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    Clinical Trial Results:
    A Double-blind, Placebo-controlled Study to Evaluate New or Worsening Lens Opacifications in Subjects With Non-metastatic Prostate Cancer Receiving Denosumab for Bone Loss due to Androgen-Deprivation Therapy

    Summary
    EudraCT number
    		 2009-012076-26
    Trial protocol
    		 FR   CZ   PL   LV   GR   SK   BG   HU   SI  
    Global end of trial date
    12 May 2016

    Results information
    Results version number
    		 v1(current)
    This version publication date
    13 May 2017
    First version publication date
    13 May 2017
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    20080560
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00925600
    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)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    12 May 2016
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    12 May 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    This is a phase 3, randomized, double-blind, placebo-controlled study to evaluate new or worsening lens opacifications in subjects with non-metastatic prostate cancer receiving denosumab for bone loss due to androgen deprivation therapy.
    Protection of trial subjects
    This study was conducted in accordance with International Conference on Harmonisation (ICH) Good Clinical Practice (GCP) and other regulations as applicable. The study protocol and all amendments, subject information, and informed consent form were reviewed and approved by the respective independent ethics committee or institutional review board for each study center before Amgen’s recruitment of subjects into the study and shipment of investigational product. All subjects provided written informed consent after the aims, methods, and potential hazards of the study were adequately explained; the appropriate informed consent was obtained before any protocol-specific screening procedures or any investigational products were administered.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    30 Nov 2009
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Australia: 15
    Country: Number of subjects enrolled
    Bulgaria: 8
    Country: Number of subjects enrolled
    Canada: 77
    Country: Number of subjects enrolled
    Czech Republic: 72
    Country: Number of subjects enrolled
    France: 8
    Country: Number of subjects enrolled
    Greece: 33
    Country: Number of subjects enrolled
    Hungary: 134
    Country: Number of subjects enrolled
    India: 13
    Country: Number of subjects enrolled
    Latvia: 14
    Country: Number of subjects enrolled
    Mexico: 11
    Country: Number of subjects enrolled
    New Zealand: 22
    Country: Number of subjects enrolled
    Poland: 65
    Country: Number of subjects enrolled
    Russian Federation: 32
    Country: Number of subjects enrolled
    Slovakia: 79
    Country: Number of subjects enrolled
    Slovenia: 3
    Country: Number of subjects enrolled
    South Africa: 49
    Country: Number of subjects enrolled
    Ukraine: 22
    Country: Number of subjects enrolled
    United States: 112
    Worldwide total number of subjects
    769
    EEA total number of subjects
    416
    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)
    0
    Adults (18-64 years)
    139
    From 65 to 84 years
    618
    85 years and over
    12

    Subject disposition

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    Recruitment
    Recruitment details
    		 This study was conducted at 125 centers in 18 countries: Australia, Bulgaria, Canada, the Czech Republic, France, Greece, Hungary, India, Latvia, Mexico, New Zealand, Poland, Russia, Slovakia, Slovenia, South Africa, Ukraine, and the United States. The first participant enrolled on 30 November 2009 and the last participant enrolled on 04 May 2015.

    Pre-assignment
    Screening details
    		 Participants were randomly assigned to receive denosumab or placebo in a 1:1 allocation ratio. Randomization was stratified on the basis of screening Lens Opacities Classification System (LOCS) III status (< 3.0 at all sites versus ≥ 3.0 at any site); age group (< 75, ≥ 75 years), and patient-reported history of cataract (yes/no).

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo
    Arm description
    		 Participants randomized to receive placebo administered by subcutaneous injection on Day 1 and at Month 6.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Prefilled syringe for subcutaneous (SC) injection

    Arm title
    		 Denosumab
    Arm description
    		 Participants randomized to receive denosumab 60 mg administered by subcutaneous injection on Day 1 and at Month 6.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Denosumab
    Investigational medicinal product code
    AMG 162
    Other name
    Prolia®
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Prefilled syringe for subcutaneous (SC) injection administered at a dose of 60 mg

    Number of subjects in period 1
    		Placebo Denosumab
    Started
    386
    383
    Received Treatment
    383
    382
    Completed
    354
    355
    Not completed
    32
    28
         Consent withdrawn by subject
    16
    14
         Ineligibility Determined
    2
    -
         Protocol Deviation
    -
    1
         Death
    4
    3
         Other
    3
    1
         Administrative Decision
    1
    1
         Adverse event
    1
    2
         Lost to follow-up
    2
    2
         Requirement for Alternative Therapy
    -
    1
         Disease Progression
    1
    3
         Noncompliance
    2
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Participants randomized to receive placebo administered by subcutaneous injection on Day 1 and at Month 6.

    Reporting group title
    Denosumab
    Reporting group description
    		 Participants randomized to receive denosumab 60 mg administered by subcutaneous injection on Day 1 and at Month 6.

