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    Clinical Trial Results:
    Multicenter, Single-arm Open-label Extension Study to Assess Long-term Safety and Efficacy of Current or Prior Treatment With Denosumab in Children/Young Adults With Osteogenesis Imperfecta

    Summary
    EudraCT number
    		 2018-000550-21
    Trial protocol
    		 HU   PL   BE   DE   GB   ES   CZ   FR   BG   IT  
    Global end of trial date
    28 Mar 2022

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

    Trial information

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    Trial identification
    Sponsor protocol code
    20170534
    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, 91320
    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
    28 Mar 2022
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    28 Mar 2022
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The primary objective was to evaluate long-term safety of denosumab in subjects with pediatric osteogenesis imperfecta (OI) who completed Study 20130173 (EudraCT Number: 2014-000184-40).
    Protection of trial subjects
    This study was conducted in accordance with International Council for Harmonisation (ICH) Good Clinical Practice (GCP) regulations/guidelines. The study protocol and all amendments, the informed consent form, and any accompanying materials provided to the subjects were reviewed and approved by an Institutional Review Board (IRB) or Independent Ethics Committee (IEC) at each study center. The investigator or his/her designee informed the subject of all aspects pertaining to the subject’s participation in the study before any screening procedures were performed.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    26 Jul 2018
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety
    Long term follow-up duration
    		 6 Months
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Belgium: 3
    Country: Number of subjects enrolled
    Czechia: 2
    Country: Number of subjects enrolled
    France: 2
    Country: Number of subjects enrolled
    Germany: 29
    Country: Number of subjects enrolled
    Hungary: 4
    Country: Number of subjects enrolled
    Italy: 6
    Country: Number of subjects enrolled
    Poland: 1
    Country: Number of subjects enrolled
    Spain: 3
    Country: Number of subjects enrolled
    United Kingdom: 8
    Country: Number of subjects enrolled
    Canada: 10
    Country: Number of subjects enrolled
    United States: 7
    Worldwide total number of subjects
    75
    EEA total number of subjects
    50
    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)
    24
    Adolescents (12-17 years)
    42
    Adults (18-64 years)
    9
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 This study was conducted at 22 centers in North America, Europe, and Australia from July 2018 to March 2022.

    Pre-assignment
    Screening details
    		 Subjects enrolled in Study 20130173 were eligible for this study if they completed Study 20130173 end of study visit, did not reconsent/reassent to transition to the Q3M dosing regimen, or early terminated due to meeting BMD Z-score investigational product stopping criteria.

    Period 1
    Period 1 title
    Open-label Extension (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Alternative Medications / Observational
    Arm description
    		 Participants who received non-denosumab alternative therapy during the study or who were not receiving any medication at baseline. Alternative osteoporosis medication(s) were determined at the investigator’s discretion and per standard of care and local guidelines.
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 Denosumab 1 mg/kg Q6M
    Arm description
    		 Participants who received at least 1 dose of 1 mg/kg denosumab administered once every 6 months (Q6M) administered by subcutaneous injection, but no Q3M denosumab during this study.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Denosumab
    Investigational medicinal product code
    AMG 162
    Other name
    Prolia®
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Administered by subcutaneous injection once every 6 months

    Arm title
    		 Denosumab 1 mg/kg Q3M
    Arm description
    		 Participants who received at least one dose of 1 mg/kg denosumab administered once every 3 months (Q3M) by subcutaneous injection during this study.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Denosumab
    Investigational medicinal product code
    AMG 162
    Other name
    Prolia®
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Administered by subcutaneous injection once every 3 months

    Number of subjects in period 1
    		Alternative Medications / Observational Denosumab 1 mg/kg Q6M Denosumab 1 mg/kg Q3M
    Started
    21
    27
    27
    Completed
    5
    8
    1
    Not completed
    16
    19
    26
         Consent withdrawn by subject
    1
    7
    6
         Sponsor decision
    15
    12
    19
         Lost to follow-up
    -
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Alternative Medications / Observational
    Reporting group description
    		 Participants who received non-denosumab alternative therapy during the study or who were not receiving any medication at baseline. Alternative osteoporosis medication(s) were determined at the investigator’s discretion and per standard of care and local guidelines.

