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    Clinical Trial Results:
    The use of buffered soluble alendronate 70 mg (Steovess/Binosto) after denosumab discontinuation to prevent increase in bone turnover.

    Summary
    EudraCT number
    		 2019-003570-11
    Trial protocol
    		 BE  
    Global end of trial date
    09 Mar 2023

    Results information
    Results version number
    		 v1(current)
    This version publication date
    19 Apr 2024
    First version publication date
    19 Apr 2024
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    BC-6072
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Ghent University Hospital
    Sponsor organisation address
    Corneel Heymanslaan 10, Ghent, Belgium,
    Public contact
    HIRUZ, Ghent University Hospital, +32 93320500, hiruz.ctu@uzgent.be
    Scientific contact
    HIRUZ, Ghent University Hospital, +32 93320500, hiruz.ctu@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
    12 Jan 2024
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    09 Mar 2022
    Global end of trial reached?
    Yes
    Global end of trial date
    09 Mar 2023
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To investigate if weekly intake of 70mg effervescent alendronate can prevent increases in bone turnover above the premenopausal reference range
    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
    13 Nov 2019
    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: 30
    Worldwide total number of subjects
    30
    EEA total number of subjects
    30
    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)
    16
    From 65 to 84 years
    14
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 This is an open label extension study with patients from a RCT with denosumab (EUDRACT CT 2015-003223-53) aiming to show efficacy in erosive hand osteoarthritis. At the end of this former trial, patients were given given the opportunity to enter this current study after having received denosumab 60mg every 3 months for 2 or 3 years.

    Pre-assignment
    Screening details
    		 Exclusion criteria were: presence of hypocalcaemia, presence or history of severe gastro-intestinal disease including ulcers bleedings or oesophagus abnormalities, pregnancy or breast-feeding, hypersensitivity to any components of effervescent alendronate and history of osteonecrosis of the jaw and/or recent or upcoming tooth extraction

    Period 1
    Period 1 title
    The Use of Steovess after Denosumab (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Investigator, Subject

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Alendronate 24 weeks
    Arm description
    		 Subjects receiving alendronate treatment for 24 weeks (n = 15)
    Arm type
    		 Experimental

    Investigational medicinal product name
    Steovess/Binosto
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects will receive weekly 70mg effervescent alendronate [Steovess 70mg/weekly] for 24 or 48 weeks. All subjects will receive Calcium/vit D supplementation.

    Arm title
    		 Alendronate 48 weeks
    Arm description
    		 Subjects receiving alendronate treatment for 48 weeks (n = 15)
    Arm type
    		 Experimental

    Investigational medicinal product name
    Steovess/Binosto
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects will receive weekly 70mg effervescent alendronate [Steovess 70mg/weekly] for 24 or 48 weeks. All subjects will receive Calcium/vit D supplementation.

    Number of subjects in period 1
    		Alendronate 24 weeks Alendronate 48 weeks
    Started
    15
    15
    Completed
    13
    13
    Not completed
    2
    2
         Adverse event, non-fatal
    1
    1
         Lost to follow-up
    1
    -
         Protocol deviation
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Alendronate 24 weeks
    Reporting group description
    		 Subjects receiving alendronate treatment for 24 weeks (n = 15)

    Reporting group title
    Alendronate 48 weeks
    Reporting group description
    		 Subjects receiving alendronate treatment for 48 weeks (n = 15)

    Reporting group values
    		 Alendronate 24 weeks Alendronate 48 weeks Total
    Number of subjects
    		 15 15 30
    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
        median (standard deviation)
    		 63.3 ± 7.7 64.7 ± 8.9 -
    Gender categorical
    Units: Subjects
        Female
    		 12 11 23
        Male
    		 3 4 7
    Mean treatment duration with denosumab
    Mean treatment duration with denosumab (days)
    Units: days
        arithmetic mean (standard deviation)
    		 813 ± 165 751 ± 174 -
    Mean time since last denosumab injection
    Mean time since last denosumab injection (days)
    Units: Days
        arithmetic mean (standard deviation)
    		 89 ± 7 94 ± 8 -
    PINP
    Bone marker PINP
    Units: microgram/L
        arithmetic mean (standard deviation)
    		 10.15 ± 5.5 8.97 ± 10.6 -
    CTX-I
    Bone turnover marker CTX-I
    Units: ng/ml
        arithmetic mean (standard deviation)
    		 0.057 ± 0.03 0.071 ± 0.06 -
    Bone mineral density hip
    Bone mineral density hip (g/cm2)
    Units: g/cm2
        arithmetic mean (standard deviation)
    		 0.85 ± 0.10 0.80 ± 0.08 -
    Bone mineral density spine
    Bone mineral density spine (g/cm2)
    Units: g/cm2
        arithmetic mean (standard deviation)
    		 1.16 ± 0.11 1.11 ± 0.16 -