    Reporting group values
    		 Placebo Denosumab Total
    Number of subjects
    		 386 383 769
    Age Categorical
    Units: Subjects
        18 - 64 years
    		 73 66 139
        65 - 74 years
    		 189 194 383
        75 - 84 years
    		 119 116 235
        ≥ 85 years
    		 5 7 12
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 71 ( 7 ) 71.1 ( 7.2 ) -
    Gender, Male/Female
    Units: Subjects
        Female
    		 0 0 0
        Male
    		 386 383 769
    Race/Ethnicity, Customized
    Units: Subjects
        White
    		 359 346 705
        Black (or African American)
    		 12 11 23
        Hispanic/Latino
    		 1 9 10
        Other
    		 7 8 15
        Asian
    		 7 7 14
        Japanese
    		 0 1 1
        Native Hawaiian or Other Pacific Islander
    		 0 1 1
    Presence of Cataract(s)
    From baseline medical history
    Units: Subjects
        Yes
    		 59 63 122
        No
    		 327 320 647
    Presence of Diabetes
    Units: Subjects
        Yes
    		 70 61 131
        No
    		 316 322 638
    Received Androgen-deprivation Therapy (ADT)
    Units: Subjects
        Yes
    		 350 353 703
        No
    		 36 30 66
    Orchiectomy (Surgical Castration)
    Units: Subjects
        Yes
    		 58 51 109
        No
    		 328 332 660
    Screening Lens Opacities Classification System (LOCS) III Status
    The Lens Opacities Classification System III (LOCS III) is a slit lamp based opacification grading method. Photographs of slit lamp cross-sections of the lens are used as references for grading nuclear opalescence (NO) and nuclear color (NC), and photographs of the lens seen by retroillumination are used as references for grading cortical (C) and posterior subcapsular (P) cataract. Opacification severity is graded on a decimal scale, scores can range from 0.1 to 6.9 for NO and NC and from 0.1 to 5.9 for C and P. For each opacification type the higher grading scores indicate greater severity.
    Units: Subjects
        < 3.0 at all sites [P, C, and NO]
    		 299 299 598
        ≥ 3.0 at any of these sites
    		 87 84 171
    Participant-reported History of Cataract
    Participant-reported history of cataracts was a study stratification factor.
    Units: Subjects
        Yes
    		 35 35 70
        No
    		 351 348 699

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Participants randomized to receive placebo administered by subcutaneous injection on Day 1 and at Month 6.

    Reporting group title
    Denosumab
    Reporting group description
    		 Participants randomized to receive denosumab 60 mg administered by subcutaneous injection on Day 1 and at Month 6.

    Subject analysis set title
    Placebo - Left Eye
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Participants received placebo subcutaneous injection on Day 1 and at Month 6.

    Subject analysis set title
    Placebo - Right Eye
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Participants received placebo subcutaneous injection on Day 1 and at Month 6.

    Subject analysis set title
    Denosumab - Left Eye
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Participants received denosumab 60 mg administered by subcutaneous injection on Day 1 and at Month 6.

    Subject analysis set title
    Denosumab - Right Eye
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Participants received denosumab 60 mg administered by subcutaneous injection on Day 1 and at Month 6.

    Subject analysis set title
    Placebo
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Participants received placebo administered by subcutaneous injection on Day 1 and at Month 6. The safety analysis set includes all enrolled subjects who received at least one dose of study drug. Subjects were analyzed according to their actual treatment received.

    Subject analysis set title
    Denosumab
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Participants who received denosumab 60 mg administered by subcutaneous injection on Day 1 and/or at Month 6. The safety analysis set includes all enrolled subjects who received at least one dose of study drug. Subjects were analyzed according to their actual treatment received. This group includes three participants randomized to the placebo group who received at least 1 dose of denosumab in error.

    Subject analysis set title
    Placebo
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Participants in the Lens Opacification Analysis Set received placebo administered by subcutaneous injection on Day 1 and at Month 6. The lens opacification analysis set, for the primary endpoint, includes all randomized subjects who received at least one dose of study drug, had an evaluable baseline LOCS III assessment, and at least one evaluable post-baseline LOCS III assessment at the corresponding lens site. Subjects in the lens opacification analysis set were analyzed according to their actual treatment received.

    Subject analysis set title
    Denosumab
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Participants in the Lens Opacification Analysis Set received denosumab 60 mg administered by subcutaneous injection on Day 1 and at Month 6. The lens opacification analysis set, for the primary endpoint, includes all randomized subjects who received at least one dose of study drug, had an evaluable baseline LOCS III assessment, and at least one evaluable post-baseline LOCS III assessment at the corresponding lens site. Subjects in the lens opacification analysis set were analyzed according to their actual treatment received. This group includes three participants randomized to the placebo group who received at least 1 dose of denosumab in error.

