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    Clinical Trial Results:
    Zoledronic acid in the management of malignant pleural mesothelioma - a feasibility study

    Summary
    EudraCT number
    		 2015-004433-26
    Trial protocol
    		 GB  
    Global end of trial date
    24 Jul 2018

    Results information
    Results version number
    		 v1(current)
    This version publication date
    07 Aug 2019
    First version publication date
    07 Aug 2019
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    3638
    Additional study identifiers
    ISRCTN number
    		 ISRCTN45536692
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    North Bristol NHS Trust
    Sponsor organisation address
    Learning and Research , Bristol, United Kingdom,
    Public contact
    Duneesha de Fonseka, North Bristol NHS Trust, 0044 1174148041, duneesha.defonseka@sth.nhs.uk
    Scientific contact
    Duneesha de Fonseka, North Bristol NHS Trust, 0044 1174148041, duneesha.defonseka@sth.nhs.uk
    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
    24 Jul 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    24 May 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    24 Jul 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    As this is a feasibility study there are no primary or secondary objectives to the trial. The overarching question is whether it would be feasible to run a full trial to determine if the addition of Zoledronic acid to 1st line chemotherapy would confer a further benefit to patients with mesothelioma, with regards to survival. The feasibility of this trial will be assessed along the following criteria: 1. Feasibility of randomising 50 patients in 12 months 2. Acceptability of recruitment procedures, consent and randomisation, and data collection methods 3. Acceptability of ZA in MPM patients, and the optimal timing and location for ZA administration 4. Qualitative assessment in a subgroup of 10 patients (from the randomised and non-randomised groups) to evaluate patients' experience 5. Quantification of drop-out and data completeness rates 6. Estimates of outcome event rates eg survival times, measures of mean response and outcome variance to use for calculating full trial size
    Protection of trial subjects
    Patients must be well enough to be eligible for first line chemotherapy to be considered for inclusion into the trial. Calcium levels and possible side effects are monitored regularly throughout trial participation. The Trial Steering Committee meets regularly and the Independent Data Safety Monitoring Committee report dated 05/09/2017 concluded that “neither expert clinical appraisal of adverse event details nor statistical analysis indicates a higher risk of an adverse or serious adverse event (or either) associated with one treatment group”. As well as an information sheet outlining potential side effects and an emergency contact card with details of what to do in an emergency, patients were provided with an appointments schedule to help patients manage their varying chemotherapy, trial visits and scans which occurred in different locations. This included further contact details for the various appointments.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    30 Sep 2016
    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
    United Kingdom: 22
    Worldwide total number of subjects
    22
    EEA total number of subjects
    22
    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)
    2
    From 65 to 84 years
    18
    85 years and over
    2

    Subject disposition

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    Recruitment
    Recruitment details
    		 The recruitment period took place 30/09/2016 to 03/11/2017 in the UK.

    Pre-assignment
    Screening details
    		 Patients with a diagnosis of mesothelioma eligible for first line chemotherapy are potential candidates for this trial. 47 assessed for eligibility 25 excluded (15 did not meet screening criteria, 10 declined to participate) 22 consented (15 to RCT, 7 to open label arm)

    Period 1
    Period 1 title
    Baseline
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 zoledronic acid
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    zoledronic acid
    Investigational medicinal product code
    Other name
    Zometa 4 mg/5 ml concentrate for solution for infusion
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    4 mg/5 ml concentrate for solution for infusion every 3 weeks alongside chemotherapy for a maximum of 6 cycles

    Arm title
    		 Placebo
    Arm description
    		 -
    Arm type
    		 Placebo

    Investigational medicinal product name
    Saline
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    100ml 0.9% Saline infusion administered every 3 weeks alongside chemotherapy

    Arm title
    		 Open label arm
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    zoledronic acid
    Investigational medicinal product code
    Other name
    Zometa 4 mg/5 ml concentrate for solution for infusion
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    4 mg/5 ml concentrate for solution for infusion every 3 weeks for a maximum of 6 cycles

    Number of subjects in period 1
    		zoledronic acid Placebo Open label arm
    Started
    7
    8
    7
    Completed
    7
    8
    7
    Period 2
    Period 2 title
    Treatment period
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer, Assessor
    Blinding implementation details
    Patients in the zoledronic acid and placebo arms were randomised to receive either zoledronic acid or placebo alongside chemotherapy and blinding was double blind. Patients in the Open label arm were not randomised as declined chemotherapy and chose to have open labelled zoledronic acid on its own (not blinded).

