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    Clinical Trial Results:
    FEASIBILITY of IBIS 3. An International Breast Intervention Study investigating Prevention Of Late Recurrence in ER+ breast cancer survivors following 5 years of adjuvant treatment

    Summary
    EudraCT number
    2014-004430-26
    Trial protocol
    GB  
    Global end of trial date
    23 May 2018

    Results information
    Results version number
    v1(current)
    This version publication date
    05 Jan 2019
    First version publication date
    05 Jan 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    010207QM
    Additional study identifiers
    ISRCTN number
    ISRCTN93764730
    US NCT number
    -
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Queen Mary University of London
    Sponsor organisation address
    Joint Research Management Office QM Innovation Building, 5 Walden Street, London, United Kingdom, EC1M 6BQ
    Public contact
    Mays Jawad, Queen Mary University of London, +44 020 7882 7265, research.governance@qmul.ac.uk
    Scientific contact
    Mays Jawad, Queen Mary University of London, 2078827265 020 7882 7265, research.governance@qmul.ac.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
    23 May 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    26 Mar 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    23 May 2018
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    To determine acceptability and feasibility of recruitment, recruitment rate and number of sites required for a main trial. This larger trial will investigate the prevention of late recurrence with an aromatase inhibitor and/or metformin and/or zoledronic acid or standard care (no treatment) in high risk breast cancer survivors.
    Protection of trial subjects
    Aromatase inhibitors (AIs) are associated with reduced bone-mineral density leading to increased risk of fracture. To address this concern a baseline bone density scan (DXA) will be performed on all women taking part in this randomisation to identify those who may have osteoporosis. In addition, osteopenic women randomised to an AI will be given a repeat DXA scan at final visit if last DXA was more than 12 months ago. Osteoporotic patients will be managed in accordance with local clinical procedures for treatment of such women i.e., take bisphosphonate treatment and have regular DXA scans. For metformin. the initial side effect of bloating, nausea and diarrhoea will be mitigated by use of a run-in one month dose escalation. It is recommended that patients take loperamide (Imodium®) to help ease these side effects. For zoledronic acid, osteonecrosis of the jaw (ONJ) is a rare complication. This complication is usually observed in cancer patients, probably due to the repeated dosage regimen and the prolonged exposure. The annual dosage regimen used in postmenopausal osteoporosis, on the other hand, is considered safe with regard to the risk of ONJ. Before zoledronic acid is initiated, patients should undergo an oral examination and appropriate preventive dentistry and be advised on maintaining good oral hygiene. Patients should avoid invasive dental procedures (extractions and implants) during therapy if possible. Any dental surgery must be completed before starting treatment on zoledronic acid. It is recommended that patients have a dental check-up within 6 months before randomisation in case any dental treatment is required, delaying zoledronic acid treatment. Should any side effect become intolerable, the patient can try a treatment holiday, with the option of withdrawing from trial treatment always being an option.
    Background therapy
    N/A
    Evidence for comparator
    The evidence that aromatase inhibitors are effective as treatment for ER+ positive breast cancer in post-menopausal women is now overwhelming and has been summarised in an overview (Dowsett et al, 2010). The potential role of AIs in prevention has been reviewed by Cuzick et al (2011) and the IBIS-II trial confirmed the effectiveness of anastrozole in preventing breast cancer (Cuzick et al, 2014). The appropriate duration of treatment of AIs is unclear. This trial will allow a randomised evaluation of the extension of the treatment interval by 2 years. The evidence in favour of repurposing metformin as an active drug for breast cancer has recently been summarised (Thompson, 2014). In essence there is epidemiological, in vivo and human phase II and emerging phase III trial evidence. Two robust phase II trials in women with breast cancer (Hadad et al 2011; Niraula et al 2012), show that metformin reduces tumour proliferation and suppresses serum insulin levels. This is thought to work both through direct anti-tumour effects (via AMPK and mitochondrial mechanisms) and via systemic insulin based mechanisms. Several randomised adjuvant studies have shown that bisphosphonates reduce the risk of recurrence in early breast cancer when used at the time of diagnosis (Powles et al, 2006; Ha et al 2007; Gnant et al, 2009; deBoer et al, 2011). Bisphosphonates have also been shown to abrogate the bone loss associated with use of an AI, and to reduce recurrence and death rates in one trial when used in combination with either tamoxifen or an aromatase inhibitor after treatment with the LHRH (Luteinizing-hormone-releasing hormone) agonist goserelin in premenopausal women (ABCSG12: Gnant et al, 2009 ). Although negative results overall have also been reported in the AZURE trial (Coleman et al, 2011), there was a benefit in women who were more than 5 years past the menopause (most of the patients in this study will also have been post-menopausal for at least 4 years).
    Actual start date of recruitment
    27 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: 89
    Worldwide total number of subjects
    89
    EEA total number of subjects
    89
    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)
    40
    From 65 to 84 years
    49
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Patients were recruited over a 12 month period from 27th September 2016-26th September 2017 from 13 UK centres. Patients were recruited via breast cancer clinics at local sites and also via GPs acting as Patient Identification Centres (PICs).

