Flag of the European Union EU Clinical Trials Register Help

Clinical trials

The European Union Clinical Trials Register   allows you to search for protocol and results information on:
  • interventional clinical trials that were approved in the European Union (EU)/European Economic Area (EEA) under the Clinical Trials Directive 2001/20/EC
  • clinical trials conducted outside the EU/EEA that are linked to European paediatric-medicine development

    • EU/EEA interventional clinical trials approved under or transitioned to the Clinical Trial Regulation 536/2014 are publicly accessible through the
    Clinical Trials Information System (CTIS).

    The EU Clinical Trials Register currently displays   43871   clinical trials with a EudraCT protocol, of which   7290   are clinical trials conducted with subjects less than 18 years old.   The register also displays information on   18700   older paediatric trials (in scope of Article 45 of the Paediatric Regulation (EC) No 1901/2006).

    Phase 1 trials conducted solely on adults and that are not part of an agreed paediatric investigation plan (PIP) are not publicly available (see Frequently Asked Questions ).  
     
    Examples: Cancer AND drug name. Pneumonia AND sponsor name.
    How to search [pdf]
    Search Tips: Under advanced search you can use filters for Country, Age Group, Gender, Trial Phase, Trial Status, Date Range, Rare Diseases and Orphan Designation. For these items you should use the filters and not add them to your search terms in the text field.
    Advanced Search: Search tools
     

    < Back to search results

    Download PDF

    Clinical Trial Results:
    An Open label, Multi center, Phase 2 Study of Denosumab in Subjects with Giant Cell Tumor of Bone

    Summary
    EudraCT number
    		 2008-001606-16
    Trial protocol
    		 NL   DE   AT   FR   ES   GB   PL   IT   SE   Outside EU/EEA  
    Global end of trial date
    17 May 2018

    Results information
    Results version number
    		 v1(current)
    This version publication date
    29 Nov 2018
    First version publication date
    29 Nov 2018
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    20062004
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00680992
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Amgen Inc.
    Sponsor organisation address
    One Amgen Center Drive, Thousand Oaks, CA, United States,
    Public contact
    IHQ Medical Info-Clinical Trials, Amgen (EUROPE) GmbH, MedInfoInternational@amgen.com
    Scientific contact
    IHQ Medical Info-Clinical Trials, Amgen (EUROPE) GmbH, MedInfoInternational@amgen.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-000145-PIP01-07
    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
    17 May 2018
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    17 May 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the safety profile of denosumab in participants with giant cell tumor of bone (GCTB).
    Protection of trial subjects
    This study was conducted in accordance with International Council for Harmonisation Good Clinical Practice, Declaration of Helsinki, and applicable national or regional regulations/guidelines.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    09 Sep 2008
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United States: 144
    Country: Number of subjects enrolled
    France: 75
    Country: Number of subjects enrolled
    Australia: 41
    Country: Number of subjects enrolled
    Austria: 10
    Country: Number of subjects enrolled
    Canada: 22
    Country: Number of subjects enrolled
    Germany: 26
    Country: Number of subjects enrolled
    Italy: 83
    Country: Number of subjects enrolled
    Netherlands: 26
    Country: Number of subjects enrolled
    Poland: 39
    Country: Number of subjects enrolled
    Spain: 24
    Country: Number of subjects enrolled
    Sweden: 18
    Country: Number of subjects enrolled
    United Kingdom: 24
    Worldwide total number of subjects
    532
    EEA total number of subjects
    325
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    28
    Adults (18-64 years)
    481
    From 65 to 84 years
    23
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 Adults and skeletally mature adolescents (≥12 years of age) were enrolled in this open-label single-arm study. The study was conducted at 30 centers in North America, Europe, and Australia from 09 Sep 2008 to study completion on 17 May 2018. The planned study duration for each participant was at least 60 months (following protocol amendment 7).

    Pre-assignment
    Screening details
    		 3 participants from study 20040215 (NCT00396279) were enrolled directly into safety follow-up phase without retreatment. They were excluded from all defined analysis sets and results are reported for the 532 participants enrolled into the treatment phase. Non-completion reasons are summarized for the on-study period (ie, initial treatment phase).

    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 (Denosumab 120 mg Q4W)
    Arm description
    		 Participants with surgically unsalvageable disease (eg, sacral, spinal GCTB, or multiple lesions including pulmonary metastases) were enrolled into cohort 1.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Denosumab
    Investigational medicinal product code
    AMG 162
    Other name
    Immunoglobulin G2 human monoclonal antibody to RANK ligand
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    The dosing schedule was 120 milligrams (mg) subcutaneously (SC) every 4 weeks (Q4W) with a loading dose of 120 mg on study days 8 and 15. Denosumab was supplied as a sterile, clear, colorless to slightly yellow, preservative-free liquid in single-use 3.0 milliliter (mL) glass vials containing a deliverable dose of 1.7 mL.

    Arm title
    		 Cohort 2 (Denosumab 120 mg Q4W)
    Arm description
    		 Participants with surgically salvageable disease whose planned initial on-study surgery was associated with severe morbidity (eg, joint resection, limb amputation, or hemipelvectomy) were enrolled into cohort 2.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Denosumab
    Investigational medicinal product code
    AMG 162
    Other name
    Immunoglobulin G2 human monoclonal antibody to RANK ligand
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    The dosing schedule was 120 mg SC Q4W with a loading dose of 120 mg on study days 8 and 15. Denosumab was supplied as a sterile, clear, colorless to slightly yellow, preservative-free liquid in single-use 3.0 mL glass vials containing a deliverable dose of 1.7 mL.

