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    Clinical Trial Results:
    BONATHIAD - Bone Association with Thiazide Diuretics.

    Summary
    EudraCT number
    		 2015-001059-63
    Trial protocol
    		 DK  
    Global end of trial date
    05 Mar 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    07 Oct 2020
    First version publication date
    07 Oct 2020
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    2015.009
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Aalborg University Hospital
    Sponsor organisation address
    Mølleparkvej 4, Aalborg, Denmark,
    Public contact
    Peter Vestergaard, Aalborg University, 45 99403791, pev@dcm.aau.dk
    Scientific contact
    Peter Vestergaard, Aalborg University, 45 99403791, pev@dcm.aau.dk
    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
    03 Sep 2020
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    05 Mar 2019
    Global end of trial reached?
    Yes
    Global end of trial date
    05 Mar 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To examine if bendroflumethiazide with potassium supplements augment the effect of oral bisphosphonates on preventing progression of osteoporosis.
    Protection of trial subjects
    No painful procedures were performed. The trial was overseen by licensed doctors, any discrepancies from normal results in CT or DXA scans or biochemical abnormalities led to appropriate supplementary diagnostics and treatment and the participants were referred to specialist or GP for follow-up. Results of DXA scans were communicated to the patients GPs at study end.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Sep 2015
    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: 139
    Worldwide total number of subjects
    139
    EEA total number of subjects
    139
    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)
    71
    From 65 to 84 years
    68
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Participants were recruited from the osteoporosis clinic at Aalborg University Hospital in Denmark from July 2016 to March 2018.

    Pre-assignment
    Screening details
    		 The study population included postmenopausal women over the age of 50 years with osteoporosis diagnosed using traditional dual energy x-ray absorptiometry (DXA) scans. All participants were treated with oral bisphosphonates prior to inclusion and throughout the study.

    Period 1
    Period 1 title
    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, Carer, Assessor
    Blinding implementation details
    Active and placebo tablet made to look exactly similar

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 24 wks placebo
    Arm description
    		 24 weeks placebo, 24 weeks washout
    Arm type
    		 Placebo

    Investigational medicinal product name
    placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo

    Arm title
    		 24 wks active
    Arm description
    		 24 weeks bendroflumethiazide followed by 24 weeks of washout
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Bendroflumethiazide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    2.5 mg bendroflumethiazide and 573 mg potassium chloride p.o. once daily

    Arm title
    		 48 wks active
    Arm description
    		 48 weeks bendroflumethiazide
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Bendroflumethiazide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    2.5 mg bendroflumethiazide and 573 mg potassium chloride p.o. once daily

    Arm title
    		 48 wks placebo
    Arm description
    		 Placebo for 48 weeks
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo

    Number of subjects in period 1
    		24 wks placebo 24 wks active 48 wks active 48 wks placebo
    Started
    27
    25
    44
    43
    Completed
    17
    23
    35
    34
    Not completed
    10
    2
    9
    9
         Lost to follow-up
    10
    2
    9
    9

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    24 wks placebo
    Reporting group description
    		 24 weeks placebo, 24 weeks washout

    Reporting group title
    24 wks active
    Reporting group description
    		 24 weeks bendroflumethiazide followed by 24 weeks of washout

    Reporting group title
    48 wks active
    Reporting group description
    		 48 weeks bendroflumethiazide

    Reporting group title
    48 wks placebo
    Reporting group description
    		 Placebo for 48 weeks

    Reporting group values
    		 24 wks placebo 24 wks active 48 wks active 48 wks placebo Total
    Number of subjects
    		 27 25 44 43 139
    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)
    		 65.0 ± 1.3 63.7 ± 1.5 65.0 ± 1.0 64.9 ± 1.1 -
    Gender categorical
    Units: Subjects
        Female
    		 27 25 44 43 139
        Male
    		 0 0 0 0 0

    End points

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    End points reporting groups
    Reporting group title
    24 wks placebo
    Reporting group description
    		 24 weeks placebo, 24 weeks washout

    Reporting group title
    24 wks active
    Reporting group description
    		 24 weeks bendroflumethiazide followed by 24 weeks of washout

    Reporting group title
    48 wks active
    Reporting group description
    		 48 weeks bendroflumethiazide

    Reporting group title
    48 wks placebo
    Reporting group description
    		 Placebo for 48 weeks

    Primary: Change in femoral neck BMD after 48 weeks

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    End point title
    		 Change in femoral neck BMD after 48 weeks
    End point description
    Change in femoral neck BMD from baseline to 48 weeks
    End point type
    Primary
    End point timeframe
    48 weeks
    End point values
    		 24 wks placebo 24 wks active 48 wks active 48 wks placebo
    Number of subjects analysed
    17
    23
    35
    34
    Units: Femoral neck BMD
        arithmetic mean (standard error)
    0.016 ± 0.0034
    0.0086 ± 0.0043
    -0.00035 ± 0.0046
    0.012 ± 0.004
    Statistical analysis title
    		 t test
    Comparison groups
    24 wks placebo v 24 wks active v 48 wks active v 48 wks placebo
    Number of subjects included in analysis
    109
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 < 5
    Method
    		 ANOVA
    Parameter type
    		 Mean difference (final values)
    Confidence interval

    Primary: Change in total hip BMD after 48 weeks

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    End point title
    		 Change in total hip BMD after 48 weeks
    End point description
    Change in total hip BMD after 48 weeks
    End point type
    Primary
    End point timeframe
    48 weeks
    End point values
    		 24 wks placebo 24 wks active 48 wks active 48 wks placebo
    Number of subjects analysed
    17
    23
    35
    34
    Units: Total hip BMd (g/cm2)
        arithmetic mean (standard error)
    0.012 ± 0.0039
    0.0081 ± 0.0035
    0.0066 ± 0.0096
    0.011 ± 0.0028
    Statistical analysis title
    		 ANOVA
    Comparison groups
    24 wks placebo v 24 wks active v 48 wks active v 48 wks placebo
    Number of subjects included in analysis
    109
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 < 5
    Method
    		 ANOVA
    Confidence interval

