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    Clinical Trial Results:
    Denosumab in enhancement of bone bonding of hip prosthesis in postmenopausal women: a randomized, double-blind, placebo-controlled study

    Summary
    EudraCT number
    		 2011-000628-14
    Trial protocol
    		 FI  
    Global end of trial date
    17 Oct 2018

    Results information
    Results version number
    		 v1(current)
    This version publication date
    19 Oct 2024
    First version publication date
    19 Oct 2024
    Other versions
    Summary report(s)
    		 Publication JBMR_Plus

    Trial information

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    Trial identification
    Sponsor protocol code
    ISS20109714
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01926158
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Amgen AB
    Sponsor organisation address
    Keilaranta 16, Espoo, Finland, 02150
    Public contact
    Sivuliike Suomessa , Amgen AB, 358 954900500, paivi.lakkakorpi@amgen.com
    Scientific contact
    Sivuliike Suomessa , Amgen AB, 358 954900500, paivi.lakkakorpi@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
    17 Oct 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    17 Oct 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    17 Oct 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary hypothesis for this trial is that denosumab compared with placebo is effective in preventing periprosthetic bone loss in the proximal femur of female patients after total hip replacement
    Protection of trial subjects
    No need of specific methods of protection
    Background therapy
    		 No background therapy
    Evidence for comparator
    		 Comparison with placebo
    Actual start date of recruitment
    01 Sep 2013
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety
    Long term follow-up duration
    		 2 Years
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Finland: 67
    Worldwide total number of subjects
    67
    EEA total number of subjects
    67
    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)
    15
    From 65 to 84 years
    52
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Recruitment between November 2013 and June 2015

    Pre-assignment
    Screening details
    		 Postmenopausal women between 60 and 85 years of age with primary hip osteoarthritis as the indicaction for the need of hip replacement. 205 subjects assessed for eligibility. 140 excluded for the following reasons: not meeting inclusion criteria (n=63), declined to participate (n=35) and other reasons (n=42).

    Pre-assignment period milestones
    Number of subjects started
    		 67
    Number of subjects completed
    		 67

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Allocated to denosumab treatment
    Arm description
    		 Denosumab treatment (60 mg every 6 months) for one year
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Prolia
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Epicutaneous use
    Dosage and administration details
    Subcutaneous injection of denosumab 60 mg every 6 months

    Arm title
    		 Allocated to placebo
    Arm description
    		 Placebo injection every 6 moths for one year
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Injection
    Dosage and administration details
    Subcutaneous injection every 6 months for one year

    Number of subjects in period 1
    		Allocated to denosumab treatment Allocated to placebo
    Started
    33
    34
    Completed
    33
    32
    Not completed
    0
    2
         Consent withdrawn by subject
    -
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Allocated to denosumab treatment
    Reporting group description
    		 Denosumab treatment (60 mg every 6 months) for one year

    Reporting group title
    Allocated to placebo
    Reporting group description
    		 Placebo injection every 6 moths for one year

    Reporting group values
    		 Allocated to denosumab treatment Allocated to placebo Total
    Number of subjects
    		 33 34 67
    Age categorical
    Units: Subjects
        In utero
    		 0
        Preterm newborn infants (gestational age < 37 wks)
    		 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)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 69 ( 5 ) 69 ( 6 ) -
    Gender categorical
    Units: Subjects
        Female
    		 33 34 67
        Male
    		 0 0 0
    Low BMD
    BMD measured by DXA
    Units: Subjects
        Osteopenia
    		 15 17 32
        Osteoporosis
    		 2 0 2
        Normal BMD
    		 16 17 33
    History of low-energy fractures
    Number of subjects with a history of low-energy fractures
    Units: Subjects
        Fracture - yes
    		 9 8 17
        Fracture - no
    		 24 26 50

    End points

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    End points reporting groups
    Reporting group title
    Allocated to denosumab treatment
    Reporting group description
    		 Denosumab treatment (60 mg every 6 months) for one year

    Reporting group title
    Allocated to placebo
    Reporting group description
    		 Placebo injection every 6 moths for one year

    Primary: Percentage change of periprosthetic calcar BMD (Gruen 7)

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    End point title
    		 Percentage change of periprosthetic calcar BMD (Gruen 7)
    End point description
    Periprosthetic BMD measured by DXA immediately after fracture and at 48 weeks
    End point type
    Primary
    End point timeframe
    During the first 48 weeks after surgery
    End point values
    		 Allocated to denosumab treatment Allocated to placebo
    Number of subjects analysed
    33
    32
    Units: percent
        least squares mean (confidence interval 95%)
    5.3 (2.2 to 8.5)
    18.1 (14.5 to 21.6)
    Attachments
    		 Periprosthetic BMD after surgery
    Statistical analysis title
    		 Statistical analysis
    Statistical analysis description
    The primary and secondary endpoints (the outcome measured at week 48) were analyzed using linear mixed‐effects models for repeated measures. The method was also applied to evaluate intergroup differences at each time point (12, 22, and 48 weeks) as the exploratory endpoints of the different outcome parameters. No data were excluded.
    Comparison groups
    Allocated to denosumab treatment v Allocated to placebo
    Number of subjects included in analysis
    65
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 < 0.05
    Method
    		 Mixed models analysis
    Confidence interval