    Arm title
    		 Cohort 3 (Denosumab 120 mg Q4W)
    Arm description
    		 Participants who participated in study 20040215 and were eligible to enroll in the current study (20062004) for continuation of treatment were enrolled into cohort 3.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Denosumab
    Investigational medicinal product code
    AMG 162
    Other name
    Immunoglobulin G2 human monoclonal antibody to RANK ligand
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    The dosing schedule was 120 mg SC Q4W. Denosumab was supplied as a sterile, clear, colorless to slightly yellow, preservative-free liquid in single-use 3.0 mL glass vials containing a deliverable dose of 1.7 mL.

    Number of subjects in period 1
    		Cohort 1 (Denosumab 120 mg Q4W) Cohort 2 (Denosumab 120 mg Q4W) Cohort 3 (Denosumab 120 mg Q4W)
    Started
    268
    252
    12
    Safety analysis set
    265
    249
    12
    Efficacy analysis set
    260
    242
    11
    Completed
    0
    0
    0
    Not completed
    268
    252
    12
         Administrative Decision
    83
    42
    5
         Disease Progression
    21
    9
    -
         Consent withdrawn by subject
    33
    11
    1
         Complete Resection (as per protocol)
    25
    121
    -
         Ineligibility Determined
    -
    1
    -
         Adverse event, non-fatal
    21
    19
    1
         Other
    19
    14
    1
         Death
    5
    1
    -
         End of Trial
    32
    12
    3
         Pregnancy
    5
    -
    1
         Lost to follow-up
    12
    14
    -
         Requirement for Alternative Therapy
    8
    2
    -
         Noncompliance
    4
    6
    -

    Baseline characteristics

    		 Close Top of page
    Baseline characteristics reporting groups
    Reporting group title
    Cohort 1 (Denosumab 120 mg Q4W)
    Reporting group description
    		 Participants with surgically unsalvageable disease (eg, sacral, spinal GCTB, or multiple lesions including pulmonary metastases) were enrolled into cohort 1.

    Reporting group title
    Cohort 2 (Denosumab 120 mg Q4W)
    Reporting group description
    		 Participants with surgically salvageable disease whose planned initial on-study surgery was associated with severe morbidity (eg, joint resection, limb amputation, or hemipelvectomy) were enrolled into cohort 2.

    Reporting group title
    Cohort 3 (Denosumab 120 mg Q4W)
    Reporting group description
    		 Participants who participated in study 20040215 and were eligible to enroll in the current study (20062004) for continuation of treatment were enrolled into cohort 3.

    Reporting group values
    		 Cohort 1 (Denosumab 120 mg Q4W) Cohort 2 (Denosumab 120 mg Q4W) Cohort 3 (Denosumab 120 mg Q4W) Total
    Number of subjects
    		 268 252 12 532
    Age Categorical
    Units: Subjects
        In utero
    		 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0
        Adolescents (12-17 years)
    		 14 14 0 28
        Adults (18-64 years)
    		 238 231 12 481
        From 65-84 years
    		 16 7 0 23
        85 years and over
    		 0 0 0 0
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 36.4 ± 14.6 35.1 ± 13.5 36.1 ± 14.9 -
    Gender Categorical
    Units: Subjects
        Female
    		 154 142 5 301
        Male
    		 114 110 7 231
    Race/Ethnicity, Customized
    Units: Subjects
        White or Caucasian
    		 221 208 11 440
        Black or African American
    		 18 12 0 30
        Hispanic or Latino
    		 13 13 1 27
        Asian
    		 11 14 0 25
        Native Hawaiian or Other Pacific Islander
    		 0 1 0 1
        Other
    		 5 4 0 9
    GCTB Disease Type
    Units: Subjects
        Primary resectable
    		 0 167 0 167
        Primary unresectable
    		 93 0 2 95
        Recurrent resectable
    		 0 85 0 85
        Recurrent unresectable
    		 175 0 10 185

    End points

    		 Close Top of page
    End points reporting groups
    Reporting group title
    Cohort 1 (Denosumab 120 mg Q4W)
    Reporting group description
    		 Participants with surgically unsalvageable disease (eg, sacral, spinal GCTB, or multiple lesions including pulmonary metastases) were enrolled into cohort 1.

    Reporting group title
    Cohort 2 (Denosumab 120 mg Q4W)
    Reporting group description
    		 Participants with surgically salvageable disease whose planned initial on-study surgery was associated with severe morbidity (eg, joint resection, limb amputation, or hemipelvectomy) were enrolled into cohort 2.

    Reporting group title
    Cohort 3 (Denosumab 120 mg Q4W)
    Reporting group description
    		 Participants who participated in study 20040215 and were eligible to enroll in the current study (20062004) for continuation of treatment were enrolled into cohort 3.

    Subject analysis set title
    Adolescent PK Subset (Denosumab 120 mg Q4W)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Adolescent participants enrolled in the pharmacokinetic (PK) substudy who received at least 1 dose of denosumab with baseline PK measurement and at least 1 post-baseline PK measurement were included in the adolescent PK analysis set. Participants received denosumab 120 mg SC Q4W, starting on study day 1, with loading doses of 120 mg SC on days 8 and 15 in the first month of treatment for those enrolled in cohorts 1 or 2.

    Subject analysis set title
    Adult PK Subset (Denosumab 120 mg Q4W)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Adult participants enrolled in the PK substudy who received at least 1 dose of denosumab with baseline PK measurement and at least 1 post-baseline PK measurement were included in the adult PK analysis set. Participants received denosumab 120 mg SC Q4W, starting on study day 1, with loading doses of 120 mg SC on days 8 and 15 in the first month of treatment for those enrolled in cohorts 1 or 2.