    End points

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    End points reporting groups
    Reporting group title
    Alendronate 24 weeks
    Reporting group description
    		 Subjects receiving alendronate treatment for 24 weeks (n = 15)

    Reporting group title
    Alendronate 48 weeks
    Reporting group description
    		 Subjects receiving alendronate treatment for 48 weeks (n = 15)

    Primary: CTX Bone Turnover Marker Levels

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    End point title
    		 CTX Bone Turnover Marker Levels
    End point description
    Difference in bone turnover marker (CTX-I) after 48 weeks. Comparisons made within and between both treatment arms
    End point type
    Primary
    End point timeframe
    48 weeks
    End point values
    		 Alendronate 24 weeks Alendronate 48 weeks
    Number of subjects analysed
    15
    15
    Units: ng/ml
        geometric mean (standard error)
    0.63 ± 0.33
    0.33 ± 0.33
    Statistical analysis title
    		 Linear mixed model
    Statistical analysis description
    linear mixed models were used to compare bone turnover markers (CTX-I) between both treatment groups. These models were performed with an intention to treat approach, where drop-outs were considered as non-responders. The models accounted for repeated measures.
    Comparison groups
    Alendronate 24 weeks v Alendronate 48 weeks
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.01
    Method
    		 Mixed models analysis
    Parameter type
    		 estimated marginal mean
    Point estimate
    -0.31
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.53
         upper limit
    		 -0.09
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.11

    Primary: PINP bone turnover marker levels

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    End point title
    		 PINP bone turnover marker levels
    End point description
    Difference in Bone Turnover Marker (PINP) After 48 Weeks. Comparisons are made both within and between both treatment arms.
    End point type
    Primary
    End point timeframe
    48 weeks
    End point values
    		 Alendronate 24 weeks Alendronate 48 weeks
    Number of subjects analysed
    15
    15
    Units: microgram/L
        geometric mean (standard error)
    78.9 ± 0.44
    39.5 ± 0.44
    Statistical analysis title
    		 Linear mixed model
    Statistical analysis description
    linear mixed models were used to compare bone turnover markers (PINP) between both treatment groups. These models were performed with an intention to treat approach, where drop-outs were considered as non-responders. The models accounted for repeated measures.
    Comparison groups
    Alendronate 24 weeks v Alendronate 48 weeks
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.05
    Method
    		 Mixed models analysis
    Parameter type
    		 estimated marginal mean
    Point estimate
    -1.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.37
         upper limit
    		 -0.43
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.75

    Secondary: The number of patients with CTXI levels above the reference range at week 48

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    End point title
    		 The number of patients with CTXI levels above the reference range at week 48
    End point description
    48 weeks
    End point type
    Secondary
    End point timeframe
    The number of patients that do not maintain CTx-I levels within the bone turnover marker reference range at week 48.
    End point values
    		 Alendronate 24 weeks Alendronate 48 weeks
    Number of subjects analysed
    15
    15
    Units: patients
    5
    0
    Statistical analysis title
    		 Fisher's exact test
    Statistical analysis description
    A Fisher’s exact test was used to assess differences in patient numbers exceeding reference ranges between both treatment groups at week 48.
    Comparison groups
    Alendronate 24 weeks v Alendronate 48 weeks
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.042
    Method
    		 Fisher exact
    Confidence interval

    Secondary: The Number of Patients with PINP levels Above Reference Range at Week 48

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    End point title
    		 The Number of Patients with PINP levels Above Reference Range at Week 48
    End point description
    The number of patients that do not maintain PINP levels within the bone turnover marker reference range at week 48
    End point type
    Secondary
    End point timeframe
    48 weeks
    End point values
    		 Alendronate 24 weeks Alendronate 48 weeks
    Number of subjects analysed
    15
    15
    Units: patients
    5
    0
    Statistical analysis title
    		 Fisher's exact test
    Statistical analysis description
    A Fisher’s exact test was used to assess differences in patient numbers exceeding reference ranges between both treatment groups.
    Comparison groups
    Alendronate 24 weeks v Alendronate 48 weeks
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.042
    Method
    		 Fisher exact
    Confidence interval