    Primary: Percentage of Participants with Lens Opacification Event Development or Progression by Month 12

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    End point title
    		 Percentage of Participants with Lens Opacification Event Development or Progression by Month 12
    End point description
    The Lens Opacities Classification System III (LOCS III) is a slit lamp based opacification grading method. Photographs of slit lamp cross-sections of the lens are used as references for grading nuclear opalescence (NO) and nuclear color (NC), and photographs of the lens seen by retroillumination are used as references for grading cortical (C) and posterior subcapsular (P) cataract. Opacification severity is graded on a decimal scale, scores can range from 0.1 to 6.9 for NO and NC and from 0.1 to 5.9 for C and P. Higher grading scores indicate greater severity. Lens opacification event development or progression was based on a change of ≥ 1.0 in P, ≥ 1.0 in C, or ≥ 0.7 in NO in the LOCS III score from baseline. The analysis was conducted in the lens opacification analysis set, which includes participants who received at least 1 dose of study drug, had an evaluable baseline LOCS III assessment, and at least 1 evaluable post-baseline LOCS III assessment at the corresponding lens site.
    End point type
    Primary
    End point timeframe
    12 months
    End point values
    		 Placebo Denosumab
    Number of subjects analysed
    374
    379
    Units: percentage of participants
        number (not applicable)
    33.2
    33.5
    Statistical analysis title
    		 Primary Analysis
    Statistical analysis description
    The primary endpoint was summarized with the point estimate of absolute risk difference (difference in incidence rates, denosumab minus placebo) and the corresponding 95% confidence interval using the Mantel-Haenszel method adjusting for the stratification factors: baseline LOCS III status (< 3.0 at all sites [P, C, and NO] vs. ≥ 3.0 at any of these sites), age group (< 75, ≥ 75 years), and patient-reported history of cataract (yes/no).
    Comparison groups
    Placebo v Denosumab
    Number of subjects included in analysis
    753
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [1]
    P-value
    		 = 0.0026
    Method
    		 Mantel-Haenszel
    Parameter type
    		 Risk difference (RD)
    Point estimate
    0.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.3
         upper limit
    		 7.2
    Variability estimate
    Standard error of the mean
    Dispersion value
    3.4
    Notes
    [1] - Non-inferiority was demonstrated if the upper bound of the 97.5% one-sided confidence interval, or equivalently upper bound of two-sided 95% confidence interval was less than the pre-specified non-inferiority bound of 10%.

    Other pre-specified: Percentage of Participant with Lens Opacification Event Development or Progression by Month 12 Based on a Change of ≥ 1.5 in P, ≥ 1.5 in C, or ≥ 1.5 in NO in the LOCS III score

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    End point title
    		 Percentage of Participant with Lens Opacification Event Development or Progression by Month 12 Based on a Change of ≥ 1.5 in P, ≥ 1.5 in C, or ≥ 1.5 in NO in the LOCS III score
    End point description
    LOCS III is a slit lamp based opacification grading method. Photographs of slit lamp cross-sections of the lens are used as references for grading nuclear opalescence (NO) and nuclear color (NC), and photographs of the lens seen by retroillumination are used as references for grading cortical (C) and posterior subcapsular (P) cataract. Opacification severity is graded on a decimal scale, scores can range from 0.1 to 6.9 for NO and NC and from 0.1 to 5.9 for C and P. For each opacification type the higher grading scores indicate greater severity. Lens opacification event development or progression by month 12 was based on a change ≥ 1.5 in P, ≥ 1.5 in C, or ≥ 1.5 in NO in the LOCS III score from baseline. The analysis was conducted in the lens opacification analysis set which includes all randomized subjects who received at least 1 dose of study drug, an evaluable baseline LOCS III assessment, and at least 1 evaluable post-baseline LOCS III assessment at the corresponding lens site.
    End point type
    Other pre-specified
    End point timeframe
    12 months
    End point values
    		 Placebo Denosumab
    Number of subjects analysed
    374
    379
    Units: percentage of participants
        number (not applicable)
    10.7
    8.4
    Statistical analysis title
    		 Risk Difference
    Statistical analysis description
    The point estimate of absolute risk difference (difference in incidence rates, denosumab minus placebo) and the corresponding 95% confidence interval was constructed using the Mantel-Haenszel method adjusting for the stratification factors: baseline LOCS III status (< 3.0 at all sites [P, C, and NO] vs. ≥ 3.0 at any of these sites), age group (< 75, ≥ 75 years), and patient-reported history of cataract (yes/no).
    Comparison groups
    Placebo v Denosumab
    Number of subjects included in analysis
    753
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Risk difference (RD)
    Point estimate
    -2.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.4
         upper limit
    		 2
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.1

    Other pre-specified: Percentage of Participants with Lens Opacification Event Development or Progression by Month 6

