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    Clinical Trial Results:
    An Open-label, Ascending Multiple-dose Study to Evaluate Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Romosozumab in Children and Adolescents With Osteogenesis Imperfecta

    Summary
    EudraCT number
    		 2017-004972-74
    Trial protocol
    		 HU   DE   GR   IT   AT  
    Global end of trial date
    30 Mar 2023

    Results information
    Results version number
    		 v1(current)
    This version publication date
    13 Oct 2023
    First version publication date
    13 Oct 2023
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    20160227
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT04545554
    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-001075-PIP04-15
    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
    30 Mar 2023
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    30 Mar 2023
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of the study is to evaluate the pharmacokinetic (PK) profile following multiple subcutaneous (SC) doses of romosozumab in children and adolescents with osteogenesis imperfecta.
    Protection of trial subjects
    The study was conducted in accordance with International Council for Harmonisation Good Clinical Practice and other regulations/guidelines. The investigator or his/her designee informed the participant of all aspects pertaining to the participant's participation in the study before any screening procedures were performed. The study protocol and all amendments, the informed consent form, and any accompanying materials provided to the participants were reviewed and approved by an Institutional Review Board or Institutional Ethics Committee at each study center.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    21 Jan 2021
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety
    Long term follow-up duration
    		 3 Months
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Austria: 1
    Country: Number of subjects enrolled
    Hungary: 9
    Country: Number of subjects enrolled
    Turkey: 7
    Country: Number of subjects enrolled
    Germany: 1
    Country: Number of subjects enrolled
    Greece: 3
    Country: Number of subjects enrolled
    Italy: 1
    Country: Number of subjects enrolled
    Spain: 3
    Worldwide total number of subjects
    25
    EEA total number of subjects
    18
    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)
    13
    Adolescents (12-17 years)
    12
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Participants were enrolled at 15 study centers in Austria, Germany, Greece, Hungary, Italy, Spain, Turkey, and the United States, and participated from 21 January 2021 until 30 March 2023.

    Pre-assignment
    Screening details
    		 Ambulatory children (5 to < 12 years of age) and adolescents (12 to < 18 years of age) with osteogenesis imperfecta were enrolled to receive 1 of 3 SC dose levels of romosozumab. Specific doses are blinded due to the protection of propriety information.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Cohort 1: Romosozumab Dose A (12 to < 18 Years of Age)
    Arm description
    		 Participants received multiple SC doses of romosozumab Dose A (low dose).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Romosozumab
    Investigational medicinal product code
    Other name
    Evenity®
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Romosozumab Dose A was administered SC.

    Arm title
    		 Cohort 2: Romosozumab Dose A (5 to < 12 Years of Age)
    Arm description
    		 Participants received multiple SC doses of romosozumab Dose A (low dose).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Romosozumab
    Investigational medicinal product code
    Other name
    Evenity®
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Romosozumab Dose A was administered SC.

    Arm title
    		 Cohort 3: Romosozumab Dose B (12 to < 18 Years of Age)
    Arm description
    		 Participants received multiple SC doses of romosozumab Dose B (medium dose).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Romosozumab
    Investigational medicinal product code
    Other name
    Evenity®
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Romosozumab Dose B was administered SC.

    Arm title
    		 Cohort 4: Romosozumab Dose B (5 to < 12 Years of Age)
    Arm description
    		 Participants received multiple SC doses of romosozumab Dose B (medium dose).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Romosozumab
    Investigational medicinal product code
    Other name
    Evenity®
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Romosozumab Dose B was administered SC.

    Arm title
    		 Cohort 5: Romosozumab Dose C (12 to < 18 Years of Age)
    Arm description
    		 Participants received multiple SC doses of romosozumab Dose C (high dose).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Romosozumab
    Investigational medicinal product code
    Other name
    Evenity®
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Romosozumab Dose C was administered SC.

    Arm title
    		 Cohort 6: Romosozumab Dose C (5 to < 12 Years of Age)
    Arm description
    		 Participants received multiple SC doses of romosozumab Dose C (high dose).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Romosozumab
    Investigational medicinal product code
    Other name
    Evenity®
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Romosozumab Dose C was administered SC.

    Number of subjects in period 1
    		Cohort 1: Romosozumab Dose A (12 to < 18 Years of Age) Cohort 2: Romosozumab Dose A (5 to < 12 Years of Age) Cohort 3: Romosozumab Dose B (12 to < 18 Years of Age) Cohort 4: Romosozumab Dose B (5 to < 12 Years of Age) Cohort 5: Romosozumab Dose C (12 to < 18 Years of Age) Cohort 6: Romosozumab Dose C (5 to < 12 Years of Age)
    Started
    4
    4
    4
    5
    4
    4
    Received at least 1 dose romosozumab
    4
    4
    4
    5
    4
    4
    Received all doses of romosozumab
    4
    4
    4
    4
    4
    4
    Completed
    4
    4
    4
    4
    4
    4
    Not completed
    0
    0
    0
    1
    0
    0
         Consent withdrawn by subject
    -
    -
    -
    1
    -
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Cohort 1: Romosozumab Dose A (12 to < 18 Years of Age)
    Reporting group description
    		 Participants received multiple SC doses of romosozumab Dose A (low dose).

    Reporting group title
    Cohort 2: Romosozumab Dose A (5 to < 12 Years of Age)
    Reporting group description
    		 Participants received multiple SC doses of romosozumab Dose A (low dose).

    Reporting group title
    Cohort 3: Romosozumab Dose B (12 to < 18 Years of Age)
    Reporting group description
    		 Participants received multiple SC doses of romosozumab Dose B (medium dose).

    Reporting group title
    Cohort 4: Romosozumab Dose B (5 to < 12 Years of Age)
    Reporting group description
    		 Participants received multiple SC doses of romosozumab Dose B (medium dose).

    Reporting group title
    Cohort 5: Romosozumab Dose C (12 to < 18 Years of Age)
    Reporting group description
    		 Participants received multiple SC doses of romosozumab Dose C (high dose).