    Secondary: Implant 3D-migration

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    End point title
    		 Implant 3D-migration
    End point description
    Baseline RSA measurements at day 3. Measurement of 3D-translation and 3D-rotation at 12, 22 and 48 weeks.
    End point type
    Secondary
    End point timeframe
    0, 12, 22, 48 weeks
    End point values
    		 Allocated to denosumab treatment Allocated to placebo
    Number of subjects analysed
    33
    32
    Units: degrees
        arithmetic mean (confidence interval 95%)
    2.4 (1.6 to 3.3)
    2.3 (1.5 to 3.2)
    Attachments
    		 Implant migration
    Statistical analysis title
    		 Statistical analysis
    Statistical analysis description
    The primary and secondary endpoints (the outcome measured at week 48) were analyzed using linear mixed‐effects models for repeated measures. The method was also applied to evaluate intergroup differences at each time point (12, 22, and 48 weeks) as the exploratory endpoints of the different outcome parameters. No data were excluded.
    Comparison groups
    Allocated to denosumab treatment v Allocated to placebo
    Number of subjects included in analysis
    65
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 < 0.05
    Method
    		 Mixed models analysis
    Confidence interval

    Other pre-specified: Patient-reported outcome measures

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    End point title
    		 Patient-reported outcome measures
    End point description
    Harris hip score, WOMAC score, Rand-36 score, BPI-pain score
    End point type
    Other pre-specified
    End point timeframe
    0, 12, 22, 48 weeks
    End point values
    		 Allocated to denosumab treatment Allocated to placebo
    Number of subjects analysed
    33
    32
    Units: scores
        arithmetic mean (confidence interval 95%)
    78 (74 to 82)
    72 (68 to 76)
    Attachments
    		 Untitled (Filename: Patient-reported outcome measures.pdf)
    Statistical analysis title
    		 Statistical analysis
    Statistical analysis description
    The primary and secondary endpoints (the outcome measured at week 48) were analyzed using linear mixed‐effects models for repeated measures. The method was also applied to evaluate intergroup differences at each time point (12, 22, and 48 weeks) as the exploratory endpoints of the different outcome parameters. No data were excluded.
    Comparison groups
    Allocated to denosumab treatment v Allocated to placebo
    Number of subjects included in analysis
    65
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 < 0.05
    Method
    		 Mixed models analysis
    Confidence interval

    Other pre-specified: Walking speed and walking activity

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    End point title
    		 Walking speed and walking activity
    End point description
    Walking speed and walking activity measured repeatedly during the first year after hip replacement
    End point type
    Other pre-specified
    End point timeframe
    Walking speed at 0, 3, 6, 12, 24 and 36 weeks. Walking activity measured at 3, 6, and 12 months.
    End point values
    		 Allocated to denosumab treatment Allocated to placebo
    Number of subjects analysed
    33
    32
    Units: m/sec or counts
        arithmetic mean (confidence interval 95%)
    1.16 (1.10 to 1.23)
    1.20 (1.07 to 1.24)
    Attachments
    		 Walking speed and walking activity
    Statistical analysis title
    		 Statistical analysis
    Statistical analysis description
    The primary and secondary endpoints (the outcome measured at week 48) were analyzed using linear mixed‐effects models for repeated measures. The method was also applied to evaluate intergroup differences at each time point (12, 22, and 48 weeks) as the exploratory endpoints of the different outcome parameters. No data were excluded.
    Comparison groups
    Allocated to denosumab treatment v Allocated to placebo
    Number of subjects included in analysis
    65
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 < 0.05
    Method
    		 Mixed models analysis
    Confidence interval

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    The first year after hip replacement
    Adverse event reporting additional description
    The incidence of adverse events and serious adverse events
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedVED
    Dictionary version
    3
    Reporting groups
    Reporting group title
    AEs and SAEs
    Reporting group description
    		 The incidence of AEs and SAEs during the 1-year trial period was balanced between the two groups. The most common AE was low back pain.

    Serious adverse events
    		 AEs and SAEs
    Total subjects affected by serious adverse events
         subjects affected / exposed
    7 / 65 (10.77%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Cardiac disorders
    Bradycardia. Mild infarct.
         subjects affected / exposed
    7 / 65 (10.77%)
         occurrences causally related to treatment / all
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 AEs and SAEs
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    31 / 65 (47.69%)
    Musculoskeletal and connective tissue disorders
    Low back pain
         subjects affected / exposed
    31 / 65 (47.69%)
         occurrences all number
    31

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    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

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/31687650
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