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

    		 Close Top of page
    End point title
    		 Number of Participants with Treatment-Emergent Adverse Events (TEAEs) [1]
    End point description
    AE: any untoward medical occurrence in clinical trial participant. Serious AE: AE that is fatal, life threatening, requires in-patient hospitalization/prolongation of existing hospitalization, results in persistent or significant disability/incapacity, congenital anomaly/birth defect or other significant medical hazard. Severity of AEs assessed according to Common Terminology Criteria for Adverse Events (CTCAE, v3.0) based on guideline: Grade 1: Mild; Grade 2: Moderate; Grade 3: Severe; Grade 4: Life-threatening or disabling; Grade 5: Death related to AE. Investigator assessed AEs for relatedness to study drug. Results presented for treatment-emergent events (TEAEs) (i.e. all AEs from first dose in initial treatment phase to end of initial treatment phase [or for participants entering retreatment, from first dose in initial treatment phase until end of retreatment phase]). Safety analysis set included all enrolled participants who received at least 1 dose of denosumab on the study.
    End point type
    Primary
    End point timeframe
    From first dose of study drug up to last study visit for treatment-emergent period (until data cut-off for study completion; a maximum of approximately 111 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: Only descriptive analyses were performed as planned.
    End point values
    		 Cohort 1 (Denosumab 120 mg Q4W) Cohort 2 (Denosumab 120 mg Q4W) Cohort 3 (Denosumab 120 mg Q4W)
    Number of subjects analysed
    265
    249
    12
    Units: Participants
    number (not applicable)
        Any TEAE
    260
    231
    12
        Serious TEAE
    98
    39
    5
        Fatal TEAE
    8
    3
    0
        TEAE leading to treatment phase discontinuation
    27
    24
    1
        TEAE leading to study drug discontinuation
    27
    23
    1
        CTCAE Grade 3, 4, or 5
    121
    59
    6
        Any TEAE related to study drug
    184
    136
    9
    No statistical analyses for this end point

    Primary: Number of Participants who Experienced the Maximum Toxicity Grade (CTCAE Grade ≥ 3) in the Indicated Clinical Chemistry Parameters

    		 Close Top of page
    End point title
    		 Number of Participants who Experienced the Maximum Toxicity Grade (CTCAE Grade ≥ 3) in the Indicated Clinical Chemistry Parameters [2]
    End point description
    Serum samples for clinical chemistry were collected on study day 1 (baseline), day 15, week 5 and each study visit Q4W thereafter until last study visit for the on-study period (ie, until end of initial treatment phase). The parameters included albumin, calcium (albumin-adjusted), creatinine, magnesium and phosphate. Results are presented for number of participants who experienced the maximum toxicity grade for each of these clinical parameters. The maximum toxicity grade experienced by each participant was based on CTCAE, v3.0, and are summarized for Grade 3 and 4. Increases and decreases in relationship to the normal parameter ranges are indicated as 'Above' and 'Below' respectively. Safety analysis set included all enrolled participants who received at least 1 dose of denosumab on the study.
    End point type
    Primary
    End point timeframe
    Baseline (day 1) up to last study visit for initial treatment phase (median duration approximately 30 months up to a maximum of approximately 109 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: Only descriptive analyses were performed as planned.
    End point values
    		 Cohort 1 (Denosumab 120 mg Q4W) Cohort 2 (Denosumab 120 mg Q4W) Cohort 3 (Denosumab 120 mg Q4W)
    Number of subjects analysed
    265
    249
    12
    Units: Participants
    number (not applicable)
        Calcium corrected Grade 3 (Above)
    0
    1
    0
        Calcium corrected Grade 4 (Above)
    1
    1
    0
        Calcium corrected Grade 3 (Below)
    1
    0
    0
        Calcium corrected Grade 4 (Below)
    2
    0
    0
        Phosphate Grade 3 (Below)
    60
    41
    4
        Magnesium Grade 3 (Above)
    4
    5
    2
        Magnesium Grade 3 (Below)
    1
    0
    0
        Creatinine Grade 3 (Above)
    0
    1
    0
        Albumin Grade 3 (Below)
    1
    0
    0
    No statistical analyses for this end point

    Secondary: Time to Disease Progression or Recurrence During the On-Study Period for Cohort 1, Presented as Kaplan-Meier Estimates of Probability

    		 Close Top of page
    End point title
    		 Time to Disease Progression or Recurrence During the On-Study Period for Cohort 1, Presented as Kaplan-Meier Estimates of Probability [3]
    End point description
    Time to disease progression or recurrence during the on-study period defined as time interval (in days) from date of first dose of study drug to date of earliest Progressive Disease (PD) during initial treatment phase. PD defined as response of progressive disease, locally recurrent disease or relapse as captured in Disease Status page of Case Report Form. If a participant had not had PD by end of initial treatment phase, time to disease progression or recurrence were censored at her/his end of initial treatment phase date. Median time to disease progression or recurrence for participants in cohort 1 was not reached so Kaplan-Meier estimates for probability (expressed as a percentage) of participants in cohort 1 to have disease progression or recurrence at months 6, 12, 24, 36 and 60 are presented. Efficacy analysis set included all enrolled participants who were eligible for the study and who received at least 1 dose of denosumab on the study. Analysis performed on cohort 1 only.
    End point type
    Secondary
    End point timeframe
    From first dose of study drug up to the end of the initial treatment phase (median duration approximately 30 months up to a maximum of approximately 109 months).
    Notes
    [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: The secondary endpoint for time to disease progression applied to cohort 1 only.
    End point values
    		 Cohort 1 (Denosumab 120 mg Q4W)
    Number of subjects analysed
    260
    Units: Percent probability
    number (confidence interval 95%)
        Month 6
    1.9 (0.3 to 3.6)
        Month 12
    4.3 (1.8 to 6.8)
        Month 24
    6.1 (3.1 to 9.0)
        Month 36
    8.2 (4.6 to 11.8)
        Month 60
    11.7 (7.1 to 16.2)
    No statistical analyses for this end point