    Reporting group title
    Cohort 6: Romosozumab Dose C (5 to < 12 Years of Age)
    Reporting group description
    		 Participants received multiple SC doses of romosozumab Dose C (high dose).

    Reporting group values
    		 Cohort 1: Romosozumab Dose A (12 to < 18 Years of Age) Cohort 2: Romosozumab Dose A (5 to < 12 Years of Age) Cohort 3: Romosozumab Dose B (12 to < 18 Years of Age) Cohort 4: Romosozumab Dose B (5 to < 12 Years of Age) Cohort 5: Romosozumab Dose C (12 to < 18 Years of Age) Cohort 6: Romosozumab Dose C (5 to < 12 Years of Age) Total
    Number of subjects
    		 4 4 4 5 4 4 25
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0 0 0 0
        Children (2-11 years)
    		 0 4 0 5 0 4 13
        Adolescents (12-17 years)
    		 4 0 4 0 4 0 12
        Adults (18-64 years)
    		 0 0 0 0 0 0 0
        From 65-84 years
    		 0 0 0 0 0 0 0
        85 years and over
    		 0 0 0 0 0 0 0
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 14.3 ( 1.9 ) 6.0 ( 1.4 ) 14.3 ( 0.5 ) 8.4 ( 2.4 ) 14.0 ( 1.8 ) 6.5 ( 0.6 ) -
    Sex: Female, Male
    Units: participants
        Female
    		 1 0 1 4 2 1 9
        Male
    		 3 4 3 1 2 3 16
    Race/Ethnicity, Customized
    Units: Subjects
        Asian
    		 0 0 0 0 0 1 1
        White
    		 4 4 4 4 4 2 22
        Other
    		 0 0 0 1 0 1 2
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 0 0 0 2 1 0 3
        Not Hispanic or Latino
    		 4 4 4 3 3 4 22
        Unknown or Not Reported
    		 0 0 0 0 0 0 0

    End points

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    End points reporting groups
    Reporting group title
    Cohort 1: Romosozumab Dose A (12 to < 18 Years of Age)
    Reporting group description
    		 Participants received multiple SC doses of romosozumab Dose A (low dose).

    Reporting group title
    Cohort 2: Romosozumab Dose A (5 to < 12 Years of Age)
    Reporting group description
    		 Participants received multiple SC doses of romosozumab Dose A (low dose).

    Reporting group title
    Cohort 3: Romosozumab Dose B (12 to < 18 Years of Age)
    Reporting group description
    		 Participants received multiple SC doses of romosozumab Dose B (medium dose).

    Reporting group title
    Cohort 4: Romosozumab Dose B (5 to < 12 Years of Age)
    Reporting group description
    		 Participants received multiple SC doses of romosozumab Dose B (medium dose).

    Reporting group title
    Cohort 5: Romosozumab Dose C (12 to < 18 Years of Age)
    Reporting group description
    		 Participants received multiple SC doses of romosozumab Dose C (high dose).

    Reporting group title
    Cohort 6: Romosozumab Dose C (5 to < 12 Years of Age)
    Reporting group description
    		 Participants received multiple SC doses of romosozumab Dose C (high dose).

    Primary: Maximum Observed Serum Concentration (Cmax) of Romosozumab

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    End point title
    		 Maximum Observed Serum Concentration (Cmax) of Romosozumab [1]
    End point description
    Mean Cmax values following single and multiple SC administrations of romosozumab are presented. Pharmacokinetic (PK) Analysis Set: all participants for whom at least 1 PK parameter or endpoint could be adequately tested.
    End point type
    Primary
    End point timeframe
    Day 1 to Day 169
    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 comparative statistical analysis was planned for this endpoint; summary statistics were provided for the primary endpoint.
    End point values
    		 Cohort 1: Romosozumab Dose A (12 to < 18 Years of Age) Cohort 2: Romosozumab Dose A (5 to < 12 Years of Age) Cohort 3: Romosozumab Dose B (12 to < 18 Years of Age) Cohort 4: Romosozumab Dose B (5 to < 12 Years of Age) Cohort 5: Romosozumab Dose C (12 to < 18 Years of Age) Cohort 6: Romosozumab Dose C (5 to < 12 Years of Age)
    Number of subjects analysed
    4
    4
    4
    4
    4
    4
    Units: μg/mL
    arithmetic mean (standard deviation)
        Single Dose
    2.64 ( 1.06 )
    1.74 ( 0.825 )
    13.8 ( 6.32 )
    10.3 ( 1.70 )
    25.7 ( 3.02 )
    21.3 ( 6.45 )
        Multiple Doses
    2.43 ( 1.36 )
    5.55 ( 2.11 )
    12.8 ( 6.31 )
    9.14 ( 7.50 )
    22.8 ( 10.5 )
    19.4 ( 2.14 )
    No statistical analyses for this end point

    Primary: Time to Cmax (tmax) of Romosozumab

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    End point title
    		 Time to Cmax (tmax) of Romosozumab [2]
    End point description
    Median tmax values following single and multiple SC administrations of romosozumab are presented. PK Analysis Set: all participants for whom at least 1 PK parameter or endpoint could be adequately tested.
    End point type
    Primary
    End point timeframe
    Day 1 to Day 169
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No comparative statistical analysis was planned for this endpoint; summary statistics were provided for the primary endpoint.
    End point values
    		 Cohort 1: Romosozumab Dose A (12 to < 18 Years of Age) Cohort 2: Romosozumab Dose A (5 to < 12 Years of Age) Cohort 3: Romosozumab Dose B (12 to < 18 Years of Age) Cohort 4: Romosozumab Dose B (5 to < 12 Years of Age) Cohort 5: Romosozumab Dose C (12 to < 18 Years of Age) Cohort 6: Romosozumab Dose C (5 to < 12 Years of Age)
    Number of subjects analysed
    4
    4
    4
    4
    4
    4
    Units: day
    median (full range (min-max))
        Single Dose
    6.5 (5.9 to 7.9)
    7.9 (7.9 to 15)
    6.9 (6.9 to 7.0)
    6.9 (4.9 to 7.1)
    7.0 (4.9 to 8.0)
    7.5 (6.9 to 8.9)
        Multiple Doses
    7.0 (7.0 to 12)
    7.0 (6.9 to 7.0)
    7.0 (6.0 to 7.9)
    8.0 (6.0 to 11)
    7.0 (4.0 to 12)
    7.5 (6.0 to 8.8)
    No statistical analyses for this end point

