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    Clinical Trial Results:
    RANKL-blockade for the treatment of erosive osteoarthritis (OA) of interphalangeal finger joints Randomized, double blind, placebo-controlled study to evaluate the efficacy of denosumab 60mg sc every 3 months in patients with erosive osteoarthritis of the interphalangeal finger joints

    Summary
    EudraCT number
    		 2015-003223-53
    Trial protocol
    		 BE  
    Global end of trial date
    28 Apr 2021

    Results information
    Results version number
    		 v1(current)
    This version publication date
    08 Aug 2024
    First version publication date
    08 Aug 2024
    Other versions
    Summary report(s)
    		 Final Study Report

    Trial information

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    Trial identification
    Sponsor protocol code
    AGO/2015/008
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01575873
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    UZ Gent
    Sponsor organisation address
    Corneel Heymanslaan 10, Gent, Belgium, 9000
    Public contact
    Bimetra Clinics, Ghent University Hospital, +32 93320500, bimetra.clinics@uzgent.be
    Scientific contact
    Bimetra Clinics, Ghent University Hospital, +32 93320500, bimetra.clinics@uzgent.be
    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
    11 Apr 2022
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    28 Apr 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess the effect of denosumab on the reduction of radiographic erosive progression using GUSS™ (Ghent University Score System).
    Protection of trial subjects
    Ethics review and approval, informed consent, supportive care and routine monitoring.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    30 Mar 2016
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Belgium: 100
    Worldwide total number of subjects
    100
    EEA total number of subjects
    100
    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)
    60
    From 65 to 84 years
    40
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 136 patients were screened in the period from 30/03/2016 till 04/07/2018. 100 patients were included, 100 patients were randomised. 87 patients were included and completed the trial. End of trial notification was dated 28/04/2021 (last patient last visit) and submitted to EC and CA 25/05/2021

    Pre-assignment
    Screening details
    		 Main in- and exclusioncriteria

    Period 1
    Period 1 title
    Placebo controlled phase
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 patients allocated to placebo
    Arm description
    		 Patients received every 3 months placebo for denosumab in identical containers and stored/packaged the same as drug product denosumab.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Placebo for Denosumab will be presented in identical containers and stored/packaged the same as drug product denosumab.

    Arm title
    		 patient allocated to denosumab
    Arm description
    		 Patients were treated with blinded study medication containing 60 mg denosimab subcutaneously every 3 months.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Denosumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    The study drug used in this arm is denosumab 60 mg subcutaneously every 3 months. It was provided as sterile, solution for injection in 1 ml pre-filled syringes containing denosumab 60mg/ ml

    Number of subjects in period 1
    		patients allocated to placebo patient allocated to denosumab
    Started
    49
    51
    Completed
    46
    46
    Not completed
    3
    5
         Consent withdrawn by subject
    -
    1
         Adverse event, non-fatal
    3
    3
         Protocol deviation
    -
    1
    Period 2
    Period 2 title
    Open label phase
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Open label arm
    Arm description
    		 All patients were treated with denosumab 60mg subcutaneous every 3 months
    Arm type
    		 Experimental

    Investigational medicinal product name
    Denosumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled pen
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    The study drug used in open label phase is denosumab 60 mg subcutaneously every 3 months. It will be provided as sterile, solution for injection in 1 ml pre-filled syringes containing denosumab 60mg/ ml

    Number of subjects in period 2
    		Open label arm
    Started
    92
    Completed
    87
    Not completed
    5
         Consent withdrawn by subject
    5

    Baseline characteristics

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    End points

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    End points reporting groups
    Reporting group title
    patients allocated to placebo
    Reporting group description
    		 Patients received every 3 months placebo for denosumab in identical containers and stored/packaged the same as drug product denosumab.