    Secondary: Percentage of Participants without any On-Study Surgery at Month 6 for Cohort 2

    		 Close Top of page
    End point title
    		 Percentage of Participants without any On-Study Surgery at Month 6 for Cohort 2 [4]
    End point description
    The percentage of participants without any surgery at month 6 was equivalent to the number of participants without any surgery by month 6 divided by the number of cohort 2 participants who had an opportunity to complete 6 months of treatment, expressed as a percentage. Efficacy analysis set included all enrolled participants who were eligible for the study and who received at least 1 dose of denosumab on the study. Analysis performed on cohort 2 only for those who had the opportunity to be on-study for at least 6 months.
    End point type
    Secondary
    End point timeframe
    At month 6.
    Notes
    [4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The secondary endpoint for proportion of participants without any surgery at month 6 applied to cohort 2 only.
    End point values
    		 Cohort 2 (Denosumab 120 mg Q4W)
    Number of subjects analysed
    238
    Units: Percentage of participants
        number (confidence interval 95%)
    92.0 (87.8 to 95.1)
    No statistical analyses for this end point

    Secondary: Mean Serum Denosumab Trough Concentrations

    		 Close Top of page
    End point title
    		 Mean Serum Denosumab Trough Concentrations
    End point description
    Blood samples for determination of serum denosumab concentration levels were obtained from participants included in the PK substudy at baseline (prior to administration of study drug on day 1) and at scheduled time points during the study up to week 25. Analysis was performed on the PK analysis set. Only participants with available data at each indicated time point were included in the analysis.
    End point type
    Secondary
    End point timeframe
    Blood samples were collected at baseline (day 1), days 8 and 15 and weeks 5, 9, 13 and 25.
    End point values
    		 Adolescent PK Subset (Denosumab 120 mg Q4W) Adult PK Subset (Denosumab 120 mg Q4W)
    Number of subjects analysed
    10
    15
    Units: nanograms / milliliter
    arithmetic mean (standard deviation)
        Day 1 (n=10, n=15)
    0.0 ± 0.0
    0.0 ± 0.0
        Day 8 (n=9, n=14)
    11800 ± 4130
    12000 ± 4300
        Day 15 (n=9, n=13)
    21800 ± 5620
    24200 ± 9050
        Week 5 (n=9, n=14)
    30400 ± 6150
    33500 ± 8970
        Week 9 (n=9, n=15)
    25100 ± 6450
    30000 ± 10300
        Week 13 (n=7, n=12)
    22300 ± 6840
    29100 ± 10000
        Week 17 (n=7, n=13)
    23600 ± 4370
    28300 ± 11600
        Week 25 (n=8, n=11)
    22400 ± 6690
    25400 ± 10800
    No statistical analyses for this end point

    Adverse events

    		 Close Top of page
    Adverse events information
    Timeframe for reporting adverse events
    From first dose of study drug until last study visit; a maximum of approximately 113 months. The planned study duration for each participant was at least 60 months (following protocol amendment 7).
    Adverse event reporting additional description
    Data are presented for the entire study duration and include AEs occurring during the treatment-emergent period (comprising both the initial treatment phase and retreatment phase) and AEs occurring after the treatment-emergent period (ie, during the safety follow-up phase).
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    21.0
    Reporting groups
    Reporting group title
    Denosumab 120 mg Q4W (All Cohorts)
    Reporting group description
    		 All participants received denosumab 120 mg SC Q4W, starting on study day 1, with loading doses of 120 mg SC on days 8 and 15 in the first month of treatment for those enrolled in cohorts 1 or 2.