    Primary: Area Under the Serum Concentration Time Curve (AUC) During the Dosing Interval (AUCtau) of Romosozumab

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    End point title
    		 Area Under the Serum Concentration Time Curve (AUC) During the Dosing Interval (AUCtau) of Romosozumab [3]
    End point description
    Mean AUCtau values following single and multiple SC administrations of romosozumab are presented. PK Analysis Set: all participants for whom at least 1 PK parameter or endpoint could be adequately tested.
    End point type
    Primary
    End point timeframe
    Day 1 to Day 85
    Notes
    [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No comparative statistical analysis was planned for this endpoint; summary statistics were provided for the primary endpoint.
    End point values
    		 Cohort 1: Romosozumab Dose A (12 to < 18 Years of Age) Cohort 2: Romosozumab Dose A (5 to < 12 Years of Age) Cohort 3: Romosozumab Dose B (12 to < 18 Years of Age) Cohort 4: Romosozumab Dose B (5 to < 12 Years of Age) Cohort 5: Romosozumab Dose C (12 to < 18 Years of Age) Cohort 6: Romosozumab Dose C (5 to < 12 Years of Age)
    Number of subjects analysed
    4
    4
    4
    4
    4
    4
    Units: day*μg/mL
    arithmetic mean (standard deviation)
        Single Dose
    30.9 ( 13.5 )
    16.9 ( 5.78 )
    163 ( 89.1 )
    113 ( 50.3 )
    344 ( 106 )
    234 ( 93.7 )
        Multiple Doses
    27.4 ( 15.1 )
    50.5 ( 20.7 )
    153 ( 86.7 )
    95.1 ( 76.1 )
    293 ( 134 )
    203 ( 40.7 )
    No statistical analyses for this end point

    Primary: Accumulation Ratio of Romosozumab

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    End point title
    		 Accumulation Ratio of Romosozumab [4]
    End point description
    The accumulation ratio was calculated as AUCtau after multiple doses/AUCtau Dose 1. PK Analysis Set: all participants for whom at least 1 PK parameter or endpoint could be adequately tested.
    End point type
    Primary
    End point timeframe
    Day 1 to Day 85
    Notes
    [4] - 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 comparative statistical analysis was planned for this endpoint; summary statistics were provided for the primary endpoint.
    End point values
    		 Cohort 1: Romosozumab Dose A (12 to < 18 Years of Age) Cohort 2: Romosozumab Dose A (5 to < 12 Years of Age) Cohort 3: Romosozumab Dose B (12 to < 18 Years of Age) Cohort 4: Romosozumab Dose B (5 to < 12 Years of Age) Cohort 5: Romosozumab Dose C (12 to < 18 Years of Age) Cohort 6: Romosozumab Dose C (5 to < 12 Years of Age)
    Number of subjects analysed
    4
    4
    4
    4
    4
    4
    Units: ratio
        arithmetic mean (standard deviation)
    0.885 ( 0.487 )
    3.6 ( 2.56 )
    0.922 ( 0.0673 )
    0.724 ( 0.392 )
    0.843 ( 0.260 )
    0.935 ( 0.283 )
    No statistical analyses for this end point

    Primary: Terminal Half-life of Romosozumab

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    End point title
    		 Terminal Half-life of Romosozumab [5]
    End point description
    Median terminal half-life values following multiple SC administrations of romosozumab are presented. PK Analysis Set: all participants for whom at least 1 PK parameter or endpoint could be adequately tested. Data is presented for participants with evaluable data. 99999 = data is not available.
    End point type
    Primary
    End point timeframe
    Day 1 to Day 169
    Notes
    [5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No comparative statistical analysis was planned for this endpoint; summary statistics were provided for the primary endpoint.
    End point values
    		 Cohort 1: Romosozumab Dose A (12 to < 18 Years of Age) Cohort 2: Romosozumab Dose A (5 to < 12 Years of Age) Cohort 3: Romosozumab Dose B (12 to < 18 Years of Age) Cohort 4: Romosozumab Dose B (5 to < 12 Years of Age) Cohort 5: Romosozumab Dose C (12 to < 18 Years of Age) Cohort 6: Romosozumab Dose C (5 to < 12 Years of Age)
    Number of subjects analysed
    0 [6]
    2
    0 [7]
    1
    3
    0 [8]
    Units: day
        median (full range (min-max))
    ( to )
    9.41 (7.62 to 11.2)
    ( to )
    7.01 (7.01 to 7.01)
    6.11 (5.58 to 6.56)
    ( to )
    Notes
    [6] - No participants were evaluated in Cohort 1 for this endpoint.
    [7] - No participants were evaluated in Cohort 3 for this endpoint.
    [8] - No participants were evaluated in Cohort 6 for this endpoint.
    No statistical analyses for this end point

    Secondary: Number of Participants with Treatment-Emergent Adverse Events (TEAEs)

