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    Clinical Trial Results:
    Osseointegrated transdermal femoral amputation prostheses - Denusomab Trial

    Summary
    EudraCT number
    		 2012-003574-66
    Trial protocol
    		 DK  
    Global end of trial date
    06 Sep 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    21 Dec 2019
    First version publication date
    21 Dec 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    34964
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Aarhus University Hospital
    Sponsor organisation address
    Palle Juul-Jensens Blvd. 99, Aarhuc, Denmark, 8200
    Public contact
    Rehne Hansen, Ortopædkirurgisk Forskning , 0045 78450000,
    Scientific contact
    Rehne Hansen, Ortopædkirurgisk Forskning , 0045 78450000,
    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
    16 Jan 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    06 Sep 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    06 Sep 2017
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    Investigate the possibility to optimize patients' rehabilitation progress through the assessment of BMD at the OI-prosthesis and prescription of denusomab H1: BMD increases in the group Denusomab (DXA) compared to controls.
    Protection of trial subjects
    Patients were given the recommended dose of denusomab with 6 months interval and followed closely in the outpatient clinic.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    10 Oct 2013
    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
    Denmark: 6
    Worldwide total number of subjects
    6
    EEA total number of subjects
    6
    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)
    5
    From 65 to 84 years
    1
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Recruitment was based on a medical evaluation

    Pre-assignment
    Screening details
    		 Recruitment was based on a medical evaluation

    Pre-assignment period milestones
    Number of subjects started
    		 6
    Number of subjects completed
    		 6

    Period 1
    Period 1 title
    Intervention (Overall trial) (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
    		 Intervention
    Arm description
    		 The test drug was injected subcutaneously in the shoulder region using an aseptic procedure with a syringe containing 1ml of denosumab solution 60mg/ml (Prolia, Amgen)
    Arm type
    		 Experimental

    Investigational medicinal product name
    Denosumab (Prolia, Amgen)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    It was injected subcutaneously in the shoulder region using an aseptic procedure with a syringe containing 1ml denosumab solution 60mg/ml (Prolia, Amgen)

    Arm title
    		 Placebo
    Arm description
    		 The placebo drug was injected subcutaneously in the shoulder region using an aseptic procedure with a syringe containing 1ml of saline solution 9 mg/ml (Takeda Pharma
    Arm type
    		 Placebo

    Investigational medicinal product name
    Saline solution (Takeda Pharma)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    It was injected subcutaneously in the shoulder region using an aseptic procedure with a syringe containing 1ml of saline solution 9 mg/ml (Takeda Pharma)

    Number of subjects in period 1
    		Intervention Placebo
    Started
    3
    3
    Completed
    3
    3

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Intervention (Overall trial)
    Reporting group description
    		 -

    Reporting group values
    		 Intervention (Overall trial) Total
    Number of subjects
    		 6 6
    Age categorical
    Units: Subjects
        18-65
    		 6 6
    Age continuous
    Units: years
        arithmetic mean (full range (min-max))
    		 55.5 (36 to 66) -
    Gender categorical
    Units: Subjects
        Female
    		 0 0
        Male
    		 6 6
    Subject analysis sets

    Subject analysis set title
    Group difference at 18 months follow-up
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    The analysis is based on a pilot analysis, defined as reaching 18 months follow-up for three patients in each treatment arm. As the study is underpowered due to a small study population the data are analysed using 99% confidence interval (99% CI) and the significance level was set to p <0.01.

    Subject analysis sets values
    		 Group difference at 18 months follow-up
    Number of subjects
    6
    Age categorical
    Units: Subjects
        18-65
    6
    Age continuous
    Units: years
        arithmetic mean (full range (min-max))
    Gender categorical
    Units: Subjects
        Female
    0
        Male
    6

    End points

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    End points reporting groups
    Reporting group title
    Intervention
    Reporting group description
    		 The test drug was injected subcutaneously in the shoulder region using an aseptic procedure with a syringe containing 1ml of denosumab solution 60mg/ml (Prolia, Amgen)

    Reporting group title
    Placebo
    Reporting group description
    		 The placebo drug was injected subcutaneously in the shoulder region using an aseptic procedure with a syringe containing 1ml of saline solution 9 mg/ml (Takeda Pharma

    Subject analysis set title
    Group difference at 18 months follow-up
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    The analysis is based on a pilot analysis, defined as reaching 18 months follow-up for three patients in each treatment arm. As the study is underpowered due to a small study population the data are analysed using 99% confidence interval (99% CI) and the significance level was set to p <0.01.

