
        Male
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
        Not Hispanic or Latino
        Unknown or Not Reported
    Race/Ethnicity, Customized
    Units: Subjects
        Asian
        Black or African American
        White
        Other
        Multiple

    End points

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    End points reporting groups
    Reporting group title
    Denosumab
    Reporting group description
    		 Participants received denosumab 1 mg/kg (up to a maximum of 60 mg) subcutaneously every 6 months (Q6M) for up to 36 months. Participants were dose adjusted from Q6M to every 3 months (Q3M) after early efficacy and pharmacokinetic (PK) data were analyzed. Participants enrolled and still receiving denosumab were transitioned from Q6M to Q3M dosing schedule. Participants could transition to Q3M dosing schedule up to and including the date they attended for their Month 36 visit under the Q6M dosing regimen. Those participants received denosumab during the Q3M dosing regimen for 12 months. Participants who transitioned to Q3M at month 18 of the Q6M dosing regimen received denosumab Q3M for up to 18 months.
    Reporting group title
    Denosumab
    Reporting group description
    		 Participants received denosumab 1 mg/kg (up to a maximum of 60 mg) subcutaneously every 6 months (Q6M) for up to 36 months. Participants were dose adjusted from Q6M to every 3 months (Q3M) after early efficacy and pharmacokinetic (PK) data were analyzed. Participants enrolled and still receiving denosumab were transitioned from Q6M to Q3M dosing schedule. Participants could transition to Q3M dosing schedule up to and including the date they attended for their Month 36 visit under the Q6M dosing regimen. Those participants received denosumab during the Q3M dosing regimen for 12 months. Participants who transitioned to Q3M at month 18 of the Q6M dosing regimen received denosumab Q3M for up to 18 months.

    Subject analysis set title
    6-Month Dosing Regimen Safety Analysis Set
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    All participants who were enrolled in the study who received at least 1 dose of denosumab in the Q6M dosing regimen.

    Subject analysis set title
    3-Month Dosing Regimen Safety Analysis Set
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    All participants who were enrolled in the study who received at least 1 dose of denosumab in the Q3M dosing regimen.

    Primary: Change from Baseline in Lumbar Spine Bone Mineral Density (BMD) Z-Score at 12 Months

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    End point title
    		 Change from Baseline in Lumbar Spine Bone Mineral Density (BMD) Z-Score at 12 Months [1]
    End point description
    Lumbar spine BMD was measured by dual-energy X-ray absorptiometry (DXA) adjusted for age, sex, and race/ethnicity. The results were then converted to Z-scores. The Z-score indicated the number of standard deviations away from the reference population and a score of 0 is equal to the mean. Positive changes from Baseline indicated an improvement in lumbar spine BMD. DXA Analysis Set included all participants in the FAS with Baseline and Month 12 DXA assessment on the Q3M dosing regimen for lumbar spine as provided by the central imaging vendor.
    End point type
    Primary
    End point timeframe
    Baseline and 12 months
    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: No formal statistics were planned.
    End point values
    		 Denosumab
    Number of subjects analysed
    45
    Units: Z-score
        least squares mean (standard error)
    1.009 ( 0.119 )
    No statistical analyses for this end point

    Secondary: Change from Baseline in Lumbar Spine BMD Z-score at 6 Months

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    End point title
    		 Change from Baseline in Lumbar Spine BMD Z-score at 6 Months
    End point description
    Lumbar spine BMD was measured by DXA adjusted for age, sex, and race/ethnicity. The results were then converted to Z-scores. The Z-score indicated the number of standard deviations away from the reference population and a score of 0 is equal to the mean. Positive changes from Baseline indicated an improvement in lumbar spine BMD. DXA Analysis Set included all participants in the FAS with Baseline and Month 12 DXA assessment on the Q3M dosing regimen for lumbar spine as provided by the central imaging vendor.
    End point type
    Secondary
    End point timeframe
    Baseline and 6 months
    End point values
    		 Denosumab
    Number of subjects analysed
    54
    Units: Z-score
        least squares mean (standard error)
    0.925 ( 0.078 )
    No statistical analyses for this end point