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    End point title
    		 Number of Participants with Treatment-Emergent Adverse Events (TEAEs)
    End point description
    TEAEs were adverse events (AEs) that started on or after first dose of investigational product up to the end of study (up to Day 169). Any clinically significant changes in vital signs, electrocardiogram parameters, physical exam findings, and clinical laboratory parameters were reported as TEAEs. Injection site reactions were events of interest (EOI) for this study. Safety Analysis Set: all participants enrolled in the study who received at least 1 dose of investigational product.
    End point type
    Secondary
    End point timeframe
    Day 1 to end of study (up to Day 169); median duration on study was 5.55 months
    End point values
    		 Cohort 1: Romosozumab Dose A (12 to < 18 Years of Age) Cohort 2: Romosozumab Dose A (5 to < 12 Years of Age) Cohort 3: Romosozumab Dose B (12 to < 18 Years of Age) Cohort 4: Romosozumab Dose B (5 to < 12 Years of Age) Cohort 5: Romosozumab Dose C (12 to < 18 Years of Age) Cohort 6: Romosozumab Dose C (5 to < 12 Years of Age)
    Number of subjects analysed
    4
    4
    4
    5
    4
    4
    Units: participants
        Any TEAE
    1
    1
    2
    4
    1
    3
        Any Treatment-emergent EOI
    0
    0
    0
    0
    1
    1
    No statistical analyses for this end point

    Secondary: Number of Participants with Changes from Baseline in Cranial Nerve VII Examination Findings at Day 57, Day 85, and Day 169

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    End point title
    		 Number of Participants with Changes from Baseline in Cranial Nerve VII Examination Findings at Day 57, Day 85, and Day 169
    End point description
    Facial nerve (cranial nerve VII) function was assessed clinically by facial symmetry inspection at rest, followed by assessment of the symmetry of specific facial movements: raising eyebrows, closing the eyes, blowing out the cheeks, smiling, pursing and closing the lips. Results of the cranial nerve examination were classed as 0 = Normal; 1 = Abnormal not clinically significant; and 2 = Abnormal clinically significant. An increase from baseline indicates an increase in abnormal clinical findings on the cranial nerve VII examination. Safety Analysis Set: all participants enrolled in the study who received at least 1 dose of investigational product. Participants with data available at each time point are presented.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1), Day 57, Day 85, and Day 169
    End point values
    		 Cohort 1: Romosozumab Dose A (12 to < 18 Years of Age) Cohort 2: Romosozumab Dose A (5 to < 12 Years of Age) Cohort 3: Romosozumab Dose B (12 to < 18 Years of Age) Cohort 4: Romosozumab Dose B (5 to < 12 Years of Age) Cohort 5: Romosozumab Dose C (12 to < 18 Years of Age) Cohort 6: Romosozumab Dose C (5 to < 12 Years of Age)
    Number of subjects analysed
    4
    4
    4
    5
    4
    4
    Units: participants
        Day 57: Blowing out of cheeks - No change (0)
    4
    4
    4
    3
    4
    4
        Day 57: Blowing out of cheeks - Undetermined
    0
    0
    0
    2
    0
    0
        Day 57: Closing eyes - No change (0)
    4
    4
    4
    3
    4
    4
        Day 57: Closing eyes - Undetermined
    0
    0
    0
    2
    0
    0
        Day 57: Closing of lips - No change (0)
    4
    4
    4
    3
    4
    4
        Day 57: Closing of lips - Undetermined
    0
    0
    0
    2
    0
    0
        Day 57: Pursing of lips - No change (0)
    4
    4
    4
    3
    4
    4
        Day 57: Pursing of lips - Undetermined
    0
    0
    0
    2
    0
    0
        Day 57: Raising eyebrows - No change (0)
    4
    4
    4
    3
    4
    4
        Day 57: Raising eyebrows - Undetermined
    0
    0
    0
    2
    0
    0
        Day 57: Smiling - No change (0)
    4
    4
    4
    3
    4
    4
        Day 57: Smiling - Undetermined
    0
    0
    0
    2
    0
    0
        Day 85: Blowing out of cheeks - No change (0)
    4
    4
    4
    4
    4
    4
        Day 85: Blowing out of cheeks - Undetermined
    0
    0
    0
    1
    0
    0
        Day 85: Closing eyes - No change (0)
    4
    4
    4
    4
    4
    4
        Day 85: Closing eyes - Undetermined
    0
    0
    0
    1
    0
    0
        Day 85: Closing of lips - No change (0)
    4
    3
    4
    4
    4
    4
        Day 85: Closing of lips - Increase (to 1)
    0
    1
    0
    0
    0
    0
        Day 85: Closing of lips - Undetermined
    0
    0
    0
    1
    0
    0
        Day 85: Pursing of lips - No change (0)
    4
    4
    4
    4
    4
    4
        Day 85: Pursing of lips - Undetermined
    0
    0
    0
    1
    0
    0
        Day 85: Raising eyebrows - No change (0)
    4
    4
    4
    4
    4
    4
        Day 85: Raising eyebrows - Undetermined
    0
    0
    0
    1
    0
    0
        Day 85: Smiling - No change (0)
    4
    4
    4
    4
    4
    4
        Day 85: Smiling - Undetermined
    0
    0
    0
    1
    0
    0
        Day 169: Blowing out of cheeks - No change (0)
    4
    4
    4
    4
    4
    4
        Day 169: Blowing out of cheeks - Undetermined
    0
    0
    0
    1
    0
    0
        Day 169: Closing eyes - No change (0)
    4
    4
    4
    4
    4
    4
        Day 169: Closing eyes - Undetermined
    0
    0
    0
    1
    0
    0
        Day 169: Closing of lips - No change (0)
    4
    4
    4
    4
    4
    4
        Day 169: Closing of lips - Undetermined
    0
    0
    0
    1
    0
    0
        Day 169: Pursing of lips - No change (0)
    4
    4
    4
    4
    4
    4
        Day 169: Pursing of lips - Undetermined
    0
    0
    0
    1
    0
    0
        Day 169: Raising eyebrows - No change (0)
    4
    4
    4
    4
    4
    4
        Day 169: Raising eyebrows - Undetermined
    0
    0
    0
    1
    0
    0
        Day 169: Smiling - No change (0)
    4
    4
    4
    4
    4
    4
        Day 169: Smiling - Undetermined
    0
    0
    0
    1
    0
    0
    No statistical analyses for this end point