    Serious adverse events
    		 Denosumab 120 mg Q4W (All Cohorts)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    176 / 526 (33.46%)
         number of deaths (all causes)
    26
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Adenocarcinoma of colon
         subjects affected / exposed
    1 / 526 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Basal cell carcinoma
         subjects affected / exposed
    1 / 526 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Bone giant cell tumour
         subjects affected / exposed
    19 / 526 (3.61%)
         occurrences causally related to treatment / all
    2 / 21
         deaths causally related to treatment / all
    0 / 5
    Bone neoplasm
         subjects affected / exposed
    1 / 526 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Bone sarcoma
         subjects affected / exposed
    2 / 526 (0.38%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    1 / 2
    Breast cancer
         subjects affected / exposed
    1 / 526 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Breast cancer stage I
         subjects affected / exposed
    1 / 526 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Invasive ductal breast carcinoma
         subjects affected / exposed
    2 / 526 (0.38%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Ganglioneuroma
         subjects affected / exposed
    1 / 526 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Lung neoplasm malignant
         subjects affected / exposed
    1 / 526 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Metastases to lung
         subjects affected / exposed
    3 / 526 (0.57%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 2
    Myeloproliferative neoplasm
         subjects affected / exposed
    1 / 526 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Neoplasm
         subjects affected / exposed
    1 / 526 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Neuroendocrine tumour
         subjects affected / exposed
    1 / 526 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Oncologic complication
         subjects affected / exposed
    1 / 526 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Oesophageal adenocarcinoma
         subjects affected / exposed
    1 / 526 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Osteosarcoma
         subjects affected / exposed
    3 / 526 (0.57%)
         occurrences causally related to treatment / all
    1 / 3
         deaths causally related to treatment / all
    0 / 1
    Pelvic neoplasm
         subjects affected / exposed
    1 / 526 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Renal cancer
         subjects affected / exposed
    1 / 526 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Rhabdomyosarcoma
         subjects affected / exposed
    1 / 526 (0.19%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    1 / 1
    Sarcoma
         subjects affected / exposed
    5 / 526 (0.95%)
         occurrences causally related to treatment / all
    3 / 5
         deaths causally related to treatment / all
    1 / 2
    Second primary malignancy
         subjects affected / exposed
    1 / 526 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Spindle cell sarcoma
         subjects affected / exposed
    1 / 526 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Thyroid cancer
         subjects affected / exposed
    1 / 526 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Thyroid cancer metastatic
         subjects affected / exposed
    1 / 526 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Tumour haemorrhage
         subjects affected / exposed
    1 / 526 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Tumour pain
         subjects affected / exposed
    2 / 526 (0.38%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    Vascular disorders
    Circulatory collapse
         subjects affected / exposed
    1 / 526 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Haematoma
         subjects affected / exposed
    1 / 526 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hypertension
         subjects affected / exposed
    1 / 526 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Orthostatic hypotension
         subjects affected / exposed
    1 / 526 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Thrombophlebitis superficial
         subjects affected / exposed
    1 / 526 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Vasculitis
         subjects affected / exposed
    1 / 526 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Surgical and medical procedures
    Bone lesion excision
         subjects affected / exposed
    2 / 526 (0.38%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Leg amputation
         subjects affected / exposed
    1 / 526 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Spinal operation
         subjects affected / exposed
    1 / 526 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    2 / 526 (0.38%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Chest pain
         subjects affected / exposed
    1 / 526 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Death
         subjects affected / exposed
    4 / 526 (0.76%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 4
    Disease recurrence
         subjects affected / exposed
    1 / 526 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hernia
         subjects affected / exposed
    1 / 526 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Impaired healing
         subjects affected / exposed
    2 / 526 (0.38%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Malaise
         subjects affected / exposed
    1 / 526 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Mucosal inflammation
         subjects affected / exposed
    1 / 526 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    1 / 526 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pyrexia
         subjects affected / exposed
    4 / 526 (0.76%)
         occurrences causally related to treatment / all
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    Reproductive system and breast disorders
    Dysmenorrhoea
         subjects affected / exposed
    1 / 526 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pelvic pain
         subjects affected / exposed
    1 / 526 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Bronchial haemorrhage
         subjects affected / exposed
    1 / 526 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Haemoptysis
         subjects affected / exposed
    1 / 526 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pharyngeal fistula
         subjects affected / exposed
    1 / 526 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Lung disorder
         subjects affected / exposed
    1 / 526 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pneumothorax
         subjects affected / exposed
    1 / 526 (0.19%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    2 / 526 (0.38%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Respiratory failure
         subjects affected / exposed
    2 / 526 (0.38%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 2
    Psychiatric disorders
    Completed suicide
         subjects affected / exposed
    1 / 526 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Suicide attempt
         subjects affected / exposed
    2 / 526 (0.38%)
         occurrences causally related to treatment / all
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    Product issues
    Device breakage
         subjects affected / exposed
    1 / 526 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Device failure
         subjects affected / exposed
    1 / 526 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Device loosening
         subjects affected / exposed
    1 / 526 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Device occlusion
         subjects affected / exposed
    1 / 526 (0.19%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Injury, poisoning and procedural complications
    Ankle fracture
         subjects affected / exposed
    1 / 526 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Atypical femur fracture
         subjects affected / exposed
    1 / 526 (0.19%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Cervical vertebral fracture
         subjects affected / exposed
    1 / 526 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Endotracheal intubation complication
         subjects affected / exposed
    1 / 526 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Femoral neck fracture
         subjects affected / exposed
    1 / 526 (0.19%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Femur fracture
         subjects affected / exposed
    3 / 526 (0.57%)
         occurrences causally related to treatment / all
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    Fracture displacement
         subjects affected / exposed
    1 / 526 (0.19%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Gun shot wound
         subjects affected / exposed
    1 / 526 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Joint dislocation
         subjects affected / exposed
    1 / 526 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Lumbar vertebral fracture
         subjects affected / exposed
    1 / 526 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Meniscus injury
         subjects affected / exposed
    1 / 526 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Overdose
         subjects affected / exposed
    1 / 526 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Post procedural fistula
         subjects affected / exposed
    1 / 526 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Postoperative respiratory failure
         subjects affected / exposed
    1 / 526 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Procedural haemorrhage
         subjects affected / exposed