    Secondary: Change from Baseline in Proximal Femur BMD Z-score at 6 and 12 Months

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    End point title
    		 Change from Baseline in Proximal Femur BMD Z-score at 6 and 12 Months
    End point description
    Proximal femur (total hip and femoral neck) BMD Z-score was measured by DXA adjusted for age, sex, and race/ethnicity. The results were then converted to Z-scores. The Z-score indicated the number of standard deviations away from the reference population and a score of 0 is equal to the mean. Positive changes from Baseline indicated an improvement in lumbar spine BMD. DXA Analysis Set included all participants in the FAS with Baseline, Month 6 and Month 12 DXA assessment on the Q3M dosing regimen for lumbar spine as provided by the central imaging vendor. Only participants 5 years of age or older are included.
    End point type
    Secondary
    End point timeframe
    Baseline, 6 and 12 months
    End point values
    		 Denosumab
    Number of subjects analysed
    32
    Units: Z score
    least squares mean (standard error)
        Total hip BMD Z-score - 6 Months
    0.799 ( 0.082 )
        Total hip BMD Z-score - 12 Months
    0.793 ( 0.154 )
        Femoral neck BMD Z-score - 6 Months
    0.769 ( 0.067 )
        Femoral neck BMD Z-score - 12 Months
    0.689 ( 0.131 )
    No statistical analyses for this end point

    Secondary: Percentage of Participants with at least 1 X-ray Confirmed Long Bone or New and Worsening Vertebral Fracture

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    End point title
    		 Percentage of Participants with at least 1 X-ray Confirmed Long Bone or New and Worsening Vertebral Fracture
    End point description
    Q3M Dosing Regimen Safety Analysis Set: includes all participants in the FAS who received ≥ 1 dose of Q3M dosing regimen.
    End point type
    Secondary
    End point timeframe
    Q6M Dosing Regimen: Last 12 months of treatment (median treatment duration was 730.0 days); Q3M Dosing Regimen: Day 1 up to 12 months
    End point values
    		 Denosumab Denosumab
    Number of subjects analysed
    60
    60
    Units: Percentage of participants
        number (not applicable)
    28.3
    26.7
    No statistical analyses for this end point

    Secondary: Percentage of Participants with at least 1 X-ray Confirmed New and Worsening Vertebral Fracture

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    End point title
    		 Percentage of Participants with at least 1 X-ray Confirmed New and Worsening Vertebral Fracture
    End point description
    The Vertebral Fracture Analysis Set: includes all participants in the FAS who had a readable non-missing baseline and ≥1 non-missing postbaseline X-ray vertebral evaluation on the Q3M dosing regimen as provided by the central imaging vendor.
    End point type
    Secondary
    End point timeframe
    Q6M Dosing Regimen: Last 12 months of treatment (median treatment duration was 730.0 days); Q3M Dosing Regimen: Day 1 up to 12 months
    End point values
    		 Denosumab Denosumab
    Number of subjects analysed
    60
    60
    Units: Percentage of participants
        number (not applicable)
    12.8
    8.5
    No statistical analyses for this end point

    Secondary: Percentage of Participants wth at least 1 X-ray Confirmed Improving Vertebral Fracture

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    End point title
    		 Percentage of Participants wth at least 1 X-ray Confirmed Improving Vertebral Fracture
    End point description
    The Vertebral Fracture Analysis Set: includes all participants in the FAS who had a readable non-missing baseline and ≥1 non-missing postbaseline X-ray vertebral evaluation on the Q3M dosing regimen as provided by the central imaging vendor.
    End point type
    Secondary
    End point timeframe
    Q3M Dosing Regimen: Baseline up to 12 months
    End point values
    		 Denosumab
    Number of subjects analysed
    47
    Units: Percentage of participants
        number (not applicable)
    27.7
    No statistical analyses for this end point

    Secondary: Percentage of Participants with at least 1 X-ray Confirmed New Vertebral Fracture

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    End point title
    		 Percentage of Participants with at least 1 X-ray Confirmed New Vertebral Fracture
    End point description
    The Vertebral Fracture Analysis Set: includes all participants in the FAS who had a readable non-missing baseline and ≥1 non-missing postbaseline X-ray vertebral evaluation on the Q3M dosing regimen as provided by the central imaging vendor.
    End point type
    Secondary
    End point timeframe
    Q6M Dosing Regimen: Last 12 months of treatment (median treatment duration was 730.0 days); Q3M Dosing Regimen: Day 1 up to 12 months
    End point values
    		 Denosumab Denosumab
    Number of subjects analysed
    47
    47
    Units: Percentage of participants
        number (not applicable)
    10.6
    6.4
    No statistical analyses for this end point