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 zoledronic acid
    Arm description
    		 randomised to either zoledronic acid or placebo (double blind) every 3 weeks alongside chemotherapy for a maximum of 6 cycles
    Arm type
    		 Experimental

    Investigational medicinal product name
    zoledronic acid
    Investigational medicinal product code
    Other name
    Zometa 4 mg/5 ml concentrate for solution for infusion
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    4 mg/5 ml concentrate for solution for infusion every 3 weeks alongside chemotherapy for a maximum of 6 cycles

    Arm title
    		 Placebo
    Arm description
    		 randomised to either zoledronic acid or placebo (double blind) every 3 weeks alongside chemotherapy for a maximum of 6 cycles
    Arm type
    		 Placebo

    Investigational medicinal product name
    Saline
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    100ml 0.9% Saline infusion administered every 3 weeks alongside chemotherapy

    Arm title
    		 Open label arm
    Arm description
    		 A non-randomised subgroup of patients who declined chemotherapy in favour of ZA open labelled on its own.
    Arm type
    		 Experimental

    Investigational medicinal product name
    zoledronic acid
    Investigational medicinal product code
    Other name
    Zometa 4 mg/5 ml concentrate for solution for infusion
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    4 mg/5 ml concentrate for solution for infusion every 3 weeks for a maximum of 6 cycles

    Number of subjects in period 2
    		zoledronic acid Placebo Open label arm
    Started
    7
    8
    7
    Completed
    2
    4
    3
    Not completed
    5
    4
    4
         Adverse event, serious fatal
    -
    1
    1
         Adverse event, non-fatal
    -
    -
    2
         trial treatment stopped when chemotherapy stopped
    5
    3
    -
         Lost to follow-up
    -
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    zoledronic acid
    Reporting group description
    		 -

    Reporting group title
    Placebo
    Reporting group description
    		 -

    Reporting group title
    Open label arm
    Reporting group description
    		 -

    Reporting group values
    		 zoledronic acid Placebo Open label arm Total
    Number of subjects
    		 7 8 7 22
    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)
    		 70.0 ± 6.2 74.2 ± 4.6 82.3 ± 5.2 -
    Gender categorical
    Units: Subjects
        Female
    		 1 0 1 2
        Male
    		 6 8 6 20
    WHO performance status
    Units: Subjects
        PS0
    		 2 4 0 6
        PS1
    		 5 4 7 16
    Previous 5-year significant medical history
    Units: Subjects
        Yes
    		 6 4 5 15
        No
    		 1 4 2 7
    Length of symptoms
    Units: Subjects
        <1 month
    		 1 2 0 3
        1-2 months
    		 1 2 0 3
        >2 months
    		 5 4 7 16
    Laterality
    Units: Subjects
        Left
    		 5 3 2 10
        Right
    		 2 5 5 12
    Mode of diagnosis
    Units: Subjects
        LA thoracoscopy
    		 3 3 5 11
        Image guided
    		 3 2 1 6
        VATS
    		 1 3 1 5
    Cell type
    Units: Subjects
        Epitheliod
    		 6 5 5 16
        Sarcomatoid
    		 1 1 1 3
        Biphasic
    		 0 1 1 2
        Mesothelioma NOS
    		 0 1 0 1
    Previous pleurodesis
    Units: Subjects
        Yes
    		 2 2 1 5
        No
    		 5 6 6 17
    Intracystic papillary carcinoma in situ
    Units: Subjects
        Yes
    		 4 2 1 7
        No
    		 3 6 6 15
    TNM staging
    Units: Subjects
        000
    		 0 1 0 1
        100
    		 1 3 5 9
        110
    		 1 1 0 2
        121
    		 0 1 0 1
        210
    		 1 0 0 1
        300
    		 1 1 0 2
        320
    		 1 0 0 1
        321
    		 1 0 0 1
        400
    		 1 0 1 2
        410
    		 0 0 1 1
        Not recorded
    		 0 1 0 1
    BMI
    Units: m/kg
        arithmetic mean (standard deviation)
    		 25.2 ± 2.1 25.0 ± 3.5 22.8 ± 2.4 -
    Subject analysis sets