    1 / 526 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pubis fracture
         subjects affected / exposed
    1 / 526 (0.19%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Radiation myelopathy
         subjects affected / exposed
    1 / 526 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Spinal compression fracture
         subjects affected / exposed
    1 / 526 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Stress fracture
         subjects affected / exposed
    2 / 526 (0.38%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Thoracic vertebral fracture
         subjects affected / exposed
    1 / 526 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Tibia fracture
         subjects affected / exposed
    2 / 526 (0.38%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Upper limb fracture
         subjects affected / exposed
    1 / 526 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Vena cava injury
         subjects affected / exposed
    1 / 526 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Wound
         subjects affected / exposed
    1 / 526 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Wound dehiscence
         subjects affected / exposed
    2 / 526 (0.38%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Wrist fracture
         subjects affected / exposed
    1 / 526 (0.19%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Congenital, familial and genetic disorders
    Aplasia
         subjects affected / exposed
    1 / 526 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiac disorders
    Bradycardia
         subjects affected / exposed
    1 / 526 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    1 / 526 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiac failure
         subjects affected / exposed
    2 / 526 (0.38%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    Supraventricular tachycardia
         subjects affected / exposed
    1 / 526 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Nervous system disorders
    Cauda equina syndrome
         subjects affected / exposed
    1 / 526 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Central nervous system lesion
         subjects affected / exposed
    1 / 526 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    1 / 526 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Dizziness
         subjects affected / exposed
    1 / 526 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Facial neuralgia
         subjects affected / exposed
    1 / 526 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Headache
         subjects affected / exposed
    1 / 526 (0.19%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Lethargy
         subjects affected / exposed
    1 / 526 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Nerve compression
         subjects affected / exposed
    1 / 526 (0.19%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Peripheral sensory neuropathy
         subjects affected / exposed
    1 / 526 (0.19%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Presyncope
         subjects affected / exposed
    1 / 526 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Spinal cord compression
         subjects affected / exposed
    1 / 526 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Seizure
         subjects affected / exposed
    2 / 526 (0.38%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    Transient ischaemic attack
         subjects affected / exposed
    1 / 526 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Syncope
         subjects affected / exposed
    1 / 526 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    8 / 526 (1.52%)
         occurrences causally related to treatment / all
    0 / 11
         deaths causally related to treatment / all
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    1 / 526 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Leukopenia
         subjects affected / exposed
    1 / 526 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Microcytic anaemia
         subjects affected / exposed
    1 / 526 (0.19%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    1 / 526 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    2 / 526 (0.38%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Colitis
         subjects affected / exposed
    1 / 526 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    1 / 526 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Diarrhoea
         subjects affected / exposed
    1 / 526 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Enterocolitis
         subjects affected / exposed
    1 / 526 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastritis
         subjects affected / exposed
    2 / 526 (0.38%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Large intestine perforation
         subjects affected / exposed
    1 / 526 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Melaena
         subjects affected / exposed
    1 / 526 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Nausea
         subjects affected / exposed
    3 / 526 (0.57%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Pancreatic failure
         subjects affected / exposed
    1 / 526 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Peptic ulcer
         subjects affected / exposed
    1 / 526 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    1 / 526 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Vomiting
         subjects affected / exposed
    2 / 526 (0.38%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    2 / 526 (0.38%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    2 / 526 (0.38%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Skin and subcutaneous tissue disorders
    Dermatitis psoriasiform
         subjects affected / exposed
    1 / 526 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    3 / 526 (0.57%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    Bladder prolapse
         subjects affected / exposed
    1 / 526 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Dysuria
         subjects affected / exposed
    1 / 526 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Nephrolithiasis
         subjects affected / exposed
    2 / 526 (0.38%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Renal colic
         subjects affected / exposed
    1 / 526 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Renal failure
         subjects affected / exposed
    2 / 526 (0.38%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Urethral fistula
         subjects affected / exposed
    1 / 526 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Urge incontinence
         subjects affected / exposed
    1 / 526 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Endocrine disorders
    Hyperparathyroidism
         subjects affected / exposed
    2 / 526 (0.38%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Toxic nodular goitre
         subjects affected / exposed
    1 / 526 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    5 / 526 (0.95%)
         occurrences causally related to treatment / all
    1 / 5
         deaths causally related to treatment / all
    0 / 0
    Arthralgia
         subjects affected / exposed
    5 / 526 (0.95%)
         occurrences causally related to treatment / all
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    Bone pain
         subjects affected / exposed
    1 / 526 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Exposed bone in jaw
         subjects affected / exposed
    1 / 526 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Intervertebral disc protrusion
         subjects affected / exposed
    1 / 526 (0.19%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Lumbar spinal stenosis
         subjects affected / exposed
    1 / 526 (0.19%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Muscular weakness
         subjects affected / exposed
    1 / 526 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Musculoskeletal pain
         subjects affected / exposed
    1 / 526 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Myositis
         subjects affected / exposed
    1 / 526 (0.19%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Osteitis
         subjects affected / exposed
    3 / 526 (0.57%)
         occurrences causally related to treatment / all
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    Osteonecrosis
         subjects affected / exposed
    4 / 526 (0.76%)
         occurrences causally related to treatment / all
    5 / 6
         deaths causally related to treatment / all
    0 / 0
    Osteonecrosis of jaw
         subjects affected / exposed
    25 / 526 (4.75%)
         occurrences causally related to treatment / all
    27 / 27
         deaths causally related to treatment / all
    0 / 0
    Pain in extremity
         subjects affected / exposed
    3 / 526 (0.57%)
         occurrences causally related to treatment / all
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    Pain in jaw
         subjects affected / exposed
    1 / 526 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pathological fracture
         subjects affected / exposed
    1 / 526 (0.19%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Pseudarthrosis
         subjects affected / exposed
    1 / 526 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Tendonitis
         subjects affected / exposed
    1 / 526 (0.19%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Abdominal abscess
         subjects affected / exposed
    1 / 526 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Abdominal wall infection
         subjects affected / exposed
    1 / 526 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Abscess
         subjects affected / exposed
    2 / 526 (0.38%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Abscess jaw
         subjects affected / exposed