    Secondary: Percentage of Participants with at least 1 Vertebral and Nonvertebral Fracture

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    End point title
    		 Percentage of Participants with at least 1 Vertebral and Nonvertebral Fracture
    End point description
    Q3M Dosing Regimen Safety Analysis Set: includes all participants in the FAS who received ≥ 1 dose of Q3M dosing regimen. Only participants 5 years of age or older are included.
    End point type
    Secondary
    End point timeframe
    Q6M Dosing Regimen: Last 12 months of treatment (median treatment duration was 730.0 days); Q3M Dosing Regimen: Day 1 up to 12 months
    End point values
    		 Denosumab Denosumab
    Number of subjects analysed
    56
    56
    Units: Percentage of participants
        number (not applicable)
    28.6
    30.4
    No statistical analyses for this end point

    Secondary: Change from Baseline in Child Health Questionnaire–Parent Form Physical Summary Score (CHQ-PF-50) at 12 Months

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    End point title
    		 Change from Baseline in Child Health Questionnaire–Parent Form Physical Summary Score (CHQ-PF-50) at 12 Months
    End point description
    The CHQ-PF-50 was a 50-item questionnaire completed by the parents or guardians of children between 5 and 18 years of age. The 50 questions measure 14 domains which were summarized as the physical and psychological summary scores. Each summary score was transformed and could range from 0 to 100, with higher score indicating better physical and psychosocial health. A negative change from Baseline indicates decreased well-being. Patient Reported Outcomes (PRO) Analysis Set: includes all participants in the FAS who had a baseline and ≥ 1 postbaseline valid PRO response on Q3M dosing regimen for the CHQ-PF-50. The CHQ-PF-50 analysis set only includes participants 5 years of age and older at screening.
    End point type
    Secondary
    End point timeframe
    Baseline and 12 months
    End point values
    		 Denosumab
    Number of subjects analysed
    45
    Units: Score on a scale
        arithmetic mean (standard deviation)
    -0.98 ( 15.41 )
    No statistical analyses for this end point

    Secondary: Change from Baseline in CHQ-PF-50 Psychological Summary Score at 12 Months

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    End point title
    		 Change from Baseline in CHQ-PF-50 Psychological Summary Score at 12 Months
    End point description
    The CHQ-PF-50 was a 50-item questionnaire completed by the parents or guardians of children between 5 and 18 years of age. The 50 questions measure 14 domains which were summarized as the physical and psychological summary scores. Each summary score was transformed and could range from 0 to 100, with higher score indicating better physical and psychosocial health. A positive change from Baseline indicates improved well-being. Patient Reported Outcomes (PRO) Analysis Set: includes all participants in the FAS who had a baseline and ≥ 1 postbaseline valid PRO response on Q3M dosing regimen for the CHQ-PF-50. The CHQ-PF-50 analysis set only includes participants 5 years of age and older at screening. PRO Analysis Set includes all participants in the FAS who had a baseline and ≥ 1 postbaseline valid PRO response on Q3M dosing regimen for the CHQ-PF-50. The CHQ-PF-50 analysis set only includes participants 5 years of age and older at screening
    End point type
    Secondary
    End point timeframe
    Baseline and 12 months
    End point values
    		 Denosumab
    Number of subjects analysed
    45
    Units: Score on a scale
        arithmetic mean (standard deviation)
    0.85 ( 8.57 )
    No statistical analyses for this end point

    Secondary: Change from Baseline in Childhood Health Assessment Questionnaire (CHAQ) Disability Index Score at 12 Months