    Reporting group title
    Denosumab 1 mg/kg Q6M
    Reporting group description
    		 Participants who received at least 1 dose of 1 mg/kg denosumab administered once every 6 months (Q6M) administered by subcutaneous injection, but no Q3M denosumab during this study.

    Reporting group title
    Denosumab 1 mg/kg Q3M
    Reporting group description
    		 Participants who received at least one dose of 1 mg/kg denosumab administered once every 3 months (Q3M) by subcutaneous injection during this study.

    Reporting group values
    		 Alternative Medications / Observational Denosumab 1 mg/kg Q6M Denosumab 1 mg/kg Q3M Total
    Number of subjects
    		 21 27 27 75
    Age Categorical
    Units: Subjects
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 12.5 ± 3.5 13.2 ± 2.5 14.3 ± 4.8 -
    Gender Categorical
    Units: Subjects
        Female
    		 8 9 13 30
        Male
    		 13 18 14 45
    Race
    Units: Subjects
        Asian
    		 0 0 1 1
        Black or African American
    		 1 1 0 2
        White
    		 20 25 23 68
        Other
    		 0 1 1 2
        Multiple
    		 0 0 2 2
    Subject analysis sets

    Subject analysis set title
    Any Treatment
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants who were enrolled in the study and received denosumab Q3M or Q6M, alternative treatment or did not receive any treatment.

    Subject analysis sets values
    		 Any Treatment
    Number of subjects
    75
    Age Categorical
    Units: Subjects
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    13.4 ± 3.8
    Gender Categorical
    Units: Subjects
        Female
    30
        Male
    45
    Race
    Units: Subjects
        Asian
    1
        Black or African American
    2
        White
    68
        Other
    2
        Multiple
    2

    End points

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    End points reporting groups
    Reporting group title
    Alternative Medications / Observational
    Reporting group description
    		 Participants who received non-denosumab alternative therapy during the study or who were not receiving any medication at baseline. Alternative osteoporosis medication(s) were determined at the investigator’s discretion and per standard of care and local guidelines.

    Reporting group title
    Denosumab 1 mg/kg Q6M
    Reporting group description
    		 Participants who received at least 1 dose of 1 mg/kg denosumab administered once every 6 months (Q6M) administered by subcutaneous injection, but no Q3M denosumab during this study.

    Reporting group title
    Denosumab 1 mg/kg Q3M
    Reporting group description
    		 Participants who received at least one dose of 1 mg/kg denosumab administered once every 3 months (Q3M) by subcutaneous injection during this study.

    Subject analysis set title
    Any Treatment
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants who were enrolled in the study and received denosumab Q3M or Q6M, alternative treatment or did not receive any treatment.

    Primary: Number of Participants with Adverse Events, Serious Adverse Events, and Adverse Events of Special Interest

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    End point title
    		 Number of Participants with Adverse Events, Serious Adverse Events, and Adverse Events of Special Interest [1]
    End point description
    Adverse events of special interest included changes in growth plate morphology, severe or symptomatic hypocalcemia, hypersensitivity, bacterial cellulitis, osteonecrosis of the jaw (ONJ), abnormal molar eruption, hypercalcemia, and abnormal mandibular shaping.
    End point type
    Primary
    End point timeframe
    From enrollment to end of study, including 24 weeks after last dose of denosumab for participants who received denosumab; the maximum time on study was 24 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: This study was descriptive in nature and did not involve testing formal hypotheses.
    End point values
    		 Alternative Medications / Observational Denosumab 1 mg/kg Q6M Denosumab 1 mg/kg Q3M
    Number of subjects analysed
    21
    27
    27
    Units: participants
        Any adverse event
    18
    22
    19
        Serious adverse events
    6
    5
    6
        Adverse events of special interest
    5
    5
    9
        Hypocalcemia
    0
    0
    1
        Hypercalcemia
    3
    4
    9
        Hypersensitivity
    0
    0
    0
        Bacterial cellulitis (skin infection)
    0
    0
    0
        Typical osteogenesis imperfecta femur fractures
    2
    1
    2
    No statistical analyses for this end point