    1 / 526 (0.19%)
         occurrences causally related to treatment / all
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    Abscess neck
         subjects affected / exposed
    1 / 526 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Abscess oral
         subjects affected / exposed
    1 / 526 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Appendicitis
         subjects affected / exposed
    4 / 526 (0.76%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    Arthritis infective
         subjects affected / exposed
    1 / 526 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Aspergillus infection
         subjects affected / exposed
    1 / 526 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Bacteraemia
         subjects affected / exposed
    1 / 526 (0.19%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Bacteroides bacteraemia
         subjects affected / exposed
    1 / 526 (0.19%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Catheter site infection
         subjects affected / exposed
    1 / 526 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Bone abscess
         subjects affected / exposed
    1 / 526 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cellulitis
         subjects affected / exposed
    2 / 526 (0.38%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    Device related infection
         subjects affected / exposed
    4 / 526 (0.76%)
         occurrences causally related to treatment / all
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    3 / 526 (0.57%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Infected cyst
         subjects affected / exposed
    1 / 526 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infected skin ulcer
         subjects affected / exposed
    1 / 526 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infectious colitis
         subjects affected / exposed
    1 / 526 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infection
         subjects affected / exposed
    1 / 526 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Muscle abscess
         subjects affected / exposed
    1 / 526 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Orchitis
         subjects affected / exposed
    1 / 526 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Osteomyelitis
         subjects affected / exposed
    4 / 526 (0.76%)
         occurrences causally related to treatment / all
    6 / 6
         deaths causally related to treatment / all
    0 / 0
    Osteomyelitis bacterial
         subjects affected / exposed
    1 / 526 (0.19%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Peritonsillar abscess
         subjects affected / exposed
    1 / 526 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pharyngitis
         subjects affected / exposed
    1 / 526 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pneumonia
         subjects affected / exposed
    4 / 526 (0.76%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    Postoperative wound infection
         subjects affected / exposed
    1 / 526 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    1 / 526 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Scrotal abscess
         subjects affected / exposed
    1 / 526 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Sepsis
         subjects affected / exposed
    3 / 526 (0.57%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Staphylococcal infection
         subjects affected / exposed
    1 / 526 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Staphylococcal osteomyelitis
         subjects affected / exposed
    1 / 526 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Subcutaneous abscess
         subjects affected / exposed
    2 / 526 (0.38%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Tooth infection
         subjects affected / exposed
    1 / 526 (0.19%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    3 / 526 (0.57%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Wound infection
         subjects affected / exposed
    2 / 526 (0.38%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Wound infection staphylococcal
         subjects affected / exposed
    1 / 526 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    1 / 526 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hypercalcaemia
         subjects affected / exposed
    4 / 526 (0.76%)
         occurrences causally related to treatment / all
    6 / 8
         deaths causally related to treatment / all
    0 / 0
    Hypertriglyceridaemia
         subjects affected / exposed
    1 / 526 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    1 / 526 (0.19%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Denosumab 120 mg Q4W (All Cohorts)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    480 / 526 (91.25%)
    Investigations
    Weight increased
         subjects affected / exposed
    30 / 526 (5.70%)
         occurrences all number
    69
    Injury, poisoning and procedural complications
    Procedural pain
         subjects affected / exposed
    39 / 526 (7.41%)
         occurrences all number
    49
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    34 / 526 (6.46%)
         occurrences all number
    46
    Headache
         subjects affected / exposed
    134 / 526 (25.48%)
         occurrences all number
    300
    Hypoaesthesia
         subjects affected / exposed
    38 / 526 (7.22%)
         occurrences all number
    46
    Paraesthesia
         subjects affected / exposed
    48 / 526 (9.13%)
         occurrences all number
    59
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    30 / 526 (5.70%)
         occurrences all number
    67
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    142 / 526 (27.00%)
         occurrences all number
    266
    Asthenia
         subjects affected / exposed
    48 / 526 (9.13%)
         occurrences all number
    65
    Influenza like illness
         subjects affected / exposed
    27 / 526 (5.13%)
         occurrences all number
    28
    Oedema peripheral
         subjects affected / exposed
    46 / 526 (8.75%)
         occurrences all number
    60
    Pyrexia
         subjects affected / exposed
    47 / 526 (8.94%)
         occurrences all number
    72
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    49 / 526 (9.32%)
         occurrences all number
    80
    Constipation
         subjects affected / exposed
    60 / 526 (11.41%)
         occurrences all number
    71
    Dental caries
         subjects affected / exposed
    32 / 526 (6.08%)
         occurrences all number
    41
    Diarrhoea
         subjects affected / exposed
    60 / 526 (11.41%)
         occurrences all number
    93
    Nausea
         subjects affected / exposed
    122 / 526 (23.19%)
         occurrences all number
    172
    Toothache
         subjects affected / exposed
    68 / 526 (12.93%)
         occurrences all number
    86
    Vomiting
         subjects affected / exposed
    66 / 526 (12.55%)
         occurrences all number
    114
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    54 / 526 (10.27%)
         occurrences all number
    63
    Oropharyngeal pain
         subjects affected / exposed
    36 / 526 (6.84%)
         occurrences all number
    49
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    33 / 526 (6.27%)
         occurrences all number
    36
    Rash
         subjects affected / exposed
    45 / 526 (8.56%)
         occurrences all number
    57
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    29 / 526 (5.51%)
         occurrences all number
    37
    Depression
         subjects affected / exposed
    31 / 526 (5.89%)
         occurrences all number
    35
    Insomnia
         subjects affected / exposed
    45 / 526 (8.56%)
         occurrences all number
    53
    Musculoskeletal and connective tissue disorders
    Bone pain
         subjects affected / exposed
    41 / 526 (7.79%)
         occurrences all number
    47
    Back pain
         subjects affected / exposed
    154 / 526 (29.28%)
         occurrences all number
    263
    Arthralgia
         subjects affected / exposed
    192 / 526 (36.50%)
         occurrences all number
    325
    Muscle spasms
         subjects affected / exposed
    37 / 526 (7.03%)
         occurrences all number
    53
    Joint swelling
         subjects affected / exposed
    28 / 526 (5.32%)
         occurrences all number
    31
    Musculoskeletal pain
         subjects affected / exposed
    70 / 526 (13.31%)
         occurrences all number
    102
    Myalgia
         subjects affected / exposed
    42 / 526 (7.98%)
         occurrences all number
    51
    Neck pain
         subjects affected / exposed
    29 / 526 (5.51%)
         occurrences all number
    43
    Pain in extremity
         subjects affected / exposed
    146 / 526 (27.76%)
         occurrences all number
    237
    Pain in jaw
         subjects affected / exposed
    40 / 526 (7.60%)
         occurrences all number
    50
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    28 / 526 (5.32%)
         occurrences all number
    35
    Influenza
         subjects affected / exposed
    44 / 526 (8.37%)
         occurrences all number
    73
    Nasopharyngitis
         subjects affected / exposed
    76 / 526 (14.45%)
         occurrences all number
    184
    Upper respiratory tract infection
         subjects affected / exposed
    48 / 526 (9.13%)
         occurrences all number
    72
    Metabolism and nutrition disorders
    Hypercalcaemia
         subjects affected / exposed
    29 / 526 (5.51%)
         occurrences all number
    47
    Hypocalcaemia
         subjects affected / exposed
    36 / 526 (6.84%)
         occurrences all number
    48
    Hypophosphataemia
         subjects affected / exposed
    66 / 526 (12.55%)
         occurrences all number
    121