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    End point title
    		 Change from Baseline in Childhood Health Assessment Questionnaire (CHAQ) Disability Index Score at 12 Months
    End point description
    The disability domain (questions 1-54) of the CHAQ was used to measure the participant's assessment of physical functioning or the parent’s assessment of the child’s physical functioning. The disability index comprised of 8 categories (dressing and grooming, arising, eating, walking, hygiene, reaching, gripping, and activities). Scoring ranged from 1 to 5; 1 was “without any difficulty,” 2 was “with some difficulty,” 3 was “with much difficulty,” and 4 was “unable to do.” An answer of “not applicable” was scored as a 5, but was not counted. If a child required assistance from another person or used an aid or other device for any of the 8 categories, the minimum score for that category was recorded as a 3. The CHAQ questions were scored and converted to a total index score ranging from 0 to 3. Negative change from Baseline indicates an improvement. PRO Analysis Set all participants in the FAS who had a baseline and ≥ 1 postbaseline valid PRO response on Q3M dosing regimen.
    End point type
    Secondary
    End point timeframe
    Baseline and 12 months
    End point values
    		 Denosumab
    Number of subjects analysed
    51
    Units: Score on a scale
        arithmetic mean (standard deviation)
    -0.06 ( 0.46 )
    No statistical analyses for this end point

    Secondary: Change from Baseline in Wong-Baker Faces Pain Rating Scale (WBFPRS) at 12 Months

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    End point title
    		 Change from Baseline in Wong-Baker Faces Pain Rating Scale (WBFPRS) at 12 Months
    End point description
    Participants were asked to report their level of pain by choosing a face that best described their own pain (the corresponding number: 0, 2, 4, 6, 8, 10) were then recorded. The WBFPRS ranged from 0, "no hurt," to 10, "hurts worst". A negative change from baseline indicates an improvement. Patient Reported Outcomes (PRO) Analysis Set: includes all participants in the FAS who had a baseline and ≥ 1 postbaseline valid PRO response on Q3M dosing regimen for the WBFPRS.
    End point type
    Secondary
    End point timeframe
    Baseline and 12 months
    End point values
    		 Denosumab
    Number of subjects analysed
    49
    Units: Score on a scale
        arithmetic mean (standard deviation)
    0.0 ( 1.7 )
    No statistical analyses for this end point

    Secondary: Serum Concentration of Denosumab

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    End point title
    		 Serum Concentration of Denosumab
    End point description
    99999 represents data that were not evaluable. PK Analysis Set includes all participants in the 3QM dosing regimen safety analysis set who had ≥ 1 serum denosumab reported result on 3QM dosing regimen.
    End point type
    Secondary
    End point timeframe
    Days 1 (pre-dose), 10, 30, and 60 and Months 3, 6, 9, 12, 15, and 18
    End point values
    		 Denosumab
    Number of subjects analysed
    25
    Units: ng/mL
    arithmetic mean (standard deviation)
        Age 11-17; Day 1 (N = 15)
    0.00 ( 0.00 )
        Age 11-17; Day 10 (N = 10)
    6580 ( 1350 )
        Age 11-17; Day 30 (N = 12)
    4380 ( 1360 )
        Age 11-17; Day 60 (N = 13)
    2280 ( 924 )
        Age 11-17; Month 3 (N = 13)
    1140 ( 772 )
        Age 11-17; Month 6 (N = 13)
    1380 ( 969 )
        Age 11-17; Month 9 (N = 15)
    1810 ( 1000 )
        Age 11-17; Month 12 (N = 12)
    1560 ( 1010 )
        Age 11-17; Month 15 (N = 1)
    956 ( 99999 )
        Age 11-17; Month 18 (N = 0)
    99999 ( 99999 )
        Age 7-10; Day 1 (N = 19)
    0.00 ( 0.00 )
        Age 7-10; Day 10 (N = 11)
    6580 ( 2020 )
        Age 7-10; Day 30 (N = 18)
    3980 ( 1320 )
        Age 7-10; Day 60 (N = 16)
    1300 ( 823 )
        Age 7-10; Month 3 (N = 18)
    222 ( 313 )
        Age 7-10; Month 6 (N = 19)
    561 ( 744 )
        Age 7-10; Month 9 (N = 18)
    655 ( 754 )
        Age 7-10; Month 12 (N = 13)
    691 ( 659 )
        Age 7-10; Month 15 (N = 2)
    1420 ( 99999 )
        Age 7-10; Month 18 (N = 1)
    1940 ( 99999 )
        Age 2-6; Day 1 (N = 25)
    0.00 ( 0.00 )
        Age 2-6; Day 10 (N = 15)
    7080 ( 2120 )
        Age 2-6; Day 30 (N = 21)
    3500 ( 1230 )
        Age 2-6; Day 60 (N = 22)
    699 ( 544 )
        Age 2-6; Month 3 (N = 22)
    159 ( 393 )
        Age 2-6; Month 6 (N = 23)
    196 ( 328 )
        Age 2-6; Month 9 (N = 19)
    237 ( 469 )
        Age 2-6; Month 12 (N = 14)
    278 ( 589 )
        Age 2-6; Month 18 (N = 0)
    99999 ( 99999 )
    No statistical analyses for this end point