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    End point title
    		 Percentage of Participants with Lens Opacification Event Development or Progression by Month 6
    End point description
    LOCS III is a slit lamp based opacification grading method. Photographs of slit lamp cross-sections of the lens are used as references for grading nuclear opalescence (NO) and nuclear color (NC), and photographs of the lens seen by retroillumination are used as references for grading cortical (C) and posterior subcapsular (P) cataract. Opacification severity is graded on a decimal scale, scores range from 0.1 to 6.9 for NO and NC and from 0.1 to 5.9 for C and P; higher grading scores indicate greater severity. Lens opacification event development or progression by month 6 was based on a change of ≥ 1.0 in P, ≥ 1.0 in C, or ≥ 0.7 in NO in the LOCS III score from baseline. The analysis was conducted in the lens opacification analysis set which includes all randomized subjects who received at least 1 dose of study drug, had an evaluable baseline LOCS III assessment and at least 1 evaluable post-baseline LOCS III assessment at the corresponding lens site at or before month 6.
    End point type
    Other pre-specified
    End point timeframe
    6 months
    End point values
    		 Placebo Denosumab
    Number of subjects analysed
    374
    379
    Units: percentage of participants
        number (not applicable)
    19.3
    19
    Statistical analysis title
    		 Risk Difference
    Statistical analysis description
    The point estimate of absolute risk difference (difference in incidence rates, denosumab minus placebo) and the corresponding 95% confidence interval was constructed using the Mantel-Haenszel method adjusting for the stratification factors: baseline LOCS III status (< 3.0 at all sites [P, C, and NO] vs. ≥ 3.0 at any of these sites), age group (< 75, ≥ 75 years), and patient-reported history of cataract (yes/no).
    Comparison groups
    Placebo v Denosumab
    Number of subjects included in analysis
    753
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Risk difference (RD)
    Point estimate
    -0.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.9
         upper limit
    		 5.3
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.9

    Other pre-specified: Percentage of Participants with Confirmed Lens Opacification Event Development or Progression by Month 12

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    End point title
    		 Percentage of Participants with Confirmed Lens Opacification Event Development or Progression by Month 12
    End point description
    The Lens Opacities Classification System III (LOCS III) is a slit lamp based opacification grading method. Photographs of slit lamp cross-sections of the lens are used as references for grading nuclear opalescence (NO) and nuclear color (NC), and photographs of the lens seen by retroillumination are used as references for grading cortical (C) and posterior subcapsular (P) cataract. Opacification severity is graded on a decimal scale, scores can range from 0.1 to 6.9 for NO and NC and from 0.1 to 5.9 for C and P. Higher scores indicate greater severity. Lens opacification event development or progression was based on a change of ≥ 1.0 in P, ≥ 1.0 in C, or ≥ 0.7 in NO in the LOCS III score from baseline. Confirmed lens opacification event development or progression was defined as 2 directly subsequent events at the same location (P, C, NO). The analysis was conducted in the lens opacification analysis set with at least 2 post-baseline LOCS III measurements by month 12.
    End point type
    Other pre-specified
    End point timeframe
    12 months
    End point values
    		 Placebo Denosumab
    Number of subjects analysed
    361
    367
    Units: percentage of participants
        number (not applicable)
    18.3
    16.1
    Statistical analysis title
    		 Risk Difference
    Statistical analysis description
    The point estimate of absolute risk difference (difference in incidence rates, denosumab minus placebo) and the corresponding 95% confidence interval was constructed using the Mantel-Haenszel method adjusting for the stratification factors: baseline LOCS III status (< 3.0 at all sites [P, C, and NO] vs. ≥ 3.0 at any of these sites), age group (< 75, ≥ 75 years), and patient-reported history of cataract (yes/no).
    Comparison groups
    Placebo v Denosumab
    Number of subjects included in analysis
    728
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Risk difference (RD)
    Point estimate
    -2.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -7.6
         upper limit
    		 3.3
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.8

    Other pre-specified: Percentage of Participants with a Decrease from Baseline in Best Corrected Visual Acuity (BCVA) of ≥ 10 Letters

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    End point title
    		 Percentage of Participants with a Decrease from Baseline in Best Corrected Visual Acuity (BCVA) of ≥ 10 Letters
    End point description
    The best corrected visual acuity (BCVA) is the best vision one can achieve with correction (such as eye glasses) as measured on an eye chart. BCVA was assessed by a trained ophthalmologist using the Early Treatment Diabetic Retinopathy Study (ETDRS) eye chart at 4 meters. The modified University of Crete ETDRS chart was used in Ukraine, Greece, Russia and Bulgaria, which do not use the Roman alphabet. The 2000 series revised ETDRS chart was used to assess the change in all other countries. The letter score was calculated based on the number of letters that were correctly identified; higher letter scores correspond to better visual acuity. This analysis was conducted in the lens opacification analysis set with evaluable assessments at both baseline and the time point of interest in the same eye.
    End point type
    Other pre-specified
    End point timeframe
    Baseline and Months 3, 6, 9 and 12
    End point values
    		 Placebo Denosumab
    Number of subjects analysed
    374
    379
    Units: percentage of participants
    number (not applicable)
        Month 3 (n = 372, 375)
    5.4
    6.1
        Month 6 (n = 355, 357)
    4.2
    6.4
        Month 9 (n = 350, 346)
    4.6
    6.6
        Month 12 (n = 343, 342)
    5.2
    7.3
    No statistical analyses for this end point