    Primary: Number of Participants with Anti-denosumab Antibodies

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    End point title
    		 Number of Participants with Anti-denosumab Antibodies [2] [3]
    End point description
    Blood samples were collected (from denosumab treated subjects only) for the measurement of anti-denosumab binding antibodies. Samples positive for anti-denosumab binding antibodies were further tested for neutralizing antibodies.
    End point type
    Primary
    End point timeframe
    From enrollment to end of study, including 24 weeks after last dose of denosumab for participants who received denosumab; the maximum time on study was 24 months
    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: This study was descriptive in nature and did not involve testing formal hypotheses.
    [3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Participants in the Alternative Medications / Observational group were not tested for anti-denosumab antibodies.
    End point values
    		 Denosumab 1 mg/kg Q6M Denosumab 1 mg/kg Q3M
    Number of subjects analysed
    27
    27
    Units: participants
        Anti-denosumab binding antibodies
    0
    0
        Anti-denosumab neutralizing antibodies
    0
    0
    No statistical analyses for this end point

    Primary: Number of Participants with Clinical Laboratory Toxicities Grade ≥ 3

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    End point title
    		 Number of Participants with Clinical Laboratory Toxicities Grade ≥ 3 [4]
    End point description
    Laboratory abnormalities were graded according to the Common Terminology Criteria for Adverse Events (CTCAE), Version 4.0. The grades refer to the severity of the finding: Grade 1 = Mild; Grade 2 = Moderate; Grade 3 = Severe or medically significant; Grade 4 = Life-threatening consequences, urgent intervention indicated.
    End point type
    Primary
    End point timeframe
    From enrollment to end of study, including 24 weeks after last dose of denosumab for participants who received denosumab; the maximum time on study was 24 months
    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: This study was descriptive in nature and did not involve testing formal hypotheses.
    End point values
    		 Alternative Medications / Observational Denosumab 1 mg/kg Q6M Denosumab 1 mg/kg Q3M
    Number of subjects analysed
    21
    27
    27
    Units: participants
    0
    0
    0
    No statistical analyses for this end point

    Primary: Number of Participants with Clinically Significant Vital Sign Findings

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    End point title
    		 Number of Participants with Clinically Significant Vital Sign Findings [5]
    End point description
    Vital sign measurements included systolic and diastolic blood pressure, heart rate, respiratory rate, and temperature. The investigator assessed vital sign results and determined whether any abnormal changes represented a clinically significant change from the participant's baseline values.
    End point type
    Primary
    End point timeframe
    From enrollment to end of study, including 24 weeks after last dose of denosumab for participants who received denosumab; the maximum time on study was 24 months
    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: This study was descriptive in nature and did not involve testing formal hypotheses.
    End point values
    		 Alternative Medications / Observational Denosumab 1 mg/kg Q6M Denosumab 1 mg/kg Q3M
    Number of subjects analysed
    21
    27
    27
    Units: participants
    0
    0
    0
    No statistical analyses for this end point

    Primary: Number of Participants with Metaphyseal Index Z-score Above Age-appropriate Normal Range