    Primary: ROI1

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    End point title
    		 ROI1
    End point description
    End point type
    Primary
    End point timeframe
    18 months followup
    End point values
    		 Intervention Placebo Group difference at 18 months follow-up
    Number of subjects analysed
    3 [1]
    3 [2]
    6 [3]
    Units: g/cm2
        arithmetic mean (confidence interval 99%)
    0.01 (-0.69 to 0.70)
    -0.24 (-1.06 to 0.59)
    0.24 (-0.26 to 0.74)
    Notes
    [1] - 3 in intervention arm
    [2] - 3 in placebo arm
    [3] - group difference
    Statistical analysis title
    		 analysis
    Comparison groups
    Intervention v Placebo
    Number of subjects included in analysis
    6
    Analysis specification
    Pre-specified
    Analysis type
    		 other [4]
    P-value
    		 = 0.09
    Method
    		 two sample ttest
    Confidence interval
    Notes
    [4] - Normal distribution was assessed by qq-plots and equal variance was checked by f-test. Parametric data were analysed using paired t tests

    Primary: ROI2

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    End point title
    		 ROI2
    End point description
    End point type
    Primary
    End point timeframe
    18 months follow-up
    End point values
    		 Intervention Placebo Group difference at 18 months follow-up
    Number of subjects analysed
    3 [5]
    3 [6]
    Units: g/cm2
        arithmetic mean (confidence interval 99%)
    0.18 (-0.03 to 0.38)
    -0.18 (-1.55 to 1.19)
    0.35 (-0.29 to 1)
    Notes
    [5] - intervention
    [6] - placebo
    Statistical analysis title
    		 analysis roi2
    Comparison groups
    Intervention v Placebo
    Number of subjects included in analysis
    6
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.06
    Method
    		 two sample ttest
    Confidence interval

    Primary: ROI3

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    End point title
    		 ROI3
    End point description
    End point type
    Primary
    End point timeframe
    18 months follow-up
    End point values
    		 Intervention Placebo Group difference at 18 months follow-up
    Number of subjects analysed
    3 [7]
    3 [8]
    6 [9]
    Units: g/cm2
        arithmetic mean (confidence interval 99%)
    0.08 (-0.53 to 0.68)
    -0.43 (-1.55 to 0.69)
    0.51 (-0.08 to 1.10)
    Notes
    [7] - intervention
    [8] - placebo
    [9] - group difference
    Statistical analysis title
    		 analysis
    Comparison groups
    Intervention v Placebo
    Number of subjects included in analysis
    6
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.02
    Method
    		 two sample ttest
    Confidence interval

    Primary: ROI4

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    End point title
    		 ROI4
    End point description
    End point type
    Primary
    End point timeframe
    18 months follow-up
    End point values
    		 Intervention Placebo Group difference at 18 months follow-up
    Number of subjects analysed
    3 [10]
    3 [11]
    6 [12]
    Units: g/cm2
        arithmetic mean (confidence interval 99%)
    0.07 (-0.93 to 1.08)
    -0.51 (-2.06 to 1.04)
    0.58 (-0.28 to 1.44)
    Notes
    [10] - intervention
    [11] - placebo
    [12] - group difference
    Statistical analysis title
    		 analysis
    Comparison groups
    Intervention v Placebo
    Number of subjects included in analysis
    6
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.04
    Method
    		 two sample ttest
    Confidence interval

    Primary: ROI5

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    End point title
    		 ROI5
    End point description
    End point type
    Primary
    End point timeframe
    18 months follow-up
    End point values
    		 Intervention Placebo Group difference at 18 months follow-up
    Number of subjects analysed
    3 [13]
    3 [14]
    6 [15]
    Units: g/cm2
        arithmetic mean (confidence interval 99%)
    0.14 (-0.72 to 1.00)
    -0.35 (-1.66 to 0.96)
    0.49 (-0.24 to 1.22)
    Notes
    [13] - intervention
    [14] - placebo
    [15] - group difference
    Statistical analysis title
    		 analysis
    Comparison groups
    Intervention v Placebo
    Number of subjects included in analysis
    6
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.04
    Method
    		 two sample ttest
    Confidence interval