    Secondary: Serum Bone Turnover Marker (BTM) - Serum Type I Collagen C Telopeptide

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    End point title
    		 Serum Bone Turnover Marker (BTM) - Serum Type I Collagen C Telopeptide
    End point description
    99999 represents data that were not evaluable. BTM Analysis Set: includes all participants in the 3QM dosing regimen safety analysis set who had baseline and ≥ 1 postbaseline assessment for the BTM endpoint of interest on Q3M dosing regimen.
    End point type
    Secondary
    End point timeframe
    Baseline and Days 10 and 30, and Months 3, 6, 9, 12, 15 and 18
    End point values
    		 Denosumab
    Number of subjects analysed
    54
    Units: ng/L
    arithmetic mean (standard deviation)
        Baseline (N = 54)
    1136.5 ( 569.7 )
        Day 10 (N = 50)
    174.4 ( 64.7 )
        Day 30 (N = 48)
    176.5 ( 87.9 )
        Month 3 (N = 50)
    498.47 ( 332.0 )
        Month 6 (N = 49)
    537.1 ( 427.1 )
        Month 9 (N = 48)
    539.0 ( 425.0 )
        Month 12 (N = 42)
    681.2 ( 563.1 )
        Month 15 (N = 13)
    1050.8 ( 758.8 )
        Month 18 (N = 1)
    1290.0 ( 99999 )
    No statistical analyses for this end point

    Secondary: BTM - Bone-specific Alkaline Phosphatase (BSAP)

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    End point title
    		 BTM - Bone-specific Alkaline Phosphatase (BSAP)
    End point description
    99999 represents data that were not evaluable. BTM Analysis Set: includes all participants in the 3QM dosing regimen safety analysis set who had baseline and ≥ 1 postbaseline assessment for the BTM endpoint of interest on Q3M dosing regimen.
    End point type
    Secondary
    End point timeframe
    Baseline and Days 10 and 30, and Months 3, 6, 9, 12, and 15
    End point values
    		 Denosumab
    Number of subjects analysed
    59
    Units: μg/L
    arithmetic mean (standard deviation)
        Baseline; N = 59
    69.22 ( 34.26 )
        Day 10; N = 56
    70.88 ( 32.77 )
        Day 30; N = 53
    56.28 ( 28.32 )
        Month 3; N = 57
    48.92 ( 25.45 )
        Month 6; N = 54
    40.30 ( 22.58 )
        Month 9; N = 55
    51.17 ( 106.27 )
        Month 12; N = 47
    40.02 ( 27.64 )
        Month 15; N = 14
    49.49 ( 31.20 )
    No statistical analyses for this end point