    More information

    		 Close Top of page

    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    12 Dec 2008
    • Key inclusion criteria updated to include skeletally mature adolescents ≥12 years of age and clarify that skeletally mature adolescents must weigh at least 45 kilograms. • Key exclusion criteria updated to exclude women of child bearing potential who are evidently pregnant or breastfeeding and participants enrolled in or who have not yet completed at least 30 days since ending other investigational device or drug study(s), or participants receiving other investigational agents. • Sample size was clarified to include approximately 100 participants and the supporting sample size considerations were detailed. • The safety follow-up phase of the study was extended from 6 months for up to 12 months after the end of the study date.
    11 Jan 2010
    • Study sample size increased from 100 participants to approximately 250 participants. • Secondary objective and endpoint clarified to include participants who do not require any surgery. • Eligibility criteria excluding women of childbearing potential who are evidently pregnant or breastfeeding was updated. • Exploratory endpoints were added to the protocol. • Addition of interim analysis corresponding with the increased sample size.
    14 May 2010
    • Protocol updated to allow enrollment of participants from Amgen Study 20040215. • The exploratory objectives and endpoints were updated to include the proportion of participants who are able to undergo a less morbid surgical procedure compared with the planned surgical procedure at baseline for cohort 2 and disease status changes over time for all participants.
    15 Nov 2010
    • Study sample size increased from 250 participants to 375 participants. • Secondary endpoints clarified. • Analysis of safety data from the safety follow-up clarified in Section 10.6.3 of the protocol.
    05 May 2011
    • Exclusion criteria modified for contraception to include 2 methods of highly effective contraception during treatment and for 7 months after the end of treatment. • Criteria for a participant to receive retreatment were clarified. • The frequency of interim analysis was modified.
    30 Aug 2011
    • Study sample size increased from approximately 375 participants to approximately 500 participants.
    15 May 2013
    • Protocol amended to include PK analyses for an additional approximately 20 participants, approximately 10 adolescents and 10 adults. • The end of the clinical trial defined as when participants enrolled through November 2012 (before Amendment 7) complete a minimum of 60 months on study, or until death or lost to follow-up, whichever comes first. • Objectives, endpoints, sample collection and analyses were added consistent with the PK subset. • Clarification that participants who rolled over from Study 20040215 will follow the Study 20062004 schedule under Amendment 7. • End of treatment visit and safety follow-up visits clarified. • Added oral examinations for all participants and provided additional guidance regarding investigational product dosing and oral/dental procedures. • Safety reporting timelines clarified. • Added updated pregnancy and lactation reporting section, with additional instructions regarding counseling women of childbearing potential on the risks of pregnancy while receiving denosumab and discussing methods to decrease the risk.
    15 Sep 2015
    • Updated safety follow-up period information and listed AEs of interest to align the protocol language with postmarketing data collection requirements, and to increase compliance with long-term follow-up data requirements. • Removed interim analysis 4 as it was not a regulatory requirement, and no study report was expected from this interim analysis per regulatory requirements. • Updated medical history section for clarification and aligned with other sections of the protocol. • Modified the dose escalation and stopping rules section to clarify that the planned dose may be given up to 7 days before the scheduled visit, as long as there are 21 days between doses. • Updated calcium and vitamin D information to match XGEVA product information. • Updated Protocol Synopsis, Investigational Product Dosage and Administration sections with text regarding supplementation of all participants with calcium and vitamin D. • Updated the number of birth control methods and amount of washout time required between the end of treatment and pregnancy or breastfeeding to align with the informed consent and current safety information. • Pregnancy reporting was changed from the Pregnancy Surveillance Program to Amgen Global Patient Safety as per current Amgen standard.
    15 Dec 2017
    • Added guidance about monitoring participants for hypercalcemia upon discontinuation or interruption of denosumab, including: ◦ Clarification added to AEs of Interest. ◦ Language for calcium and vitamin D supplementation. • Updated End of Study language to clarify definitions of the ‘End of Treatment’, End of Safety Follow-up Phase, and ‘End of Study’ visits.

    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
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

    European Medicines Agency © 1995-Thu May 02 01:58:23 CEST 2024 | Domenico Scarlattilaan 6, 1083 HS Amsterdam, The Netherlands
    EMA HMA