    Pre-assignment
    Screening details
    434 patients were approached to join the study. Main reasons for non-participation included no response, not interested in clinical research, concerns of drug side effects, ineligible and no desire to undergo screening tests. 100 of those patients wanted to join but 11 of these failed screening tests (eGFR and insulin in blood samples & DXA scan)

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    No

    Arm title
    Aromatase Inhibitor
    Arm description
    -
    Arm type
    Experimental

    Investigational medicinal product name
    Anastrozole
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    1 x 1mg daily dose of the AI will be taken orally, and should be swallowed whole with water. The tablet should be taken at the same time each day and it does not matter if it is taken before, with or after food. In the case a patient misses a dose or vomits she should continue to take one dose the next day. She should not double the dose.

    Investigational medicinal product name
    Exemestane
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    1 x 25mg daily dose of the AI will be taken orally, and should be swallowed whole with water. The tablet should be taken at the same time each day and it does not matter if it is taken before, with or after food. In the case a patient misses a dose or vomits she should continue to take one dose the next day. She should not double the dose.

    Investigational medicinal product name
    Letrozole
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    1 x 2.5mg daily dose of the AI will be taken orally, and should be swallowed whole with water. The tablet should be taken at the same time each day and it does not matter if it is taken before, with or after food. In the case a patient misses a dose or vomits she should continue to take one dose the next day. She should not double the dose.

    Arm title
    Metformin
    Arm description
    -
    Arm type
    Experimental

    Investigational medicinal product name
    Metformin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    1 x 500mg daily from day to day 14; 1 x 850mg daily from day 15 to day 28; 1 x 850mg twice dailiy from day 29 to end of trial. The daily dose of metformin will be increased slowly up to one tablet taken twice daily, and will be taken orally. Serum creatinine should be measured at year 1 (if on zoledronic acid too this will be measured every 6 months) and treatment should be withheld if renal function has deteriorated (calculated eGFR < 45mls/min or > 20% reduction in eGFR from baseline). The tablets should be taken at the same time each day with or just after food to lower the chance of stomach upset, and should be swallowed whole with water. In the case a patient misses a dose she should take one dose

    Arm title
    Zoledronic acid
    Arm description
    -
    Arm type
    Experimental

    Investigational medicinal product name
    Zoledronic acid
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for dispersion for infusion, Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    4mg/100ml solution for infusion OR 4mg/5ml concentrate for infusion

    Arm title
    No treatment
    Arm description
    Randomised to no treatment - standard care at time when trial began
    Arm type
    No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    AI + Met
    Arm description
    -
    Arm type
    Experimental

    Investigational medicinal product name
    Anastrozole
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    1 x 1mg daily dose of the AI will be taken orally, and should be swallowed whole with water. The tablet should be taken at the same time each day and it does not matter if it is taken before, with or after food. In the case a patient misses a dose or vomits she should continue to take one dose the next day. She should not double the dose.