    Secondary: Change from Baseline in Growth Velocity at 12 Months

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    End point title
    		 Change from Baseline in Growth Velocity at 12 Months
    End point description
    Change from baseline in growth velocity was determined by calculating age-adjusted Z-scores for height, weight and BMI. Height-for-age Z-score was defined as the difference between the participant's height and the median height for the population with the same age and gender, divided by the population SD. The definitions of growth velocity based on weight and BMI were analogously calculated. To programmatically calculate the Z-scores, the National Center for Health Statistics percentiles growth charts, based on the 2000 Center for Disease Control and Prevention (CDC) (http://www.cdc.gov/growthcharts/c c_charts.htm), and the CDC Anthropometric Software Package 3.0 Z-scores were used. During normal growth, the change in z-score should equal 0. A positive change in any of the three = growth acceleration, whereas a negative change = deceleration. Growth Velocity Analysis Set: all participants with non-missing height, weight, or BMI at baseline and postbaseline on the Q3M dosing regimen.
    End point type
    Secondary
    End point timeframe
    Baseline and 12 months
    End point values
    		 Denosumab
    Number of subjects analysed
    48 [2]
    Units: Z-score
    arithmetic mean (standard deviation)
        Height -for-age Z-score
    -0.01 ( 0.43 )
        Weight-for-age Z-score
    0.01 ( 0.53 )
        BMI-for-age Z-score
    -0.07 ( 0.52 )
    Notes
    [2] - Only participants with observed data at Baseline and Month 12 are included.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    6QM dosing regimen: Day 1 up to 36 months 3QM dosing regimen: Day 1 up to 24 weeks after last dose (median duration of treatment was 253 days)
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    25.0
    Reporting groups
    Reporting group title
    Denosumab 6-Month Dosing Regimen
    Reporting group description
    		 Participants received denosumab 1 mg/kg (up to a maximum of 60 mg) subcutaneously every 6 months (Q6M) for up to 36 months.

    Reporting group title
    Denosumab3-Month Dosing Regimen
    Reporting group description
    		 Early efficacy and PK data from Q6M dosing supported adjustment of the dosing regimen from Q6M to every 3 months (Q3M). Participants enrolled and still receiving denosumab were transitioned from Q6M to Q3M dosing schedule. Participants could transition to Q3M dosing schedule up to and including the date they attended for their month 36 visit under the Q6M dosing regimen. Those participants received denosumab during the Q3M dosing regimen for 12 months. Participants who transition to Q3M at month 18 of the Q6M dosing regimen received denosumab Q3M for up to 18 months.