    Secondary: Bone Mass Density at the Spine After 48 Weeks

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    End point title
    		 Bone Mass Density at the Spine After 48 Weeks
    End point description
    Difference in Bone Mass Density at the hip After 48 Weeks. Comparisons are made both within and between both treatment arms.
    End point type
    Secondary
    End point timeframe
    48 weeks
    End point values
    		 Alendronate 24 weeks Alendronate 48 weeks
    Number of subjects analysed
    15
    15
    Units: g/cm2
        geometric mean (standard error)
    1.10 ± 0.03
    1.11 ± 0.03
    Statistical analysis title
    		 Linear mixed model
    Comparison groups
    Alendronate 24 weeks v Alendronate 48 weeks
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 estimated marginal mean
    Point estimate
    0.05
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.03
         upper limit
    		 0.07
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.01

    Secondary: Bone Mass Density at the Hip After 48 Weeks

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    End point title
    		 Bone Mass Density at the Hip After 48 Weeks
    End point description
    Difference in Bone Mass Density at the hip After 48 Weeks. Comparisons are made both within and between both treatment arms.
    End point type
    Secondary
    End point timeframe
    48 weeks
    End point values
    		 Alendronate 24 weeks Alendronate 48 weeks
    Number of subjects analysed
    15
    15
    Units: g/cm2
        geometric mean (standard error)
    0.85 ± 0.03
    0.81 ± 0.03
    Statistical analysis title
    		 Linear mixed model
    Comparison groups
    Alendronate 48 weeks v Alendronate 24 weeks
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.68
    Method
    		 Mixed models analysis
    Parameter type
    		 estimated marginal mean
    Point estimate
    0.007
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.032
         upper limit
    		 0.046
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.02

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events data was collected during the 48 weeks of the trial duration.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    25
    Reporting groups
    Reporting group title
    Alendronate 24 weeks
    Reporting group description
    		 -

    Reporting group title
    Alendronate 48 weeks
    Reporting group description
    		 -

    Serious adverse events
    		 Alendronate 24 weeks Alendronate 48 weeks
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 15 (0.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Gastrointestinal disorders
    Colonic ulcers
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 15 (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: 0%
    Non-serious adverse events
    		 Alendronate 24 weeks Alendronate 48 weeks
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    10 / 15 (66.67%)
    12 / 15 (80.00%)
    Cardiac disorders
    Cardiovascular event
    Additional description: Cardiovascular events like atrial fibrillation, arterial hypertension
         subjects affected / exposed
    2 / 15 (13.33%)
    2 / 15 (13.33%)
         occurrences all number
    3
    2
    Nervous system disorders
    Nervous system events
    Additional description: Adverse events affecting the nervous system mostly including Dizziness and headache
         subjects affected / exposed
    3 / 15 (20.00%)
    1 / 15 (6.67%)
         occurrences all number
    3
    1
    General disorders and administration site conditions
    General malaise
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Ear and labyrinth disorders
    Ear nose throat events
    Additional description: Averse events effection the ear, nose and throat mainly including throat pain and tinnitus
         subjects affected / exposed
    1 / 15 (6.67%)
    1 / 15 (6.67%)
         occurrences all number
    1
    1
    Eye disorders
    Eye events
    Additional description: Adverse events affecting the eye including swollen eyes, dry eyes and blurry vision
         subjects affected / exposed
    1 / 15 (6.67%)
    2 / 15 (13.33%)
         occurrences all number
    1
    2
    Gastrointestinal disorders
    Gastro-intestinal events
    Additional description: Gastro-intestinal adverse events including stomach pain, diarrhoa, loss of appetite, nausea,..
         subjects affected / exposed
    5 / 15 (33.33%)
    6 / 15 (40.00%)
         occurrences all number
    9
    8
    Respiratory, thoracic and mediastinal disorders
    Pulmonary events
    Additional description: Pulmonary adverse events mainly including cough symptoms (non-infectious)
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Skin and subcutaneous tissue disorders
    Dermatologic events
    Additional description: Dermatologic events affecting skin and hair mainly including itch and alopecia
         subjects affected / exposed
    1 / 15 (6.67%)
    1 / 15 (6.67%)
         occurrences all number
    1
    1
    Musculoskeletal and connective tissue disorders
    Musculoskeletal events
    Additional description: Musculoskeletal adverse events including muscular and joint pain. No bone fractures were reported.
         subjects affected / exposed
    4 / 15 (26.67%)
    5 / 15 (33.33%)
         occurrences all number
    6
    8
    Infections and infestations
    Infections
    Additional description: mostly being upper airway infections
         subjects affected / exposed
    3 / 15 (20.00%)
    4 / 15 (26.67%)
         occurrences all number
    3
    7

    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.
    The target number of participants was not reached and therefore underpowered. The study should be repeated on a higher number of participants and with a longer follow-up time to estimate clinical consequences on long term.
    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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