    Subject analysis set title
    number of eligible patients
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All consented patients

    Subject analysis sets values
    		 number of eligible patients
    Number of subjects
    22
    Age categorical
    Units: Subjects
        In utero
        Preterm newborn infants (gestational age < 37 wks)
        Newborns (0-27 days)
        Infants and toddlers (28 days-23 months)
        Children (2-11 years)
        Adolescents (12-17 years)
        Adults (18-64 years)
        From 65-84 years
        85 years and over
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    ±
    Gender categorical
    Units: Subjects
        Female
        Male
    WHO performance status
    Units: Subjects
        PS0
        PS1
    Previous 5-year significant medical history
    Units: Subjects
        Yes
    15
        No
    7
    Length of symptoms
    Units: Subjects
        <1 month
        1-2 months
        >2 months
    Laterality
    Units: Subjects
        Left
        Right
    Mode of diagnosis
    Units: Subjects
        LA thoracoscopy
        Image guided
        VATS
    Cell type
    Units: Subjects
        Epitheliod
        Sarcomatoid
        Biphasic
        Mesothelioma NOS
    Previous pleurodesis
    Units: Subjects
        Yes
        No
    Intracystic papillary carcinoma in situ
    Units: Subjects
        Yes
        No
    TNM staging
    Units: Subjects
        000
        100
        110
        121
        210
        300
        320
        321
        400
        410
        Not recorded
    BMI
    Units: m/kg
        arithmetic mean (standard deviation)
    24.4 ± 2.8

    End points

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    End points reporting groups
    Reporting group title
    zoledronic acid
    Reporting group description
    		 -

    Reporting group title
    Placebo
    Reporting group description
    		 -

    Reporting group title
    Open label arm
    Reporting group description
    		 -
    Reporting group title
    zoledronic acid
    Reporting group description
    		 randomised to either zoledronic acid or placebo (double blind) every 3 weeks alongside chemotherapy for a maximum of 6 cycles

    Reporting group title
    Placebo
    Reporting group description
    		 randomised to either zoledronic acid or placebo (double blind) every 3 weeks alongside chemotherapy for a maximum of 6 cycles

    Reporting group title
    Open label arm
    Reporting group description
    		 A non-randomised subgroup of patients who declined chemotherapy in favour of ZA open labelled on its own.

    Subject analysis set title
    number of eligible patients
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All consented patients

    Primary: Number of patients randomised from those that consented

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    End point title
    		 Number of patients randomised from those that consented [1]
    End point description
    End point type
    Primary
    End point timeframe
    Number of patients who were randomised into the trial from those that were consented
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: As the study is a feasibility study, no formal comparisons will be made in any of the analyses.
    End point values
    		 number of eligible patients
    Number of subjects analysed
    22
    Units: participants
        number (confidence interval 95%)
    15 (10.4 to 18.4)
    No statistical analyses for this end point

    Other pre-specified: Drop out rate

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    End point title
    		 Drop out rate
    End point description
    Number of participants who withdrew
    End point type
    Other pre-specified
    End point timeframe
    Number of withdrawals
    End point values
    		 zoledronic acid Placebo Open label arm
    Number of subjects analysed
    7
    8
    7
    Units: participants
    0
    0
    1
    No statistical analyses for this end point

    Other pre-specified: Overall survival rate

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    End point title
    		 Overall survival rate
    End point description
    End point type
    Other pre-specified
    End point timeframe
    Number of patients still alive at the end of the trial
    End point values
    		 zoledronic acid Placebo Open label arm
    Number of subjects analysed
    7
    8
    7
    Units: consented participants
    7
    7
    4
    No statistical analyses for this end point

    Other pre-specified: Progression free survival rate

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    End point title
    		 Progression free survival rate
    End point description
    Number of participants alive or without progression at the end of the trial
    End point type
    Other pre-specified
    End point timeframe
    progression measured by modified RECIST criteria on CT
    End point values
    		 zoledronic acid Placebo Open label arm
    Number of subjects analysed
    7
    8
    7
    Units: consented participants
    7
    6
    4
    No statistical analyses for this end point