    Serious adverse events
    		 Denosumab 6-Month Dosing Regimen Denosumab3-Month Dosing Regimen
    Total subjects affected by serious adverse events
         subjects affected / exposed
    52 / 153 (33.99%)
    12 / 60 (20.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Testis cancer
         subjects affected / exposed
    1 / 153 (0.65%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Concussion
         subjects affected / exposed
    1 / 153 (0.65%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Contusion
         subjects affected / exposed
    1 / 153 (0.65%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fibula fracture
         subjects affected / exposed
    7 / 153 (4.58%)
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    0 / 10
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    1 / 153 (0.65%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    15 / 153 (9.80%)
    2 / 60 (3.33%)
         occurrences causally related to treatment / all
    3 / 22
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Foot fracture
         subjects affected / exposed
    1 / 153 (0.65%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Humerus fracture
         subjects affected / exposed
    8 / 153 (5.23%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    1 / 8
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Joint dislocation
         subjects affected / exposed
    1 / 153 (0.65%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lumbar vertebral fracture
         subjects affected / exposed
    5 / 153 (3.27%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    1 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Patella fracture
         subjects affected / exposed
    2 / 153 (1.31%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pelvic fracture
         subjects affected / exposed
    1 / 153 (0.65%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post-traumatic pain
         subjects affected / exposed
    1 / 153 (0.65%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Procedural pain
         subjects affected / exposed
    1 / 153 (0.65%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rib fracture
         subjects affected / exposed
    1 / 153 (0.65%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Radius fracture
         subjects affected / exposed
    5 / 153 (3.27%)
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Scapula fracture
         subjects affected / exposed
    2 / 153 (1.31%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tibia fracture
         subjects affected / exposed
    10 / 153 (6.54%)
    2 / 60 (3.33%)
         occurrences causally related to treatment / all
    0 / 15
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ulna fracture
         subjects affected / exposed
    4 / 153 (2.61%)
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thoracic vertebral fracture
         subjects affected / exposed
    1 / 153 (0.65%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Right ventricular dilatation
         subjects affected / exposed
    1 / 153 (0.65%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Complex regional pain syndrome
         subjects affected / exposed
    1 / 153 (0.65%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pregnancy, puerperium and perinatal conditions
    Abortion complete
         subjects affected / exposed
    1 / 153 (0.65%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Pain
         subjects affected / exposed
    1 / 153 (0.65%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    0 / 153 (0.00%)
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Procedural failure
         subjects affected / exposed
    1 / 153 (0.65%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain upper
         subjects affected / exposed
    1 / 153 (0.65%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal pain
         subjects affected / exposed
    1 / 153 (0.65%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Adnexal torsion
         subjects affected / exposed
    1 / 153 (0.65%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Knee deformity
         subjects affected / exposed
    1 / 153 (0.65%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemarthrosis
         subjects affected / exposed
    1 / 153 (0.65%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteochondrosis
         subjects affected / exposed
    1 / 153 (0.65%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Limb deformity
         subjects affected / exposed
    2 / 153 (1.31%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tenosynovitis
         subjects affected / exposed
    1 / 153 (0.65%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Scoliosis
         subjects affected / exposed
    1 / 153 (0.65%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain in extremity
         subjects affected / exposed
    2 / 153 (1.31%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Gastroenteritis viral
         subjects affected / exposed
    1 / 153 (0.65%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Product issues
    Device dislocation
         subjects affected / exposed
    4 / 153 (2.61%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device failure
         subjects affected / exposed
    1 / 153 (0.65%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device loosening
         subjects affected / exposed
    1 / 153 (0.65%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hypercalcaemia
         subjects affected / exposed
    0 / 153 (0.00%)
    8 / 60 (13.33%)
         occurrences causally related to treatment / all
    0 / 0
    6 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    1 / 153 (0.65%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolic acidosis
         subjects affected / exposed
    1 / 153 (0.65%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Denosumab 6-Month Dosing Regimen Denosumab3-Month Dosing Regimen
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    141 / 153 (92.16%)
    38 / 60 (63.33%)
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    16 / 153 (10.46%)
    0 / 60 (0.00%)
         occurrences all number
    21
    0
    Fall
         subjects affected / exposed
    25 / 153 (16.34%)
    6 / 60 (10.00%)
         occurrences all number
    45
    8
    Femur fracture
         subjects affected / exposed
    16 / 153 (10.46%)
    2 / 60 (3.33%)
         occurrences all number
    26
    2
    Fibula fracture
         subjects affected / exposed
    8 / 153 (5.23%)
    3 / 60 (5.00%)
         occurrences all number
    9
    3
    Hand fracture
         subjects affected / exposed
    15 / 153 (9.80%)
    1 / 60 (1.67%)
         occurrences all number
    23
    1
    Foot fracture
         subjects affected / exposed
    16 / 153 (10.46%)
    2 / 60 (3.33%)
         occurrences all number
    20
    2
    Humerus fracture
         subjects affected / exposed
    12 / 153 (7.84%)
    3 / 60 (5.00%)
         occurrences all number
    14
    4
    Ligament sprain
         subjects affected / exposed
    12 / 153 (7.84%)
    1 / 60 (1.67%)
         occurrences all number
    12
    1
    Post-traumatic pain
         subjects affected / exposed
    6 / 153 (3.92%)
    3 / 60 (5.00%)
         occurrences all number
    7
    3
    Lumbar vertebral fracture
         subjects affected / exposed
    11 / 153 (7.19%)
    2 / 60 (3.33%)
         occurrences all number
    12
    2
    Thoracic vertebral fracture
         subjects affected / exposed
    10 / 153 (6.54%)
    3 / 60 (5.00%)
         occurrences all number
    11
    5
    Radius fracture
         subjects affected / exposed
    14 / 153 (9.15%)
    2 / 60 (3.33%)
         occurrences all number
    14
    2
    Tibia fracture
         subjects affected / exposed
    17 / 153 (11.11%)
    3 / 60 (5.00%)
         occurrences all number
    26
    3
    Ulna fracture
         subjects affected / exposed
    16 / 153 (10.46%)
    2 / 60 (3.33%)
         occurrences all number
    25
    2
    Nervous system disorders
    Headache
         subjects affected / exposed
    21 / 153 (13.73%)
    4 / 60 (6.67%)
         occurrences all number
    28
    5
    General disorders and administration site conditions
    Pain
         subjects affected / exposed
    12 / 153 (7.84%)
    2 / 60 (3.33%)
         occurrences all number
    17
    2
    Pyrexia
         subjects affected / exposed
    18 / 153 (11.76%)
    1 / 60 (1.67%)
         occurrences all number
    26
    1
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    13 / 153 (8.50%)
    0 / 60 (0.00%)
         occurrences all number
    16
    0
    Abdominal pain upper
         subjects affected / exposed
    9 / 153 (5.88%)
    2 / 60 (3.33%)
         occurrences all number
    12
    2
    Dental caries
         subjects affected / exposed
    9 / 153 (5.88%)
    1 / 60 (1.67%)
         occurrences all number
    27
    1
    Vomiting
         subjects affected / exposed
    13 / 153 (8.50%)
    2 / 60 (3.33%)
         occurrences all number
    19
    2
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    13 / 153 (8.50%)
    2 / 60 (3.33%)
         occurrences all number
    19
    2
    Epistaxis
         subjects affected / exposed
    11 / 153 (7.19%)
    2 / 60 (3.33%)
         occurrences all number
    16
    3
    Renal and urinary disorders
    Hypercalciuria
         subjects affected / exposed
    49 / 153 (32.03%)
    5 / 60 (8.33%)
         occurrences all number
    87
    8
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    70 / 153 (45.75%)
    15 / 60 (25.00%)
         occurrences all number
    186
    30
    Back pain
         subjects affected / exposed
    50 / 153 (32.68%)
    5 / 60 (8.33%)
         occurrences all number
    76
    5
    Bone pain
         subjects affected / exposed
    21 / 153 (13.73%)
    1 / 60 (1.67%)
         occurrences all number
    31
    4
    Myalgia
         subjects affected / exposed
    8 / 153 (5.23%)
    0 / 60 (0.00%)
         occurrences all number
    9
    0
    Pain in extremity
         subjects affected / exposed
    57 / 153 (37.25%)
    11 / 60 (18.33%)
         occurrences all number
    125
    20
    Infections and infestations
    Gastroenteritis
         subjects affected / exposed
    8 / 153 (5.23%)
    0 / 60 (0.00%)
         occurrences all number
    9
    0
    Influenza
         subjects affected / exposed
    13 / 153 (8.50%)
    0 / 60 (0.00%)
         occurrences all number
    14
    0
    Nasopharyngitis
         subjects affected / exposed
    23 / 153 (15.03%)
    7 / 60 (11.67%)
         occurrences all number
    30
    7
    Upper respiratory tract infection
         subjects affected / exposed
    9 / 153 (5.88%)
    1 / 60 (1.67%)
         occurrences all number
    12
    1
    Metabolism and nutrition disorders
    Hypercalcaemia
         subjects affected / exposed
    28 / 153 (18.30%)
    15 / 60 (25.00%)
         occurrences all number
    39
    23
    Hypocalcaemia
         subjects affected / exposed
    15 / 153 (9.80%)
    6 / 60 (10.00%)
         occurrences all number
    20
    7