    Reporting group title
    patient allocated to denosumab
    Reporting group description
    		 Patients were treated with blinded study medication containing 60 mg denosimab subcutaneously every 3 months.
    Reporting group title
    Open label arm
    Reporting group description
    		 All patients were treated with denosumab 60mg subcutaneous every 3 months

    Primary: Primary radiographic efficacy endpoint

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    End point title
    		 Primary radiographic efficacy endpoint
    End point description
    End point type
    Primary
    End point timeframe
    Change in total GUSS in the denosumab group compared to the placebo group at week 24.
    End point values
    		 patients allocated to placebo patient allocated to denosumab
    Number of subjects analysed
    49
    51
    Units: Incidence of new erosive joints
        number (not applicable)
    5.1
    2.3
    Statistical analysis title
    		 ITT approach on the FAS population
    Statistical analysis description
    Changes in GUSS (Ghent University Score System) will be analyzed at joint level with generalized estimating equations (GEE), accounting for within-patient clustering. Robust standard errors will be used and the working correlation structure specified exchangeable. Data from baseline, week 12 and week 24 will be used. The independent variables included in the model are treatment group, visit number, interaction between treatment group and visit number, and the baseline value of dependent variable
    Comparison groups
    patients allocated to placebo v patient allocated to denosumab
    Number of subjects included in analysis
    100
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority
    P-value
    		 < 0.05 [1]
    Method
    		 t-test, 2-sided
    Confidence interval
    Notes
    [1] - Allefficacy analyses will be presented by a point estimate of the difference between the treatment groups, with a 95% confidence interval (95%CI) and the two-sided p-value. A p-value below 0.05 (p<0.05) will be considered statistically significant.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events were reported between the first dose administration of trial medication and the last trial related activity.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    25
    Reporting groups
    Reporting group title
    patients allocated to placebo
    Reporting group description
    		 -

    Reporting group title
    patients allocated to denosumab
    Reporting group description
    		 -

    Reporting group title
    Open label group
    Reporting group description
    		 -