    Arm title
    AI + ZA
    Arm description
    -
    Arm type
    Experimental

    Investigational medicinal product name
    Anastrozole
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    1 x 1mg daily dose of the AI will be taken orally, and should be swallowed whole with water. The tablet should be taken at the same time each day and it does not matter if it is taken before, with or after food. In the case a patient misses a dose or vomits she should continue to take one dose the next day. She should not double the dose.

    Investigational medicinal product name
    Letrozole
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    A 2.5mg tablet taken orally once a day

    Investigational medicinal product name
    Exemestane
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    A 25mg tablet taken orally once a day

    Arm title
    Met + ZA
    Arm description
    -
    Arm type
    Experimental

    Investigational medicinal product name
    Anastrozole
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    1 x 1mg daily dose of the AI will be taken orally, and should be swallowed whole with water. The tablet should be taken at the same time each day and it does not matter if it is taken before, with or after food. In the case a patient misses a dose or vomits she should continue to take one dose the next day. She should not double the dose.

    Arm title
    AI + Met + ZA
    Arm description
    -
    Arm type
    Experimental

    Investigational medicinal product name
    Anastrozole
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    1 x 1mg daily dose of the AI will be taken orally, and should be swallowed whole with water. The tablet should be taken at the same time each day and it does not matter if it is taken before, with or after food. In the case a patient misses a dose or vomits she should continue to take one dose the next day. She should not double the dose.

    Number of subjects in period 1
    Aromatase Inhibitor Metformin Zoledronic acid No treatment AI + Met AI + ZA Met + ZA AI + Met + ZA
    Started
    6
    19
    16
    20
    6
    4
    15
    3
    Completed
    6
    14
    11
    20
    6
    3
    13
    3
    Not completed
    0
    5
    5
    0
    0
    1
    2
    0
         Declined dental review
    -
    -
    1
    -
    -
    -
    -
    -
         Protocol deviation
    -
    3
    2
    -
    -
    -
    2
    -
         Patient aware of premature end of study
    -
    1
    -
    -
    -
    -
    -
    -
         Patient had appointment changed and was unhappy
    -
    -
    1
    -
    -
    -
    -
    -
         Patient choice due to other medical issues
    -
    -
    -
    -
    -
    1
    -
    -
         Adverse event, non-fatal
    -
    1
    1
    -
    -
    -
    -
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall trial (overall period)
    Reporting group description
    All randomised patients.

    Reporting group values
    Overall trial (overall period) Total
    Number of subjects
    89 89
    Age categorical
    Units: Subjects
        In utero
    0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0
        Newborns (0-27 days)
    0 0
        Infants and toddlers (28 days-23 months)
    0 0
        Children (2-11 years)
    0 0
        Adolescents (12-17 years)
    0 0
        Adults (18-64 years)
    40 40
        From 65-84 years
    49 49
        85 years and over
    0 0
    Gender categorical
    Units: Subjects
        Female
    89 89
        Male
    0 0
    Subject analysis sets

    Subject analysis set title
    Final IBIS-3
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Final analysis of all 89 randomised patients into the IBIS-3 feasibility study.

    Subject analysis sets values
    Final IBIS-3
    Number of subjects
    89
    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)
    40
        From 65-84 years
    49
        85 years and over
    Age continuous
    Units: years
        
    ±
    Gender categorical
    Units: Subjects
        Female
    89
        Male
    0

    End points

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    End points reporting groups
    Reporting group title
    Aromatase Inhibitor
    Reporting group description
    -

    Reporting group title
    Metformin
    Reporting group description
    -

    Reporting group title
    Zoledronic acid
    Reporting group description
    -

    Reporting group title
    No treatment
    Reporting group description
    Randomised to no treatment - standard care at time when trial began

    Reporting group title
    AI + Met
    Reporting group description
    -

    Reporting group title
    AI + ZA
    Reporting group description
    -

    Reporting group title
    Met + ZA
    Reporting group description
    -

    Reporting group title
    AI + Met + ZA
    Reporting group description
    -

    Subject analysis set title
    Final IBIS-3
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Final analysis of all 89 randomised patients into the IBIS-3 feasibility study.