    Other pre-specified: Change from Baseline in Refraction Needed to Achieve BCVA

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    End point title
    		 Change from Baseline in Refraction Needed to Achieve BCVA
    End point description
    Refraction error was measured using a phoropter. The change from baseline in spherical refraction error needed to achieve BCVA is reported. The analysis was conducted in the lens opacification analysis set with evaluable assessments at both baseline and the time point of interest in the same eye; n = the number of evaluable eyes in the lens opacification analysis set at the corresponding time point.
    End point type
    Other pre-specified
    End point timeframe
    Baseline and months 3, 6, 9, and 12
    End point values
    		 Placebo - Left Eye Placebo - Right Eye Denosumab - Left Eye Denosumab - Right Eye
    Number of subjects analysed
    374
    374
    379
    379
    Units: diopters
    arithmetic mean (standard deviation)
        Month 3 (n = 362, 358, 358, 359)
    0.01 ( 0.6 )
    0.01 ( 0.49 )
    0.05 ( 0.73 )
    0.04 ( 0.51 )
        Month 6 (n = 347, 343, 341, 344)
    -0.01 ( 0.8 )
    0.06 ( 0.7 )
    0.06 ( 0.9 )
    0.04 ( 0.59 )
        Month 9 (n = 341, 339, 332, 332)
    0 ( 0.84 )
    0.01 ( 0.73 )
    0.04 ( 0.75 )
    0.01 ( 0.62 )
        Month 12 (n = 336, 334, 328, 329)
    -0.03 ( 0.7 )
    -0.04 ( 0.59 )
    0.03 ( 0.77 )
    0 ( 0.48 )
    No statistical analyses for this end point

    Other pre-specified: Number of Participants with Adverse Events

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    End point title
    		 Number of Participants with Adverse Events
    End point description
    Adverse events (AEs) were assessed for severity by the investigator according to the Common Terminology Criteria for Adverse Events (CTCAE) severity grading scale, version 3.0, where Grade 1 = Mild AE, Grade 2 = Moderate AE, Grade 3 = Severe AE, Grade 4 =Life-threatening AE and Grade 5 = Death due to AE. Treatment-related AEs (TRAEs) include only events for which the investigator indicated there was a reasonable possibility they may have been caused by the study drug. This analysis was conducted in all enrolled participants who received at least one dose of study drug. Three participants randomized to the placebo group received at least 1 dose of denosumab in error, and are included in the denosumab group for safety.
    End point type
    Other pre-specified
    End point timeframe
    12 months
    End point values
    		 Placebo Denosumab
    Number of subjects analysed
    380
    385 [2]
    Units: participants
        Any adverse event
    193
    191
        Serious adverse events
    52
    42
        AE leading to discontinuation of study drug
    5
    7
        AE leading to discontinuation from study
    2
    4
        Fatal adverse events
    4
    3
        AE grade 3, 4, or 5
    53
    46
        Treatment-related adverse events
    19
    21
        Serious treatment-related adverse events
    1
    2
        TRAE leading to discontinuation of study drug
    1
    3
        TRAE leading to discontinuation from study
    0
    1
        Fatal treatment-related adverse events
    0
    0
        TRAE grade 3, 4, or 5
    2
    2
    Notes
    [2] - Includes 3 participants who received denosumab in error
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    12 Months
    Adverse event reporting additional description
    Analysis includes all enrolled participants who received at least one dose of study drug. Three participants randomized to the placebo group received at least 1 dose of denosumab in error, and are included in the denosumab group for safety.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19.0
    Reporting groups
    Reporting group title
    Denosumab
    Reporting group description
    		 Participants who received denosumab 60 mg administered by subcutaneous injection on Day 1 and/or at Month 6.

    Reporting group title
    Placebo
    Reporting group description
    		 Participants received placebo administered by subcutaneous injection on Day 1 and at Month 6.