    Serious adverse events
    		 patients allocated to placebo patients allocated to denosumab Open label group
    Total subjects affected by serious adverse events
         subjects affected / exposed
    6 / 49 (12.24%)
    5 / 51 (9.80%)
    9 / 92 (9.78%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Cancer
         subjects affected / exposed
    3 / 49 (6.12%)
    0 / 51 (0.00%)
    0 / 92 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Acute Coronary Syndrome
         subjects affected / exposed
    0 / 49 (0.00%)
    1 / 51 (1.96%)
    0 / 92 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Surgical and medical procedures
    Surgical and medical procedures
         subjects affected / exposed
    1 / 49 (2.04%)
    3 / 51 (5.88%)
    3 / 92 (3.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Confusional state
         subjects affected / exposed
    0 / 49 (0.00%)
    0 / 51 (0.00%)
    1 / 92 (1.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Gastrointestinal disorder
         subjects affected / exposed
    0 / 49 (0.00%)
    0 / 51 (0.00%)
    1 / 92 (1.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Cystopexie
         subjects affected / exposed
    1 / 49 (2.04%)
    0 / 51 (0.00%)
    0 / 92 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Musculoskeletal complaints
         subjects affected / exposed
    1 / 49 (2.04%)
    2 / 51 (3.92%)
    5 / 92 (5.43%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Infections
         subjects affected / exposed
    1 / 49 (2.04%)
    1 / 51 (1.96%)
    0 / 92 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 patients allocated to placebo patients allocated to denosumab Open label group
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    46 / 49 (93.88%)
    44 / 51 (86.27%)
    80 / 92 (86.96%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Benign melanoma
         subjects affected / exposed
    1 / 49 (2.04%)
    0 / 51 (0.00%)
    0 / 92 (0.00%)
         occurrences all number
    1
    0
    0
    Vascular disorders
    Vascular disorders
         subjects affected / exposed
    1 / 49 (2.04%)
    0 / 51 (0.00%)
    4 / 92 (4.35%)
         occurrences all number
    1
    0
    4
    Surgical and medical procedures
    Surgical and medical procedures
         subjects affected / exposed
    4 / 49 (8.16%)
    1 / 51 (1.96%)
    5 / 92 (5.43%)
         occurrences all number
    4
    1
    5
    Teeth problems
         subjects affected / exposed
    4 / 49 (8.16%)
    3 / 51 (5.88%)
    12 / 92 (13.04%)
         occurrences all number
    7
    3
    16
    Immune system disorders
    Immune system disorders
         subjects affected / exposed
    1 / 49 (2.04%)
    1 / 51 (1.96%)
    2 / 92 (2.17%)
         occurrences all number
    1
    1
    2
    Reproductive system and breast disorders
    Reproductive system
         subjects affected / exposed
    1 / 49 (2.04%)
    1 / 51 (1.96%)
    1 / 92 (1.09%)
         occurrences all number
    1
    1
    1
    Respiratory, thoracic and mediastinal disorders
    Respiratory and thoracic disorders
         subjects affected / exposed
    21 / 49 (42.86%)
    20 / 51 (39.22%)
    27 / 92 (29.35%)
         occurrences all number
    30
    27
    37
    Psychiatric disorders
    depression
         subjects affected / exposed
    0 / 49 (0.00%)
    1 / 51 (1.96%)
    1 / 92 (1.09%)
         occurrences all number
    0
    1
    1
    Cardiac disorders
    cardiac disorders
         subjects affected / exposed
    3 / 49 (6.12%)
    1 / 51 (1.96%)
    4 / 92 (4.35%)
         occurrences all number
    3
    1
    4
    Nervous system disorders
    Nervous system disorder
         subjects affected / exposed
    12 / 49 (24.49%)
    5 / 51 (9.80%)
    6 / 92 (6.52%)
         occurrences all number
    18
    6
    10
    Blood and lymphatic system disorders
    Blood and lymphatic system disorders
         subjects affected / exposed
    1 / 49 (2.04%)
    0 / 51 (0.00%)
    5 / 92 (5.43%)
         occurrences all number
    4
    0
    5
    Ear and labyrinth disorders
    Ear disorders
         subjects affected / exposed
    2 / 49 (4.08%)
    2 / 51 (3.92%)
    0 / 92 (0.00%)
         occurrences all number
    2
    2
    0
    Eye disorders
    Eye disorders
         subjects affected / exposed
    3 / 49 (6.12%)
    0 / 51 (0.00%)
    6 / 92 (6.52%)
         occurrences all number
    5
    0
    9
    Gastrointestinal disorders
    Gastrointestinal disorders
         subjects affected / exposed
    10 / 49 (20.41%)
    12 / 51 (23.53%)
    8 / 92 (8.70%)
         occurrences all number
    12
    14
    8
    Hepatobiliary disorders
    Hepatobiliary disorders
         subjects affected / exposed
    1 / 49 (2.04%)
    0 / 51 (0.00%)
    5 / 92 (5.43%)
         occurrences all number
    1
    0
    5
    Skin and subcutaneous tissue disorders
    Skin and subcutaneous disorders
         subjects affected / exposed
    2 / 49 (4.08%)
    6 / 51 (11.76%)
    8 / 92 (8.70%)
         occurrences all number
    3
    6
    8
    Renal and urinary disorders
    Renal and urinary disorders
         subjects affected / exposed
    3 / 49 (6.12%)
    4 / 51 (7.84%)
    5 / 92 (5.43%)
         occurrences all number
    9
    9
    11
    Endocrine disorders
    Endocrine disorders
         subjects affected / exposed
    0 / 49 (0.00%)
    1 / 51 (1.96%)
    1 / 92 (1.09%)
         occurrences all number
    0
    1
    1
    Musculoskeletal and connective tissue disorders
    Musculoskeletal and connective tissue disorders
         subjects affected / exposed
    22 / 49 (44.90%)
    17 / 51 (33.33%)
    38 / 92 (41.30%)
         occurrences all number
    40
    26
    55
    Infections and infestations
    Infections ans infestations
         subjects affected / exposed
    8 / 49 (16.33%)
    6 / 51 (11.76%)
    17 / 92 (18.48%)
         occurrences all number
    8
    7
    17

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    16 Feb 2016
    This amendment considers an administrative error and is considered to be not substantial. The overall reason for the amendment: The overall reason for the amendment is based upon standard clinical practice and patients’ best interest. No new exams will be added only the time points of the exams will be changed.
    17 Oct 2018
    The overall reason for the amendment: The overall reason for the amendment is based upon the request for a study extension with another 48 weeks.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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