    Other pre-specified: CT scan total tumour measurement

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    End point title
    		 CT scan total tumour measurement
    End point description
    End point type
    Other pre-specified
    End point timeframe
    Baseline
    End point values
    		 zoledronic acid Placebo Open label arm
    Number of subjects analysed
    7
    7
    7
    Units: mm
        geometric mean (geometric coefficient of variation)
    66.1 ± 0.8
    44.9 ± 0.4
    39.0 ± 0.3
    No statistical analyses for this end point

    Other pre-specified: Response on CT scan

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    End point title
    		 Response on CT scan
    End point description
    End point type
    Other pre-specified
    End point timeframe
    After 3 cycles
    End point values
    		 zoledronic acid Placebo Open label arm
    Number of subjects analysed
    7
    7
    5
    Units: participants
        Complete response
    1
    2
    2
        Partial response
    2
    1
    0
        Stable disease
    3
    0
    0
        Progressive disease
    1
    4
    3
    No statistical analyses for this end point

    Other pre-specified: Response on CT scan

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    End point title
    		 Response on CT scan
    End point description
    End point type
    Other pre-specified
    End point timeframe
    6-month
    End point values
    		 zoledronic acid Placebo Open label arm
    Number of subjects analysed
    7
    5
    3
    Units: participants
        Complete response
    2
    2
    1
        Partial response
    1
    0
    0
        Stable disease
    2
    0
    0
        Progressive disease
    2
    3
    2
    No statistical analyses for this end point

    Other pre-specified: Total Glycolytic Volume (TGV) on PET-CT scan

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    End point title
    		 Total Glycolytic Volume (TGV) on PET-CT scan
    End point description
    End point type
    Other pre-specified
    End point timeframe
    Baseline
    End point values
    		 zoledronic acid Placebo Open label arm
    Number of subjects analysed
    7
    8
    7
    Units: na
        geometric mean (geometric coefficient of variation)
    579.5 ± 3.4
    1062.0 ± 2.1
    588.7 ± 1.1
    No statistical analyses for this end point

    Other pre-specified: CT scan total tumour measurement

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    End point title
    		 CT scan total tumour measurement
    End point description
    End point type
    Other pre-specified
    End point timeframe
    After 3 cycles
    End point values
    		 zoledronic acid Placebo Open label arm
    Number of subjects analysed
    7
    7
    5
    Units: mm
        geometric mean (geometric coefficient of variation)
    45.0 ± 0.9
    33.7 ± 1.0
    78.7 ± 0.1
    No statistical analyses for this end point

    Other pre-specified: CT scan total tumour measurement

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    End point title
    		 CT scan total tumour measurement
    End point description
    End point type
    Other pre-specified
    End point timeframe
    6-month follow up
    End point values
    		 zoledronic acid Placebo Open label arm
    Number of subjects analysed
    7
    5
    3
    Units: mm
        geometric mean (geometric coefficient of variation)
    48.6 ± 0.6
    71.3 ± 0.2
    69.0 ± 0.9
    No statistical analyses for this end point

    Other pre-specified: Total Glycolytic Volume (TGV) on PET-CT scan

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    End point title
    		 Total Glycolytic Volume (TGV) on PET-CT scan
    End point description
    End point type
    Other pre-specified
    End point timeframe
    After 3 cycles
    End point values
    		 zoledronic acid Placebo Open label arm
    Number of subjects analysed
    7
    6
    4
    Units: na
        geometric mean (geometric coefficient of variation)
    80.4 ± 5.8
    253.5 ± 6.1
    446.7 ± 0.3
    No statistical analyses for this end point

    Other pre-specified: Quality of Life index score

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    End point title
    		 Quality of Life index score
    End point description
    End point type
    Other pre-specified
    End point timeframe
    Baseline
    End point values
    		 zoledronic acid Placebo Open label arm
    Number of subjects analysed
    7
    8
    7
    Units: score
        arithmetic mean (confidence interval 95%)
    0.636 (0.357 to 0.916)
    0.727 (0.559 to 0.895)
    0.694 (0.503 to 0.884)
    No statistical analyses for this end point