    Secondary: Number of Participants with Anti-romosozumab Antibodies

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    End point title
    		 Number of Participants with Anti-romosozumab Antibodies
    End point description
    Treatment-boosted anti-romosozumab antibody was defined as binding antibody positive at baseline with a >4 x increase in magnitude post-baseline. Transient results were defined as negative results at the participant's last time point tested within the study period. Safety Analysis Set: all participants enrolled in the study who received at least 1 dose of investigational product. Ab - antibody; NAb = neutralizing antibody; +ve = positive; -ve = negative; BL = baseline; tran = transient
    End point type
    Secondary
    End point timeframe
    Blood samples for anti-romosozumab antibodies were taken Day 1 (baseline), Day 15, Day 29, Day 85, and Day 169
    End point values
    		 Cohort 1: Romosozumab Dose A (12 to < 18 Years of Age) Cohort 2: Romosozumab Dose A (5 to < 12 Years of Age) Cohort 3: Romosozumab Dose B (12 to < 18 Years of Age) Cohort 4: Romosozumab Dose B (5 to < 12 Years of Age) Cohort 5: Romosozumab Dose C (12 to < 18 Years of Age) Cohort 6: Romosozumab Dose C (5 to < 12 Years of Age)
    Number of subjects analysed
    4
    4
    4
    5
    4
    4
    Units: participants
        Binding Ab +ve anytime
    0
    1
    2
    0
    1
    1
        NAb +ve anytime
    0
    0
    2
    0
    1
    0
        Binding Ab +ve at/before BL
    0
    0
    0
    0
    0
    0
        NAb +ve at/before baseline
    0
    0
    0
    0
    0
    0
        Treatment boosted Ab +ve
    0
    0
    0
    0
    0
    0
        Binding Ab +ve post-BL with -ve/no results at BL
    0
    1
    2
    0
    1
    1
        Tran binding Ab +ve post-BL with -ve/no results BL
    0
    0
    0
    0
    0
    0
        NAb +ve post-BL with -ve/no result at BL
    0
    0
    2
    0
    1
    0
        Tran NAb +ve post-BL with -ve/no result BL
    0
    0
    0
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Percentage Change from Baseline in Serum Concentrations of Serum Type 1 Collagen C-Telopeptide (CTX)

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    End point title
    		 Percentage Change from Baseline in Serum Concentrations of Serum Type 1 Collagen C-Telopeptide (CTX)
    End point description
    Serum concentrations of the bone turnover marker CTX were determined at pre-specified time points. PD Analysis Set: all participants for whom at least 1 PD parameter or endpoint could be adequately estimated. Participants with data available at each time point are presented.
    End point type
    Secondary
    End point timeframe
    Blood samples were taken Day 1 (baseline), Day 8, Day 15, Day 29, Day 57, Days 64, 71, 85, 113, and 169
    End point values
    		 Cohort 1: Romosozumab Dose A (12 to < 18 Years of Age) Cohort 2: Romosozumab Dose A (5 to < 12 Years of Age) Cohort 3: Romosozumab Dose B (12 to < 18 Years of Age) Cohort 4: Romosozumab Dose B (5 to < 12 Years of Age) Cohort 5: Romosozumab Dose C (12 to < 18 Years of Age) Cohort 6: Romosozumab Dose C (5 to < 12 Years of Age)
    Number of subjects analysed
    4
    4
    4
    5
    4
    4
    Units: percentage change
    arithmetic mean (standard deviation)
        Day 8 (N=4,3,4,5,4,4)
    2.65 ( 27.91 )
    -19.93 ( 33.97 )
    8.79 ( 19.21 )
    -19.38 ( 20.01 )
    -12.33 ( 12.93 )
    7.14 ( 29.89 )
        Day 15 (N=3,4,4,4,4,3)
    12.26 ( 28.20 )
    -3.24 ( 41.30 )
    -2.14 ( 52.91 )
    -20.24 ( 21.12 )
    -17.22 ( 17.39 )
    42.62 ( 54.95 )
        Day 29 (N=4,4,4,4,4,4)
    -4.67 ( 21.35 )
    -6.67 ( 39.99 )
    26.00 ( 15.11 )
    -7.43 ( 18.63 )
    -16.09 ( 27.05 )
    3.76 ( 24.72 )
        Day 57 (N=4,4,4,4,4,4)
    1.03 ( 34.14 )
    -7.34 ( 25.32 )
    -0.32 ( 32.21 )
    -7.66 ( 13.16 )
    -1.40 ( 38.10 )
    44.17 ( 95.30 )
        Day 64 (N=3,4,4,3,3,2)
    -13.37 ( 36.33 )
    -18.26 ( 49.19 )
    19.91 ( 43.95 )
    -10.60 ( 36.12 )
    10.95 ( 23.38 )
    -28.14 ( 11.51 )
        Day 71 (N=4,4,4,3,4,4)
    18.20 ( 53.85 )
    -25.30 ( 50.43 )
    35.26 ( 68.16 )
    -3.37 ( 8.25 )
    15.14 ( 51.39 )
    60.12 ( 106.28 )
        Day 85 (N=4,4,4,4,4,4)
    -10.56 ( 22.18 )
    -37.50 ( 14.12 )
    9.95 ( 30.71 )
    5.08 ( 24.34 )
    0.71 ( 44.55 )
    15.77 ( 58.40 )
        Day 113 (N=4,4,4,4,4,4)
    -3.83 ( 22.30 )
    -30.38 ( 19.59 )
    25.94 ( 39.76 )
    6.98 ( 37.98 )
    7.03 ( 40.23 )
    -19.58 ( 10.98 )
        Day 169 (N=4,4,4,4,4,4)
    -6.15 ( 54.87 )
    -29.78 ( 31.60 )
    -1.72 ( 40.42 )
    11.08 ( 16.19 )
    -8.07 ( 16.73 )
    8.08 ( 49.45 )
    No statistical analyses for this end point

    Secondary: Percentage Change from Baseline in Serum Concentrations of Procollagen Type 1 N-terminal Propeptide (P1NP)