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    End point title
    		 Number of Participants with Metaphyseal Index Z-score Above Age-appropriate Normal Range [6]
    End point description
    Anteroposterior radiographs of both knees (unless prohibited by the presence of hardware such as implants) were used to calculate the metaphyseal index Z-score of each knee in participants with open growth plates; the knee selected for assessment during the study was the knee with the higher Z-score at baseline. The metaphyseal index (MI) was calculated by the central imaging vendor as the ratio of femoral width over distal femoral growth plate width, and the Z-score for each subject, relative to the subject’s age as: MI Z-score = (subject value – mean)/SD, where mean and standard deviation (SD) are the corresponding values based on a reference population for the subject’s age group at the time of the assessment. Metaphyseal index Z-score above age-appropriate normal range is defined as a MI Z-score > 2. The metaphyseal analysis set includes subjects with open growth plates and no hardware preventing accurate calculation of MI at baseline and knee X-ray at baseline and postbaseline.
    End point type
    Primary
    End point timeframe
    Baseline, month 12 and month 24
    Notes
    [6] - 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: This study was descriptive in nature and did not involve testing formal hypotheses.
    End point values
    		 Alternative Medications / Observational Denosumab 1 mg/kg Q6M Denosumab 1 mg/kg Q3M
    Number of subjects analysed
    3 [7]
    4 [8]
    4 [9]
    Units: participants
        Baseline (N = 3, 4, 4)
    2
    1
    0
        Month 12 (N = 3, 4, 4)
    2
    1
    0
        Month 24 (N = 1, 1, 0)
    1
    0
    0
    Notes
    [7] - Metaphyseal analysis set; subjects with available data at each time point
    [8] - Metaphyseal analysis set; subjects with available data at each time point
    [9] - Metaphyseal analysis set ; subjects with available data at each time point
    No statistical analyses for this end point

    Primary: Number of Participants with Abnormal Molar Eruption of the First or Second Molar Based on Radiological Findings

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    End point title
    		 Number of Participants with Abnormal Molar Eruption of the First or Second Molar Based on Radiological Findings [10]
    End point description
    Participants underwent a visual inspection under natural light for the presence of the first and second molars. Participants were referred to a dentist to perform radiographic assessment of the unerupted molar(s) if: - A participant was age 7 to 12 years and appeared to have an unerupted upper or lower first molar (ie, not all 4 first molars were visible/detectable). - A participant was age 13 years or older and appeared to have an unerupted upper or lower (first or) second molar (ie, not all 4 first molars and all 4 second molars were visible/detectable). Abnormal molar eruptions includes the number of participants 7 to 12 years of age with 1st unerupted or partially erupted molars and participants 13 years of age or older with 2nd unerupted or partially erupted molars. The analysis at each time point includes participants with radiologic assessments.
    End point type
    Primary
    End point timeframe
    Baseline, month 12, and month 24
    Notes
    [10] - 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: This study was descriptive in nature and did not involve testing formal hypotheses.
    End point values
    		 Alternative Medications / Observational Denosumab 1 mg/kg Q6M Denosumab 1 mg/kg Q3M
    Number of subjects analysed
    21
    27
    27
    Units: participants
        Baseline (N = 19, 22, 17)
    2
    3
    1
        Month 12 (N = 10, 8, 6)
    0
    0
    2
        Month 24 (N = 2, 8, 1)
    1
    1
    0
    No statistical analyses for this end point