    Serious adverse events
    		 Denosumab Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    42 / 385 (10.91%)
    52 / 380 (13.68%)
         number of deaths (all causes)
    3
    4
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Colon cancer
         subjects affected / exposed
    1 / 385 (0.26%)
    0 / 380 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastases to central nervous system
         subjects affected / exposed
    0 / 385 (0.00%)
    1 / 380 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Plasma cell myeloma
         subjects affected / exposed
    1 / 385 (0.26%)
    0 / 380 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Prostate cancer
         subjects affected / exposed
    1 / 385 (0.26%)
    0 / 380 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Squamous cell carcinoma of skin
         subjects affected / exposed
    0 / 385 (0.00%)
    1 / 380 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    0 / 385 (0.00%)
    1 / 380 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral ischaemia
         subjects affected / exposed
    0 / 385 (0.00%)
    1 / 380 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 385 (0.00%)
    1 / 380 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cyst
         subjects affected / exposed
    0 / 385 (0.00%)
    1 / 380 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral swelling
         subjects affected / exposed
    0 / 385 (0.00%)
    1 / 380 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pseudoangina
         subjects affected / exposed
    0 / 385 (0.00%)
    1 / 380 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    1 / 385 (0.26%)
    0 / 380 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory failure
         subjects affected / exposed
    0 / 385 (0.00%)
    1 / 380 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    0 / 385 (0.00%)
    1 / 380 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic respiratory failure
         subjects affected / exposed
    0 / 385 (0.00%)
    1 / 380 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epistaxis
         subjects affected / exposed
    1 / 385 (0.26%)
    0 / 380 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    2 / 385 (0.52%)
    2 / 380 (0.53%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary fibrosis
         subjects affected / exposed
    0 / 385 (0.00%)
    1 / 380 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Depression
         subjects affected / exposed
    0 / 385 (0.00%)
    1 / 380 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Product issues
    Device dislocation
         subjects affected / exposed
    1 / 385 (0.26%)
    0 / 380 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device malfunction
         subjects affected / exposed
    1 / 385 (0.26%)
    0 / 380 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Cystitis radiation
         subjects affected / exposed
    1 / 385 (0.26%)
    0 / 380 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Foot fracture
         subjects affected / exposed
    0 / 385 (0.00%)
    1 / 380 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fracture
         subjects affected / exposed
    1 / 385 (0.26%)
    0 / 380 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lumbar vertebral fracture
         subjects affected / exposed
    1 / 385 (0.26%)
    1 / 380 (0.26%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    0 / 385 (0.00%)
    1 / 380 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multiple injuries
         subjects affected / exposed
    1 / 385 (0.26%)
    0 / 380 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Patella fracture
         subjects affected / exposed
    0 / 385 (0.00%)
    1 / 380 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Radiation proctitis
         subjects affected / exposed
    1 / 385 (0.26%)
    0 / 380 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urethral stricture postoperative
         subjects affected / exposed
    1 / 385 (0.26%)
    1 / 380 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Angina pectoris
         subjects affected / exposed
    2 / 385 (0.52%)
    0 / 380 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    1 / 385 (0.26%)
    1 / 380 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    1 / 385 (0.26%)
    0 / 380 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    0 / 385 (0.00%)
    1 / 380 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac fibrillation
         subjects affected / exposed
    0 / 385 (0.00%)
    1 / 380 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardio-respiratory arrest
         subjects affected / exposed
    1 / 385 (0.26%)
    0 / 380 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cardiogenic shock
         subjects affected / exposed
    0 / 385 (0.00%)
    1 / 380 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    1 / 385 (0.26%)
    2 / 380 (0.53%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronary artery insufficiency
         subjects affected / exposed
    0 / 385 (0.00%)
    1 / 380 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronary artery stenosis
         subjects affected / exposed
    0 / 385 (0.00%)
    1 / 380 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ischaemic cardiomyopathy
         subjects affected / exposed
    1 / 385 (0.26%)
    0 / 380 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    1 / 385 (0.26%)
    2 / 380 (0.53%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Myocardial ischaemia
         subjects affected / exposed
    3 / 385 (0.78%)
    1 / 380 (0.26%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tachycardia paroxysmal
         subjects affected / exposed
    1 / 385 (0.26%)
    0 / 380 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ventricular tachycardia
         subjects affected / exposed
    1 / 385 (0.26%)
    0 / 380 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Aphasia
         subjects affected / exposed
    0 / 385 (0.00%)
    1 / 380 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    1 / 385 (0.26%)
    4 / 380 (1.05%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dementia
         subjects affected / exposed
    0 / 385 (0.00%)
    1 / 380 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    0 / 385 (0.00%)
    2 / 380 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Encephalomalacia