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    25 Jul 2014
    • updated the exclusion criteria: ­ - added history of rare hereditary problems of fructose intolerance ­ - modified exclusion criteria related to HIV, hepatitis B, and hepatitis C - added serological tests for HIV, hepatitis B and hepatitis C to screening visit • clarified acceptable methods of contraception
    28 Aug 2014
    • updated the exclusion criteria regarding serum vitamin D levels at screening and duration of prior use of PTH or PTH derivatives • removed blood pressure measurement as a required procedure • added option for at-home blood collection for visits occurring on days 2 to 30
    11 Feb 2015
    • added additional visits to monitor serum calcium in the sentinel cohort
    24 Mar 2016
    • updated secondary objectives and endpoints and exclusion criteria to reflect approved modifications to the PIP • updated pregnancy and lactation reporting language and safety language to align with changes to the protocol template • clarified rescreening requirements and guidelines
    11 Mar 2020
    • changed the dosing regimen from Q6M to Q3M
    19 Nov 2020
    • added incidence of X-ray confirmed new and worsening vertebral fractures and incidence of new vertebral fractures from last 12 months on Q6M dosing regimen to 12 months on Q3M dosing regimen as secondary endpoints • added additional serum calcium samples at days 10 and 30 after investigational product dosing at weeks 12 and 24
    14 Jan 2021
    • corrected inconsistencies throughout
    22 Oct 2021
    • updated text throughout based on early study termination due to urgent safety measure • added immediate discontinuation of all subjects from study treatment followed by a 24-week safety follow-up period
    26 Nov 2021
    • added additional safety assessments to week 12 visit • removed PRO assessments from week 12 visit

    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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