    Primary: The recruitment of 100 patients within 12 months from first randomisation

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    End point title
    The recruitment of 100 patients within 12 months from first randomisation
    End point description
    To determine acceptability and feasibility of recruitment, recruitment rate and number of sites required for main trial.
    End point type
    Primary
    End point timeframe
    12 months
    End point values
    Aromatase Inhibitor Metformin Zoledronic acid No treatment AI + Met AI + ZA Met + ZA AI + Met + ZA
    Number of subjects analysed
    6
    19
    16
    20
    6
    4
    15
    3
    Units: patients
    6
    19
    16
    20
    6
    4
    15
    3
    Statistical analysis title
    Feasibility study
    Statistical analysis description
    For the primary endpoint/outcome there is no formal statistical analysis. The primary outcome was to see whether breast cancer patients can be recruited into this study. All boxes ticked below done so that the form can be saved and closed.
    Comparison groups
    Aromatase Inhibitor v Metformin v Zoledronic acid v No treatment v AI + Met v AI + ZA v Met + ZA v AI + Met + ZA
    Number of subjects included in analysis
    89
    Analysis specification
    Pre-specified
    Analysis type
    other [1]
    P-value
    = 0.05
    Method
    NA
    Parameter type
    NA
    Point estimate
    1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.95
         upper limit
    1.05
    Variability estimate
    Standard deviation
    Dispersion value
    1
    Notes
    [1] - For the primary endpoint/outcome there is no formal statistical analysis. The primary outcome was to see whether breast cancer patients can be recruited into this study.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    AEs should be reported from date of randomisation until Last Patient Last Visit (LPLV) plus an additional 14 days if receiving zoledronic acid at final visit.
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    20
    Reporting groups
    Reporting group title
    Aromatase Inhibitor
    Reporting group description
    Patients on AI who reported AE(s)

    Reporting group title
    Metformin
    Reporting group description
    Patients on metformin reporting AE(s)