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    End point title
    		 Percentage Change from Baseline in Serum Concentrations of Procollagen Type 1 N-terminal Propeptide (P1NP)
    End point description
    Serum concentrations of the bone turnover marker P1NP were determined at pre-specified time points. PD Analysis Set: all participants for whom at least 1 PD parameter or endpoint could be adequately estimated. Participants with data available at each time point are presented.
    End point type
    Secondary
    End point timeframe
    Blood samples were taken Day 1 (baseline), Day 8, Day 15, Day 29, Day 57, Days 64, 71, 85, 113, and 169
    End point values
    		 Cohort 1: Romosozumab Dose A (12 to < 18 Years of Age) Cohort 2: Romosozumab Dose A (5 to < 12 Years of Age) Cohort 3: Romosozumab Dose B (12 to < 18 Years of Age) Cohort 4: Romosozumab Dose B (5 to < 12 Years of Age) Cohort 5: Romosozumab Dose C (12 to < 18 Years of Age) Cohort 6: Romosozumab Dose C (5 to < 12 Years of Age)
    Number of subjects analysed
    4
    4
    4
    5
    4
    4
    Units: percentage change
    arithmetic mean (standard deviation)
        Day 8 (N=4,3,4,5,4,4)
    19.81 ( 20.96 )
    12.75 ( 13.03 )
    65.12 ( 17.75 )
    31.77 ( 11.69 )
    35.91 ( 21.89 )
    35.35 ( 47.08 )
        Day 15 (N=3,4,4,4,4,3)
    11.03 ( 13.94 )
    12.43 ( 13.07 )
    52.25 ( 29.71 )
    10.52 ( 14.72 )
    58.58 ( 54.61 )
    28.35 ( 55.00 )
        Day 29 (N=4,4,4,4,4,4)
    5.24 ( 12.87 )
    6.18 ( 18.64 )
    21.52 ( 25.01 )
    1.96 ( 9.22 )
    32.13 ( 59.10 )
    -11.54 ( 11.35 )
        Day 57 (N=4,4,4,4,4,4)
    -2.11 ( 20.26 )
    -22.37 ( 19.82 )
    14.57 ( 36.09 )
    -6.36 ( 17.51 )
    19.07 ( 56.24 )
    -14.26 ( 12.93 )
        Day 64 (N=3,4,4,3,3,4)
    14.82 ( 28.86 )
    19.12 ( 40.48 )
    39.63 ( 31.92 )
    25.42 ( 16.73 )
    77.17 ( 109.07 )
    17.51 ( 35.74 )
        Day 71 (N=4,4,4,3,4,4)
    12.19 ( 21.37 )
    -5.72 ( 28.50 )
    49.37 ( 37.99 )
    16.79 ( 12.29 )
    42.16 ( 59.39 )
    5.12 ( 29.54 )
        Day 85 (N=4,4,4,4,4,4)
    -7.34 ( 22.50 )
    -23.50 ( 13.42 )
    26.12 ( 48.97 )
    -0.72 ( 21.29 )
    5.79 ( 23.45 )
    -11.78 ( 30.09 )
        Day 113 (N=4,4,4,4,4,4)
    -1.13 ( 13.42 )
    -13.75 ( 19.11 )
    21.10 ( 40.61 )
    2.53 ( 42.46 )
    -5.02 ( 21.00 )
    -26.95 ( 10.23 )
        Day 169 (N=4,4,4,4,4,4)
    -6.62 ( 30.96 )
    -3.13 ( 10.54 )
    18.10 ( 57.53 )
    -2.24 ( 23.99 )
    -14.30 ( 19.41 )
    -21.85 ( 16.18 )
    No statistical analyses for this end point

    Secondary: Percentage Change from Baseline in Bone Mineral Density (BMD) of the Lumbar Spine

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    End point title
    		 Percentage Change from Baseline in Bone Mineral Density (BMD) of the Lumbar Spine
    End point description
    BMD was assessed by dual energy X-ray absorptiometry (DXA) scans of the anteroposterior lumbar spine (L1 through L4) and analyzed by a central imaging laboratory. At least 2 lumbar vertebrae from L1 - L4 must be evaluable by DXA. The BMD Analysis Set: all participants who have a baseline lumbar spine DXA BMD measurement and at least 1 post-baseline lumbar spine DXA BMD measurement. Participants with data available at each time point are presented.
    End point type
    Secondary
    End point timeframe
    DXA scans were during screening (baseline) and at Day 85 and Day 169
    End point values
    		 Cohort 1: Romosozumab Dose A (12 to < 18 Years of Age) Cohort 2: Romosozumab Dose A (5 to < 12 Years of Age) Cohort 3: Romosozumab Dose B (12 to < 18 Years of Age) Cohort 4: Romosozumab Dose B (5 to < 12 Years of Age) Cohort 5: Romosozumab Dose C (12 to < 18 Years of Age) Cohort 6: Romosozumab Dose C (5 to < 12 Years of Age)
    Number of subjects analysed
    4
    4
    4
    5
    4
    4
    Units: percentage change
    arithmetic mean (standard deviation)
        Day 85 (N=4,4,4,4,4,4)
    4.84 ( 3.29 )
    7.94 ( 5.32 )
    12.91 ( 2.60 )
    7.78 ( 9.16 )
    7.88 ( 1.99 )
    13.07 ( 13.45 )
        Day 169 (N=4,4,4,4,4,4)
    7.80 ( 2.23 )
    9.24 ( 7.98 )
    15.04 ( 4.32 )
    7.09 ( 7.03 )
    7.10 ( 6.58 )
    12.70 ( 12.86 )
    No statistical analyses for this end point

    Secondary: Percentage Change from Baseline in Bone Mineral Content (BMC) of the Lumbar Spine