    Primary: Percent Change from Baseline in Mandibular Shaping Parameters

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    End point title
    		 Percent Change from Baseline in Mandibular Shaping Parameters [11]
    End point description
    Lateral cephalogram was performed to enable assessment of mandibular shaping. The lateral cephalogram is a profile X-ray of the skull and soft tissues and is used to assess the relation of the teeth in the jaws, the relation of the jaws to the skull, and the relation of the soft tissues to the teeth and jaws. The following anatomical angles and dimensions were measured to evaluate the correct proportions of the mandible and its position relative to the skull/maxilla: Gonial angle; Sella-Nasion-A Point Angle (SNA angle); Sella-Nasion-B Point Angle (SNB angle); and A Point - Nasion-B Point Angle (ANB Angle). The analysis at each time point includes participants with radiologic assessments. "99999" indicates Not Applicable.
    End point type
    Primary
    End point timeframe
    Baseline and month 12 and month 24
    Notes
    [11] - 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: This study was descriptive in nature and did not involve testing formal hypotheses.
    End point values
    		 Alternative Medications / Observational Denosumab 1 mg/kg Q6M Denosumab 1 mg/kg Q3M
    Number of subjects analysed
    21
    27
    27
    Units: percent change
    arithmetic mean (standard deviation)
        Gonial Angle at Month 12 (N = 8, 8, 1)
    0.5 ± 2.4
    -1.4 ± 1.7
    -1.0 ± 99999
        Gonial Angle at Month 24 (N = 2, 7, 0)
    -2.1 ± 3.1
    -1.4 ± 2.2
    99999 ± 99999
        SNA Angle at Month 12 (N = 8, 8, 1)
    1.38 ± 2.09
    0.37 ± 2.41
    0.20 ± 99999
        SNA Angle at Month 24 (N = 2, 7, 0)
    -0.07 ± 0.73
    -1.70 ± 1.79
    99999 ± 99999
        SNB Angle at Month 12 (N = 6, 8, 1)
    0.98 ± 1.56
    1.75 ± 2.36
    0.70 ± 99999
        SNB Angle at Month 24 (N = 1, 4, 0)
    1.28 ± 99999
    -1.60 ± 3.18
    99999 ± 99999
        ANB Angle at Month 12 (N = 6, 8, 1)
    -81.06 ± 199.39
    127.48 ± 312.99
    -16.26 ± 99999
        ANB Angle at Month 24 (N = 1, 4, 0)
    -79.69 ± 99999
    15.65 ± 84.75
    99999 ± 99999
    No statistical analyses for this end point

    Secondary: Change from Baseline in Lumbar Spine Bone Mineral Density (BMD) Z-score

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    End point title
    		 Change from Baseline in Lumbar Spine Bone Mineral Density (BMD) Z-score
    End point description
    Bone densitometry assessments of the lumbar spine were performed using dual X-ray absorptiometry (DXA). The Z-score indicates the number of standard deviations away from the mean of an average person of the same age, sex, race, and weight. A Z-score of 0 is equal to the mean of the matched population, negative Z-scores indicate a BMD lower than the mean of the matched population, and positive Z-scores indicate a higher BMD than that of the matched population. A positive change from baseline indicates an improvement in lumbar spine BMD. The DXA analysis set includes all subjects with baseline and ≥ 1 postbaseline valid DXA assessments for lumbar spine as provided by the central imaging vendor.
    End point type
    Secondary
    End point timeframe
    Baseline and months 6, 12, and 24
    End point values
    		 Any Treatment
    Number of subjects analysed
    58 [12]
    Units: Z-score
    arithmetic mean (standard deviation)
        Month 6 (N = 29)
    -0.11 ± 0.60
        Month 12 (N = 39)
    -0.01 ± 0.48
        Month 24 (N = 18)
    0.21 ± 0.49
    Notes
    [12] - DXA analysis set; subjects with available data at each time point
    No statistical analyses for this end point

    Secondary: Change from Baseline in Total Hip BMD Z-score

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    End point title
    		 Change from Baseline in Total Hip BMD Z-score
    End point description
    Bone densitometry assessments of the hip were performed using dual X-ray absorptiometry (DXA). The Z-score indicates the number of standard deviations away from the mean of an average person of the same age, sex, race, and weight. A Z-score of 0 is equal to the mean of the matched population, negative Z-scores indicate a BMD lower than the mean of the matched population, and positive Z-scores indicate a higher BMD than that of the matched population. A positive change from baseline indicates an improvement in total hip BMD. The DXA analysis set includes all subjects with baseline and ≥ 1 postbaseline valid DXA assessments for the total hip as provided by the central imaging vendor.
    End point type
    Secondary
    End point timeframe
    Baseline, months 6, 12, and 24
    End point values
    		 Any Treatment
    Number of subjects analysed
    35 [13]
    Units: Z-score
    arithmetic mean (standard deviation)
        Month 6 (N = 16)
    -0.07 ± 0.40
        Month 12 (N = 25)
    0.24 ± 0.42
        Month 24 (N = 15)
    0.50 ± 0.54
    Notes
    [13] - DXA analysis set; subjects with available data at each time point
    No statistical analyses for this end point