    Reporting group title
    Zoledronic acid
    Reporting group description
    -

    Reporting group title
    AI + Met
    Reporting group description
    -

    Reporting group title
    AI + ZA
    Reporting group description
    -

    Reporting group title
    Met + ZA
    Reporting group description
    -

    Reporting group title
    AI + Met + ZA
    Reporting group description
    -

    Reporting group title
    No treatment
    Reporting group description
    -

    Serious adverse events
    Aromatase Inhibitor Metformin Zoledronic acid AI + Met AI + ZA Met + ZA AI + Met + ZA No treatment
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 19 (0.00%)
    1 / 16 (6.25%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    1 / 20 (5.00%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Vascular disorders
    Syncope
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Cellulitis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 19 (0.00%)
    1 / 16 (6.25%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Aromatase Inhibitor Metformin Zoledronic acid AI + Met AI + ZA Met + ZA AI + Met + ZA No treatment
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    3 / 6 (50.00%)
    8 / 19 (42.11%)
    8 / 16 (50.00%)
    6 / 6 (100.00%)
    2 / 4 (50.00%)
    9 / 15 (60.00%)
    3 / 3 (100.00%)
    3 / 20 (15.00%)
    Vascular disorders
    Flushed face
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 19 (0.00%)
    1 / 16 (6.25%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    Haemorrhoids
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    0 / 15 (0.00%)
    1 / 3 (33.33%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    2
    0
    Hot flush
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    Hypertension
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 19 (0.00%)
    1 / 16 (6.25%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    Surgical and medical procedures
    Elective knee placement surgery
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    1 / 4 (25.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    Immune system disorders
    Urticaria
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 19 (5.26%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    General disorders and administration site conditions
    Cold sweat
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    1 / 15 (6.67%)
    0 / 3 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    Discomfort of swollen lymph node
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 19 (5.26%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    Fatigue
         subjects affected / exposed
    1 / 6 (16.67%)
    2 / 19 (10.53%)
    5 / 16 (31.25%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
    0 / 15 (0.00%)
    1 / 3 (33.33%)
    0 / 20 (0.00%)
         occurrences all number
    1
    2
    6
    1
    0
    0
    1
    0
    Lethargy
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 19 (5.26%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    Severe fatigue
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    0 / 15 (0.00%)
    1 / 3 (33.33%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    Psychiatric disorders
    Feeling low
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 19 (5.26%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    Mood altered
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    1 / 4 (25.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    Reproductive system and breast disorders
    Vaginal dryness
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    Injury, poisoning and procedural complications
    Fracture of radius
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 19 (0.00%)
    1 / 16 (6.25%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    Investigations
    Blood urine present
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    1 / 15 (6.67%)
    0 / 3 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    2
    0
    0
    Cardiac disorders
    Palpitations
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    0 / 15 (0.00%)
    1 / 3 (33.33%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    Congenital, familial and genetic disorders
    Dry eye
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    Blood and lymphatic system disorders
    Atrial fibrillation
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 19 (0.00%)
    1 / 16 (6.25%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 19 (0.00%)
    1 / 16 (6.25%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    0
    0
    0
    Flu like symptoms
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 19 (0.00%)
    4 / 16 (25.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
    2 / 15 (13.33%)
    1 / 3 (33.33%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    4
    1
    0
    2
    2
    0
    Influenza
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 19 (5.26%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    Rib pain
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    1 / 4 (25.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    1 / 15 (6.67%)
    0 / 3 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    Headache
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 19 (5.26%)
    1 / 16 (6.25%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
    2 / 15 (13.33%)
    1 / 3 (33.33%)
    0 / 20 (0.00%)
         occurrences all number
    0
    1
    2
    3
    0
    2
    1
    0
    Parasthesia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    Taste changed
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    0
    0
    0
    Gastrointestinal disorders
    Diarrhoea
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 19 (5.26%)
    0 / 16 (0.00%)
    6 / 6 (100.00%)
    0 / 4 (0.00%)
    5 / 15 (33.33%)
    1 / 3 (33.33%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    0
    8
    0
    7
    2
    1
    Constipation
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    1 / 15 (6.67%)
    0 / 3 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    1
    Abdominal pain
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    1 / 15 (6.67%)
    0 / 3 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    Abdominal discomfort
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 19 (5.26%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    2 / 15 (13.33%)
    0 / 3 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    0
    0
    0