    Other pre-specified: Quality of Life index score

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    End point title
    		 Quality of Life index score
    End point description
    End point type
    Other pre-specified
    End point timeframe
    Pre-cycle 2
    End point values
    		 zoledronic acid Placebo Open label arm
    Number of subjects analysed
    6
    6
    7
    Units: index score
        arithmetic mean (confidence interval 95%)
    0.576 (0.39 to 0.762)
    0.582 (0.231 to 0.933)
    0.611 (0.411 to 0.81)
    No statistical analyses for this end point

    Other pre-specified: Quality of Life index score

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    End point title
    		 Quality of Life index score
    End point description
    End point type
    Other pre-specified
    End point timeframe
    Pre-cycle 3
    End point values
    		 zoledronic acid Placebo Open label arm
    Number of subjects analysed
    7
    4
    5
    Units: index score
        arithmetic mean (confidence interval 95%)
    0.575 (0.336 to 0.817)
    0.798 (0.542 to 1.054)
    0.644 (0.422 to 0.866)
    No statistical analyses for this end point

    Other pre-specified: Quality of Life index score

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    End point title
    		 Quality of Life index score
    End point description
    End point type
    Other pre-specified
    End point timeframe
    Pre-cycle 4
    End point values
    		 zoledronic acid Placebo Open label arm
    Number of subjects analysed
    7
    6
    4
    Units: index score
        arithmetic mean (confidence interval 95%)
    0.718 (0.587 to 0.85)
    0.866 (0.696 to 1.036)
    0.578 (0.068 to 1.087)
    No statistical analyses for this end point

    Other pre-specified: Quality of Life index score

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    End point title
    		 Quality of Life index score
    End point description
    End point type
    Other pre-specified
    End point timeframe
    Pre-cycle 5
    End point values
    		 zoledronic acid Placebo Open label arm
    Number of subjects analysed
    5
    4
    4
    Units: index score
        arithmetic mean (confidence interval 95%)
    0.673 (0.582 to 0.764)
    0.88 (0.753 to 1.007)
    0.514 (0.184 to 0.844)
    No statistical analyses for this end point

    Other pre-specified: Quality of Life index score

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    End point title
    		 Quality of Life index score
    End point description
    End point type
    Other pre-specified
    End point timeframe
    Pre-cycle 6
    End point values
    		 zoledronic acid Placebo Open label arm
    Number of subjects analysed
    4
    3
    3
    Units: index score
        arithmetic mean (confidence interval 95%)
    0.722 (0.599 to 0.845)
    0.846 (0.708 to 0.984)
    0.496 (-0.144 to 1.135)
    No statistical analyses for this end point

    Other pre-specified: Quality of Life index score

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    End point title
    		 Quality of Life index score
    End point description
    End point type
    Other pre-specified
    End point timeframe
    End of Treatment follow up
    End point values
    		 zoledronic acid Placebo Open label arm
    Number of subjects analysed
    6
    4
    1
    Units: index score
        arithmetic mean (confidence interval 95%)
    0.625 (0.506 to 0.744)
    0.867 (0.713 to 1.021)
    0.221 (0.221 to 0.221)
    No statistical analyses for this end point

    Other pre-specified: Quality of Life index score

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    End point title
    		 Quality of Life index score
    End point description
    End point type
    Other pre-specified
    End point timeframe
    6 month follow up
    End point values
    		 zoledronic acid Placebo Open label arm
    Number of subjects analysed
    7
    3
    3
    Units: index score
        arithmetic mean (confidence interval 95%)
    0.655 (0.54 to 0.77)
    0.55 (-0.554 to 1.653)
    0.439 (-0.375 to 1.253)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From randomisation until final trial follow up completed (6 months post randomisation)
    Adverse event reporting additional description
    Adverse events are assessed at every follow up visit or triggered by information provided by participants/participant's families
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    1
    Reporting groups
    Reporting group title
    Zoledronic Acid
    Reporting group description
    		 Participants randomised to receive Zoledronic Acid alongside chemotherapy

    Reporting group title
    Placebo
    Reporting group description
    		 Participants randomised to receive Placebo alongside chemotherapy