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    End point title
    		 Percentage Change from Baseline in Bone Mineral Content (BMC) of the Lumbar Spine
    End point description
    BMC was assessed by DXA scans of the anteroposterior lumbar spine (L1 through L4) and analyzed by a central imaging laboratory. At least 2 lumbar vertebrae from L1 - L4 must be evaluable by DXA. The BMD Analysis Set: all participants who have a baseline lumbar spine DXA BMD measurement and at least 1 post-baseline lumbar spine DXA BMD measurement. Participants with data available at each time point are presented.
    End point type
    Secondary
    End point timeframe
    DXA scans were during screening (baseline) and at Day 85 and Day 169
    End point values
    		 Cohort 1: Romosozumab Dose A (12 to < 18 Years of Age) Cohort 2: Romosozumab Dose A (5 to < 12 Years of Age) Cohort 3: Romosozumab Dose B (12 to < 18 Years of Age) Cohort 4: Romosozumab Dose B (5 to < 12 Years of Age) Cohort 5: Romosozumab Dose C (12 to < 18 Years of Age) Cohort 6: Romosozumab Dose C (5 to < 12 Years of Age)
    Number of subjects analysed
    4
    4
    4
    5
    4
    4
    Units: percentage change
    arithmetic mean (standard deviation)
        Day 85 (N=4,4,4,4,4,4)
    7.68 ( 8.10 )
    10.13 ( 6.05 )
    18.16 ( 7.86 )
    8.41 ( 6.90 )
    14.62 ( 3.39 )
    16.03 ( 8.32 )
        Day 169 (N=4,4,4,4,4,4)
    12.64 ( 4.07 )
    11.40 ( 7.82 )
    21.29 ( 11.31 )
    7.98 ( 7.77 )
    14.27 ( 5.52 )
    12.42 ( 10.72 )
    No statistical analyses for this end point

    Secondary: Percentage Change from Baseline in Lumbar Spine Bone Area

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    End point title
    		 Percentage Change from Baseline in Lumbar Spine Bone Area
    End point description
    Bone area was assessed by DXA scans of the anteroposterior lumbar spine (L1 through L4) and analyzed by a central imaging laboratory. At least 2 lumbar vertebrae from L1 - L4 must be evaluable by DXA. The BMD Analysis Set: all participants who have a baseline lumbar spine DXA BMD measurement and at least 1 post-baseline lumbar spine DXA BMD measurement. Participants with data available at each time point are presented.
    End point type
    Secondary
    End point timeframe
    DXA scans were during screening (baseline) and at Day 85 and Day 169
    End point values
    		 Cohort 1: Romosozumab Dose A (12 to < 18 Years of Age) Cohort 2: Romosozumab Dose A (5 to < 12 Years of Age) Cohort 3: Romosozumab Dose B (12 to < 18 Years of Age) Cohort 4: Romosozumab Dose B (5 to < 12 Years of Age) Cohort 5: Romosozumab Dose C (12 to < 18 Years of Age) Cohort 6: Romosozumab Dose C (5 to < 12 Years of Age)
    Number of subjects analysed
    4
    4
    4
    5
    4
    4
    Units: percentage change
    arithmetic mean (standard deviation)
        Day 85 (N=4,4,4,4,4,4)
    2.72 ( 6.99 )
    2.03 ( 1.62 )
    4.60 ( 5.00 )
    0.80 ( 4.62 )
    6.23 ( 2.15 )
    3.44 ( 11.05 )
        Day 169 (N=4,4,4,4,4,4)
    4.53 ( 4.92 )
    1.92 ( 0.66 )
    5.30 ( 6.06 )
    0.82 ( 1.95 )
    6.87 ( 5.14 )
    -0.09 ( 4.27 )
    No statistical analyses for this end point

    Secondary: Mean Change from Baseline in Lumbar Spine BMD Z-Score

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    End point title
    		 Mean Change from Baseline in Lumbar Spine BMD Z-Score
    End point description
    Lumbar spine BMD was assessed by DXA scans. 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. The BMD Analysis Set: all participants who have a baseline lumbar spine DXA BMD measurement and at least 1 post-baseline lumbar spine DXA BMD measurement. Participants with data available at each time point are presented.
    End point type
    Secondary
    End point timeframe
    DXA scans were during screening (baseline) and at Day 85 and Day 169
    End point values
    		 Cohort 1: Romosozumab Dose A (12 to < 18 Years of Age) Cohort 2: Romosozumab Dose A (5 to < 12 Years of Age) Cohort 3: Romosozumab Dose B (12 to < 18 Years of Age) Cohort 4: Romosozumab Dose B (5 to < 12 Years of Age) Cohort 5: Romosozumab Dose C (12 to < 18 Years of Age) Cohort 6: Romosozumab Dose C (5 to < 12 Years of Age)
    Number of subjects analysed
    4
    4
    4
    5
    4
    4
    Units: Z-score
    arithmetic mean (standard deviation)
        Day 85 (N=4,3,4,4,4,4)
    0.20 ( 0.39 )
    0.45 ( 0.37 )
    0.50 ( 0.12 )
    0.33 ( 0.53 )
    0.33 ( 0.26 )
    0.53 ( 0.79 )
        Day 169 (N=4,4,4,4,4,4)
    0.33 ( 0.46 )
    0.48 ( 0.51 )
    0.48 ( 0.21 )
    0.25 ( 0.39 )
    0.23 ( 0.56 )
    0.50 ( 0.62 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events were collected from first dose of study drug to the end of study visit (up to Day 169); median duration of treatment was 5.55 months.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    26.0
    Reporting groups
    Reporting group title
    Cohort 1: Romosozumab Dose A (12 to < 18 Years of Age)
    Reporting group description
    		 Participants received multiple SC doses of romosozumab Dose A (low dose).

    Reporting group title
    Cohort 2: Romosozumab Dose A (5 to < 12 Years of Age)
    Reporting group description
    		 Participants received multiple SC doses of romosozumab Dose A (low dose).

    Reporting group title
    Cohort 3: Romosozumab Dose B (12 to < 18 Years of Age)
    Reporting group description
    		 Participants received multiple SC doses of romosozumab Dose B (medium dose).

    Reporting group title
    Cohort 4: Romosozumab Dose B (5 to < 12 Years of Age)
    Reporting group description
    		 Participants received multiple SC doses of romosozumab Dose B (medium dose).