    Secondary: Change from Baseline in Femoral Neck BMD Z-score

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    End point title
    		 Change from Baseline in Femoral Neck BMD Z-score
    End point description
    Bone densitometry assessments of the femoral neck were performed using dual X-ray absorptiometry (DXA). The Z-score indicates the number of standard deviations away from the mean of an average person of the same age, sex, race, and weight. A Z-score of 0 is equal to the mean of the matched population, negative Z-scores indicate a BMD lower than the mean of the matched population, and positive Z-scores indicate a higher BMD than that of the matched population. A positive change from baseline indicates an improvement in femoral neck BMD. The DXA analysis set includes all subjects with baseline and ≥ 1 postbaseline valid DXA assessments for the femoral neck as provided by the central imaging vendor.
    End point type
    Secondary
    End point timeframe
    Baseline, month 6, 12, and 24
    End point values
    		 Any Treatment
    Number of subjects analysed
    35 [14]
    Units: Z-score
    arithmetic mean (standard deviation)
        Month 6 (N = 16)
    0.08 ± 0.44
        Month 12 (N = 25)
    0.24 ± 0.39
        Month 24 (N = 15)
    0.45 ± 0.58
    Notes
    [14] - DXA analysis set; subjects with available data at each time point
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From enrollment to end of study, including 24 weeks after last dose of denosumab for participants who received denosumab; the maximum time on study was 24 months.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    25.0
    Reporting groups
    Reporting group title
    Alternative Medications / Observational
    Reporting group description
    		 Participants who received non-denosumab alternative therapy during the study or who were not receiving any medication at baseline. Alternative osteoporosis medication(s) were determined at the investigator’s discretion and per standard of care and local guidelines.

    Reporting group title
    Denosumab 1 mg/kg Q3M
    Reporting group description
    		 Participants who received at least one dose of 1 mg/kg denosumab administered once every 3 months (Q3M) by subcutaneous injection during this study.

    Reporting group title
    Denosumab 1 mg/kg Q6M
    Reporting group description
    		 Participants who received at least 1 dose of 1 mg/kg denosumab administered once every 6 months (Q6M) administered by subcutaneous injection, but no Q3M denosumab during this study.