    Primary: Change in lumber spine BMD (g/cm2) 48 weeks

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    End point title
    		 Change in lumber spine BMD (g/cm2) 48 weeks
    End point description
    Change in lumbar spine BMD from baseline to 48 weeks
    End point type
    Primary
    End point timeframe
    48 weeks
    End point values
    		 24 wks placebo 24 wks active 48 wks active 48 wks placebo
    Number of subjects analysed
    17
    23
    35
    34
    Units: Change in lumbar spine BMD
        arithmetic mean (standard error)
    0.015 ± 0.0087
    0.015 ± 0.0075
    0.020 ± 0.006
    0.016 ± 0.0055
    Statistical analysis title
    		 ANOVA
    Comparison groups
    24 wks placebo v 24 wks active v 48 wks active v 48 wks placebo
    Number of subjects included in analysis
    109
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 < 5
    Method
    		 ANOVA
    Parameter type
    		 Mean difference (final values)
    Confidence interval

    Primary: Change in lumbar spine QCT 48 weeks

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    End point title
    		 Change in lumbar spine QCT 48 weeks
    End point description
    Change from baseline to 48 weeks in lumbar spine QCT (mg/cm3)
    End point type
    Primary
    End point timeframe
    48 weeks
    End point values
    		 24 wks placebo 24 wks active 48 wks active 48 wks placebo
    Number of subjects analysed
    17
    23
    35
    34
    Units: Change in spine QCT (mg/cm3) at 48 weeks
        arithmetic mean (standard error)
    0.07 ± 0.2
    -0.1 ± 0.1
    3.26 ± 1.63
    -3.55 ± 2.01
    Statistical analysis title
    		 ANOVA
    Comparison groups
    24 wks placebo v 24 wks active v 48 wks active v 48 wks placebo
    Number of subjects included in analysis
    109
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 < 5
    Method
    		 ANOVA
    Confidence interval

    Primary: Change in femoral neck QCT (mg/cm3)at 48 weeks

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    End point title
    		 Change in femoral neck QCT (mg/cm3)at 48 weeks
    End point description
    Change in femoral neck QCT from baseline to 48 weeks in femoral neck QCT (mg/cm3)
    End point type
    Primary
    End point timeframe
    48 weeks
    End point values
    		 24 wks placebo 24 wks active 48 wks active 48 wks placebo
    Number of subjects analysed
    17
    23
    35
    34
    Units: Change in femoral neck QCT (mg/cm3)
        arithmetic mean (standard error)
    0.0093 ± 0.0096
    0.011 ± 0.019
    0.0059 ± 0.010
    0.0022 ± 0.0018
    Statistical analysis title
    		 ANOVA
    Comparison groups
    24 wks placebo v 24 wks active v 48 wks active v 48 wks placebo
    Number of subjects included in analysis
    109
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 < 5
    Method
    		 ANOVA
    Parameter type
    		 Mean difference (final values)
    Confidence interval

    Secondary: Change in serum sodium 48 weeks

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    End point title
    		 Change in serum sodium 48 weeks
    End point description
    Change in serum sodium from baseline to 48 weeks (mmol/l)
    End point type
    Secondary
    End point timeframe
    48 weeks
    End point values
    		 24 wks placebo 24 wks active 48 wks active 48 wks placebo
    Number of subjects analysed
    17
    23
    35
    34
    Units: Change in serum sodium 48 weeks
        arithmetic mean (standard error)
    0.2 ± 0.4
    0.4 ± 0.6
    -0.08 ± 0.6
    -0.1 ± 0.4
    No statistical analyses for this end point

    Secondary: change in serum calcium 48 weeks

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    End point title
    		 change in serum calcium 48 weeks
    End point description
    End point type
    Secondary
    End point timeframe
    Change in serum albumin adjusted calcium from baseline to 48 weeks (mmol/l)
    End point values
    		 24 wks placebo 24 wks active 48 wks active 48 wks placebo
    Number of subjects analysed
    17
    23
    35
    34
    Units: change in serum calcium 48 weeks
        arithmetic mean (standard error)
    -0.02 ± 0.02
    0.0007 ± 0.03
    0.02 ± 0.02
    -0.003 ± 0.02
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    48 weeks
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 SNOMED CT
    Dictionary version
    1
    Reporting groups
    Reporting group title
    48 weeks active
    Reporting group description
    		 -

    Reporting group title
    48 weeks placebo
    Reporting group description
    		 -

    Reporting group title
    24 weeks placebo, 24 weeks washout
    Reporting group description
    		 -

    Reporting group title
    24 weeks active, 24 weeks washout
    Reporting group description
    		 -

    Serious adverse events
    		 48 weeks active 48 weeks placebo 24 weeks placebo, 24 weeks washout 24 weeks active, 24 weeks washout
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 43 (0.00%)
    0 / 27 (0.00%)
    0 / 25 (0.00%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 48 weeks active 48 weeks placebo 24 weeks placebo, 24 weeks washout 24 weeks active, 24 weeks washout
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    1 / 44 (2.27%)
    1 / 43 (2.33%)
    1 / 27 (3.70%)
    1 / 25 (4.00%)
    Infections and infestations
    Influenza
         subjects affected / exposed
    1 / 44 (2.27%)
    1 / 43 (2.33%)
    1 / 27 (3.70%)
    1 / 25 (4.00%)
         occurrences all number
    1
    1
    1
    1

    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
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    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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