    Reporting group title
    Open label ZA
    Reporting group description
    		 Participants who declined to receive chemotherapy and received open label Zoledronic Acid alone

    Serious adverse events
    		 Zoledronic Acid Placebo Open label ZA
    Total subjects affected by serious adverse events
         subjects affected / exposed
    5 / 8 (62.50%)
    3 / 7 (42.86%)
    3 / 7 (42.86%)
         number of deaths (all causes)
    0
    0
    3
         number of deaths resulting from adverse events
    0
    0
    0
    General disorders and administration site conditions
    Death
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    2 / 7 (28.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    Pain
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 7 (14.29%)
    1 / 7 (14.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Neutrophil count decreased
    Additional description: also low platelets and white cell count, as well as an elevated ALT and generally feeling unwell
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 7 (0.00%)
    0 / 7 (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
    Respiratory, thoracic and mediastinal disorders
    Respiratory tract infection
    Additional description: drug reaction to penicillin antibiotic
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 7 (14.29%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 7 (0.00%)
    0 / 7 (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
    Infections and infestations
    Neutropenic sepsis
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 7 (0.00%)
    0 / 7 (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
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Zoledronic Acid Placebo Open label ZA
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    8 / 8 (100.00%)
    7 / 7 (100.00%)
    7 / 7 (100.00%)
    General disorders and administration site conditions
    Nausea
         subjects affected / exposed
    2 / 8 (25.00%)
    2 / 7 (28.57%)
    1 / 7 (14.29%)
         occurrences all number
    3
    3
    1
    Appetite disorder
    Additional description: poor appetite
         subjects affected / exposed
    1 / 8 (12.50%)
    1 / 7 (14.29%)
    1 / 7 (14.29%)
         occurrences all number
    1
    1
    1
    Fatigue
         subjects affected / exposed
    3 / 8 (37.50%)
    4 / 7 (57.14%)
    2 / 7 (28.57%)
         occurrences all number
    3
    7
    2
    Dizziness
    alternative assessment type: Non-systematic
         subjects affected / exposed
    2 / 8 (25.00%)
    0 / 7 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    2
    0
    1
    Weight decreased
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    2 / 7 (28.57%)
         occurrences all number
    0
    0
    2
    Blood and lymphatic system disorders
    Anaemia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 8 (0.00%)
    2 / 7 (28.57%)
    0 / 7 (0.00%)
         occurrences all number
    0
    4
    0
    Gastrointestinal disorders
    Constipation
    alternative assessment type: Non-systematic
         subjects affected / exposed
    4 / 8 (50.00%)
    2 / 7 (28.57%)
    2 / 7 (28.57%)
         occurrences all number
    5
    3
    3
    Vomiting
         subjects affected / exposed
    2 / 8 (25.00%)
    2 / 7 (28.57%)
    1 / 7 (14.29%)
         occurrences all number
    2
    3
    1
    Respiratory, thoracic and mediastinal disorders
    Pain
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 7 (14.29%)
    2 / 7 (28.57%)
         occurrences all number
    0
    1
    2
    breathlessness
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 8 (0.00%)
    2 / 7 (28.57%)
    1 / 7 (14.29%)
         occurrences all number
    0
    2
    1
    infection
    Additional description: chest infection
         subjects affected / exposed
    1 / 8 (12.50%)
    2 / 7 (28.57%)
    3 / 7 (42.86%)
         occurrences all number
    1
    2
    3
    Upper respiratory tract infection
    Additional description: common cold
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 7 (14.29%)
    1 / 7 (14.29%)
         occurrences all number
    0
    3
    1
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    2 / 8 (25.00%)
    3 / 7 (42.86%)
    0 / 7 (0.00%)
         occurrences all number
    2
    3
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    22 Sep 2016
    Removed the need for 'measurable disease on CT' to be measured by modified RECIST criteria
    16 Feb 2017
    Removed inclusion criteria 'measurable disease on CT (tumour thickness > 5mm)'
    15 Sep 2017
    Added option to invite patients who declined to participate to be interviewed
    26 Sep 2017
    Extended recruitment period by one month

    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.
    As the study is a feasibility study, no formal comparisons are made in any of the analyses.

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/30157910
    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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