    Reporting group title
    Cohort 5: Romosozumab Dose C (12 to < 18 Years of Age)
    Reporting group description
    		 Participants received multiple SC doses of romosozumab Dose C (high dose).

    Reporting group title
    Cohort 6: Romosozumab Dose C (5 to < 12 Years of Age)
    Reporting group description
    		 Participants received multiple SC doses of romosozumab Dose C (high dose).

    Serious adverse events
    		 Cohort 1: Romosozumab Dose A (12 to < 18 Years of Age) Cohort 2: Romosozumab Dose A (5 to < 12 Years of Age) Cohort 3: Romosozumab Dose B (12 to < 18 Years of Age) Cohort 4: Romosozumab Dose B (5 to < 12 Years of Age) Cohort 5: Romosozumab Dose C (12 to < 18 Years of Age) Cohort 6: Romosozumab Dose C (5 to < 12 Years of Age)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    1 / 5 (20.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    Injury, poisoning and procedural complications
    Lower limb fracture
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 5 (20.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Cohort 1: Romosozumab Dose A (12 to < 18 Years of Age) Cohort 2: Romosozumab Dose A (5 to < 12 Years of Age) Cohort 3: Romosozumab Dose B (12 to < 18 Years of Age) Cohort 4: Romosozumab Dose B (5 to < 12 Years of Age) Cohort 5: Romosozumab Dose C (12 to < 18 Years of Age) Cohort 6: Romosozumab Dose C (5 to < 12 Years of Age)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    2 / 4 (50.00%)
    4 / 5 (80.00%)
    1 / 4 (25.00%)
    3 / 4 (75.00%)
    Investigations
    SARS-CoV-2 test positive
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 5 (20.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Ankle fracture
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Femur fracture
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Tooth fracture
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 5 (20.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Neck injury
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Nervous system disorders
    Headache
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    2 / 4 (50.00%)
         occurrences all number
    0
    0
    0
    0
    0
    3
    General disorders and administration site conditions
    Injection site swelling
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    1 / 4 (25.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    Injection site erythema
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    1 / 4 (25.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    0
    0
    1
    2
    Injection site pain
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    0
    0
    0
    2
    Pyrexia
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 5 (20.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    0
    1
    0
    1
    Eye disorders
    Ocular hyperaemia
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 5 (20.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Constipation
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 5 (20.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    0
    Abnormal faeces
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 5 (20.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Toothache
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Haematochezia
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 5 (20.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    0
    Abdominal pain
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Catarrh
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 5 (20.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    0
    3
    0
    0
    Increased upper airway secretion
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 5 (20.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Cough
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    2 / 4 (50.00%)
         occurrences all number
    0
    0
    0
    0
    0
    4
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Rash maculo-papular
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 5 (20.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 5 (20.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Renal and urinary disorders
    Dysuria
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 5 (20.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 5 (20.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    0
    3
    0
    1
    Back pain
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    1 / 5 (20.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    0
    Muscle contracture
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Muscle swelling
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Musculoskeletal chest pain
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 5 (20.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Pain in extremity
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 5 (20.00%)
    0 / 4 (0.00%)
    2 / 4 (50.00%)
         occurrences all number
    0
    0
    0
    1
    0
    3
    Infections and infestations
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    2 / 4 (50.00%)
         occurrences all number
    0
    0
    0
    0
    0
    2
    Nasopharyngitis
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 5 (20.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    0
    1
    0
    3
    COVID-19
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 5 (20.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    0
    1
    1
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    27 Apr 2020
    - The placebo group was removed from the study. - Increased number of participants with active treatment from 3 to 4 for better understanding of PK variability at each dose level. - Hip DXA was removed. - BMD, BMC, and bone area were added as DXA parameters in the secondary endpoints. - ECG assessment was added on Day 29. - Serum PK collection was added to Day 169 and removed from Day 61. Anti-drug antibody collection was added to Day 15. - Pregnancy testing at screening was to be done using serum samples, but all other pregnancy assessments remained unchanged using urine samples. - Exclusion criteria were updated to exclude participants with body weight < 10 kg and > 90 kg; to add conditions associated with increased risk of cardiovascular disease; to clarify that removal of baby teeth was not considered an invasive dental procedure; to exclude participants within 12 months of prior denosumab used. - Common Terminology Criteria for Adverse Events grading scale was replaced with the Amgen Standard Grading Scale as it was more appropriate for the study design and population. - Tanner staging was removed. A history of menarche was to be solely used to determine whether female participants would undergo pregnancy testing. - Adjudication of atypical femoral fractures and potential cardiovascular events was removed. - Disease-related events were removed from the protocol to align with Amgen's current processes for reporting adverse events. The anticipated serious adverse event definition was removed because all serious adverse events were to be reported to health authorities in an expedited manner.
    26 May 2020
    - Updated participant screening number assignment to using interactive response technology.
    19 Feb 2021
    - Updated Schedule of Assessments table and protocol to include visits 2 hours post-dose and removed Day 61 visit; updated to include information about home care services and assessments that could be performed at home; and updated alcohol and drug testing and ECG, telephonic safety assessments at screening visits. - Updated study design to include the participant monitoring details for 2 hours after the first and subsequent dosing of romosozumab. - Pediatric risk assessment language was updated to include risk of valvular heart disease and safety monitoring to include neurological assessments; and to add details of potential COVID-19 risks. - Study rationale was updated to include details of romosozumab PK model for children. - Exclusion criteria were updated to include clinically significant valvular heart disease. - Added details regarding drug substances of abuse along with alcohol and tobacco restrictions. - Updated the contraceptive requirements to include progesterone-only hormonal contraception language and removed two-barrier methods. - Updated the text to include adverse event reporting after signing the informed consent form through to end of study. - Removed language for the worldwide reporting regulations for all adverse events unblinding from reporting procedures for serious adverse events. - Included the BMD analysis set. - Remove 'by treatment group' for statistical considerations.
    28 Feb 2023
    - Corrected text regarding laboratory assessments to be completed by the central laboratory as the Schedule of Assessments erroneously listed them to be completed by the local laboratory.

    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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