    2
    0
    1
    Acid reflux (oesophagus)
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    1 / 15 (6.67%)
    0 / 3 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    Abdominal bloating
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
    1 / 15 (6.67%)
    0 / 3 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    2
    0
    0
    Abdominal pain generalised
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 19 (5.26%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    Gastrointestinal pain
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    0
    0
    0
    Indigestion
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    0 / 15 (0.00%)
    1 / 3 (33.33%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    2
    0
    Indigestion and acid relux
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    Loose stools
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 19 (5.26%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    0
    0
    0
    Nausea
         subjects affected / exposed
    0 / 6 (0.00%)
    3 / 19 (15.79%)
    1 / 16 (6.25%)
    3 / 6 (50.00%)
    0 / 4 (0.00%)
    6 / 15 (40.00%)
    1 / 3 (33.33%)
    0 / 20 (0.00%)
         occurrences all number
    0
    3
    2
    3
    0
    6
    1
    0
    Nausea and vomiting
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 19 (5.26%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    Oesophagitis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    0
    0
    0
    Stomach upset
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    1 / 15 (6.67%)
    0 / 3 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    Vomiting
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 19 (0.00%)
    2 / 16 (12.50%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    0
    0
    0
    Renal and urinary disorders
    Urgency of mict
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 19 (0.00%)
    1 / 16 (6.25%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    Rash
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    Seborrheic Keratoses
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    Musculoskeletal and connective tissue disorders
    Aching in limb
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    0
    0
    0
    Ankle stiffness
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    Infusion associated chills
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    1 / 15 (6.67%)
    0 / 3 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    Joint stiffness
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 19 (5.26%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    1 / 15 (6.67%)
    0 / 3 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    1
    0
    0
    Knee pain
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    1 / 15 (6.67%)
    0 / 3 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    1
    0
    0
    Muscle and joint pain
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    1 / 4 (25.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    Other back pain with radiating symptoms
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 19 (0.00%)
    1 / 16 (6.25%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    Right hip pain
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    Shivers
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 19 (0.00%)
    1 / 16 (6.25%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    Stiff neck
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 19 (0.00%)
    1 / 16 (6.25%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    Swollen wrists
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    0 / 15 (0.00%)
    1 / 3 (33.33%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    Leg cramps
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
    1 / 6 (16.67%)
    0 / 4 (0.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    Metabolism and nutrition disorders
    Anorexia and bulimia syndrome
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 19 (5.26%)
    1 / 16 (6.25%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    1 / 15 (6.67%)
    1 / 3 (33.33%)
    0 / 20 (0.00%)
         occurrences all number
    0
    1
    1
    0
    0
    1
    1
    0
    Increased thirst
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 19 (5.26%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    Decreased appetite
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 19 (0.00%)
    1 / 16 (6.25%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    1 / 15 (6.67%)
    1 / 3 (33.33%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    1
    1
    0
    Weight loss
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 19 (5.26%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    Infections and infestations
    Cellulitis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 19 (0.00%)
    1 / 16 (6.25%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    Chest infection
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    1 / 15 (6.67%)
    0 / 3 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    Infection upper respiratory
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    0 / 15 (0.00%)
    1 / 3 (33.33%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    Shingles
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    1 / 15 (6.67%)
    0 / 3 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    Tooth infection
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 19 (0.00%)
    1 / 16 (6.25%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    Upper respiratory infection
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 19 (0.00%)
    1 / 16 (6.25%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    2
    Urinary tract infection
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 19 (0.00%)
    0 / 16 (0.00%)
    0 / 6 (0.00%)
    0 / 4 (0.00%)
    0 / 15 (0.00%)
    0 / 3 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    05 Oct 2015
    • Update on SAE reporting from the trials unit to the sponsor • Update to TMG membership • Clarification of dose adjustment schedule for Zoledronic acid in the appendix • Update that Completion of CIOMs form is no longer required as it is not a requirement for CTIMPS within the UK • An amendment to clarify PIs can sign SAEs and SUSARs electronically within the app
    14 Mar 2016