         subjects affected / exposed
    0 / 385 (0.00%)
    1 / 380 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epilepsy
         subjects affected / exposed
    0 / 385 (0.00%)
    1 / 380 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhagic stroke
         subjects affected / exposed
    0 / 385 (0.00%)
    1 / 380 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Normal pressure hydrocephalus
         subjects affected / exposed
    1 / 385 (0.26%)
    0 / 380 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    1 / 385 (0.26%)
    1 / 380 (0.26%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    0 / 385 (0.00%)
    1 / 380 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia megaloblastic
         subjects affected / exposed
    0 / 385 (0.00%)
    1 / 380 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Tinnitus
         subjects affected / exposed
    1 / 385 (0.26%)
    0 / 380 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Optic nerve disorder
         subjects affected / exposed
    1 / 385 (0.26%)
    0 / 380 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Uveitis
         subjects affected / exposed
    1 / 385 (0.26%)
    0 / 380 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 385 (0.00%)
    1 / 380 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis ulcerative
         subjects affected / exposed
    1 / 385 (0.26%)
    0 / 380 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    0 / 385 (0.00%)
    2 / 380 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 385 (0.26%)
    0 / 380 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    0 / 385 (0.00%)
    1 / 380 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Inguinal hernia
         subjects affected / exposed
    1 / 385 (0.26%)
    1 / 380 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mechanical ileus
         subjects affected / exposed
    0 / 385 (0.00%)
    1 / 380 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal haemorrhage
         subjects affected / exposed
    1 / 385 (0.26%)
    1 / 380 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small intestinal stenosis
         subjects affected / exposed
    1 / 385 (0.26%)
    0 / 380 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Bile duct stone
         subjects affected / exposed
    1 / 385 (0.26%)
    0 / 380 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis acute
         subjects affected / exposed
    1 / 385 (0.26%)
    1 / 380 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    0 / 385 (0.00%)
    1 / 380 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Diabetic foot
         subjects affected / exposed
    0 / 385 (0.00%)
    1 / 380 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rash generalised
         subjects affected / exposed
    0 / 385 (0.00%)
    1 / 380 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 385 (0.00%)
    2 / 380 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematuria
         subjects affected / exposed
    1 / 385 (0.26%)
    1 / 380 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pelvi-ureteric obstruction
         subjects affected / exposed
    0 / 385 (0.00%)
    1 / 380 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stress urinary incontinence
         subjects affected / exposed
    0 / 385 (0.00%)
    1 / 380 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urethral stenosis
         subjects affected / exposed
    1 / 385 (0.26%)
    1 / 380 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary retention
         subjects affected / exposed
    0 / 385 (0.00%)
    2 / 380 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 385 (0.26%)
    0 / 380 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Back pain
         subjects affected / exposed
    0 / 385 (0.00%)
    1 / 380 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Connective tissue inflammation
         subjects affected / exposed
    0 / 385 (0.00%)
    1 / 380 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intervertebral disc compression
         subjects affected / exposed
    1 / 385 (0.26%)
    0 / 380 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    2 / 385 (0.52%)
    0 / 380 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal osteoarthritis
         subjects affected / exposed
    1 / 385 (0.26%)
    0 / 380 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Appendicitis perforated
         subjects affected / exposed
    0 / 385 (0.00%)
    1 / 380 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arthritis bacterial
         subjects affected / exposed
    0 / 385 (0.00%)
    1 / 380 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atypical pneumonia
         subjects affected / exposed
    0 / 385 (0.00%)
    1 / 380 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    0 / 385 (0.00%)
    2 / 380 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Herpes zoster
         subjects affected / exposed
    0 / 385 (0.00%)
    1 / 380 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Kidney infection
         subjects affected / exposed
    1 / 385 (0.26%)
    0 / 380 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Liver abscess
         subjects affected / exposed
    1 / 385 (0.26%)
    0 / 380 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 385 (0.00%)
    2 / 380 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Pyelonephritis acute
         subjects affected / exposed
    1 / 385 (0.26%)
    1 / 380 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    1 / 385 (0.26%)
    0 / 380 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetes mellitus inadequate control
         subjects affected / exposed
    1 / 385 (0.26%)
    0 / 380 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    0 / 385 (0.00%)
    1 / 380 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 1%
    Non-serious adverse events
    		 Denosumab Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    121 / 385 (31.43%)
    107 / 380 (28.16%)
    Vascular disorders
    Hot flush
         subjects affected / exposed
    7 / 385 (1.82%)
    7 / 380 (1.84%)
         occurrences all number
    7
    7
    Hypertension
         subjects affected / exposed
    8 / 385 (2.08%)
    16 / 380 (4.21%)
         occurrences all number
    8
    17
    Hypotension
         subjects affected / exposed
    1 / 385 (0.26%)
    5 / 380 (1.32%)
         occurrences all number
    1
    5