    Serious adverse events
    		 Alternative Medications / Observational Denosumab 1 mg/kg Q3M Denosumab 1 mg/kg Q6M
    Total subjects affected by serious adverse events
         subjects affected / exposed
    6 / 21 (28.57%)
    6 / 27 (22.22%)
    5 / 27 (18.52%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    Injury, poisoning and procedural complications
    Femur fracture
         subjects affected / exposed
    2 / 21 (9.52%)
    1 / 27 (3.70%)
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Fibula fracture
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 27 (0.00%)
    2 / 27 (7.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Forearm fracture
         subjects affected / exposed
    2 / 21 (9.52%)
    0 / 27 (0.00%)
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Humerus fracture
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 27 (0.00%)
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Radius fracture
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 27 (0.00%)
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lower limb fracture
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 27 (0.00%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tibia fracture
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 27 (0.00%)
    2 / 27 (7.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ulna fracture
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 27 (0.00%)
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Surgical failure
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 27 (0.00%)
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Vomiting
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 27 (3.70%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 27 (0.00%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Nephrolithiasis
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 27 (0.00%)
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Appendicitis
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 27 (0.00%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hypercalcaemia
         subjects affected / exposed
    0 / 21 (0.00%)
    5 / 27 (18.52%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    4 / 6
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Alternative Medications / Observational Denosumab 1 mg/kg Q3M Denosumab 1 mg/kg Q6M
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    15 / 21 (71.43%)
    13 / 27 (48.15%)
    21 / 27 (77.78%)
    Injury, poisoning and procedural complications
    Ankle fracture
         subjects affected / exposed
    0 / 21 (0.00%)
    2 / 27 (7.41%)
    0 / 27 (0.00%)
         occurrences all number
    0
    2
    0
    Fibula fracture
         subjects affected / exposed
    0 / 21 (0.00%)
    2 / 27 (7.41%)
    1 / 27 (3.70%)
         occurrences all number
    0
    2
    1
    Ligament sprain
         subjects affected / exposed
    1 / 21 (4.76%)
    2 / 27 (7.41%)
    0 / 27 (0.00%)
         occurrences all number
    1
    2
    0
    Tibia fracture
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 27 (0.00%)
    2 / 27 (7.41%)
         occurrences all number
    0
    0
    2
    Nervous system disorders
    Headache
         subjects affected / exposed
    3 / 21 (14.29%)
    2 / 27 (7.41%)
    1 / 27 (3.70%)
         occurrences all number
    6
    2
    2
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    0 / 21 (0.00%)
    2 / 27 (7.41%)
    0 / 27 (0.00%)
         occurrences all number
    0
    2
    0
    Gastrointestinal disorders
    Abdominal pain upper
         subjects affected / exposed
    2 / 21 (9.52%)
    0 / 27 (0.00%)
    0 / 27 (0.00%)
         occurrences all number
    2
    0
    0
    Renal and urinary disorders
    Hypercalciuria
         subjects affected / exposed
    11 / 21 (52.38%)
    1 / 27 (3.70%)
    15 / 27 (55.56%)
         occurrences all number
    29
    7
    41
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    6 / 21 (28.57%)
    4 / 27 (14.81%)
    7 / 27 (25.93%)
         occurrences all number
    6
    4
    17
    Back pain
         subjects affected / exposed
    3 / 21 (14.29%)
    3 / 27 (11.11%)
    4 / 27 (14.81%)
         occurrences all number
    6
    6
    5
    Pain in extremity
         subjects affected / exposed
    3 / 21 (14.29%)
    0 / 27 (0.00%)
    7 / 27 (25.93%)
         occurrences all number
    3
    0
    16
    Infections and infestations
    COVID-19
         subjects affected / exposed
    1 / 21 (4.76%)
    2 / 27 (7.41%)
    1 / 27 (3.70%)
         occurrences all number
    1
    2
    1
    Metabolism and nutrition disorders
    Hypercalcaemia
         subjects affected / exposed
    3 / 21 (14.29%)
    5 / 27 (18.52%)
    4 / 27 (14.81%)
         occurrences all number
    3
    6
    4

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    11 Jul 2019
    Major changes to the protocol included: • included incidence of adverse events of special interest in the primary endpoint. • clarified the treatment options for the study. • updated dose modification language.
    31 Mar 2020
    Major changes to the protocol included: • defined denosumab Q3M as the investigational product for the study. • modified inclusion criteria to allow subjects who ­did not reconsent to transition to Q3M dosing regimen in Study 20130173, or early terminated from Study 20130173 due to meeting BMD Z-score investigational product stopping criteria. • updated end of study definition. • updated dose modification language.
    30 Apr 2020
    Major changes to the protocol included: • clarified that day 10 and day 30 assessments are only required for subjects who started the Q3M dosing regimen for the first time.
    17 Nov 2020
    Major changes to the protocol included: • added additional serum calcium samples at days 10 and 30 after investigational product dosing at weeks 12 and 24. • updated definition of study day 1 and end of study.
    14 Jan 2021
    Major changes to the protocol included: • updated to harmonize content with Study 20130173 protocol after minor updates to Schedule of Activities and remove reference to the Safety Report Form.
    09 Nov 2021
    Major updates to the protocol included: • updated text throughout based on early study termination due to the risk of hypercalcemia. • added immediate discontinuation of all subjects from study treatment followed by a 24-week safety follow-up period.
    02 Feb 2022
    Major updates to the protocol included: • removed the secondary efficacy endpoints of fracture and growth velocity. • clarified that BMD Z-score and BTM will be assessed at 6, 12, and 24 months. • removed the exploratory endpoint of BMD and bone mineral content. • removed the subgroup analysis.

    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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