    Primary: ROI6

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    End point title
    		 ROI6
    End point description
    End point type
    Primary
    End point timeframe
    18 months follow-up
    End point values
    		 Intervention Placebo Group difference at 18 months follow-up
    Number of subjects analysed
    3 [16]
    3 [17]
    6 [18]
    Units: g/cm2
        arithmetic mean (confidence interval 99%)
    0.07 (-0.48 to 0.62)
    -0.58 (-2.23 to 1.07)
    0.65 (-0.16 to 1.45)
    Notes
    [16] - intervention
    [17] - placebo
    [18] - group difference
    Statistical analysis title
    		 analysis
    Comparison groups
    Intervention v Placebo
    Number of subjects included in analysis
    6
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.02
    Method
    		 two sample ttest
    Confidence interval

    Primary: ROI7

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    End point title
    		 ROI7
    End point description
    End point type
    Primary
    End point timeframe
    18 months follow-up
    End point values
    		 Intervention Placebo Group difference at 18 months follow-up
    Number of subjects analysed
    3 [19]
    3 [20]
    6 [21]
    Units: g/cm2
        arithmetic mean (confidence interval 99%)
    -0.19 (-0.72 to 0.34)
    -0.57 (-2.94 to 1.80)
    0.39 (-0.74 to 1.51)
    Notes
    [19] - 3 in intervention arm
    [20] - 3 in placebo arm
    [21] - group differenve
    Statistical analysis title
    		 analysis
    Comparison groups
    Intervention v Placebo
    Number of subjects included in analysis
    6
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.19
    Method
    		 two sample ttest
    Confidence interval

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    18 months
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 unknown
    Dictionary version
    x
    Reporting groups
    Reporting group title
    intervention
    Reporting group description
    		 One patient developed a large exostosis in the distal part of the residual femur a few months after S1-surgery and could not use the socket prothesis. Two weeks after the second dmab injection the patient developed ischaemia in the intact lower leg due to a popliteal aneurysm with a thrombosis and excessive arteriosclerosis in the anterior and posterior tibial artery. The patient was successfully treated with thrombolysis and vascular surgery. One patient reported pain during partial weightbearing after one year and was not able to successfully weight bear on the external prosthesis. Due to septic loosening ( staphylococcus aureus) the implant was later removed

    Reporting group title
    placebo
    Reporting group description
    		 One patient suffered an iatrogenic fissure in the distal femur bone at S1-surgery. The patient reported pain during partial weight bearing after S2 surgery which gradually improved during the following nine months. Another patient had a traumatic incident one year after S1 surgery that caused the prosthetic leg to rotate externally without releasing the safety device (OPRA AXOR II, Integrum AB, Sweden), thus the torsion was transferred to the bone-anchored fixture. Afterwards, the abutment could rotate a few degrees from side to side (bone fixation was lost), weight bearing on the implant was painful and the implant (fixture + abutment) was removed at 18-month follow-up.

    Serious adverse events
    		 intervention placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 3 (0.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Vascular disorders
    thrombosis
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 intervention placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    1 / 3 (33.33%)
    2 / 3 (66.67%)
    Musculoskeletal and connective tissue disorders
    periprosthetic changes
         subjects affected / exposed
    1 / 3 (33.33%)
    2 / 3 (66.67%)
         occurrences all number
    1
    2

    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? Yes
    Date
    Interruption
    Restart date
    01 Jun 2016
    Even though information letters regarding the project were sent to all collaborators in the primary sector of the Danish Central Region inclusion of new patients was stopped by June 2016 after a long period of no new patient referrals.
    -

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    This study was designed as a Level 1 prospective, randomised study, but only six out of 16 planned patients were included before the trial ended and the pilot analysis was conducted. Due to a small sample size the risk of type-II error pertained to t
    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.

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