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    6 / 385 (1.56%)
    2 / 380 (0.53%)
         occurrences all number
    6
    2
    Oedema peripheral
         subjects affected / exposed
    7 / 385 (1.82%)
    1 / 380 (0.26%)
         occurrences all number
    8
    1
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    4 / 385 (1.04%)
    6 / 380 (1.58%)
         occurrences all number
    4
    7
    Dyspnoea
         subjects affected / exposed
    4 / 385 (1.04%)
    3 / 380 (0.79%)
         occurrences all number
    4
    3
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    6 / 385 (1.56%)
    3 / 380 (0.79%)
         occurrences all number
    6
    3
    Investigations
    Prostatic specific antigen increased
         subjects affected / exposed
    4 / 385 (1.04%)
    0 / 380 (0.00%)
         occurrences all number
    4
    0
    Injury, poisoning and procedural complications
    Chest injury
         subjects affected / exposed
    0 / 385 (0.00%)
    4 / 380 (1.05%)
         occurrences all number
    0
    4
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    4 / 385 (1.04%)
    3 / 380 (0.79%)
         occurrences all number
    4
    3
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    6 / 385 (1.56%)
    4 / 380 (1.05%)
         occurrences all number
    6
    4
    Headache
         subjects affected / exposed
    6 / 385 (1.56%)
    3 / 380 (0.79%)
         occurrences all number
    7
    3
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    2 / 385 (0.52%)
    4 / 380 (1.05%)
         occurrences all number
    2
    4
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    6 / 385 (1.56%)
    0 / 380 (0.00%)
         occurrences all number
    7
    0
    Eye disorders
    Vision blurred
         subjects affected / exposed
    5 / 385 (1.30%)
    2 / 380 (0.53%)
         occurrences all number
    5
    2
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    8 / 385 (2.08%)
    16 / 380 (4.21%)
         occurrences all number
    8
    17
    Diarrhoea
         subjects affected / exposed
    2 / 385 (0.52%)
    6 / 380 (1.58%)
         occurrences all number
    3
    6
    Renal and urinary disorders
    Dysuria
         subjects affected / exposed
    5 / 385 (1.30%)
    4 / 380 (1.05%)
         occurrences all number
    5
    4
    Haematuria
         subjects affected / exposed
    3 / 385 (0.78%)
    4 / 380 (1.05%)
         occurrences all number
    3
    5
    Pollakiuria
         subjects affected / exposed
    7 / 385 (1.82%)
    6 / 380 (1.58%)
         occurrences all number
    7
    6
    Urinary incontinence
         subjects affected / exposed
    1 / 385 (0.26%)
    4 / 380 (1.05%)
         occurrences all number
    1
    4
    Urinary retention
         subjects affected / exposed
    2 / 385 (0.52%)
    4 / 380 (1.05%)
         occurrences all number
    2
    5
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    12 / 385 (3.12%)
    10 / 380 (2.63%)
         occurrences all number
    12
    10
    Back pain
         subjects affected / exposed
    11 / 385 (2.86%)
    10 / 380 (2.63%)
         occurrences all number
    11
    10
    Musculoskeletal pain
         subjects affected / exposed
    3 / 385 (0.78%)
    5 / 380 (1.32%)
         occurrences all number
    3
    5
    Myalgia
         subjects affected / exposed
    5 / 385 (1.30%)
    2 / 380 (0.53%)
         occurrences all number
    5
    2
    Osteoarthritis
         subjects affected / exposed
    7 / 385 (1.82%)
    2 / 380 (0.53%)
         occurrences all number
    8
    2
    Pain in extremity
         subjects affected / exposed
    6 / 385 (1.56%)
    10 / 380 (2.63%)
         occurrences all number
    6
    12
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    6 / 385 (1.56%)
    4 / 380 (1.05%)
         occurrences all number
    6
    4
    Nasopharyngitis
         subjects affected / exposed
    10 / 385 (2.60%)
    7 / 380 (1.84%)
         occurrences all number
    11
    7
    Sinusitis
         subjects affected / exposed
    4 / 385 (1.04%)
    3 / 380 (0.79%)
         occurrences all number
    4
    4
    Upper respiratory tract infection
         subjects affected / exposed
    5 / 385 (1.30%)
    6 / 380 (1.58%)
         occurrences all number
    7
    8
    Urinary tract infection
         subjects affected / exposed
    5 / 385 (1.30%)
    5 / 380 (1.32%)
         occurrences all number
    6
    8
    Metabolism and nutrition disorders
    Diabetes mellitus
         subjects affected / exposed
    5 / 385 (1.30%)
    5 / 380 (1.32%)
         occurrences all number
    5
    5
    Type 2 diabetes mellitus
         subjects affected / exposed
    1 / 385 (0.26%)
    4 / 380 (1.05%)
         occurrences all number
    1
    4

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    06 Nov 2009
    • changed the laboratory analyses from local laboratories to a central laboratory. • added testosterone and prostate-specific antigen as analytes at specific time points during treatment. • increased the potential number of sites from 100 to 120, and modified the regions in which the study may be conducted. • clarified the pupil dilation criteria and the contraceptive language in the exclusion criteria. • clarified the description of the eye examination (adding Nuclear Color), and masking of the examiner to previous scores. • updated the schedule of assessments to reflect changes in the protocol.
    10 Jan 2012
    • investigational product would be supplied in prefilled syringes. • clarified screening examinations to be used for eligibility and stratification. • clarified that eye examination exclusion criterion applied to both eyes. • added additional sites and countries. • extended the enrollment duration. • clarified the provision of calcium and vitamin D supplements. • updated the protocol glossary.
    25 Jun 2013
    • clarified in the objectives and endpoints descriptions that the Lens Opacities Classification System III system evaluated “lens opacifications”; changed “cataract” to “lens opacifications.” • deleted eligibility criteria that required male patients who were receiving a large molecule such as denosumab to use any form of Contraception. • revised safety reporting language. • added implementation of periodic reviews by an external data monitoring committee.

    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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