    • Update membership of the TSC • Change of trial statistician • Removal of reference to long-term follow-up • Clarification of eligibility criteria • Clarification that patients can withdraw from any/all treatments • Request for information on IMP brand and storage requirements to be provided to the trials office • If nurse collects IMP on behalf of patient, a Chain of Custody form should be completed • Clarification that screening blood samples should be taken at same time as research samples; if patients are then deemed ineligible, research blood samples will be kept and stored and may be used for future research • Definition of physical examination and who can perform it • Reference to document providing guidance for nurses on bone health, alcohol and oral hygiene advice • Clarification of type and amounts for blood samples to be collected • Instruction to schedule follow-up appointments 2 weeks before due date • Removal of active 30 day post-treatment SAE reporting • Explanation of how to report SAEs on patients who have stopped treatment • Reference to REC changed to HRA • Clarification that IBIS 3 CCO is within Barts CTU which is part of QMUL and that it is not registered under the Data Protection Act. • Change for removal of plasma to take place at local sites • Information to sites that patient identifiable information should be blacked out from any CRFs or documents when transferring to trials office • Clarification that DMC will meet at least annually rather than every 6 months to be consistent with DMC Charter. • Clarification of when screening ID is allocated, definition of what Patient identifiable information is collected, purpose and how it is stored • Deletion of Study Documents section as not necessary • Clarification that information on screening log is ‘pseudoanonymised’ rather than ‘anonymised’
    28 Jul 2016
    • Deletion of text ‘(Note: death is an outcome and not an event)’ to clarify that death is not an outcome and should be reported as an SAE • Clarification of TSC members’ roles from ‘observers’ to ‘non-voting members’
    21 Mar 2017
    • Allowance of a baseline bone mineral density (BMD) scan to have been done between 12-24 months before joining the trial providing FRAX tool probability of 10 year fracture (%) is estimated and this is defined as low risk. • For baseline DXA scans, explanation that it is acceptable to have hip (femoral neck or proximal femur) OR lumbar spine should T score only be available for one site (due to, for example, prosthesis or artefacts/osteophytes) and the T score for this site is >0. • Allowance of a suitably qualified Advanced Nurse Practitioner to do prescriptions • Recommendation that patients have a dental check-up within 6 months before randomisation in case any dental treatment is required, delaying zoledronic acid treatment. • Addition of ‘currently being treated with a bisphosphonate’ to exclusion criteria for zoledronic acid • Addition of ‘previous intolerance to AIs resulting in unsuitability to extended AI treatment’ to exclusion criteria for aromatase inhibitors • Change from date of randomisation to date of screening of timeframe for screening tests • Correction of a typo (CKD-EPI) • Addition that members of the Coordinating Centre may visit hospital sites to assist with screening patients by viewing medical records and databases. • To minimize patient waiting time for IMP and/or additional visits, it was decided that patient does not need to be present for randomisation. Eligibility can be re-checked on the phone before randomisation and within 72 hours of patient visit to collect IMP and complete patient questionnaires.
    06 Jun 2017
    • Allowance of a baseline bone mineral density (BMD) scan to have been done between 12-24 months before joining the trial providing FRAX tool probability of 10 year fracture (%) is estimated and this is defined as low risk. • For baseline DXA scans, explanation that it is acceptable to have hip (femoral neck or proximal femur) OR lumbar spine should T score only be available for one site (due to, for example, prosthesis or artefacts/osteophytes) and the T score for this site is >0. • Allowance of a suitably qualified Advanced Nurse Practitioner to do prescriptions • Recommendation that patients have a dental check-up within 6 months before randomisation in case any dental treatment is required, delaying zoledronic acid treatment. • Addition of ‘currently being treated with a bisphosphonate’ to exclusion criteria for zoledronic acid • Addition of ‘previous intolerance to AIs resulting in unsuitability to extended AI treatment’ to exclusion criteria for aromatase inhibitors • Change from date of randomisation to date of screening of timeframe for screening tests • Correction of a typo (CKD-EPI) • To minimize patient waiting time for IMP and/or additional visits, it was decided that patient does not need to be present for randomisation. Eligibility can be re-checked on the phone before randomisation and within 72 hours of patient visit to collect IMP and complete patient questionnaires.
    27 Nov 2017
    Change of treatment duration from 2 years to 6-18 months (dependent on date of randomisation) • Final visit to be scheduled by 26th March 2018 and end-of-trial blood sample to be collected (as originally planned) • End-of-trial dose of zoledronic acid (ZA) to be administered if previous dose given more than 5 months earlier. The last ZA dose was originally scheduled at 18 months if trial treatment had continued for 24 months (i.e. no ZA dose at the end-of-trial visit). This ensures that all patients randomised to ZA receive the benefit of treatment at last visit. Final visit apppointments for ZA patients should be scheduled for at least 2 weeks before last patient last visit (26th March 2018) as there is a period of 14 days of active pharmacovigilence reporting for these patients. • DXA scan to be done for AI patients who were osteopenic at baseline if the previous scan was more than 12 months ago • Change of TMG members • Change of contact name for sponsor

    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 number of patients needed to make a main trial viable was not achieved and the decision was made to terminate earlier than planned but that all patients receive at least 6 months of treatment in order to answer secondary objectives.
    As of 1.2.2020, the UK is no longer an EU Member State. However, EU law still applies to the UK during the transition period
    EU Clinical Trials Register Service Desk: https://servicedesk.ema.europa.eu
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